Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We desi... more Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than 4 lines of prior therapy and with measurable disease were enrolled. Bendamustine 75mg/m(2) given on days 1 and 2, lenalidomide 25mg given days 1-21 and dexamethasone 40mg on days 1, 8, 15 and 22, was the recommended phase 2 dose. Seventy-one patients were accrued: 21 on phase 1 and 50 on phase 2. The median age was 62.3 years; patients had a median of 3 prior lines of therapy (range 1-4), with over 70% of the patients having received prior lenalidomide, bortezomib and/or peripheral blood stem cell transplant. Thirty-four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and non-hematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses This article is protected by copyright. All rights reserved.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 4, 2015
Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lympho... more Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lymphoma (FL) after allogeneic (allo-HCT) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. Adult patients with relapsed/refractory grade 1-2 FL undergoing 1(st) reduced-intensity allo-HCT or 1(st) autograft during 2000-2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger; more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto- vs. allo-HCT groups for non-relapse mortality (NRM) were 5% vs. 26% (p<0.0001); relapse/progression: 54% vs. 20% (p<0.0001); progression-free survival (PFS): 41% vs. 58%…
We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matc... more We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matched unrelated donor (n=1982), transplantation. Data were obtained from the Center for International Blood and Marrow Transplant Research. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88, reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737, reduced intensity conditioning regimens. In the myeloablative setting, day-30 neutrophil recovery was lower after haploidentical compared to matched unrelated donor transplants (90% versus 97%, p=0.02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96%, (p=0.25). In the myeloablative setting, 3-month acute grade ...
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing... more Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD) and facilitate a graft-versus-leukemia effect by enhancing the effect of T-regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplant started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10 and 15 mg/m(2)/day x 5 days every 6 weeks, for maximum 8 cycles. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which ≤25% of people experience dose limiting toxicities (DLT) during the 1(st) cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose-levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3/4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose-level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients have died due to: relapse (n=4), infectious complications (n=3) and GVHD (n=2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; one patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in post-allotransplant setting. Although MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred.
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple ... more Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and su...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 31, 2015
Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most ... more Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) prior to undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in complete remission (CR), 45 were in complete remission with incomplete platelet count recovery (CRp), and...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 10, 2015
Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. ... more Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem auto-HCT, post-HCT maintenance therapy and the role of allogeneic HCT for patients with MM.
We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates woul... more We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) and BM (HR 1.73; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2015
Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (AS... more Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (ASCT) typically receive a finite period of initial therapy before ASCT. It is not clear if patients with suboptimal (less than a partial) response to initial therapy benefit from additional alternative therapy with intent to maximize pretransplant response. We identified 539 patients with MM who had an ASCT after having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. These patients were then divided into 2 groups: those who received additional salvage chemotherapy before ASCT (n = 324) and those who had no additional salvage chemotherapy immediately before ASCT (n = 215). Additional pretransplant chemotherapy resulted in deepening responses in 68% (complete response in 8% and PR in 60%). On multivariate analysis there was no impact of pretransplant salvage chemotherapy on treatment-related mortality, risk for relapse, progression-free ...
The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal,... more The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident fro...
Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progres... more Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly under... more Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kB signalling was indicated by mutations in 11 members of the NF-kB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for ... more Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for relapsed and refractory multiple myeloma. Carfilzomib is administered as a 2-10-minute infusion on days , and 16 of a 28-day cycle at a starting dose of 20 mg/m 2 for cycle 1 and a target dose of 27 mg/m 2 thereafter. In the pivotal Phase II study (PX-171-003-A1), carfilzomib 20/27 mg/m 2 provided durable responses in a heavily pretreated population with relapsed and refractory multiple myeloma (n 266), with an overall response rate of 22.9% and a median duration of response of 7.8 months. In an integrated safety analysis of four Phase II studies, common adverse events (32.7%-55.5%) included fatigue, anemia, nausea, thrombocytopenia, dyspnea, and diarrhea. Grade 3/4 adverse events were generally hematologic and included thrombocytopenia (23.4%), anemia (22.4%), and lymphopenia (18.1%). Serious adverse events included pneumonia (9.9%), acute renal failure (4.2%), pyrexia (3.4%), and congestive heart failure (3.4%). New or worsening peripheral neuropathy was infrequent (13.9% overall, 1.3% grade 3, no grade 4). This review discusses findings of the integrated safety analysis and provides practical experience from a single institution in managing treatmentrelated and disease-related adverse events. Individualized treatment with proactive management of side effects and complications allows patients with advanced multiple myeloma to remain on carfilzomib for extended periods.
Objective. Chromosome 13 deletions (del[13]), detected by metaphase cytogenetics, predict poor ou... more Objective. Chromosome 13 deletions (del[13]), detected by metaphase cytogenetics, predict poor outcomes in multiple myeloma (MM), but the gene(s) responsible have not been conclusively identified. We sought to identify tumor-suppressor genes on chromosome 13 using a novel array comparative genomic hybridization (aCGH) strategy. Materials and Methods. We identified DNA copy number losses on chromosome 13 using genomic DNA isolated from CD138-enriched bone marrow cells (tumor) from 20 patients with MM, monoclonal gammopathy of undetermined significance, or amyloidosis. We used matched skin biopsy (germline) genomic DNA to control for copy number polymorphisms and a novel aCGH array dedicated to chromosome 13 to map somatic DNA gains and losses at ultra-high resolution (O385,000 probes; median probe spacing 60 bp). We analyzed microarray expression data from an additional 262 patient samples both with and without del . Results. Two distinct minimally deleted regions at 13q14 and 13q13 were defined that affected the RB1 and NBEA genes, respectively. RB1 is a canonical tumor suppressor previously implicated in MM. NBEA is implicated in membrane trafficking in neurons, protein kinase A binding, and has no known role in cancer. Noncoding RNAs on chromosome 13 were not affected by interstitial deletions. Both the RB1 and NBEA genes were deleted in 40% of cases (8 of 20; 5 patients with del[13] detected by traditional methods and 3 patients with interstitial deletions detected by aCGH). Forty-one additional MM patient samples were used for complete exonic sequencing of RB1, but no somatic mutations were found. Along with RB1, NBEA gene expression was significantly reduced in cases with del[13]. Conclusions. The NBEA gene at 13q13, and its expression are frequently disrupted in MM. Additional studies are warranted to evaluate the role of NBEA as a novel candidate tumorsuppressor gene. Ó
The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-κB. Although NF... more The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-κB. Although NF-κB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. Patients and Methods: We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m 2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. Results: During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. Conclusion: The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.
Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve af... more Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long-term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor-induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft-versus-host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1-70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2-594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor-induced neurotoxicity is frequently reversible but associated with a poor prognosis.
Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We desi... more Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than 4 lines of prior therapy and with measurable disease were enrolled. Bendamustine 75mg/m(2) given on days 1 and 2, lenalidomide 25mg given days 1-21 and dexamethasone 40mg on days 1, 8, 15 and 22, was the recommended phase 2 dose. Seventy-one patients were accrued: 21 on phase 1 and 50 on phase 2. The median age was 62.3 years; patients had a median of 3 prior lines of therapy (range 1-4), with over 70% of the patients having received prior lenalidomide, bortezomib and/or peripheral blood stem cell transplant. Thirty-four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and non-hematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses This article is protected by copyright. All rights reserved.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 4, 2015
Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lympho... more Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lymphoma (FL) after allogeneic (allo-HCT) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. Adult patients with relapsed/refractory grade 1-2 FL undergoing 1(st) reduced-intensity allo-HCT or 1(st) autograft during 2000-2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger; more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto- vs. allo-HCT groups for non-relapse mortality (NRM) were 5% vs. 26% (p<0.0001); relapse/progression: 54% vs. 20% (p<0.0001); progression-free survival (PFS): 41% vs. 58%…
We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matc... more We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matched unrelated donor (n=1982), transplantation. Data were obtained from the Center for International Blood and Marrow Transplant Research. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88, reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737, reduced intensity conditioning regimens. In the myeloablative setting, day-30 neutrophil recovery was lower after haploidentical compared to matched unrelated donor transplants (90% versus 97%, p=0.02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96%, (p=0.25). In the myeloablative setting, 3-month acute grade ...
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing... more Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD) and facilitate a graft-versus-leukemia effect by enhancing the effect of T-regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplant started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10 and 15 mg/m(2)/day x 5 days every 6 weeks, for maximum 8 cycles. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which ≤25% of people experience dose limiting toxicities (DLT) during the 1(st) cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose-levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3/4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose-level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients have died due to: relapse (n=4), infectious complications (n=3) and GVHD (n=2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; one patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in post-allotransplant setting. Although MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred.
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple ... more Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and su...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 31, 2015
Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most ... more Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) prior to undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in complete remission (CR), 45 were in complete remission with incomplete platelet count recovery (CRp), and...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 10, 2015
Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. ... more Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem auto-HCT, post-HCT maintenance therapy and the role of allogeneic HCT for patients with MM.
We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates woul... more We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) and BM (HR 1.73; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2015
Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (AS... more Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (ASCT) typically receive a finite period of initial therapy before ASCT. It is not clear if patients with suboptimal (less than a partial) response to initial therapy benefit from additional alternative therapy with intent to maximize pretransplant response. We identified 539 patients with MM who had an ASCT after having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. These patients were then divided into 2 groups: those who received additional salvage chemotherapy before ASCT (n = 324) and those who had no additional salvage chemotherapy immediately before ASCT (n = 215). Additional pretransplant chemotherapy resulted in deepening responses in 68% (complete response in 8% and PR in 60%). On multivariate analysis there was no impact of pretransplant salvage chemotherapy on treatment-related mortality, risk for relapse, progression-free ...
The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal,... more The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident fro...
Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progres... more Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly under... more Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kB signalling was indicated by mutations in 11 members of the NF-kB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for ... more Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for relapsed and refractory multiple myeloma. Carfilzomib is administered as a 2-10-minute infusion on days , and 16 of a 28-day cycle at a starting dose of 20 mg/m 2 for cycle 1 and a target dose of 27 mg/m 2 thereafter. In the pivotal Phase II study (PX-171-003-A1), carfilzomib 20/27 mg/m 2 provided durable responses in a heavily pretreated population with relapsed and refractory multiple myeloma (n 266), with an overall response rate of 22.9% and a median duration of response of 7.8 months. In an integrated safety analysis of four Phase II studies, common adverse events (32.7%-55.5%) included fatigue, anemia, nausea, thrombocytopenia, dyspnea, and diarrhea. Grade 3/4 adverse events were generally hematologic and included thrombocytopenia (23.4%), anemia (22.4%), and lymphopenia (18.1%). Serious adverse events included pneumonia (9.9%), acute renal failure (4.2%), pyrexia (3.4%), and congestive heart failure (3.4%). New or worsening peripheral neuropathy was infrequent (13.9% overall, 1.3% grade 3, no grade 4). This review discusses findings of the integrated safety analysis and provides practical experience from a single institution in managing treatmentrelated and disease-related adverse events. Individualized treatment with proactive management of side effects and complications allows patients with advanced multiple myeloma to remain on carfilzomib for extended periods.
Objective. Chromosome 13 deletions (del[13]), detected by metaphase cytogenetics, predict poor ou... more Objective. Chromosome 13 deletions (del[13]), detected by metaphase cytogenetics, predict poor outcomes in multiple myeloma (MM), but the gene(s) responsible have not been conclusively identified. We sought to identify tumor-suppressor genes on chromosome 13 using a novel array comparative genomic hybridization (aCGH) strategy. Materials and Methods. We identified DNA copy number losses on chromosome 13 using genomic DNA isolated from CD138-enriched bone marrow cells (tumor) from 20 patients with MM, monoclonal gammopathy of undetermined significance, or amyloidosis. We used matched skin biopsy (germline) genomic DNA to control for copy number polymorphisms and a novel aCGH array dedicated to chromosome 13 to map somatic DNA gains and losses at ultra-high resolution (O385,000 probes; median probe spacing 60 bp). We analyzed microarray expression data from an additional 262 patient samples both with and without del . Results. Two distinct minimally deleted regions at 13q14 and 13q13 were defined that affected the RB1 and NBEA genes, respectively. RB1 is a canonical tumor suppressor previously implicated in MM. NBEA is implicated in membrane trafficking in neurons, protein kinase A binding, and has no known role in cancer. Noncoding RNAs on chromosome 13 were not affected by interstitial deletions. Both the RB1 and NBEA genes were deleted in 40% of cases (8 of 20; 5 patients with del[13] detected by traditional methods and 3 patients with interstitial deletions detected by aCGH). Forty-one additional MM patient samples were used for complete exonic sequencing of RB1, but no somatic mutations were found. Along with RB1, NBEA gene expression was significantly reduced in cases with del[13]. Conclusions. The NBEA gene at 13q13, and its expression are frequently disrupted in MM. Additional studies are warranted to evaluate the role of NBEA as a novel candidate tumorsuppressor gene. Ó
The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-κB. Although NF... more The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-κB. Although NF-κB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. Patients and Methods: We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m 2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. Results: During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. Conclusion: The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.
Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve af... more Calcineurin inhibitor-induced central nervous system toxicities are uncommon and often resolve after discontinuation of the offending drug. The long-term outcome of these patients is, however, unknown. Resolution of symptoms occurred in 70% of 30 allografted recipients who developed calcineurin inhibitor-induced neurotoxicity. When patients were rechallenged with the same or a different calcineurin inhibitor, symptoms recurred in 41%, leading to permanent discontinuation of the drug. De novo or progressive acute graft-versus-host disease (GVHD) was observed in 54% of patients at a median of 7 d (range 1-70 d) after initial onset of neurotoxicity. The prognosis was grim, with 24 (80%) of these patients dying a median 33 d after the onset of neurotoxicity (range 2-594 d). GVHD and/or infection occurred in 54% and were the most common primary causes of death. We conclude that calcineurin inhibitor-induced neurotoxicity is frequently reversible but associated with a poor prognosis.
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Papers by Ravi Vij