[show abstract][hide abstract] ABSTRACT: Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.
In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.
A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.
This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.
Cancer Chemotherapy and Pharmacology 02/2012; 69(6):1657-67. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: As the threshold nucleated cell dose for one-unit umbilical cord blood (UCB) in adults has not to date been firmly established, we prospectively compared one- vs two-unit UCB transplantation after reduced intensity conditioning (RIC) in adult patients with hematological malignancies. Study design specified one-UCB unit if the cryopreserved total nucleated cell (TNC) dose was 2.5 × 10(7)/kg recipient weight, otherwise two units matched at minima of 4/6 HLA loci to the patient and 3/6 to each other were infused. A total of 27 patients received one unit; 23 patients received two units. Median time to ANC >500/μL was 24 days (95% confidence interval 22-28 days), 25 days for one unit and 23 days for two units (P=0.99). At day 100, ANC >500/μL was 88.4 and 91.3% in the one- and two-unit groups (P=0.99), respectively. Three-year EFS was 28.6% and 39.1% in the one- and two-unit groups (P=0.71), respectively. Infusion of two units was associated with a significantly lower relapse risk, 30.4% vs 59.3% (P=0.045). Infused cell doses (TNC, CD3(+), CD34(+) and CD56(+)CD3(neg)) did not impact on engraftment, OS or EFS. Taken together, one-unit UCB transplantation with a threshold cell dose 2.5 × 10(7)/kg recipient weight after RIC is a viable option for adults, although infusion of two units confers a lower relapse incidence.
Bone marrow transplantation 10/2011; 47(7):924-33. · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2011; 17(7):970-8. · 3.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objectives
Remission rates and survival remain limited for the majority of elderly patients with acute myeloid leukemia. Therefore, clinical trials with novel investigational strategies could be considered for these patients. We sought to evaluate the influence of age on outcome defined by survival and toxicity of 121 patients (range 28–82years) with high-risk, relapsed/refractory acute myelogenous leukemia [ECOG PS 0–3] who were enrolled on four consecutive phase I/II clinical trials between 1994 and 2008 conducted at two institutions.
Journal of Geriatric Oncology 01/2011; 2(3):215-221. · 1.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Administering adjuvant chemotherapy before breast radiotherapy decreases the risk of systemic recurrence, but delays in radiotherapy could yield higher local failure. We assessed the feasibility and efficacy of placing radiotherapy earlier in the breast-conserving treatment course for lymph node-positive breast cancer.
Between June 2000 and December 2004, 44 women with node-positive Stage II and III breast cancer were entered into this trial. Breast-conserving surgery and 4 cycles of doxorubicin (60 mg/m(2))/cyclophosphamide (600 mg/m(2)) were followed by 4 cycles of paclitaxel (175 mg/m(2)) delivered every 3 weeks. Radiotherapy was concurrent with the first 2 cycles of paclitaxel. The breast received 39.6 Gy in 22 fractions with a tumor bed boost of 14 Gy in 7 fractions. Regional lymphatics were included when indicated. Functional lung volume was assessed by use of the diffusing capacity for carbon monoxide as a proxy. Breast cosmesis was evaluated with the Harvard criteria.
The 5-year actuarial rate of disease-free survival is 88%, and overall survival is 93%. There have been no local failures. Median follow-up is 75 months. No cases of radiation pneumonitis developed. There was no significant change in the diffusing capacity for carbon monoxide either immediately after radiotherapy (p = 0.51) or with extended follow-up (p = 0.63). Volume of irradiated breast tissue correlated with acute cosmesis, and acute Grade 3 skin toxicity developed in 2 patients. Late cosmesis was not adversely affected.
Concurrent paclitaxel chemotherapy and radiotherapy after breast-conserving surgery shortened total treatment time, provided excellent local control, and was well tolerated.
International journal of radiation oncology, biology, physics 10/2010; 82(1):14-20. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.
Investigational New Drugs 09/2009; 29(1):126-30. · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m(2) on days 1-3, bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11, with rituximab 375 mg/m(2) on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4-30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.
British Journal of Haematology 07/2009; 147(1):89-96. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.
American Journal of Hematology 06/2009; 84(8):484-7. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Extranodal nasal natural killer (NK)/T-cell lymphoma is a very rare lymphoma characterized by strong association with Epstein-Barr virus infection, very aggressive clinical behavior, and poor prognosis. The typical phenotype of neoplastic natural killer cells in this entity is as follows: CD2+, CD56+, surface CD3-, cytoplasmic CD3epsilon+, and cytotoxic granule-associated protein positive. CD30 expression, a phenotype characteristic of anaplastic large-cell lymphomas, is not a typical feature of nasal NK/T-cell lymphomas. We describe the case of a 42-year-old woman with chronic nasal congestion and septal deviation who presented with progressive generalized tender erythematous plaques. A skin biopsy revealed an atypical angiocentric mononuclear cell infiltrate. Strong CD30 and CD3e immunoreactivities were noted in large atypical mononuclear cells within the infiltrate initially suggestive of a CD30+ T-cell lymphoma. However, flow cytometry of the skin lesion indicated that the cells were CD2+, CD4-, CD8-, and lacked surface CD3 more typical of a neoplasm of natural killer cells. Further studies revealed that the cells were CD56+, T-cell-restricted intracellular antigen-1+, and contained Epstein-Barr virus sequences consistent with a nasal-type NK/T-cell lymphoma. High titers of Epstein-Barr virus in the blood, evidence of sinonasal disease, and absence of a T-cell receptor gene rearrangement were additional features consistent with the diagnosis. The patient had a very aggressive clinical course and, despite combination chemotherapy, died 8 months after the onset of skin lesions. This case represents an example of nasal-type NK/T-cell lymphoma with expression of CD30. When presenting in the skin, the phenotypic and morphologic features of this lymphoma may lead to an erroneous diagnosis of a CD30+ large-T-cell lymphoma.
The American Journal of dermatopathology 01/2009; 30(6):567-71. · 1.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Erythema nodosum is an inflammatory reaction of the skin characterized by tender erythematous patches or nodules, usually located on the lower extremities. This report illustrates an association of erythema nodosum with a rare malignancy and an uncommon infectious agent in humans. There are many diseases associated with erythema nodosum; we propose that hairy cell leukemia and group C streptococcus be considered among this list.
The American Journal of dermatopathology 05/2008; 30(2):160-2. · 1.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evaluation of time to event outcomes usually is examined by the Kaplan-Meier method and Cox proportional hazards models. We developed a modified statistical model based on histologic grade and other variables to describe the time-dependent outcome for autologous stem cell transplant (autotransplant) performed for non-Hodgkin's lymphoma (NHL) based on histologic grade and other variables. One hundred and fourteen relapsed or refractory NHL patients were treated using BCNU 600 mg/m2, etoposide 2400 mg/m2, and cisplatin 200 mg/m2 IV followed by autotransplant. Median age was 53.5 (range: 25-70) years, 78 patients had aggressive NHL and 36 indolent NHL. Seventy-five patients received involved-field radiotherapy just prior to transplant. At a median follow-up of 33 (range: 3 to 118) months, the estimated 5-year Kaplan-Meier probabilities of overall survival and disease-free survival were 61% and 51%, respectively. Cox proportional hazards model analysis showed that proportionality did not hold for lymphoma grade, indicating that the relationship between the grade and disease-free survival differed over time. By piece-wise Cox model, the relative risk for experiencing relapse or death after 1 year in patients with indolent compared with patients with aggressive NHL was 2.81 (p=0.019) with 95% confidence interval (1.19, 6.65). The time-dependent effect of lymphoma grade on disease-free survival suggests the need for early (within first year) incorporation of novel therapeutic approaches in management of patients with indolent NHL undergoing autotransplant.
[show abstract][hide abstract] ABSTRACT: The dose of graft-nucleated cells and CD34(+) haematopoietic progenitor cells are predictors of allogeneic engraftment and survival in umbilical cord blood (UCB) recipients. In this single institution prospective phase II trial, flow cytometric analyses of CD34(+) progenitor and lymphocyte populations in unmodified single unit human leucocyte antigen (HLA)-disparate UCB grafts infused into 31 consecutive adults (median age 41 years, range 20-64) receiving myeloablative conditioning were compared with clinical outcomes. Median infused UCB graft-nucleated cells and CD34(+) dose was 2.2 x 10(7)/kg and 1.2 x 10(5)/kg respectively. Day to absolute neutrophil count >/=0.5 x 10(9)/l with full donor chimerism averaged 27 d (range 12-41). Univariate analyses demonstrated that UCB graft-infused cell doses of CD34(+) (P = 0.015), CD3(+) (P = 0.024) and CD34(+)HLADR(+)CD38(+) progenitors (P = 0.043) correlated with neutrophil engraftment. This same analysis did not demonstrate a correlation between CD34(+) (P = 0.11), CD3(+) (P = 0.28) or CD34(+)HLADR(+)CD38(+) (P = 0.108) cell dose and event-free survival (EFS). High-resolution matching for HLA-class II (DRB1) resulted in improved EFS (P = 0.02) and decreased risk for acute graft-versus-host disease (GVHD) (P = 0.004). Early mortality (prior to post-transplant day +28) occurred in three patients, while 26 patients achieved myeloid engraftment. These results suggest that UCB graft matching at DRB1 is an important risk factor for acute GVHD and survival, while higher UCB graft cell doses of CD34(+), committed CD34(+) progenitors and CD3(+) T cells favourably influence UCB allogeneic engraftment.
British Journal of Haematology 12/2007; 139(3):464-74. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Forty-two patients with poor prognosis AML were enrolled in a phase II study combining fludarabine, carboplatin, and topotecan (FCT) with thalidomide. Laboratory correlates included serum vascular endothelial growth factor levels (VEGF) and bone marrow microvascular density (MVD). Ten of 42 (24%) patients achieved a complete remission (CR or CRp). Serious thrombotic adverse events were observed in 5 patients suggesting that the combination of cytotoxic chemotherapy and thalidomide may be thrombogenic despite significant thrombocytopenia. VEGF did not correlate with response to therapy, while a trend towards decreased MVD was noted in patients who achieved CR. The addition of thalidomide did not significantly influence angiogenic markers. It is not clear that thalidomide adds any efficacy to the FCT regimen.
Leukemia and Lymphoma 11/2007; 48(10):1940-9. · 2.30 Impact Factor