ArticleLiterature Review

Immunotherapy in mantle cell lymphoma: Anti-CD20-based therapy and beyond

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Abstract

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity. It is more effective when used in combination with chemotherapy such as R-CHOP, R-hyperCVAD/MTX-Ara-C, or R-FCM as front-line or salvage therapy for mantle cell lymphoma. Maintenance with Rituximab was shown to prolong response duration. Although most results have suggested that combining autologous stem cell transplantation with Rituximab may lead to durable remission, the sample size was not sufficient to declare survival benefit. Anti-CD20 radioimmunoconjugates (RICs) (90)Yttrium-ibritumomab tiuxetan and (131)Iodine-tositumomab have been used in mantle cell lymphoma even when patients are relatively resistant to Rituximab-based therapy. Allogeneic stem cell transplantation is a treatment modality in advanced or relapsed MCL, particularly using reduced-intensity conditioning. MCL may have high response rates and sustained remissions after donor lymphocyte infusion. Dendritic cells (DCs) fused with MCL cells for immunostimulation have preliminarily shown anti-lymphoma effects as well. Idiotype vaccination in MCL patients following Rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells. Other immunotherapy, such as the combination of thalidomide with Rituximab, has shown substantial antitumor activity. A Phase I/II study is ongoing to determine the maximum tolerated dose (MTD) and the efficacy of lenalidomide in combination with Rituximab for relapsed/refractory MCL. This review summarizes the latest and exciting advances in MCL.

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... 42,43 Vaccine approaches also are being investigated. As described by Zhou et al, 44 tumor-derived Id antigen conjugated to a carrier protein (termed Id-KLH) and admin-istered with granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) may induce tumor-specific immunity. This is a welltolerated therapeutic approach, and phase II trials have confirmed its utility as a consolidative therapy. ...
... This is a welltolerated therapeutic approach, and phase II trials have confirmed its utility as a consolidative therapy. 44 Other agents currently in clinical trial include thalidomide (Thalomid), lenalidomide (Revlimid), the mTOR inhibitors temsirolimus (Torisel) and everolimus, the cyclin D1/CDK inhibitor flavopiridol, and the PKCb (protein kinase C-beta) inhibitor enzastaurin. [45][46][47][48][49] What follow-up is recommended for MCL patients? ...
Article
Mantle cell lymphoma (MCL), distinguished by the nuclear expression of cyclin D1 resulting from the chromosomal translocation t(11;14)(q13;q32), is a distinct subtype of non-Hodgkin lymphoma (NHL). Comprising 4%-6% of all cases of NHL, MCL is clinically heterogeneous, often pursuing an aggressive clinical course with a median survival averaging 4-5 years. Clinical trials using immunochemotherapy have shown improved responses for patients with MCL versus chemotherapy alone, although most studies have not confirmed improvement in overall survival. The use of stem-cell transplantation has promise and provides improved progression-free survival in selected patients. Most patients ultimately relapse, and a number of new therapies are available or are being evaluated in clinical trials for those with recurrent disease. This review will summarize recent treatment advances and will provide a practical approach for the diagnostic evaluation, prognostication, and follow-up of patients with MCL.
... During 2001-2012, intensified immunochemotherapy regimens containing rituximab and high-dose cytarabine (HDAC) followed by consolidative autologous stem cell transplantation (ASCT) provided the first breakthrough in clinical management of aggressive MCL by improving the response quality and duration in younger patients. The regimens include alternating R-CHOP/R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), the Nordic MCL2 protocol (rituximab with dose-escalated cyclophosphamide and doxorubicin, vincristine, prednisone [R-maxi-CHOP] alternated with HDAC), the MD Anderson protocol (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine with rituximab [R-hyper-CVAD/MA]), and deliver median overall survival (OS) over 10 years (8)(9)(10)(11)(12)(13). However, such therapies did not represent a curative approach and were associated with acute and long-term toxicity. ...
Article
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Purpose: The treatment paradigm for mantle cell lymphoma (MCL), a B-cell malignancy, has shifted considerably during the past decades. This study aimed to evaluate time trends in overall survival (OS) and disease-specific mortality (DSM) of younger (age ≤ 65 years) patients with MCL from 1995 to 2016. Methods: We used the Surveillance, Epidemiology, and End Results database. Year of diagnosis was divided into three eras: the chemotherapy-alone era (1995–2000), intensified-immunochemotherapy era (2001–2012), and targeted-therapy era (2013–2016). We used the Kaplan–Meier method, log-rank test, and subdistribution proportional hazard regression in the analysis. Results: A total 4,892 patients were identified. Median OS increased from 67 months in the chemotherapy-alone era to 107 months in the intensified-immunochemotherapy era (P < 0.001). The DSM rate decreased significantly from 1995 to 2016 (P < 0.001); the adjusted hazard ratios of MCL-specific death were 0.589 (P < 0.001) for the intensified-immunochemotherapy era and 0.459 (P < 0.001) for targeted-therapy era, as compared with the chemotherapy-alone era. Patients with advanced-stage MCL exhibited lowering risk of death across the three eras (P < 0.001). Conclusions: During 1995–2016, survival in younger patients with MCL increased significantly, especially those with advanced-stage disease, potentially reflecting the impact of advancement in treatment modalities on MCL outcome.
... MCL is among the toughest lymphomas, and is characterized by the t(11;14)(q13;q32) chromosomal translocation and overexpression of cyclin D1. Immunotherapy is an important therapeutic modality in MCL, and the combination of thalidomide with rituximab has shown substantial antitumor activity [41]. Its mechanism in treating MCL is the indirect inhibition of MCL cell viability through the enhancement of peripheral blood mononuclear cell-mediated cytotoxicity, during which rituximab-induced ADCC is increased by thalidomide. ...
Article
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The extensive autoimmune, anti-inflammatory, and anticancer applications of thalidomide have inspired a growing number of studies and clinical trials. As an inexpensive agent with relatively low toxicity, thalidomide is regarded as a promising therapeutic candidate, especially for malignant diseases. We review its therapeutic effects in hematology, including those on multiple myeloma, Waldenstroem macroglobulinemia, lymphoma, mantle-cell lymphoma, myelodysplastic syndrome, hereditary hemorrhagic telangiectasia, and graft-versus-host disease. Most studies have shown satisfactory results, although several have reported the opposite. Aside from optimal outcomes, the toxicities and adverse effects of thalidomide should also be examined. The current work includes a discussion of the mechanisms through which the novel biological effects of thalidomide occur, although more studies should be devoted to this aspect. With appropriate safeguards, thalidomide may benefit patients suffering from a broad variety of disorders, particularly refractory and resistant diseases.
... Rituximab or anti-CD20 radioimmunoconjugates are used in conjunction with a wide variety of treatment approaches for mantle cell lymphoma including various chemotherapy regimens, autologous stem cell transplantation, and immunomodulatory drugs, therefore documentation of this antigen's expression is often useful 48 . In our recent cases, CD20 was invariably positive at diagnosis (Table 5). ...
Article
Determining the immunophenotype of hematologic malignancies is now an indispensable part of diagnostic classification, and can help to guide therapy, or to predict clinical outcome. Diagnostic workup should be guided by morphologic findings and evaluate clinically important markers, but ideally should avoid the use of overly broad panels of immunostains that can reveal incidental findings of uncertain significance and give rise to increased costs. Here, we outline our approach to diagnosis of B-cell neoplasms, combining histologic and clinical data with tailored panels of immunophenotyping reagents, in the context of the 2008 World Health Organization classification. We present data from cases seen at our institution from 2004 through 2008 using this approach, to provide a practical reference for findings seen in daily diagnostic practice.
... Several lines of evidence point to manipulation of the immune system as an enticing non-cross-resistant therapeutic strategy for MCL. The demonstration that immune cells are able to kill chemotherapy-resistant tumor cells (7,8) together with the findings that T-cell responses can be elicited in vaccinated patients with MCL (9), and the encouraging responses observed in patients with relapsed/refractory MCL treated with immunomodulatory drugs (10,11) suggest that harnessing the immune system and, in particular, eliciting its exquisite specificity and long-lasting protection might lead to sustained immune responses in MCL (12). ...
Article
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Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
... These include improvement of patient outcomes when combined with chemotherapy and limited toxicity profiles, making mAbs ideal alternative options for heavily pretreated patients with relapsed/ refractory disease [24]. Rituximab (Genentech Inc, San Francisco, CA), a chimeric anti-human CD20 mAb, has been widely utilized to treat MCL patients [25,26]. As a single agent, rituximab has been tested in untreated as well as pretreated patients with RR of approximately 30% and a median response duration of 6 months [25,27]. ...
Article
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Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by short median survival despite intensive therapies. The clinical behavior of MCL may be due to the complex pathophysiology of the disease which includes its genetic hallmark, the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1, alteration in the DNA damage response, and constitutive activation of key anti-apoptotic pathways such as phosphatidyl-inositol 3-kinase (PI3K)/Akt and nuclear factor-kB (NF-kB). Collectively, these changes result in cell cycle dysregulation and give rise to profound genetic instability. Given this complex pathophysiology, the limited number of options for patients with relapsed/refractory MCL, and the difficulty in achieving long-lasting remissions with conventional approaches, it is essential to explore new treatment options targeting the numerous dysregulated pathways that are operable in MCL. We have recently reported that milatuzumab, a fully humanized anti-CD74 monoclonal antibody (mAb), in combination with anti-CD20 mAbs has significant preclinical and clinical activity in MCL. Here we discuss these results, provide additional insights into milatuzumab-mediated MCL cell death, and report preliminary data on the activity of other targeted biologic agents including PCI-32765 and CAL-101 currently undergoing evaluation at our institution and others.
... Unlike rituximab, milatuzumab does not cause cell death via antibodydependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. 22,24 Rituximab and milatuzumab target distinct antigens lacking known association and, as single agents, have demonstrated substantial antitumor activity in B-cell non-Hodgkin lymphoma (NHL) cells, 22,25 providing the rationale for exploring this combination treatment strategy in MCL. From a translational standpoint, dual antibody therapy offers several advantages including: favorable toxicity profiles that may permit frequent dosing or maintenance treatment; additional treatment options for heavily pretreated patients or patients with significant comorbidities; potentially increased efficacy compared with single agent regimens because of alternative mechanisms of action; and the ability to overcome resistance mechanisms that may evolve in the setting of single agent mAb therapy. ...
Article
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.
... Although MCL patients usually respond to first-line conventional therapy, there is no plateau in long-term disease-free survival. MCL remains incurable and novel therapeutic strategies are needed [1,2]. ...
Article
Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56(low)CD16(+) NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL.
... For example, rituximab (a chimeric monoclonal anti-CD20 antibody) revolutionized the treatment of NHL and improved survival responses. 37,38 A regimen of rituximab plus hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin[ adriamycin], and dexamethasone) alternating with rituximab plus high-dose methotrexate and cytarabine was proven to be effective in previously untreated, aggressive MCL by Romaguera et al. 39 In that study, 97% of 97 assessable patients responded, and 87% achieved a complete response or unconfirmed complete response. With a median follow-up time of 40 months, the 3year failure-free survival and overall survival rates were 64% and 82%, respectively. ...
Article
Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin's lymphoma. To the authors' knowledge, little is known regarding its incidence patterns and associated factors. The purpose of the current study was to examine the incidence of MCL over a period of 13 years and to identify the factors associated with the incidence patterns. Patients diagnosed with MCL between 1992 and 2004 were identified from the Surveillance, Epidemiology, and End Results (SEER) Tumor registries. SEER*Stat statistical software was used for analysis. Of the 87,166 patients diagnosed with non-Hodgkin's lymphoma during the 13-year period between 1992 and 2004, 2459 (2.8%) had confirmed MCL. The overall incidence of MCL (per 100,000) was 0.55, which increased with age: 0.07 in patients aged <50 years, 2.97 in patients aged 70 to 79 years, and 2.78 in those aged > or =80 years. The age-adjusted incidence rate increased from 0.27 of 100,000 in 1992 to 0.69 of 100,000 in 2004, and the annual percent change was 5.87% (P < .05). The median age at diagnosis was 68 years. The incidence of MCL was higher in men (0.84 of 100,000) than in women (0.34 of 100,000) (P < .05), and was higher in Caucasians (0.61 of 100,000) than in African Americans (0.32 of 100,000). Late-stage (III-IV) MCL was diagnosed in 74.6% of patients. There were significant geographic variations noted (P < .05). The incidence of MCL increased from 1992 to 2004, and was significantly higher in men, in Caucasians, and patients aged > or =50 years. Most patients were diagnosed with late-stage MCL, and there also were considerable geographic variations observed in incidence rate.
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Anti-tumor vaccines in lymphoproliferative disorders hold out the prospect of effective tumor therapies with minimal side effects. The addition of immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. Ideally, an antigen that is used for vaccination would be specifically expressed in the tumor; it must have an important, causal part in the multifactorial process that leads to cancer, and it must be expressed stably even after it is attacked by the immune system. Immunotherapies, which aim to activate the immune system to kill cancer cells, include strategies to increase the frequency or potency of antitumor T cells, to overcome suppressive factors in the tumor microenvironment, and to reduce T-cell suppression systemically. In this review, we focus on the results of clinical trials of vaccination in lymphoma, and discuss potential strategies to enhance the efficacy of immunotherapy in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib (CFZ), a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that CFZ induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, CFZ was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The CFZ-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, CFZ inhibited the growth and survival signaling pathways NFκB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of CFZ in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg CFZ on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that CFZ is a promising, potentially less toxic treatment for MCL. Further, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from CFZ.
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Arginine biosynthesis and nitric oxide (NO) production are important for cancer homeostasis. Degradation of arginine may be employed to inhibit liver tumors with low argininosuccinate synthetase expression. In this report, we investigated an alternative therapeutic approach by targeting argininosuccinate lyase (ASL). ASL is transcriptionally induced by endoplasmic reticulum stress and is overexpressed in some human liver tumors. Knockdown of ASL expression by shRNA in three liver cancer cell lines, ML-1, HuH-7, and HepG2, decreased colony formation in vitro and tumor growth in vivo. Furthermore, lentiviral infection of ASL shRNA inhibited tumor growth in a therapeutic animal tumor model. Analysis of ASL shRNA on the cell cycle progression revealed a G2/M delay. Among cell-cycle regulatory molecules, cyclin A2 expression was reduced. Reintroduction of exogenous cyclin A2 restored the cell growth in ASL-knockdown cells. Autophagy was observed in the cells treated with ASL shRNA, as demonstrated by an increase in LC3-II levels and autophagosome formation. The total cellular arginine level was not altered significantly. Inhibition of autophagy further attenuated cell growth, suggesting that autophagy induced by ASL shRNA plays a feedback pro-survival function. Knockdown of ASL reduced NO content, and addition of NO donor partially recovered the growth inhibition by ASL shRNA. In summary, downregulation of ASL attenuated tumor growth and the inhibition was mainly mediated by a decrease of cyclin A2 and NO.
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Background: Mantle Cell Lymphoma (MCL) is an aggressive B cell malignancy accounting for 6% of non- Hodgkin's lymphoma cases in the US. While various therapies are available to treat MCL, patients relapse within 3 to 4 years following treatment from therapy-resistant MCL, making MCL carry one of the worst prognoses of all non- Hodgkin's B cell lymphomas. A better understanding of the biological mechanisms of relapse and therapy-resistance in MCL is vital for developing mechanisms to target relapsing MCL, and providing better care for patients. Recent studies implicate the NF?B pathway and survivin in promotion of aggressive, therapy-resistant MCL. Therefore, we tested the efficacy of inhibiting this pathway in three MCL lines (GP, recently-developed GRL, and JVM2) using the protease inhibitor ritonavir (Abbott Laboratories), which has been shown to downregulate NF?B targets, including survivin, in other hematological malignancies. Methods: MCL cells were incubated with ritonavir then assessed for changes in proliferation, apoptosis, and activation of NF?B transcriptional targets. In addition, in vivo studies were performed to assess ritonavir's utility as a single agent in MCL treatment using an immune-deficient mouse model of human MCL. Results: When MCL cell lines were incubated with ritonavir in vitro, they exhibited reduced proliferation, increased apoptosis, and downregulation of NF?B pathway targets. However, no effect was seen when testing ritonavir as a single agent in vivo. Although, treatment with ritonavir plus vincristine in vitro revealed significant reduction in the proliferation of MCL compared to either treatment alone. Conclusions: These studies suggest ritonavir is not suitable as a single-agent therapy for MCL. However, studies combining ritonavir plus vincristine in vitro suggest ritonavir may be effective in multi-pronged treatment approaches for MCL. These findings necessitate further studies to determine ritonavir's utility within a multi-pronged treatment approach for treating therapy-resistant MCL.
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Mantle cell lymphoma is traditionally conceived as one of the NHL subtypes with the worst prognosis and incurable. In responders to frontline induction with CHOP-like chemotherapy autologous stem cell transplantation (ASCT) is proven superior to interferon maintenance, but does not lead to long-term disease control. The efficacy of CHOP as induction therapy before ASCT in MCL is questioned and there is now evidence that as pretreatment before ASCT, AraC + rituximab leads to deeper remission and prolongs progression-free survival compared to rituximab + CHOP. The treatment goal of complete clinical and molecular remission in younger patients with MCL, is now within reach, based on an integrated approach of intensive AraC containing immunochemotherapy with or without subsequent ASCT, and post-treatment maintenance with rituximab or lenalidomide are now being investigated. Such an integrated approach might lead to a shift of paradigm of MCL from an incurable to a curable lymphoma.
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A retrospective analysis was done using the Surveillance, Epidemiology, and End-Results (SEER) database to determine the trends in overall survival and identify prognostic factors in patients with mantle cell lymphoma (MCL). In total 5367 cases of MCL identified from 1992 to 2007 were split into three cohorts, group 1(1992-1999), group 2 (2000-2003) and group 3 (2004-2007). Survival was analyzed using the Cox proportional hazards model to correct for age, gender and stage of disease. The proportion of patients with advanced disease at diagnosis, male gender and advanced age increased over time and these were all associated with increased mortality. The overall survival remained unchanged. However, when adjusted for the increased proportion of patients with poor prognostic features noted above, we found a significant improvement in survival. The adjusted model also showed an improvement in predicted survival over time in patients with advanced stage. No change in survival was seen in patients with localized disease. Although this analysis is not designed to evaluate specific treatment modalities, these data suggest that the development of new treatment strategies over the past decade may be impacting the survival of patients with advanced MCL despite the finding that the overall survival remains unchanged in the general US population.
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Mantle cell lymphoma (MCL) is a moderately aggressive disease, which is not curable with chemo-immunotherapy. The median survival duration is short, approximately three years. Most of the patients have advanced stage disease at the time of diagnosis. Fifty percent of the patients show infiltration of the bone marrow, in 25% of the MCL patients the gastrointestinal tract is involved, in 25% of patients leukaemic transformation occurs. The tumor cells express pan-B-cell markers and the T-cell marker CD5. The overexpression of cyclin D1 was found as another marker for mantle cell lymphoma. Combined chemotherapy, chemo-immunotherapy, autologous peripheral stem cell (and allogenous) transplantation is the treatment of choice. Our two patients had prolonged survival, in spite of missing the best first line therapy. The survival time after the complex treatment (chemo-immunotherapy, irradiation, surgical intervention, autologous stem cell transplantation) was 80 and 90 months, respectively. In addition to the history of two patients, authors review the current treatment options in mantle cell lymphoma.
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Although recent progress has been made in the treatment of mantle cell lymphoma (MCL) the majority of patients experience relapse and ultimately die of their disease. The translocation t(11;14) is a prerequisite for the diagnosis of MCL and results in overexpression of cyclin D1. Its protein translation is controlled by mTOR, a key element of the PI3K/Akt pathway, and mTOR constitutes an attractive therapeutic target. Temsirolimus, a specific inhibitor of mTOR, has been evaluated in two Phase II trials in patients with relapsed MCL, and promising response rates up to 40% were found. Subsequently, a randomized Phase III trial was initiated, in which superiority in remission induction and progression-free survival could be demonstrated for a regimen of temsirolimus 175 mg for 3 weeks, followed by a 75-mg weekly application in comparison with established agents. This adds temsirolimus to the therapeutic armamentarium for the treatment of MCL. Further developments target combination therapy in MCL and other lymphoid neoplasms.
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Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.
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A retrospective analysis was performed to delineate the factors associated with response, and to determine the duration of response, in 87 patients with CD20-positive mantle-cell lymphoma (MCL) treated with Rituximab (chimeric monoclonal anti-CD20 antibody) in two prior studies. Patients with newly-diagnosed MCL (MCL1, n = 37), and previously-treated MCL (MCL2, n = 50), received single-agent Rituximab, in the context of two multicentre clinical studies using different schedules and doses, conducted in 1996 and 1997. A follow-up analysis was performed at the end of 1998, including all 81 patients who completed therapy. Statistical modeling of factors associated with response was performed using ordered logistic regression. The duration of complete (CR) and partial response (PR), and the time to disease progression (TTP), were also derived. The overall response rate (RR) was 34% (30 of 87) (81 evaluable patients, RR 37%; CR 14%), and was equivalent for MCL1 and MCL2. On univariate analysis, elevated LDH (P = 0.004); prior therapy with alkylating agents (P = 0.01) or fludarabine phosphate (P = 0.04); WHO performance status = 2 (P = 0.02); MCL2 refractory to last prior therapy (P = 0.04); and splenomegaly (P = 0.04), each at the time of treatment with Rituximab, were significantly associated with a lower RR. On multivariate analysis, only LDH (P = 0.007) and prior alkylating agents (P = 0.03) retained statistical significance. At a median follow-up of 1.4 years, the median TTP was 7 months. The median duration of response was one year, and was significantly longer for patients achieving CR vs. PR (P = 0.04). Rituximab is active in MCL, and can induce complete responses in a minority of patients. Elevated LDH at the time of therapy, and prior therapy with alkylating agents, are associated with a significantly lower RR. The duration of response of one year is similar to that previously reported in follicular lymphoma.
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Tumor-specific clonal immunoglobulin expressed by B-cell lymphomas (idiotype [Id]) can serve as a target for active immunotherapy. We have previously described the vaccination of 4 patients with follicular lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted T-cell proliferative anti-Id responses, and 4 had clinical responses--2 complete responses (CRs) (progression-free [PF] for 44 and 57 months after vaccination), 1 partial response (PR) (PF for 12 months), and 1 molecular response (PF for 75+ months). Subsequently, 25 additional patients were vaccinated after first chemotherapy, and 15 of 23 (65%) who completed the vaccination schedule mounted T-cell or humoral anti-Id responses. Induction of high-titer immunoglobulin G anti-Id antibodies required coupling of Id to the immunogenic carrier protein keyhole limpet hemocyanin (Id-KLH). These antibodies could bind to and induce tyrosine phosphorylation in autologous tumor cells. Among 18 patients with residual tumor at the time of vaccination, 4 (22%) had tumor regression, and 16 of 23 patients (70%) remain without tumor progression at a median of 43 months after chemotherapy. Six patients with disease progression after primary DC vaccination received booster injections of Id-KLH protein, and tumor regression was observed in 3 of them (2 CRs and 1 PR). We conclude that Id-pulsed DC vaccination can induce T-cell and humoral anti-Id immune responses and durable tumor regression. Subsequent boosting with Id-KLH can lead to tumor regression despite apparent resistance to the primary DC vaccine.
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Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with (131)I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of (131)I-labeled CD20-specific monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body weight, and the amount of (131)I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days later by administration of high-dose etoposide (30-60 mg/kg), cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved autologous stem cells. The 16 patients in this study had received a median of 3 prior treatments, and 7 had chemotherapy-resistant disease. The median dose of (131)I was 510 mCi (18.87 GBq). There were no therapy-related deaths. Among the 11 patients with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 91% and 100%. Fifteen patients remain alive, and 12 have had no progression of lymphoma at 6 to 57 months from transplantation and 16 to 97 months from diagnosis. Overall survival at 3 years from transplantation is estimated at 93%, and progression-free survival is estimated at 61%. High-dose treatment with (131)I-Tositumomab, etoposide, and cyclophosphamide results in a high remission rate and may provide long-term disease-free survival for patients with relapsed or refractory mantle cell lymphoma.
Article
Background: The management of MCL is a significant therapeutic challenge, especially in patients with relapsed or refractory disease, who are generally refractory to salvage chemotherapy. Although recent studies have shown the clinical utility of radioimmunotherapy (RIT) in relapsed and transformed indolent B-cell lymphoma, the clinical efficacy of this treatment modality in patients with MCL is unknown. We report the results of an ongoing phase II clinical trial of yttrium 90 ibritumomab tiuxetan (Zevalin®) in patients with relapsed and refractory MCL. Patients and Methods: Patients with relapsed or refractory MCL with measurable disease, age ≥18 years, and performance status <3 were eligible. Patients were required to have adequate function of the bone marrow (ANC ≥1,500/mm3, platelets ≥100,000/mm3), liver, and kidneys. Patients were excluded if they had prior stem cell transplantation, RIT, CNS lymphoma, HIV infection, pleural effusion, HAMA reactivity, or circulating lymphoma cell count >5000/mm3. Patients with pretreatment platelet counts ≥150,000/mm3 received a dose of Zevalin at 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with platelet counts <150,000/mm3 received 0.3 mCi 90Y/kg. Results: Twenty-two patients were enrolled and all qualified for evaluation of treatment response and toxicity. The median age was 67 years (range 51–77), and 18 patients were male. All patients had an ECOG performance status of 0 or 1 and had been previously treated with rituximab with or without other chemotherapy. The median number of prior regimens was 3 (range 1–6). Fourteen patients were previously treated with Hyper-CVAD alternating with MTX/Ara-C, 21 previously received rituximab, and 5 previously received bortezomib. Zevalin treatment was generally well tolerated, with the most common toxicities being hematologic. Objective responses were observed in 8 of 22 patients (36%), including 3 CR and 2 CRu. Seven of the eight responding patients were previously treated with 3 or less treatment regimens, and all responding patients did not have bulky disease, with the largest lesion measuring 3 cm or less. Median time to progression for CR/CRu patients was 6 months. Conclusion: The observed responses to Zevalin in heavily pretreated patients with MCL are promising, but the duration of responses has been short. Furtherinvestigation is warranted after first or second relapse, and in conjunction with front-line therapy.
Article
7560 Background: Mantle cell lymphoma remains a clinical challenge particularly for pts not candidates for consolidation with ASCT or treatment with leukemia induction regimens. Methods: We investigated sequential radioimmunotherapy (RIT) cytoreduction with tositumomab/Iodine I131 tositumomab followed by CHOP chemotherapy as initial therapy for patients either ineligible for or unwilling to undergo high dose therapy and stem cell transplantation. In addition, pts had to have less than 25% of the intratrabecular bone marrow space involved with lymphoma. Results: Twenty-five patients (pts) were enrolled but only 24 were treated with the therapeutic dose of RIT because a manufacturing problem prevented the treatment of one patient. The median age was 66 (45–80), there were 23 men and 2 women. All patients had advanced stage (III/IV) disease and bone marrow was involved in 48% and the GI tract was involved in 48% of the patients. The overall response rate (ORR) to RIT was 83% (CR/CRu 46%; PR 38%). Two pts withdrew consent following the RIT (and are censored from that point); 1 pt with disease progression requiring alternative therapy is included in EFS and OS analyses. Twenty-one pts proceeded to the CHOP consolidation and 19 completed planned therapy (1 pt died of a CVA; 1 pt chose not to complete chemotherapy after two cycles of CHOP). At the completion of delivered therapy the ORR was 86% (CR/CRu 67%, PR 19%). The median follow up is 2.1 years (0.7 to 4.2). The median EFS was 1.4 years though there have been no events beyond 1.7 years with 7 pts at risk; median OS has not been reached (92% at 2.1 years). Minimal residual disease (MRD) was evaluated with a clonotypic PCR (cPCR) capable of detecting about 1:10 ⁵ tumor cells; this assay was informative in 17 pts. Following induction with RIT 6 pts (46%) were molecularly negative in blood and bone marrow. Despite the increase in clinical CR following CHOP consolidation, no additional pts became molecularly negative. Conclusions: RIT with tositumomab/iodine I131 tositumomab is a very active agent in the treatment of MCL; unfortunately, MRD is not effectively eliminated by subsequent CHOP chemotherapy. We are planning to explore chemotherapy induction followed by RIT. [Table: see text]
Article
17522 Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. Methods: We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m ² administered on days 1, 4, 8, and 11, R at 375 mg/m ² administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. Results: Up to now, we have enrolled 10 pts (median age, 69 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 8 pts, high-dose therapy in 3 pts, and thalidomide in 5 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 8 pts evaluable for efficacy, 7 have achieved a response (3 CR, 4 PR), and 1 pt experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. 6 of 6 pts are still progression-free at 6 months after treatment initiation. Recruitment of patients is ongoing, and updated results will be presented. Conclusions: Data obtained thus far indicate that BORID has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable response. [Table: see text]
Article
7528 Background: Bendamustine HCl, a novel alkylating hybrid agent, has single-agent activity in multiple hematologic and solid tumors. In vitro data have demonstrated the multifunctional mechanisms of bendamustine by which cell death occurs via both apoptosis and mitotic catastrophe. Bendamustine has shown activity in NHL cell lines that are refractory to conventional alkylator chemotherapies. The combination of bendamustine and rituximab has shown a synergistic effect on NHL cells. The efficacy and safety of bendamustine in combination with rituximab in patients with relapsed NHL were evaluated. Methods: This phase II, multicenter study enrolled adult patients with relapsed, indolent, rituximab-sensitive B-cell or mantle-cell NHL. Patients received rituximab 375 mg/m ² IV on day 1 and bendamustine 90 mg/m ² IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m ² IV was given 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat population included 67 patients (57% males; median age, 60 years) with indolent NHL (81%) or mantle-cell NHL (16%) (data not available [3%]). A total of 81% of patients had stage III/IV disease. Patients had relapsed from a median of 1 prior therapy; 37% had prior treatment with rituximab. In the 57 evaluable patients, the overall objective response rate (ORR) was 87% (complete response [CR], 33%). The ORR for the 9 evaluable mantle-cell NHL patients was 89% (CR, 33%). For all patients, the median duration of response and progression-free survival had not been reached after a median follow-up of 3.7 months (range, 0–14.2 months). This therapy was well tolerated. Most commonly reported nonhematologic toxicities were grade 1/2 gastrointestinal events, with nausea being the greatest (38%). The primary grade 3/4 hematologic toxicity was neutropenia (29%), with 1 event of sepsis. Conclusions: Bendamustine in combination with rituximab was well tolerated and produced high response rates in patients with relapsed indolent and mantle-cell NHL. These results suggest bendamustine in combination with rituximab provides a potential benefit over single-agent rituximab therapy. [Table: see text]
Article
7555 Background: Currently, Mantle Cell Lymphoma (MCL) is an incurable disease. Patients treated with chemotherapy alone experience only transient responses, with no long-term improvement in disease-free/overall survival. While autologous hematopoietic stem cell transplantation (ASCT) in MCL patients has demonstrated prolonged survival, relapse remains the major issue. We evaluate the impact of rituximab (Rituxan, Rtx) on relapse and survival following ASCT. Method: A case-series of 83 MCL patients treated with ASCT at City of Hope (from 02/1991 to 04/2005) were examined; a total of 52 patients received Rtx (with-Rtx) as part of their induction/salvage treatment (pre-ASCT) and/or maintenance therapy (post-ASCT), 31 patients did not receive Rtx (no-Rtx) at any point pre-/post-ASCT. An assessment of baseline patient and disease characteristics (gender, age, KPS, % of pts with bone marrow involvement at diagnosis, disease stage/status at ASCT, % of pts with bulky disease B-symptoms at ASCT, and # of regimens administered prior to ASCT) showed no significant differences among the two groups. Result: To date, 23 patients have relapsed/progressed post-ASCT; 61% of the patients in the no-Rtx group remain disease free at last contact, while 79% in the with-Rtx group remain disease free. The median survival in the no-Rtx group is 77.63 months; the median survival time point for the with-Rtx group has not been reached due to shorter follow-up period. The 2-yr relapse rate for the with-Rtx/no-Rtx groups among 1st CR/PR patients were 19% (95% CI: 10–33%) and 26% (95% CI: 14–43%) (p > 0.05) respectively and the 2-yr relapse rate for the with-Rtx/no-Rtx groups among the beyond 1st CR pts were 33% and 40% respectively (p > 0.05). The survival endpoint showed similar results. The 2-yr survival probability for the with-Rtx/no-Rtx groups among the 1 st CR/PR patients were 91% (95% CI: 76–97%) and 82% (95% CI: 64–91%) (p > 0.05) respectively and the 2-yr survival probability for the with-Rtx/no-Rtx groups among the patients beyond 1st CR/PR were 59% and 63% respectively (p > 0.05). Conclusion: Using Rtx as induction/salvage and/or maintenance before and after ASCT therapy may not be associated with decreased relapse and improved survival. Nevertheless, our data indicate that outcome is better when ASCT is carried out at 1st CR/PR. No significant financial relationships to disclose.
Article
7534 Background: CD40 is a member of the TNF receptor family and is widely expressed on hematologic malignancies of B-cell origin. SGN-40 is a humanized antibody against CD40 with effector cell function and mild agonistic activity. Preclinical toxicity studies and efficacy data supported initiation of a multi-institutional phase I study to test the safety, pharmacokinetics, immunogenicity, and efficacy of SGN-40 in patients with relapsed NHL. Methods: Cohorts of 3–6 pts were treated weekly with a maximum dose of 2, 3, or 4 mg/kg/wk SGN-40. A dose escalation schedule is used such that patients receive 1 mg/kg on D1 and D4, 2 mg/kg on D8, and higher doses on weeks 3–5. Responding patients may receive a second cycle. Further dose escalation up to 8 mg/kg is planned. Results: 16 pts have been treated with multiple histologic subtypes: follicular (1), marginal zone (MZL; 1), mantle cell (4), and diffuse large B-cell (DLBCL; 10). One patient (2 mg/kg) developed a reversible Grade 3 unilateral conjunctivitis and ipsilateral loss of visual acuity. No other dose limiting toxicity has been observed up to 4 mg/kg. Preliminary pharmacokinetic data suggest that the antibody has a relatively short half-life, perhaps reflecting a route of elimination or binding that is not saturated at current doses. Two partial responses have been observed at 3 mg/kg (1 MZL, 1 DLBCL) and one partial response has been observed at 4 mg/kg dose (DLBCL relapsed after autologous stem cell transplant with small volume tumor). Conclusions: Using an intra-patient dose escalation schedule, SGN-40 has been well-tolerated at doses up to 4 mg/kg/wk. Further dose-escalation is ongoing to determine the maximum tolerated dose. Three objective responses have been seen, including two in patients with extensively treated aggressive disease. Correlative studies are underway measuring soluble CD40, cytokine release, effect of FcR polymorphisms, and SGN-40-induced immunogenicity. Given the favorable tolerability and activity, phase II studies in NHL are planned. [Table: see text]
Article
7533 Background: Radioimmunotherapy (RIT) has demonstrated high clinical efficacy in follicular lymphoma but varying results in mantle cell lymphoma (MCL). Methods: We performed a comparative analysis of two phase II studies with similar inclusion criteria to identify potential predictors of response. 32 patients with relapsed or refractory MCL, WHO performance status ≤2, appropriate hematopoesis (ANC > 1,500/mm ³ , platelets > 100,000/mm ³ ) and adequate function of liver and kidneys were treated with RIT upfront (Arm A, n = 16) or as consolidation after initial cytoreduction (Arm B, n = 16). 28 patients (88%) had been previously treated with rituximab. Patients with >25% bone marrow involvement, known CNS lymphoma, HIV infection or other severe concurrent disease were excluded. Ibritumomab tiuxetan (Zevalin) was applied at a dose of 15 MBq ⁹⁰ Y/kg, whereas patients with reduced platelet counts (<150,000/mm ³⁾ received 11 MBq ⁹⁰ Y/kg. Results: The median age was 66.9 years (range 58–72) in Arm A and 63.1 years (range 45–79) in Arm B. The median number of prior regimens was 4 (range 2–6) in Arm A and 1 (1–5) in Arm B. RIT treatment was generally well tolerated with the most common toxicities being hematologic. Thrombocytopenia grade 3 and 4 was observed in 69% of patients, one patient died of hemorrhagic stroke. Granulocytopenia grade 4 occurred in 34% of patients, one patient developed a grade 4 infectious complication. Currently 22 patients are evaluable for response rate and duration of remission (DR). In Arm A a partial response (PR) was observed in 2 of 6 evaluable patients (33.3%) with a median DR of 3.9 months only. In Arm B chemoinduction achieved 2 complete responses (CR) and 14 PR. Following RIT seven of 14 PR patients (50%) converted to CR. Currently, 13 of 16 patients (81%) are still in remission. As expected the most important adverse risk factor was bulky disease before RIT with no responses seen in this patient population. Patients with less prior therapeutic lines (< 2) had significantly higher response rates. Conclusions: In future trials, RIT should be applied earlier in the treatment algorithm of MCL after a debulking strategy with combined immuno-chemotherapy. [Table: see text]
Article
7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m ² /d days 1–3), Cyclophosphamide (200 mg/m ² /d days 1–3) and Mitoxantrone (8 mg/m ² /d day 1) (FCM) ± Rituximab (375 mg/m ² /d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m ² /d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]
Article
7503 Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate, ⁹⁰ Y-ibritumomab tiuxetan ( ⁹⁰ Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC >2,500/μl; platelets >100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg ⁹⁰ Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and ⁹⁰ Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% >1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After ⁹⁰ Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after ⁹⁰ Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After ⁹⁰ Y-RIT, responses improved in 15 of 37 pt with <CR/CRu: PR to CR/CRu (n = 12) and SD to CR (n = 1) or PR (n = 2) for a final response rate of 84% and CR rate of 45%. Conclusions: ⁹⁰ Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF. [Table: see text]
Article
7587 Background: Therapeutic options are limited in the treatment of relapsing NHL pts not suitable to HDCT. ⁹⁰ Yttrium ibritumomab tiuxetan (Zevalin) is active in DLBCL at 0.4 mCi/kg, but duration of response is usually short. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 11/05, 14 pts were enrolled. Median age was 68ys. 13/14 pts had advanced stage disease (III/IV) at diagnosis. 8 DLBCL, 4 MCL, 1 FL G3, 1 transformed MZL. Median number of prior therapies were 3, including rituximab, RT and HD-CT. Methods: 3 dose levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4 pts received 0.8, 4 pts 1.2 and 6 pts 1.5 mCi/kg. 1wk prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts received PBSC previously harvested. On d28 from reinfusion (+41 from Zevalin) engraftment was considered to be delayed if ANC <1.0×10 ⁹ /L or PLT<20.0×10 ⁹ /L. Results: Dosimetry showed acceptable radiation-absorbed doses to uninvolved organs, reaching max 20Gy. Only 1pt received 30Gy to the liver without developing toxicity. The median radiation-activity delivered was 90 mCi (range 57–150): 8 pts received a dose within 80 and 100 and 6 pts >100 mCi. Mean dose to red marrow: 0.8±0.2 mGy/MBq. All pts but 1 engrafted promptly. PLT/ANC count nadirs were observed 21/17 days after Zevalin (median values: 11×10 ⁹ /L and 0.01×10 ⁹ /L). No statistically significant difference in terms of hematological toxicity exists in PLT-recovering for pts receiving 1.5 mCi/kg and it is probably influenced by PLT count at baseline and by the several treatment previously received. Non-haematologic toxicity: 1 febrile neutropenia and 1HZV at 2nd level; 1 febrile neutropenia, 1 G3 liver toxicity, 1 bacterial pneumonia, 1HZV, 1HCV reactivation (pt died 4 months after treatment) at the 3rd level. 13/14pts are evaluable for response: 6CR, 2PR, 5PD. Conclusions: Zevalin at myeloablative activity with PBSC is feasible. It could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. Efficacy and mild toxicities suggest further investigation. We are continuing enrollment, including pts who previously received no more than 2 lines of CT. No significant financial relationships to disclose.
Article
8030 Background: MCL remains a therapeutic challenge. R targets CD20 antigen on MCL cells while Len may target the microenvironment of MCL cells and enhance the ADCC activity of R. To test this hypothesis, we initiated a single-center; open label, phase I/II study. We now report the completed phase I. Methods: Eligible patients (pts) had 1–4 lines of prior therapy including prior thalidomide or R, regardless of resistance. Each cycle of treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m ² by IV infusion weekly for 4 weeks. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. DLT was defined as grade (G) 3 or 4 non-hematologic or G4 hematologic toxicity during the first cycle. Results: The phase I portion completed enrollment with 15 pts (4 at 10 mg, 3 at 15 mg, 6 at 20 mg and 2 at 25 mg). Thirteen pts were evaluable. Median age was 73 (62–84); median prior lines of therapy were 3 (1–4); median cycles received to date were 2 (1–7). Two DLT's occurred at 25 mg. One pt had G3 hypercalcemia. The other had G4 neutropenic fever and died of sepsis (G5) during the first cycle. Three additional pts were therefore enrolled at 20 mg. Common non-hematologic toxic events included pruritis (21 G1–2), hypercalcemia (9 G1–2, 1 G3), fatigue (9 G1–2), constipation (8 G1), diarrhea (6 G1–2), fever (6 G1–2), myalgias (4 G1–2, 1 G3) and elevated LDH (4 G1–2, 1 G3). Hematologic events included neutropenia (20 G1–2, 4 G3), thrombocytopenia (6 G1–2, 2 G3) and anemia (6 G1). There were no responses at 10 mg or 15 mg. At 20 mg after 2 cycles, 5 out of 6 pts achieved responses including 1 CR, 1 PR, 3 minor responses (MRs) and only 1 pt progressed. The 1 pt with PR went on to achieve a CR after 6 cycles. The 3 pts with MRs had tumor reductions by 43%, 40% and 38% respectively. These 3 patients with MRs continue to receive Len and might later achieve PR or CR. Conclusions: The MTD for Len with R in relapsed/refractory MCL was 20 mg, orally daily on days 1–21 of a 28-day cycle. Responses observed at 20 mg are promising with a favorable toxicity profile and are being evaluated further in an ongoing phase II study. [Table: see text]
Article
We report the results of a phase II trial of an investigational new drug bortezomib (PS-341, Velcade) for the treatment of mantle cell lymphoma. Advanced stage previously untreated patients or those given up to two prior chemotherapy regimens were eligible. Additional entry criteria included measurable nodal disease, minimum laboratory requirements, and written informed consent. Central pathology review, to confirm eligibility and the presence of cyclin D1, was required after study entry. Accrual was closed July 2004 having reached the preplanned target of 30 patients. Bortezomib 1.3 mg/m2 IV bolus was given days 1, 4, 8 and 11 in 3-week cycles. Patients were assessed by CT scanning after every two cycles of therapy and response assessed according to International Working Group recommendations (Cheson B, J Clin Oncol 1999). Non progressors were to receive a maximum of 4 cycles. Responding patients were to receive bortezomib for 2 cycles following documentation of maximal partial response (PR) or complete response (CR). To date demographic data are available on 26 patients. The median age was 67 (48–78 yrs), all had stage 3 or 4 disease (55% bone marrow involvement), 7 were female and 10 had received no prior chemotherapy. A median of 4 treatment cycles has been given (range 1–7) and 25 patients are evaluable for toxicity. Grade ≥ 2 adverse effects thought to be related to study drug occurred as follows: anorexia 8%, nausea 16%, vomiting 4%, diarrhea 20%, fatigue 60%, dizziness 4%, sensory neuropathy 12%, edema 8%, hypotension 4%, vascular leak syndrome 4%, arthralgia 12%, myalgia 12%, neuropathic pain 12%, dyspnea 12%, rash 12%. Nine patients discontinued therapy because of toxic effects (6 of whom had neuropathy or myalgia). During accrual of the first 14 patients, 5 serious adverse events occurred in patients with pre-existing edema, dyspnea, and/or effusion. Therefore, the eligibility criteria were amended to exclude such patients thereafter and no further serious adverse events have occurred. To date, 24 patients are evaluable for response. Of the 10 patients having no prior chemotherapy there were 3 PR (range 2.5–14.8m) 6 SD (1.3–13.6m) and 1 PD for a response of 30%. Of the 14 previously treated patients we obtained 1 CRu (14.1m), 4 PR (2.4–13.1m), 7 SD (1.2–14.3m) and 2 PD. The overall response rate is 33% (95% C.I. 16–55%) but interestingly it is similar in both previously untreated and treated groups. We conclude that bortezomib is an active agent in mantle cell lymphoma, but at this dose and schedule complete remission is rare. Since higher doses will not be possible given the frequency of neuropathy and myalgia, alternative schedules or novel combinations with other active agents will be of interest to pursue.
Article
2719 Poster Board II-695 Background Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Article
High-dose therapy with allogeneic hematopoietic transplantation (allo-SCT) from matched sibling donors has been shown to induce durable remissions in some patients with relapsed / refractory mantle cell lymphoma (MCL). The aim of this retrospective analysis from the LWP of the EBMT was to investigate the outcome of patients with MCL treated with an unrelated donor allo-SCT (MUD-allo). From January 1994 to July 2005, 66 patients with MCL, 51 males and 15 females, with a median age of 50 years (range, 22 to 68) underwent a MUD-allo and were reported to the EBMT registry. The median time from diagnosis to MUD-allo was 34 months (range, 6–131). Thirty-five patients (53%) had previously failed an autologous procedure (ASCT). Forty-five patients (68%) had sensitive disease (including 22 patients in complete remission) at transplantation, whereas 21 patients (32%) were allografted with refractory disease. Reduced intensity conditioning regimens (RIC) were used in 44 patients (67%). Patients treated with RIC were older, more heavily pre-treated and had more frequently failed an ASCT (46% vs 30%, p = 0.01) than patients treated with a conventional conditioning protocol. Total body irradiation (TBI) was used in 68% of the patients receiving conventional protocols and low-dose TBI in 23% of the RIC patients. Grade II–IV acute graft versus host disease (GVHD) developed in 35% of the cases. The cumulative incidence (CI) of non-relapse mortality (NRM) was of 21% at 6 mo and 27% at 12 mo. The CI of relapse was 35% at 1 year and 45% at 2 years. After a median follow up of 15 months (1–73), 25 patients are alive without progression, with an estimated PFS and OS at 2 years of 28% and 42%, respectively. RIC protocols were not associated with a lower NRM or a better survival. Refractory disease at MUD-allo was an adverse prognostic factor for PFS (RR 1.7; p = 0.006). Patients allografted in sensitive disease presented a better 2-year PFS and OS (34% and 48%, respectively). In conclusion, although follow up is still short, MUD-allo is a feasible procedure in poor prognosis MCL patients, with almost one third of them being alive and progression-free in this series. RIC protocols do not seem to offer any advantage in terms of long-term outcome in relation to conventional conditioning regimens.
Article
Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL. Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The schedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy. Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse events occurring more than once were neutropenia (24.1%) and leucopenia (6.9%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Fifteen (51.7%; 95% CI: 32.5–70.6%) pts achieved a CR; only one has relapsed to date (665 days after starting therapy). Four additional pts achieved a PR. Ten pts have progressed with 4 pts progressing early at 17, 45, 46, and 71 days (two of whom have died). Ten pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. Fourteen pts (48.3%) have progressed or gone on to receive additional therapy off study. At last contact, 26 (89.7%) were alive (median follow-up 14.3 months; range: 6–34). One year survival rate is 89.3% (95% CI: 78.5–100). Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group of elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 52% achieved a complete remission. Complete remissions attained with this regimen appear to be durable, with a single relapse to date among 15 patients achieving CR.
Article
Background: Mantle cell lymphoma (MCL) has poor clinical outcome and is a significant therapeutic challenge in patients with relapsed or refractory disease due to its resistance to salvage chemotherapy. Although recent studies have shown the clinical utility of radioimmunotherapy (RIT) in relapsed and transformed indolent B-cell lymphoma, the clinical efficacy of this treatment modality in patients with MCL is not well described. We report the results of a completed phase II clinical trial of yttrium 90 ibritumomab tiuxetan (Zevalin) in patients with relapsed and refractory MCL. Patients and Methods: Patients with relapsed or refractory MCL with measurable disease, age ≥18 years, and performance status <3 were eligible. Patients were required to have adequate function of the bone marrow (ANC ≥1,500/mm3, platelets ≥100,000/mm3), liver, and kidneys. Patients were excluded if they had prior stem cell transplantation, RIT, CNS lymphoma, HIV infection, pleural effusion, HAMA reactivity, or circulating lymphoma cell count ≥5,000/mm3. Patients with pretreatment platelet counts ≥150,000/mm3 received a dose of Zevalin at 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with platelet counts <150,000/mm3 received 0.3 mCi 90Y/kg. Results: Thirty-five patients were enrolled at MDACC. The median age was 68 years (range 52–79), and 27 patients were men. All patients had an ECOG performance status of 0 or 1 and had been previously treated with rituximab with or without other chemotherapy. The median number of prior regimens was 3 (range 1–6). Twelve of the patients did not respond to their last regimen. Twenty-two patients were previously treated with Hyper-CVAD alternating with MTX/Ara-C, and 7 previously received bortezomib. Thirty-one of 35 patients are eligible for evaluation of treatment response and toxicity. There were no grade 3 or 4 non-hematologic toxic events. Grade 1 non-hematologic toxic events included fatigue in 7 and nausea in 3. Grade 2 non-hematologic toxic events included non-neutropenic fever in 1 and melana in 1. Grade 3 or 4 hematologic toxic events included thrombocytopenia in 8, neutropenia in 2 and anemia in 1. Objective responses were observed in 13/31 patients for an overall response rate (ORR) of 42% including 8 CR/CRu’s (26%) and 5 PR’s (16%). Three patients had stable disease. Among the 4 patients who received a Zevalin dose of 0.3 mCi 90Y/kg, 1 achieved a CRu while the 3 others had progressive disease. Eight of the 13 responding patients were previously treated with 3 or more regimens; two patients achieved CR after having received 4 prior lines of therapy. Median progression free survival for the responded patients was 6 months after a median follow up time of 16 months. Conclusion: Zevalin treatment was generally well tolerated; with the most common toxicity being hematological. The observed responses to Zevalin in heavily pretreated patients with MCL are promising and warrant further investigation of its activity after first or second relapse, and in conjunction with front-line therapy.
Article
Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT. Zevalin has been demonstrated active in elderly pts with resistant-primary refractory DLBCL at injected activity of 0.4 mCi/kg, however response is usually of short duration. Increasing RIT dose-intensity could improve and prolong efficacy. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. From 04/04 to 05/06, 18 pts were enrolled. Median age was 66.5ys (21–75). 17/18 pts had advanced stage disease (III/IV) at diagnosis. 11 had DLBCL, 4 MCL, 2 FL, 1 transformed MZL. Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three activity-levels were fixed: 0.8, 1.2, 1.5 mCi/kg. 4pts received 0.8, 5pts 1.2 and 9pts 1.5 mCi/kg. One week prior to Zevalin all pts underwent dosimetry: if no abnormal uptake was observed they received the planned dose. On d13 pts were reinfused with PBSC previously harvested. On d28 from reinfusion engraftment was considered to be delayed if ANC<1.0x109/L or PLT<20.0x109/L. Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases. Median adsorbed doses (mGy/MBq): 0.8±0.2 (RM), 3.0±1.7 (heart wall), 1.7±0.8 (lungs), 3.9±2.3 (liver), 2.5±1.6 (spleen), 2.2±1.1 (kidneys), 3.0±1.0 (testes), 0.6±0.1 (total-body). Only 1 pt received 30Gy to the liver, without developing toxicity. Median activity of 90Y-Zevalin delivered: 95 mCi (3,5 GBq), range 57–150 mCi (2,1 – 5, 55 GBq); 9pts received more than 100 mCi (3,7 GBq). All pts but 1 engrafted promptly. PLT and ANC nadirs were observed 21 and 17 days after Zevalin (median values: 11x109/L and 0.01x109/L). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. For all activity levels, the median time for PLTs to reach >20x109/L was + 25 days (0–35) and the median time for ANC>1.0x109/L was + 33 days (14–61). A non statistically significant difference in terms of hematologic toxicity exists in PLT recovering for pts receiving 1.5 mCi/kg, in respect to other levels, but this phenomenon is probably influenced by PLT count at baseline. A drop in PLT count occurs after engraftment in those pts who had received treatment with a PLT count <100x109/L, as a sign of late toxicity. Non-haematologic toxicity: 1febrile neutropenia, 1HZV-infection at 2nd level; 2febrile neutropenia, 1 G3 liver toxicity (quickly recovered), 1bacterial pneumonia, 1HZV-infection, 1HCV reactivation (pt died 4 months after treatment) at the 3rd level. No pulmonary, renal or cardiac toxicity was observed. All pts are evaluable for response: 7CR, 4PR, 1SD, 6PD. Conclusions: Zevalin at myeloablative activity is feasible with PBSC support and it could be safely delivered in elderly and heavily pretreated pts, including those who previously received HDCT. MTD could be defined according to dosimetry and clinical evaluation. We suggest an activity of 1.5 mCi/kg for those pts with normal PLT count, while 1.2 mCi/kg could be considered for pts with a PLT count <150x109. It is not advisable, in our opinion, to administer elevated Zevalin activity to pts having PLT counts <100x109/L and/or affected by chronic diseases of the liver. Clinical efficacy and mild treatment-related toxicities suggest further investigation.
Article
The Dutch Hemato-Oncology Study Group (HOVON) evaluated in a phase II trial the efficacy of the addition of rituximab, high dose Ara-C and autologous stem cell transplantation after BEAM conditioning to conventional CHOP in 88 previously untreated patients with mantle cell lymphoma, with respect to remission rate, failure free survival (FFS) and overall survival (OS). From 2002 to 2005, 86 eligible patients were included and evaluated. The male : female ratio was: 4 and the median age 55 years (32–66). Median follow-up of all patients still alive was 25.5 months. Patients were treated with R-CHOP21 x 3 (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 day 1 and prednisone 100 mg days 1 – 5). Stem cells were harvested after high dose Ara-C x 1 (2g/m2 BID days 1 – 4), followed by rituximab on day 11 for in vivo purging and G- CSF. After haematological recovery BEAM conditioning (carmustine 300mg/m2 day 1, Ara-C 200mg/m2 and etoposide 200 mg/m2 days 2 – 5 and melphalan 2 x 100 mg/m2 day 6) was given with autologous stem cell support day 8). After 3 x R-CHOP 17 patients did not reach PR and went off study, according to the protocol, and 5 patients were excluded for other reasons. Sixty four patients received HD Ara-C and 63 patients proceeded to BEAM. Haematological toxicity was as follows: the median time of recovery of leukocytes (> 1,0 x 109/l) from start of high dose Ara-C was 17 days (range: 0 – 59 days), from start of BEAM 26 days (range: 17 – 55). For platelets the median time to recovery (> 50 x 109/l) from start of high dose Ara-C was 23 days (range: 0 – 44 days) and from start of BEAM 25 days (range: 16 – 364). Non-hematological toxicity grade 3–4 was seen during CHOP in 13%, after HD Ara-C in 20%, mainly gastro-intestinal, and after BEAM in 51%, mainly gastro-intestinal and liver, of the patients. Grade 3–4 infections were seen during CHOP in 17%, after HD Ara-C in 30% and after BEAM in 59% of the patients. Responses to treatment are summarised in Table 1. At two years FFS was 67%, OS was 81%. An analysis restricted to the 63 patients who completed the protocol treatment showed FFS 90% and OS 98% at two years. We conclude that intensification of first line treatment with rituximab, HD Ara-C and BEAM is beneficial with respect to FFS and OS in younger MCL patients and that this regimen is well tolerated. Table 1. Response to treatment N CR PR NR/PD Not yet known after 3x CHOP 83 13 (16%) 51 (61%) 17 (20%) 2 after HD Ara-C 64 22 (34%) 28 (44%) 14 after BEAM 63 43 (68%) 13 (21%) 7 died early 1
Article
Background: We previously reported that 20 patients with newly diagnosed, stage III/IV mantle cell lymphoma (MCL) treated prospectively with an in vivo rituximab purge, autologous stem-cell transplantation (ASCT) and rituximab maintenance experienced superior progression free survival (PFS) compared to 40 matched, historical controls treated with conventional chemotherapy. We now report extended follow-up from this trial. Methods: Eligible patients were treated with 4–6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by high dose therapy (cyclophosphamide, carmustine and etoposide) and ASCT. Rituximab (375 mg/m2) was given once 5 days prior to stem cell collection (as an in vivo purge), and as two, 4-week maintenance courses 8 and 24 weeks after ASCT. Historical control patients matched for age, stage and gender were randomly selected from a lymphoma database maintained by the British Columbia Cancer Agency. Two control-patients were selected for every trial patient. All control patients were treated with either an anthracycline based-regimen, or a regimen containing fludarabine and cyclophosphamide. Results: Median follow-up is 5.3 years for the experimental cohort and 10.1 years for the control cohort. In the ASCT cohort, 8 patients have relapsed and 4 patients have died, 2 of progressive disease, 1 of a presumed cardiac event 7 months post-ASCT, and one of hepatitis B reactivation 11 months post-ASCT. Five-year OS and 5-year PFS were superior in MCL patients treated with ASCT+ rituximab compared to matched, historical MCL patients treated with conventional chemotherapy (5y OS 80% vs. 38%, P=0.0017; 5y PFS 72% vs. 19%, P=0.0001). One patient developed myelodysplastic syndrome 5.5 years after ASCT, and one patient was diagnosed with breast cancer 4.8 years after ASCT. Conclusions: With more than 5 years of follow-up MCL patients treated with ASCT plus rituximab continue to experience significantly improved OS and PFS compared to matched, historical controls. Overall Survival Overall Survival
Article
Background: The 5-yr survival rate is <20% for MCL. Standard chemotherapy for MCL includes fludarabine, cyclophosphamide, and mitoxantrone (FCM). Adding rituximab (R) to FCM increases the overall response rate (ORR) from 46% to 58%. MCL patients (pts) with large tumor burdens and no initial cytoreduction have a limited response to conventional non-myeloablative RIT. Aims: The Polish Lymphoma Research Group Trial (PLRG MCL1) assessed whether 90Y-Zevalin (Z) could consolidate the response achieved from FCM ± R and improve ORRs and time to progression (TTP). Methods: Thirty MCL pts (stage III–IV) not suitable for SCTs were enrolled in 8 PLRG centers: 13 pts were newly diagnosed, 7 pts had a PR after first-line therapy, and 10 pts were in first relapse. Tumor burden was reduced by induction therapy with 3–6 cycles of FCM ± R (375 mg/m2) in all pts and staged after the third and subsequent cycles to assess tumor regression. Pts were in CR (no palpable lymph nodes or measurable masses on CT) or PR (<25% bone marrow [BM] infiltration, <30 mm lymph node diameter, <12 cm spleen diameter, no massive extranodular involvement). All CR and PR pts with PMNs >1500/mL, PLTs >100,000/mL, and no BM hypoplasia received Z consolidation, starting with 2 doses of 250 mg/m2 R on days 1 and 8, followed by Z (0.3 or 0.4 mCi/kg, based on initial PLT count; maximum dose 32 mCi). ORR (CR + PR) and hematologic toxicity were determined. Response was monitored at 6 wk, 3 mo, and 3-mo intervals for up to 2 yr to assess TTP. Results: To date, 29 pts were evaluated. Of the 13 newly diagnosed pts 2 were in CR after completing FCM and 10 achieved CR after Z consolidation. Five of the 7 pts treated at first PR achieved a CR after Z and 2 pts achieved a PR. For the 10 pts treated at first relapse, 5 shifted from a PR after FCM to a CR after Z, 1 shifted from a CRu to a CR, and 3 pts achieved a further PR after Z. However, 5 of these 10 pts relapsed and 1 died due to hemorrhagic stroke. Of the 17 pts who shifted from PR to CR after Z, 13 continue in CR 8–20 mo after Z and 3 continue in CR 1–4 mo after Z. Overall, 19 of 20 pts treated at diagnosis or first PR are alive. Responses were accompanied by neutro- and thrombocytopenias 4–5 wk after Z, lasting 3–21 wk. To date, 7 pts required G-CSF (mean 21.3 doses; range 5–60), and 14 pts received red blood cell (mean 5.1 units; range 1–18) and/or PLT (mean 4.2 units; range 1–24) transfusions. No pts developed life-threatening infections. Hematologic toxicity was less severe in pts who had received only 3 FCM cycles, compared with patients requiring 5–6 FCM cycles. Conclusions: Following Z consolidation, 22 of 29 pts achieved a CR and 17 of these 22 shifted from a PR after FCM ± R to a CR. Therefore, Z consolidation is a feasible approach for MCL patients; it might have curative potential for pts treated at diagnosis or at first PR and may afford palliation for relapsed cases. Hematologic toxicity from FCM-Z is significant, but manageable, and correlates with the number of FCM cycles. Survival with FCM-Z seems superior to that reported for R-CHOP×4-Z. FCM-Z may be the preferred therapeutic approach.
Article
We showed recently that the dismal outcome of MCL might be improved in 28 young patients (pts) (<61 years) by an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS) supported by stem cell autograft (ASCT) (A.M. Gianni et al, Blood, 2003). Following this encouraging experience we treated other 26 pts aged<61 years with standard R-HDS and 19 aged >60 years with an age-adapted R-HDS. We report the outcome of 54 young pts (group 1), including the first 28 cases and that of 19 elderly pts (group 2). The majority of both groups had an advanced stage and bone marrow infiltration, while in elderly pts prevail B symptoms and > 1 extranodal site. One third of cases had >2 adverse prognostic features according to IPI. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, group 1 received standard R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days). Following HDS chemotherapy a conditioning program with HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) with ASCT was planned. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Elderly patients received an age-adapted R-HDS: HD-CTX (3–4 gr/sqm) and HD-Ara-C (1–1.5 g/sqm every 12 hours for 3–5 days), followed by HD-melphalan (120 mg/sqm) and HD-mitoxantrone plus melphalan (40 and 120 mg/sqm). 35 pts (65%) in group 1 and 9 (47%) in group 2 completed the planned program and a median number of 7.6 and 6.8 x 10^6 cells CD34+/kg were transplanted. After ASCT the CR rate was 88% in young and 95% in elderly patients. One young pt (2%) died during treatment, 1 developed sMDS and 5 died of late toxicity including a case of lung carcinoma. Among elderly pts only one died tardily because of cardiac disease. With a median follow-up of 48 months (range 8–101) in group 1 and 25 months (range 9–68) in group 2, the 5-year estimated OS, EFS and DFS were 77%, 60% and 71%, in group 1 and 55%, 53% and not yet achieved in group 2. The Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. We conclude that R-HDS is an effective regimen for the induction of complete remissions in pts with newly diagnosed MCL. The manageable toxicity of the program in elderly pts proved that an age-adjusted R-HDS regimen can be safely applied to this age subgroup still producing long-term remissions.
Article
Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. We have now enrolled 14 pts at a median age of 69 years (range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 12 pts, high-dose therapy in 4 pts, and thalidomide in 7 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts), vasculitic skin infiltrates in 3 pts, and hyponatremia in 1 pt. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 12 pts evaluable for efficacy, 9 have achieved a response (3 CR, 6 PR), and 2 pts experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. All 3 pts who achieved a CR are still progression-free at 12 months after treatment initiation. Among pts in PR, 3 pts have relapsed (progression-free survival 14, 11, and 6 months, respectively), and 3 pts are still progression-free beyond 6 months from initiation of treatment. In summary, the BORID treatment regimen has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable and durable response.
Article
The treatment of high-risk MCL remains a challenge. High dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been used for some of these patients (pts). However, relapse rates remain high. RIT with single agent 90Yttrium(90Y) ibritumomab tiuxetan (Zevalin®) has demonstrated activity in pts with relapsed MCL. Therefore, we postulated that the combination of 90Y with HDC and ASCT may reduce relapse rates of pts with high- risk MCL. Between 5/00 and 9/04 eighteen pts with MCL were enrolled on one of two RIT ASCT trials. The first was a phase I/II dose escalation trial of high-dose 90Y + cyclophosphamide 100mg/kg (day -4) and etoposide 60mg/kg(day-2). Pts underwent dosimetry day-21 with 5mCi Indium111 followed a week later by 90Y to deliver a maximum target dose of 1000cGy to normal organs. The second study was a phase I/II trial of standard dose 90Y (0.4mCi/kg) administered day-14 and BEAM (day-8 to day-2, BCNU300mg/m2, cytarabine 800mg/m2, etoposide 800mg/m2, melphalan 140mg/m2). Ten pts who were>60yrs or had received prior dose-limiting radiation were placed on the 90Y BEAM trial while the other 8 received high-dose 90Y. The median age at ASCT was 58 years (range 44–72). Disease status at ASCT included 1st CR -9(high or high intermediate IPI score), 1st PR-4, 1st relapse -4, 2nd CR-1. Fifty percent had received HyperCEVAD chemotherapy and 56% had Rituximab prior to ASCT. Thirteen pts had stage IV disease, 5 had stage III disease. The median 90Y dose administered was 40mCi (range 27–100). Treatment was well tolerated. Engraftment to anc>500 occurred at a median of 10 days (range 9–26). Reversible grade 3 pulmonary toxicity occurred in 5 pts. This included steroid responsive pneumonitis in four and acute respiratory distress related to sepsis in one. One pt with a prior history of heavy alcohol use died of liver failure at four months post ASCT. Four pts have relapsed and two have died of disease progression. With a median follow up of 19 months (range 6–60), the estimated overall survival and disease free survival at two years are 79% (CI 55–91) and 59% (CI 43–73) respectively. By univariate analysis 90Y dose did not correlate with risk of relapse. To date, no relapses were seen beyond the first twelve months (see figure). In conclusion 90Y based transplant conditioning regimens are well tolerated, even in older pts. The apparent plateau in the relapse rate is encouraging and suggests that this approach may lead to durable remissions in pts with high-risk MCL. Figure Figure
Article
7511 Background: Although patients (pts) with MCL have a high response rate to standard chemotherapy, they continue to relapse with no plateau in long term disease-free survival. The use of dose intense induction therapy such as HyperCVAD (M-C) ±Rituximab(R) and high-dose therapy and stem cell may improve these results. In this analysis the outcomes of pts receiving a standard anthracycline induction therapy or HyperCVAD(M-C)(±R) then followed by a stem cell transplant in first complete (CR1) or partial remission (PR1) were compared. Methods: Between 6/91 and 11/05, 124 pts with MCL received high-dose chemotherapy and a stem cell transplant. Of these pts, 80 received an autologous stem cell transplant in CR1 (N = 47) or PR1 (N = 33). A standard anthracycline based CHOP-like (±R) induction therapy was given to 48 pts compared with 32 pts who received HyperCVAD(M-C)(±R) prior to transplant. Results: The median age of pts was 56 years (range 33–70). The male:female ratio was 33:57. Bone marrow involvement prior to conditioning was present in 52% of pts. An elevated lactic dehydrogenase (LDH) was present in 58% of pts. 65% of patients received one prior chemotherapy before coming to stem cell transplant. The median follow up of pts is 38 months (range 3–143). Progression-free survival (PFS) and overall survival (OS) are outlined in table 1 . Characteristics associated with an improved OS by multivariate analysis included receiving HyperCVAD induction (p = 0.04), transplant in CR1 (p = 0.009), ≤ 3 prior chemotherapy regimens (p = 0.02) and no B symptoms at transplant (p = 0.05). Conclusions: To improve the long term disease free survival for pts with MCL, Hyper-CVAD(M-C)(±R) induction should be given to eligible patients with autolgous stem cell transplantation in CR1. [Table: see text] No significant financial relationships to disclose.
Article
We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.
Article
Background Rituximab induces clinical response in advanced B-cell lymphoma and is efficient in removing circulating B-cell from peripheral blood. We therefore postulated that rituximab might be a useful in vivo purging agent before high-dose therapy in this setting. Patients and methods Fourteen patients with relapsed follicular, marginal zone and mantle cell lymphomas (11, two and one cases, respectively) and a PCR-detectable molecular marker were treated first with rituximab, then a mobilization chemotherapeutic regimen, followed by high-dose therapy with peripheral blood stem cell transplantation. PCR analyses were performed in peripheral blood before rituximab and during follow-up, and in harvest. Results Harvests were free of PCR-detectable molecular marker in nine of the 11 studied cases (82%). After high-dose therapy, clinical complete remission was obtained in 13 (93%) patients and molecular remission in 11 (79%). With a median follow-up of 3 years, the 14 transplanted patients were alive, 11 of them remaining in clinical complete remission and eight in molecular remission at last follow-up. Conclusion Rituximab treatment followed by high dose therapy appears to be effective in achieving complete clinical and molecular response. In vivo harvest purging is predictive of prolonged clinical and molecular remission.
Article
BACKGROUND The authors evaluated the efficacy of chemotherapy combined with rituximab followed by high-dose therapy (HDT) plus autologous stem cell transplantation in patients with mantle cell lymphoma (MCL).METHODS This was a retrospective analysis of 34 patients who were treated in 2 departments of hematology, including 29 patients (85%) who received first-line treatment. Rituximab was administered as 4 injections just before harvest in 25 patients (73%) or simultaneously with chemotherapy in 9 patients (27%). HDT included total body irradiation in 26 patients (77%).RESULTSAfter induction therapy, all patients except one reached a response: There were 14 (41%) complete responses (CR) and 19 (56%) partial responses (PR). Stem cell harvest was successful in all patients but 2, with a median number of 5.9 CD34-positive cells per 106/kg. Three months after transplantation, 24 patients (71%) were in CR, and 7 patients (21%) were in PR. At 3 years from the day of transplantation, the estimated overall survival was 87%. With a median follow-up at 2.6 years, the estimated median time to disease progression was 3.4 years. Rituximab treatment before harvest did not delay hematopoietic reconstitution: The median time it took patients to recover absolute neutrophil count to > 0.5 G/L was 10 days.CONCLUSIONS Chemotherapy combined with rituximab followed by HDT improved the overall survival and progression-free survival in patients MCL without adding toxicities. Cancer 2005. © 2005 American Cancer Society.
Article
The role for high-dose therapy and autologous stem-cell transplantation in mantle-cell lymphoma (MCL) is unknown. We retrospectively analyzed patients with chemosensitive disease who underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) for MCL in first remission, as well as following relapse from conventional therapy. Between August 1985 and April 1996, 28 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total-body irradiation (TBI) and a bone marrow-purging regimen. Re-review of original tissue demonstrated that all patients had morphologic, phenotypic, and genotypic characteristics of MCL. MCL was the original diagnosis in 21 patients, whereas seven patients had a prior diagnosis of diffuse small cleaved-cell lymphoma. Twenty patients received multiple regimens before ABMT, while eight underwent ABMT in first complete remission (CR)/partial remission (PR) following CHOP induction. At bone marrow harvest, only 18% of patients were in CR and overt BM infiltration was present in 57%. Following cyclophosphamide/TBI, no treatment-related deaths were seen. Nineteen of 28 patients have relapsed at a median time of 21 months (range, 3 to 70). Of eight patients transplanted in first CR/PR, five have relapsed. Nine patients are in continuous CR with a median follow-up time of 24 months (range, 10 to 135). Disease-free survival (DFS) and overall survival (OS) are estimated to be 31% and 62% at 4 years, respectively. ABMT using cyclophosphamide/TBI conditioning may at best be effective in only a small fraction of patients with relapsed MCL. The lack of plateau with a median follow-up time of 24 months suggests cure may not be achievable. The role of this therapy in patients in first remission requires more study using better induction therapy to enhance the CR rate before ABMT.
Article
Rituximab, a chimeric monoclonal antibody that binds specifically to the CD20 antigen, induced objective responses in 50% of patients with low-grade or follicular B-cell lymphoma. Because most nonfollicular B-cell lymphomas also express the CD20 antigen, we conducted a phase II study to evaluate the efficacy and tolerability of this new agent in patients with more aggressive types of lymphoma. Patients with diffuse large B-cell lymphoma (DLCL), mantle cell lymphoma (MCL), or other intermediate- or high-grade B-cell lymphomas according to the Working Formulation were included in this prospective randomized phase II study if they were in first or second relapse, if they were refractory to initial therapy, if they progressed after a partial response to initial therapy, or if they were elderly (age >60 years) and not previously treated. The patients received 8 weekly infusions of rituximab at the dose of 375 mg/m2 in arm A or one infusion of 375 mg/m2 followed by 7 weekly infusions of 500 mg/m2 in arm B. Patients were evaluated 2 months after the last rituximab infusion. Fifty-four patients were randomized from 9 centers in Europe and Australia (28 in arm A and 26 in arm B). A total of 5 complete responses (CR) and 12 partial responses (PR) were observed among the 54 enrolled patients, with no difference between the two doses. In an intent-to-treat analysis, the CR rate was 9% (CI95%, 3% to 20%) and the PR rate was 22% (CI95%, 12% to 36%), for an overall response rate of 31% (CI95%, 20% to 46%). An analysis of prognostic factors showed that response rates were lower in patients with refractory disease, patients with lymphoma not classified as DLCL, and patients with a tumor larger than 5 cm in diameter. DLCL and MCL patients had response rates of 37% and 33%, respectively. The median time to progression exceeded 246 days for the 17 responding patients. The most frequently reported adverse events were related to an infusion syndrome and were mild: 19% of the patients had a grade 3 related adverse event, slightly more in arm B, and only 1 patient had a grade 4 related adverse event in arm A. Two patients (3.7%) withdrew from treatment because of severe adverse events, one patient in each arm. In this first trial of rituximab in DLCL and MCL, patients experienced a significant clinical activity with a low toxicity. Rituximab has significant activity in DLCL and MCL patients and should be tested in combination with chemotherapy in such patients.
Article
This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk x 4) against MCL and SLL/CLL appeared to be limited, however.
Article
Mantle cell lymphoma (MCL) responds poorly to standard chemotherapy regimens used in non-Hodgkin's lymphoma. As a result, a combination of high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is being investigated in patients with MCL. So far, however, there is no evidence for long-term remission -- believed, in part, to be due to contamination of the transfusion product with residual cancer cells. Many ex-vivo purging methods have been developed to remove tumour cells, but these are complicated, time-consuming and expensive. This study describes an in vivo purging method using rituximab to produce a tumour-free stem cell product for re-infusion following HDT. The regimen is split into a purging phase and a myeloablative phase, which together consist of four-step high-dose sequential chemotherapy (sHDT) and six infusions of rituximab immunotherapy. The sHDT comprises cyclophosphamide, cytosine arabinoside, melphalan and mitoxantrone plus melphalan. There are two separate stem cell harvests and three reinfusions. In a pilot study 28 patients with untreated MCL received standard chemotherapy followed by sHDT with rituximab in vivo purging. Preliminary results indicate that in PCR analyses of leukaphereses from 20 assessable patients, 100% lymphoma-negative harvests were achieved following in vivo purging. PCR analyses of the bone marrow following the four-step high-dose regimen with purging and transplantation showed that all patients achieved molecular remission. After a median follow-up of 22 months (range 10-42 months), two patients had died while 26 were alive and disease free. This method allows efficient in vivo purging in the context of an effective chemotherapy regimen and may have a role as first-line therapy in MCL patients who respond poorly to standard treatment.
Article
Advanced-stage mantle cell lymphoma (MCL) is a disease for which no curative treatment strategy exists. Results with standard combination chemotherapy, with or without an anthracycline, are disappointing, and new and better therapies are needed. High-dose therapy and autologous stem-cell transplantation (ASCT) have been performed in patients with MCL both up front and at relapse with varying degrees of success. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) has shown moderate response rates in patients with MCL. It has also been used safely and effectively as an in vivo purge during ASCT for patients with lymphoma. We are currently investigating an aggressive protocol in patients with newly diagnosed, untreated MCL using a combination of two promising therapeutic modalities, high-dose therapy-ASCT and rituximab. Since 1999, 13 patients with newly diagnosed MCL have been enrolled in this phase II clinical trial. CHOP (cyclophosphamide/prednisone/vincristine/doxorubicin) is used as debulking chemotherapy. Stem cells are mobilized with 5 days of granulocyte colony-stimulating factor 10 microg/kg/d, with a single infusion of rituximab 375 mg/m(2) used as an in vivo purge before stem-cell collection by large-volume leukapheresis. The transplant conditioning regimen is cyclophosphamide/carmustine/etoposide. Post-transplant consolidative immunotherapy consists of rituximab 375 mg/m(2), administered as two 4-week cycles at 2 and 6 months post-transplant. So far, 12 patients (7 men/5 women) with a median age of 55 years (range, 41 to 65 years) have been transplanted. Patients were first assessed and then transplanted a median of 40 and 201 days, respectively, from diagnosis. International Prognostic Index at diagnosis was low (n = 3), low-intermediate (n = 8), and high-intermediate (n = 1). A median of six cycles of CHOP was required to debulk tumor sufficiently for transplant. Response to CHOP was 100% with six complete responses, one complete response unconfirmed, and five partial responses. Transplantation was well tolerated. Patients engrafted quickly, with a median of 11.5 days to neutrophil engraftment and 10 days to platelet independence. Patients had modest transfusion requirements, requiring a median of four units of packed red blood cells and two and a half platelet transfusions. Six to 8 weeks post-transplant, six patients were in complete response, four in complete response unconfirmed, and two in partial response. Eight patients have received all eight maintenance rituximab treatments, and four have received only their first cycle. Following rituximab, the two patients in partial response and two in complete response unconfirmed converted to complete response. With a median follow-up of 239 days from transplant (range, 61 to 727 days), all patients remain alive and well with no documented relapses. Samples for molecular monitoring have been drawn from the stem-cell graft, and serially from the peripheral blood and bone marrow of patients at baseline, preapheresis, pretransplant, and post-transplant at 3-month intervals. This data shows that ASCT followed by rituximab immunotherapy is feasible and safe in patients with MCL. Although patient numbers are low and follow-up time is short, preliminary results are encouraging. Rituximab may convert partial responders to complete responders. The durability of responses will be determined with longer follow-up.
Article
We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.