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ABSTRACT: PURPOSELenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. PATIENTS AND METHODS
Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m(2) intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically.ResultsThe overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. CONCLUSION
The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation.
Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
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Carmen D Schweighofer,
Kevin R Coombes,
Tadeusz Majewski,
Lynn L Barron,
Susan Lerner,
Rachel L Sargent,
Susan O'Brien,
Alessandra Ferrajoli, William G Wierda,
Bogdan A Czerniak,
L Jeffrey Medeiros,
Michael J Keating,
Lynne V Abruzzo
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ABSTRACT: Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in 11p15.1 to 15.4 or 6q27) predicted time to treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time to treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 × 10(-8)). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNV and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL.
The Journal of molecular diagnostics: JMD 12/2012; · 3.48 Impact Factor
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ABSTRACT: ABSTRACT We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key nonopsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 nonneutropenic CLL patients (PMN count > 1000/mm(3)), and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the CLL patients had diminished PMN microbicidal response against bacteria but not against fungi than did the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression, or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in CLL patients were associated with the degree of hypogammaglobulinemia.
Leukemia & lymphoma 11/2012; · 2.40 Impact Factor
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ABSTRACT: Richter’s syndrome (RS) is the development of high-grade non-Hodgkin’s lymphoma (NHL) in patients with chronic lymphocytic
leukemia (CLL) or small lymphocytic lymphoma. This process may be triggered by viral infections (eg, Epstein-Barr virus infection),
which are common in immunosuppressed patients. The large cells of RS either arise through a transformation of the original
CLL clone or, less frequently, represent a new or secondary neoplasm. Karyotypic changes, including trisomy 12, chromosome
11 abnormalities, and multiple cell-cycle regulator disruptions, have been found in patients with RS. Although these genetic
defects are believed to cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities,
to transform into RS cells, none appears predominantly responsible for the transformation. The prognosis is generally poor,
and most patients do not have long-term (durable) responses to therapy. Rituximab and cytotoxic combination therapy followed
by stem cell transplantation is associated with improved clinical outcome. Curative treatment strategies are needed.
Current Hematologic Malignancy Reports 04/2012; 2(4):265-271.
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Andrew W Roberts,
John F Seymour,
Jennifer R Brown, William G Wierda,
Thomas J Kipps,
Seong Lin Khaw,
Dennis A Carney,
Simon Z He,
David C S Huang,
Hao Xiong,
Yue Cui,
Todd A Busman,
Evelyn M McKeegan,
Andrew P Krivoshik,
Sari H Enschede,
Rod Humerickhouse
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ABSTRACT: BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(l) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax.
Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology.
Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(l) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies.
BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
Journal of Clinical Oncology 12/2011; 30(5):488-96. · 18.37 Impact Factor
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ABSTRACT: B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.
Blood 12/2011; 119(5):1182-9. · 9.90 Impact Factor
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ABSTRACT: Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition-induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy.
Blood 11/2011; 119(5):1162-72. · 9.90 Impact Factor
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ABSTRACT: This study is focused on therapy-related myeloid neoplasms after the most promising frontline FCR (fludarabine, cyclophosphamide, and rituximab) therapy in previously untreated chronic lymphocytic leukemia patients. A total of 28 therapy-related myeloid neoplasm patients were identified, including 19 patients from 3 well-controlled FCR frontline trials (n=426 patients), giving an estimated frequency of 4.5% (1.9-8.3%) in a follow-up period of 44 months (range 5-122 months). Clinically, therapy-related myeloid neoplasms could emerge directly from 'prolonged myelosuppression' after FCR (10 patients), or after achieving complete hematological recovery (n=18). The overall latency was 35 months (range 3-118 months), with the former group of 23 months and the latter 42 months (P<0.001). In all, 10 cases presented as therapy-related acute myeloid leukemia and 18 as therapy-related myelodysplastic syndromes. Abnormal cytogenetics was present in 26 of 27 (96%) patients, with frequent chromosomes 5 and 7 abnormalities. The median survival was 7 months after therapy-related myeloid neoplasms. Our results indicate that the risk of therapy-related myeloid neoplasms secondary to frontline FCR therapy may not be as high as previously reported after removing the confounding factor of previous cytotoxic exposure, but this risk increased with older age and likely growth factor co-administration. Therapy-related myeloid neoplasms after FCR therapy shares clinicopathological features with therapy-related myeloid neoplasms secondary to other alkylating agents, but has a shorter latency interval indicating possible synergetic effects of the nucleotide analog fludarabine. The fact that therapy-related myeloid neoplasms can directly emerge from 'prolonged myelosuppression' warrants a bone marrow examination to rule out therapy-related myeloid neoplasms in this clinical setting.
Modern Pathology 11/2011; 25(2):237-45. · 4.79 Impact Factor
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William G Wierda,
Susan O'Brien,
Xuemei Wang,
Stefan Faderl,
Alessandra Ferrajoli,
Kim-Anh Do,
Guillermo Garcia-Manero,
Jorge Cortes,
Deborah Thomas,
Charles A Koller,
Jan A Burger,
Susan Lerner,
Ellen Schlette,
Lynne Abruzzo,
Hagop M Kantarjian,
Michael J Keating
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ABSTRACT: The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL.
Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram-a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment.
There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status.
We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials.
Journal of Clinical Oncology 11/2011; 29(31):4088-95. · 18.37 Impact Factor
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ABSTRACT: Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL).
To study the immunomodulatory effects of lenalidomide in CLL, the authors recruited 24 patients with untreated CLL enrolled in a phase 2 clinical trial of lenalidomide and obtained peripheral blood specimens for immunologic studies consisting of enumeration of T cells and assessing their ability to synthesize cytokines after activation through T-cell receptor (TCR).
After 3 cycles of therapy, patients had a significant reduction in percentage (%) and absolute lymphocyte count (ALC) and an increase in percentage of T cells, percentage of activated CD8(+) T cells producing IFN-γ, and percentage of regulatory T (T(R) ) cells when compared with their respective levels before treatment. After 15 cycles of treatment, responder patients had significant reduction in percentage of lymphocytes and ALC, percentage of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, and percentage of T(R) cells when compared with their perspective levels after 3 cycles of treatment. Furthermore, the numbers of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, activated CD8(+) T cells producing IFN-γ, and T(R) cells normalized to the range of healthy subjects.
Treatment with lenalidomide resulted in the normalization of functional T-cell subsets in responders, suggesting that lenalidomide may modulate cell-mediated immunity in patients with CLL.
Cancer 09/2011; 117(17):3999-4008. · 4.77 Impact Factor
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ABSTRACT: Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was 5.3, 5.5, and 5.6 months; and median overall survival was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions, or hematologic or infectious adverse events between subgroups. In summary, ofatumumab monotherapy was effective and well tolerated in patients with fludarabine-refractory chronic lymphocytic leukemia, including in patients with previous rituximab exposure. This trial was registered at www.clinicaltrials.gov as #NCT00349349.
Blood 08/2011; 118(19):5126-9. · 9.90 Impact Factor
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Julia Hoellenriegel,
Sarah A Meadows,
Mariela Sivina, William G Wierda,
Hagop Kantarjian,
Michael J Keating,
Neill Giese,
Susan O'Brien,
Albert Yu,
Langdon L Miller,
Brian J Lannutti,
Jan A Burger
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ABSTRACT: In lymphocytes, the phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor-induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development.
Blood 07/2011; 118(13):3603-12. · 9.90 Impact Factor
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Sameer A Parikh,
Michael J Keating,
Susan O'Brien,
Xuemei Wang,
Alessandra Ferrajoli,
Stefan Faderl,
Jan Burger,
Charles Koller,
Zeev Estrov,
Xavier Badoux,
Susan Lerner, William G Wierda
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ABSTRACT: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.
Blood 07/2011; 118(8):2062-8. · 9.90 Impact Factor
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Xavier C Badoux,
Michael J Keating,
Sijin Wen,
Bang-Ning Lee,
Mariela Sivina,
James Reuben, William G Wierda,
Susan M O'Brien,
Stefan Faderl,
Steven M Kornblau,
Jan A Burger,
Alessandra Ferrajoli
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ABSTRACT: The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.
Blood 07/2011; 118(13):3489-98. · 9.90 Impact Factor
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William G Wierda,
Thomas J Kipps,
Jan Dürig,
Laimonas Griskevicius,
Stephan Stilgenbauer,
Jirí Mayer,
Lukás Smolej,
Georg Hess,
Rasa Griniute,
Francisco J Hernandez-Ilizaliturri,
Swaminathan Padmanabhan,
Michele Gorczyca,
Chai-Ni Chang,
Geoffrey Chan,
Ira Gupta,
Tina G Nielsen,
Charlotte A Russell
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ABSTRACT: We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.
Blood 06/2011; 117(24):6450-8. · 9.90 Impact Factor
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Xavier C Badoux,
Michael J Keating,
Xuemei Wang,
Susan M O'Brien,
Alessandra Ferrajoli,
Stefan Faderl,
Jan Burger,
Charles Koller,
Susan Lerner,
Hagop Kantarjian, William G Wierda
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ABSTRACT: Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.
Blood 06/2011; 118(8):2085-93. · 9.90 Impact Factor
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ABSTRACT: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with significant variation in disease progression, response to therapy, and survival outcome. Deletions of 17p or mutations of TP53 have been identified as one of the poorest prognostic factors, being predictive of short time for disease progression, lack of response to therapy, short response duration, and short overall survival. The treatment of patients with CLL has improved significantly with the development of chemoimmunotherapy, but this benefit was not pronounced in patients with 17p deletion. We compare various treatment strategies used in these patients, including FCR-like chemoimmunotherapy, alemtuzumab, other antibody combinations, or novel targeted therapies with promising results. Allogeneic stem cell transplantation offers the possibility for long-term disease control in these patients and should be considered early in younger, transplant-eligible patients. The current state of therapy is far from optimal and resources should be applied to studying therapeutic options for patients who have CLL with loss of p53 function.
Current Hematologic Malignancy Reports 03/2011; 6(1):36-46.
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Mariela Sivina,
Elena Hartmann,
Thomas J Kipps,
Laura Rassenti,
Diana Krupnik,
Susan Lerner,
Ruth LaPushin,
Lianchun Xiao,
Xuelin Huang,
Lillian Werner,
Donna Neuberg,
Hagop Kantarjian,
Susan O'Brien, William G Wierda,
Michael J Keating,
Andreas Rosenwald,
Jan A Burger
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ABSTRACT: B-cell receptor (BCR) signaling has been inferred as an important mechanism for disease progression in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. In response to BCR activation, CLL cells secrete the chemokine CCL3, which fosters interactions between CLL cells and the leukemia microenvironment. CCL3 secretion correlates with expression of the 70-kDa ζ-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with established prognostic markers and time from diagnosis to initial therapy. We found that CCL3 plasma concentrations were strongly associated with established prognostic markers. In a Cox proportional hazards regression model, CCL3 as well as established prognostic markers (immunoglobulin heavy chain variable-region mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly associated with time to treatment. Multivariable analysis revealed that CCL3 (hazard ratio [HR] = 2.33, P < .0001), advanced clinical stage (HR = 2.75, P = .0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P = .001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic markers. Collectively, CCL3 is a novel, robust, and independent prognostic marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore should become useful for risk assessment in patients with CLL.
Blood 02/2011; 117(5):1662-9. · 9.90 Impact Factor
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Hatice Duzkale,
Carmen D Schweighofer,
Kevin R Coombes,
Lynn L Barron,
Alessandra Ferrajoli,
Susan O'Brien, William G Wierda,
John Pfeifer,
Tadeusz Majewski,
Bogdan A Czerniak,
Jeffrey L Jorgensen,
L Jeffrey Medeiros,
Emil J Freireich,
Michael J Keating,
Lynne V Abruzzo
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ABSTRACT: We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.
Blood 02/2011; 117(15):4076-84. · 9.90 Impact Factor
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Carmen D Schweighofer,
Kevin R Coombes,
Lynn L Barron,
Lixia Diao,
Rachel J Newman,
Alessandra Ferrajoli,
Susan O'Brien, William G Wierda,
Rajyalakshmi Luthra,
L Jeffrey Medeiros,
Michael J Keating,
Lynne V Abruzzo
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ABSTRACT: We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin.
PLoS ONE 01/2011; 6(12):e28277. · 4.09 Impact Factor
