Morton Coleman

Publications (66)408.53 Total impact

• Article: A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplantation in Multiple Myeloma.

  Tomer M Mark, Whitney Reid, Ruben Niesvizky, Usama Gergis, Roger Pearse, Sebastian Mayer, June Greenberg, Morton Coleman, Koen Van Besien, Tsiporah Shore
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  ABSTRACT: Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200mg/m2. Twenty-five subjects were enrolled onto 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225mg/m2 + melphalan 200mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only 1 grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment was 11 (9-14) and 13 (10-21), respectively. Disease responses at day +100 post-transplant were: progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with preexisting high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after ASCT. Bendamustine up to a dose of 225mg/m2 added to autologous stem cell transplant conditioning with high dose melphalan in multiple myeloma did not exacerbate expected toxicities.
  Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2013; · 3.15 Impact Factor
• Article: Overcoming the response plateau in multiple myeloma: A novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.

  Ruben Niesvizky, Tomer M Mark, Maureen M Ward, David S Jayabalan, Roger Pearse, Megan Manco, Jessica Stern, Paul J Christos, Lena Mathews, Tsiporah B Shore, Faiza Zafar, Karen Pekle, Jenny Xiang, Scott Ely, Donna Skerrett, Selina Chen-Kiang, Morton Coleman, Maureen E Lane
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  ABSTRACT: PURPOSE: This phase 2 study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible myeloma patients who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Experimental design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells post-bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. RESULTS: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; post-mobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 x 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. CONCLUSION: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.
  Clinical Cancer Research 01/2013; · 7.74 Impact Factor
• Article: BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long term lenalidomide therapy in previously untreated patients with multiple myeloma.

  Adriana Rossi, Tomer Mark, David Jayabalan, Paul Christos, Faiza Zafar, Karen Pekle, Roger Pearse, Selina Chen-Kiang, Morton Coleman, Ruben Niesvizky
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  ABSTRACT: The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) was evaluated as therapy for treatment-naïve symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40mg weekly, clarithromycin 500mg twice daily, and lenalidomide 25mg daily on days 1-21, of a 28 day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression free survival was 49 months. Evaluation for the development of second primary malignancies (SPM) was conducted, and no increase in incidence was noted in our cohort of patients who received front-line immunomodulatory therapy. BiRd remains a highly potent and safe regimen for front-line therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.
  Blood 01/2013; · 9.90 Impact Factor
• Article: Metronomic therapy for refractory/relapsed lymphoma: the PEP-C low-dose oral combination chemotherapy regimen.

  Morton Coleman, Gia Ruan, Rebecca L Elstrom, Peter Martin, John P Leonard
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  ABSTRACT: Metronomic therapy is the application of continuous, low dose chemotherapy. The doses of chemotherapy are usually not sufficient to destroy neoplastic cells, but impact the milieu, particularly angiogenesis. To determine if the oral PEP-C regimen, consisting of prednisone 20 mgm, etoposide 50 mgm, procarbazine 50 mgm, and cyclophosphamide 50 mgm given in either a daily, alternate day, or fractionated basis, is effective in a variety of lymphomas. One hundred twenty two patients were studied although the majority had low grade or mantle cell lymphoma. All had received at least two or more prior therapies. Overall, 75% achieved an objective response (OR) with 38% complete responses (CRs) or CRs unconfirmed, and 37% partial responses. ORs were achieved in mantle cell (85%), follicular (88%), marginal zone (71%), and small lymphocytic (67%) lymphomas. Chemosensitive disease was more responsive. Toxicity was minimal. The PEP-C regimen is an easily administered highly effective treatment for heavily pretreated mantle cell and low grade lymphomas.
  Hematology (Amsterdam, Netherlands) 04/2012; 17 Suppl 1:S90-2. · 1.33 Impact Factor
• Article: Bortezomib in combination with rituximab, dexamethasone, ifosfamide, cisplatin and etoposide chemoimmunotherapy in patients with relapsed and primary refractory diffuse large B-cell lymphoma.

  Rebecca L Elstrom, Biree Andemariam, Peter Martin, Jia Ruan, Tsiporah B Shore, Morton Coleman, John P Leonard, Richard R Furman
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  ABSTRACT: Patients with relapsed or refractory diffuse large B-cell lymphoma may experience extended survival with second-line chemotherapy and autologous stem cell transplant (ASCT). Since a major determinant of outcome after ASCT is responsiveness to second-line therapy, the development of more effective second-line treatments is desirable. We investigated the addition of bortezomib to rituximab, dexamethasone, ifosfamide, cisplatin and etoposide (VIPER). Fifteen patients were enrolled, of whom seven were refractory to first-line chemotherapy and only three had maintained first response for 1 year. Nine (60%) patients achieved objective responses, of which three (20%) were IWC-PET (International Workshop Criteria positron emission tomography) complete responses. Median progression-free survival was 3 months, and median overall survival was 10 months. At a median follow-up of 26 months, five patients (33%) remained alive. Treatment was well tolerated with no unexpected toxicity. Although response rates did not meet predefined criteria, activity was at least comparable to other second-line approaches despite a poor-prognosis patient population.
  Leukemia & lymphoma 01/2012; 53(8):1469-73. · 2.40 Impact Factor
• Article: Autologous stem cell transplant is feasible in very elderly patients with lymphoma and limited comorbidity.

  Rebecca L Elstrom, Peter Martin, Sandra Hurtado Rua, Tsiporah B Shore, Richard R Furman, Jia Ruan, Roger N Pearse, Morton Coleman, Tomer Mark, John P Leonard, Usama Gergis
  American Journal of Hematology 12/2011; 87(4):433-5. · 4.67 Impact Factor
• Article: MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

  Tricia Nardiello, Achim A Jungbluth, Anna Mei, Maurizio Diliberto, Xiangao Huang, Ania Dabrowski, Valéria C C Andrade, Rebecca Wasserstrum, Scott Ely, Ruben Niesvizky, Roger Pearse, Morton Coleman, David S Jayabalan, Nina Bhardwaj, Lloyd J Old, Selina Chen-Kiang, Hearn Jay Cho
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  ABSTRACT: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.
  Clinical Cancer Research 06/2011; 17(13):4309-19. · 7.74 Impact Factor
• Article: Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma.

  Jia Ruan, Peter Martin, Richard R Furman, Shing M Lee, Ken Cheung, Julie M Vose, Ann Lacasce, Julia Morrison, Rebecca Elstrom, Scott Ely, Amy Chadburn, Ethel Cesarman, Morton Coleman, John P Leonard
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  ABSTRACT: The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m(2) (n = 4), 1.0 mg/m(2) (n = 9), or 1.3 mg/m(2) (n = 63) on days 1 and 4 for six cycles. Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.
  Journal of Clinical Oncology 02/2011; 29(6):690-7. · 18.37 Impact Factor
• Article: Phase 1 trial of bortezomib plus R‐CHOP in previously untreated patients with aggressive non‐Hodgkin lymphoma

  Richard R. Furman MD, Peter Martin MD, PhD Jia Ruan MD, Ying-Kuen K. Cheung PhD, Julie M. Vose MD, Ann S. LaCasce MD, Rebecca Elstrom MD, Morton Coleman MD, John P. Leonard MD, Richard R. Furman, Peter Martin, Jia Ruan, Ying‐Kuen K. Cheung, Julie M. Vose, Ann S. LaCasce, Rebecca Elstrom, Morton Coleman, John P. Leonard
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  ABSTRACT: BACKGROUND:Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).METHODS:Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m2 [n = 4 patients], 1.0 mg/m2 [n = 9 patients], or 1.3 mg/m2 [n = 7 patients]) administered on Days 1 and 4 of each cycle.RESULTS:The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m2 dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m2 of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%.CONCLUSIONS:Bortezomib at a dose of 1.3 mg/m2 twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing. Cancer 2010. © 2010 American Cancer Society.
  Cancer 11/2010; 116(23):5432 - 5439. · 4.77 Impact Factor
• Article: Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma.

  Francesca Gay, S Vincent Rajkumar, Morton Coleman, Shaji Kumar, Tomer Mark, Angela Dispenzieri, Roger Pearse, Morie A Gertz, John Leonard, Martha Q Lacy, Selina Chen-Kiang, Vivek Roy, David S Jayabalan, John A Lust, Thomas E Witzig, Rafael Fonseca, Robert A Kyle, Philip R Greipp, A Keith Stewart, Ruben Niesvizky
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  ABSTRACT: The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.
  American Journal of Hematology 09/2010; 85(9):664-9. · 4.67 Impact Factor
• Source

  Available from: Ralph Boccia

  Article: Monoclonal gammopathy of undetermined significance: a consensus statement.

  James R Berenson, Kenneth C Anderson, Robert A Audell, Ralph V Boccia, Morton Coleman, Meletios A Dimopoulos, Matthew T Drake, Rafael Fonseca, Jean-Luc Harousseau, Douglas Joshua, [......], Ruben Niesvizky, Antonio Palumbo, G David Roodman, Jesus F San-Miguel, Seema Singhal, Donna M Weber, Maurizio Zangari, Eric Wirtschafter, Ori Yellin, Robert A Kyle
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  ABSTRACT: On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated.
  British Journal of Haematology 07/2010; 150(1):28-38. · 4.94 Impact Factor
• Article: Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight-year follow-up of a multicenter phase II study.

  Brian K Link, Peter Martin, Mark S Kaminski, Stanley J Goldsmith, Morton Coleman, John P Leonard
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  ABSTRACT: The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 ((131)I) -tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma. Patients received six cycles of CVP followed by one cycle of tositumomab and (131)I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety. All 30 patients enrolled completed CVP as well as tositumomab and (131)I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (> or = 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade > or = 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia. These mature data demonstrate that sequential therapy with a non-anthracycline-containing regimen comprising CVP followed by one cycle of tositumomab and (131)I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.
  Journal of Clinical Oncology 06/2010; 28(18):3035-41. · 18.37 Impact Factor
• Article: Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B-cell lymphoma: implications for the development of novel therapeutic strategies.

  Rebecca L Elstrom, Peter Martin, Katya Ostrow, Jacqueline Barrientos, Amy Chadburn, Richard Furman, Jia Ruan, Tsiporah Shore, Michael Schuster, Leandro Cerchietti, Ari Melnick, Morton Coleman, John P Leonard
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  ABSTRACT: Patients with diffuse large B-cell lymphoma (DLBCL) who are not cured by initial therapy sometimes experience disease-free survival after autologous stem cell transplantation. Chemotherapy responsiveness before transplantation is a major predictor of outcome. Patients not responding to second-line regimens may receive third-line therapy in the hopes of achieving response, but outcome data are limited. We identified patients with relapsed or refractory DLBCL at Weill Cornell Medical Center for whom data on responses to second-line chemotherapy were available. A total of 74 patients with relapsed or refractory DLBCL who underwent second-line chemotherapy between 1996 and 2007 were identified. Of these patients, 27 (36%) did not respond. The median overall survival of nonresponding patients was 4 months, and only 1 patient (4%) survived for 1 year. The choice of third-line aggressive chemotherapy instead of less intensive approaches did not confer a survival benefit. Our data demonstrate that patients with recurrent DLBCL not responding to second-line chemotherapy demonstrate dismal outcomes. Trials of novel regimens should be prioritized as management strategies for these patients. Our data provide an important benchmark in the evaluation of the potential clinical value of such approaches.
  Clinical lymphoma, myeloma & leukemia 06/2010; 10(3):192-6.
• Article: Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.

  Jia Ruan, Peter Martin, Morton Coleman, Richard R Furman, Ken Cheung, Adam Faye, Rebecca Elstrom, Mark Lachs, Katherine A Hajjar, John P Leonard
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  ABSTRACT: Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL). RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells. Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment. RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
  Cancer 03/2010; 116(11):2655-64. · 4.77 Impact Factor
• Article: Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant.

  Ruben Niesvizky, Morton Coleman, Tomer Mark
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  ABSTRACT: No survival advantage of autologous stem cell transplantation (ASCT) has been documented for patients older than 65 years, and in the era of thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid), ASCT has a diminished role in the front-line treatment of older patients with myeloma. For these individuals and for those who cannot or choose not to undergo ASCT, the initial treatment regimens now recommended by both the National Comprehensive Cancer Network and the International Myeloma Working Group are melphalan (Alkeran)/prednisone/thalidomide (MPT), bortezomib/melphalan/prednisone (VMP), and lenalidomide/low-dose dexamethasone. Melphalan/prednisone should no longer be considered the reference treatment, although it may be appropriate for a small number of patients with serious comorbidity and/or poor performance status. Advantages of VMP over MPT include rapid response, high rates of complete response, patient compliance, and more extensive evidence of efficacy in patients with certain cytogenetic abnormalities. Lenalidomide/low-dose dexamethasone is particularly appropriate for patients with preexisting neurotoxicity and those who wish to postpone ASCT. Toxicity profiles differ among the newly established and emerging regimens, and oncology teams must take care to apply the appropriate risk management measures, including dose reduction where necessary.
  Oncology (Williston Park, N.Y.) 03/2010; 24(3 Suppl 2):14-21. · 1.03 Impact Factor
• Article: Activities of SYK and PLCgamma2 predict apoptotic response of CLL cells to SRC tyrosine kinase inhibitor dasatinib.

  Zibo Song, Pin Lu, Richard R Furman, John P Leonard, Peter Martin, Lauren Tyrell, Francis Y Lee, Daniel M Knowles, Morton Coleman, Y Lynn Wang
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  ABSTRACT: B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL. Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors. Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib. Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment.
  Clinical Cancer Research 01/2010; 16(2):587-99. · 7.74 Impact Factor
• Article: Management of relapsed mantle cell lymphoma: still a treatment challenge.

  Jia Ruan, Morton Coleman, John P Leonard
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  ABSTRACT: Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma that remains incurable, and is associated with a median survival of approximately 5 years. Management of patients with relapsed or refractory disease is challenging. The major therapeutic goal in MCL management is to improve survival and quality of life whenever possible. Progress has been made in MCL therapy in the past decade based on clinical experimentation with novel agents and combinations. There is a growing list of conventional and novel agents in our armamentarium, consisting of not only additional chemotherapy combinations including high-dose approaches, but also biologically targeted reagents such as the monoclonal antibody rituximab, the proteasome inhibitor bortezomib, the mTOR inhibitor temsirolimus, immunomodulatory and antiangiogenic agents including thalidomide and lenalidomide, and cyclin-dependent kinase inhibitors, as well as a renewed interest in older compounds such as bendamustine and metronomic regimens. Efficacy evaluations for individual agents and rational combinations are in various stages of development, while treatment selection based on molecular and clinical prognostic scores is yet to be tested. In the absence of evidence demonstrating relative survival advantages of various second-line options, management of relapsed and refractory disease should be individualized. Involvement of a lymphoma center participating in clinical trials of novel MCL treatments is encouraged.
  Oncology (Williston Park, N.Y.) 08/2009; 23(8):683-90. · 1.03 Impact Factor
• Article: Durable complete remissions in HIV-associated Hodgkin lymphoma after treatment with only one cycle of chemotherapy complicated by sepsis.

  Peter Martin, John P Leonard, Morton Coleman, Richard R Furman
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  ABSTRACT: The infiltration of nonmalignant cells surrounding the Reed-Sternberg cells within the tumors of Hodgkin lymphoma (HL) might be central to the pathophysiology of the disease. Severe sepsis results in a flood of cytokines that activate the immune system and is associated with generalized lymphocyte apoptosis. We report on 2 patients with HIV infection and HL who achieved durable complete remissions following only one cycle of chemotherapy that was complicated by neutropenic sepsis. An understanding of the pathophysiology of sepsis and immunologic activation that appear to have led to these long-term remissions might lead to novel therapeutic approaches for patients with HL.
  Clinical Lymphoma & Myeloma 07/2009; 9(3):247-9. · 1.13 Impact Factor
• Article: Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results.

  Franck Morschhauser, John P Leonard, Luis Fayad, Bertrand Coiffier, Marie-Odile Petillon, Morton Coleman, Stephen J Schuster, Martin J S Dyer, Heather Horne, Nick Teoh, William A Wegener, David M Goldenberg
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  ABSTRACT: This is a multicenter phase I/II dose-finding study in relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL) evaluating veltuzumab, a humanized anti-CD20 antibody with structure-function differences from chimeric rituximab. Eighty-two patients (median age, 64 years; 79% stage III/IV, one to nine prior treatments) received four once-weekly doses of 80 to 750 mg/m(2) of veltuzumab and were assessed for safety, efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity. Veltuzumab was well tolerated, with no grade 3 to 4 drug-related adverse events despite short infusion times (typically 2 hours initially, 1 hour subsequently at doses < 375 mg/m(2)). In follicular lymphoma, 24 (44%) of 55 patients had objective responses (OR), with 15 (27%) complete responses (CRs) or CRs unconfirmed (CRus) by International Working Group criteria, and with some responses occurring despite two to five prior rituximab-containing regimens, less favorable prognosis (elevated lactate dehydrogenase, tumors > 5 cm, and Follicular Lymphoma International Prognostic Index > or = 2), and at all dose levels. The CRs/CRus were durable (median duration, 19.7 months), with five patients still ongoing (15.9 to 37.6 months duration). In marginal zone lymphoma, five (83%) of six patients had ORs, with two CRs/CRus (33%), and in diffuse large B-cell lymphoma, three (43%) of seven patients achieved partial responses. At all dose levels studied, B cells were depleted after the first infusion, veltuzumab serum half-lives were similar after the fourth infusion, and mean antibody serum levels exceeded values considered important for anti-CD20 therapy (ie, 25 microg/mL). Veltuzumab appeared safe and active at all tested doses, encouraging further study, including dose levels less than those typically used with rituximab.
  Journal of Clinical Oncology 06/2009; 27(20):3346-53. · 18.37 Impact Factor
• Article: Outcome of deferred initial therapy in mantle-cell lymphoma.

  Peter Martin, Amy Chadburn, Paul Christos, Karen Weil, Richard R Furman, Jia Ruan, Rebecca Elstrom, Ruben Niesvizky, Scott Ely, Maurizio Diliberto, Ari Melnick, Daniel M Knowles, Selina Chen-Kiang, Morton Coleman, John P Leonard
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  ABSTRACT: Treatment of mantle-cell lymphoma (MCL) is nonstandardized, though patients are commonly treated immediately at diagnosis. Because data on observation, or "watch and wait," have not been previously reported, we analyzed the outcome of deferred initial therapy. Inclusion criteria in this retrospective analysis were a diagnosis of MCL between 1997 and 2007 and known date of first treatment. Hospital and research charts were reviewed for prognostic and treatment-related information. Date of death was derived from hospital records and confirmed using an online Social Security death index. Of 97 patients with MCL evaluated at Weill Cornell Medical Center, 31 patients (32%) were observed for more than 3 months before initial systemic therapy, with median time to treatment for the observation group of 12 months (range, 4 to 128 months). The observation group (median follow-up, 55 months) had a median age of 58 years (range, 40 to 81 years). Prognostic factors in assessable patients included advanced stage (III/IV) in 75%, elevated lactate dehydrogenase in 25%, and intermediate- or high-risk Mantle Cell International Prognostic Index in 54%. Better performance status and lower-risk standard International Prognostic Index scores were more commonly present in those undergoing observation. Although time to treatment did not predict overall survival in a multivariate analysis, the survival profile of the observation group was statistically superior to that of the early treatment group (not reached v 64 months, P = .004). In selected asymptomatic patients with MCL, deferred initial treatment ("watch and wait") is an acceptable management approach.
  Journal of Clinical Oncology 03/2009; 27(8):1209-13. · 18.37 Impact Factor