ABSTRACT
PURPOSE: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). PATIENTS AND METHODS: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). RESULTS: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. CONCLUSIONS: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Histone Demethylases/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Transcriptome , Tranylcypromine/administration & dosage , Tretinoin/administration & dosage , Aged , Aged, 80 and over , Cell Line, Tumor , Female , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Tretinoin/adverse effectsABSTRACT
PURPOSE: Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis. PATIENTS AND METHODS: Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis. RESULTS: In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients. CONCLUSIONS: Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868.
Subject(s)
Primary Myelofibrosis , Aurora Kinase A , Fibrosis , Humans , Janus Kinase 2 , MegakaryocytesABSTRACT
Hepatitis B core antibody (HBcAb) seropositivity has been associated with a higher rate of hepatitis B virus (HBV) reactivation after chemotherapy, even in patients who are hepatitis B surface antigen (HBsAg) negative. However, little is known about the risk of HBV reactivation after autologous hematopoietic stem cell transplantation (auto-HCT). We evaluated the incidence of HBV reactivation, liver toxicity, and survival in patients with multiple myeloma (MM) who received auto-HCT at our institution. We retrospectively identified 107 MM patients with resolved HBV infection (HBcAb positive, HBsAg negative) and 125 patients with negative HBV serology (control subjects) who were matched for age, timing of auto-HCT from diagnosis, cytogenetics, disease status at transplant, induction therapy, and preparative regimen. All patients underwent auto-HCT between 1991 and 2013. Primary endpoints were HBV reactivation, defined as HBsAg positivity or ≥10-fold increase in HBV DNA, and hepatotoxicity, as defined in the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. In the resolved HBV infection group, 52 patients (49%) were HBsAb positive and 24 (22%) had detectable HBV DNA before auto-HCT. Only 1 patient with resolved HBV infection received pre-emptive antiviral therapy with lamivudine, whereas 4 patients received lamivudine (n = 3) or tenofovir (n = 1) at reactivation after auto-HCT for a median duration of 12 months. HBV reactivation occurred in 7 of 107 patients (6.5%) in the resolved HBV group. Median time to HBV reactivation from auto-HCT was 16 months. The cumulative incidence of grade 2 or greater hepatotoxicity was 30% in the resolved HBV infection group and 22% in the control group (hazard ratio, 1.3; 95% confidence interval, .7 to 2.3; P = .4). Nonrelapse mortality for the 2 groups was not statistically different at 2 years (P = .06), although it trended higher in the control group than in the resolved HBV infection group (8% versus 1%). The median progression-free survival (PFS) and overall survival (OS) durations in the resolved HBV infection and control groups were 21 versus 18 months (P = .5) and 53 versus 67 months (P = .2), respectively. Our data suggest that resolved HBV infection in patients undergoing auto-HCT for MM is associated with a low risk of HBV reactivation and hepatotoxicity; these complications were reversible and did not adversely affect the PFS or OS.
Subject(s)
Hepatitis B Antibodies/blood , Multiple Myeloma/therapy , Transplantation, Autologous/adverse effects , Virus Activation , Adult , Aged , Case-Control Studies , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Incidence , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/virology , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND: The optimal regimen for peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (auto-HCT) has not been established. Experience at The University of Texas MD Anderson Cancer Center suggests in addition to single-agent cyclophosphamide (Cy), modified cyclophosphamide, vincristine, doxorubicin, and dexamethasone (mCVAD), and modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone (mCBAD) may be successful chemomobilization regimens. METHODS: This retrospective review included 167 patients (66 with Cy, 74 with mCVAD, and 27 with mCBAD) with multiple myeloma undergoing mobilization for auto-HCT between January 1, 2006 and September 30, 2013. The primary objective was to evaluate and compare the successful mobilization of CD34+ cells among high-dose Cy, mCVAD or mCBAD. RESULTS: Successful mobilization (≥2×106 CD34+ cells/kg) was achieved in all patients, while 65 (98%), 72 (97%), and 27 (100%) patients achieved an optimal mobilization (≥4×106 CD34+ cells/kg) in the Cy, mCVAD, and mCBAD groups, respectively. There was no significant difference in the number of apheresis sessions (P=.63), incidence of febrile neutropenia (P=.57), or hospital admission rates (P=.55). CONCLUSION: Either Cy, mCVAD, or mCBAD can yield successful PBSC mobilization in patients with multiple myeloma undergoing auto-HCT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cyclophosphamide/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Multiple Myeloma/therapy , Peripheral Blood Stem Cell Transplantation , Autografts , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Male , Middle Aged , Vincristine/administration & dosageABSTRACT
There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.
Subject(s)
Amyloidosis/complications , Amyloidosis/therapy , Hematopoietic Stem Cell Transplantation/methods , Immunoglobulin Light Chains/metabolism , Transplantation Conditioning/methods , Transplantation, Autologous/methods , Adult , Aged , Amyloidosis/mortality , Female , Humans , Male , Middle Aged , Survival Rate , Treatment OutcomeSubject(s)
Heart Diseases/diagnosis , Hematopoietic Stem Cell Transplantation/methods , Melphalan/therapeutic use , Multiple Myeloma/therapy , Adult , Aged , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/therapeutic use , Atrial Fibrillation/diagnosis , Atrial Fibrillation/etiology , Combined Modality Therapy , Disease-Free Survival , Female , Heart Diseases/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Kaplan-Meier Estimate , Logistic Models , Male , Melphalan/adverse effects , Middle Aged , Multivariate Analysis , Time Factors , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Autologous , Treatment OutcomeABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, because of high treatment-related mortality (TRM), its role is not well defined. Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of 2 reduced-intensity conditioning regimens: fludarabine 120 mg/m(2) + melphalan 100 mg/m(2) (FM100) versus fludarabine 120 mg/m(2) + melphalan 140 mg/m(2) (FM140) before allo-HCT from related or unrelated donors. Fifty patients underwent allo-HCT using FM100 (n = 23) or FM140 (n = 27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (P = .21), acute grade II to IV graft-versus-host disease (GVHD) (P = 1.0), chronic GVHD (P = .24), response rate (P = 1.0), TRM (13% versus 15%, P = 1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, P = .12, and median overall survival (OS), 35.1 versus 19.7 months, P = .38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (P = .08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), P = .24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage
, Hematopoietic Stem Cell Transplantation/methods
, Multiple Myeloma/drug therapy
, Multiple Myeloma/surgery
, Transplantation Conditioning/methods
, Adult
, Aged
, Antineoplastic Combined Chemotherapy Protocols/adverse effects
, Combined Modality Therapy
, Dose-Response Relationship, Drug
, Female
, Graft vs Host Disease/prevention & control
, Humans
, Male
, Melphalan/administration & dosage
, Melphalan/adverse effects
, Middle Aged
, Multiple Myeloma/therapy
, Transplantation, Homologous
, Vidarabine/administration & dosage
, Vidarabine/adverse effects
, Vidarabine/analogs & derivatives
ABSTRACT
The t(11;14)(q13;q32) translocation is seen in 15%-20% patients with multiple myeloma (MM). It generally is not associated with worse outcomes. We studied the impact of t(11;14)(q13;q32) on outcome in patients with MM who received high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT). Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescence in situ hybridization (FISH) results available before auto-HCT (n = 993). The cohort was divided into 3 groups of patients: (1) normal (diploid by CC and negative by FISH; n = 869); (2) t(11;14)(q13;q32) by CC or FISH (n = 27); and (3) high-risk (HR) abnormalities by CC or FISH (n = 97). Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) and 9 had concurrent HR abnormalities. The primary objective was to compare outcomes in patients with t(11;14)(q13;q32) and patients with diploid or HR markers detected by CC or FISH studies. The median duration of follow-up in surviving patients was 37 months. The 3-year progression-free survival (PFS) was 47% for the normal group, 27% for the t(11;14)(q13;q32) group, and 13% for the HR group (P < .00001). The 3-year OS was 83% for the normal group, 63% for the t(11;14)(q13;q32) group, and 34% for the HR group (P < .00001). On multivariate analysis, t(11;14)(q13;q32) and HR abnormalities by CC or FISH and relapsed disease at auto-HCT were associated with shorter PFS, whereas t(11;14)(q13;q32) and HR abnormalities by CC or FISH, ß2 microglobulin of >3.5, and relapsed disease at the time of auto-HCT were associated with shorter OS. In conclusion, patients with t(11;14)(q13;q32) had worse outcomes than patients with normal CC or FISH studies, but better outcomes than patients with HR markers detected by CC or FISH studies.
Subject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 14 , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/genetics , Multiple Myeloma/surgery , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Cytogenetics , Female , Humans , Male , Middle Aged , Multiple Myeloma/immunology , Prognosis , Retrospective Studies , Transplantation, Autologous , Treatment OutcomeABSTRACT
A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a followup time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of RIC regimens, and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma/surgery , Transplantation, Homologous , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Consolidation Chemotherapy , Female , Follow-Up Studies , Graft Survival , Graft vs Host Disease/epidemiology , Hematopoietic Stem Cell Transplantation/mortality , Humans , Immunosuppressive Agents/therapeutic use , Incidence , Kaplan-Meier Estimate , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/mortality , Myeloablative Agonists/therapeutic use , Primary Graft Dysfunction/epidemiology , Prognosis , Retrospective Studies , Salvage Therapy , Survival Rate , Transplantation Conditioning , Transplantation, Homologous/mortalityABSTRACT
The role of donor lymphocyte infusion (DLI) in mediating the graft-versus-myeloma (GvM) effect after allogeneic hematopoietic stem cell transplant (allo-HCT) is not clearly defined. We evaluated the safety and utility of DLI in patients with either persistent or recurrent multiple myeloma (MM) after allo-HCT. Twenty-three patients with MM received DLI after allo-HCT at the University of Texas M. D. Anderson Cancer Center between July 1996 and June 2008. Eight patients received preemptive DLI for residual disease (RD) while 15 patients received DLI for the treatment of recurrent or progressive disease (PD). We evaluated the response to DLI and the factors that may predict a response. Median DLI dose was 3.3 × 10(7) CD3 + cells (range 0.5-14.8 × 10(7)). Grade II-IV acute graft-versus-host disease (GvHD) was seen in five patients (22%). Median follow-up in surviving patients was 24 months. Five of 23 patients (22%) achieved a complete or a very good partial response (two CR, three VGPR), while eight patients (34%) had stable disease (SD) after the DLI. Patients who received DLI for RD had a higher response rate (≥ VGPR 50% vs. 7%, p = 0.03), a longer overall survival (28.3 vs. 7.6 months, p = 0.03) and a trend toward longer progression-free survival (11.9 vs. 5.2 months, p = 0.1). In this largest single institution study, we conclude that the use of preemptive, non-manipulated DLI for RD after reduced-intensity conditioning allo-HCT is encouraging, and it was associated with a higher response rate and a longer overall survival when given preemptively. The role of DLI needs to be further explored in prospective clinical trials.
Subject(s)
Lymphocyte Transfusion/methods , Multiple Myeloma/therapy , Stem Cell Transplantation/methods , Transplantation, Homologous/methods , Adult , Disease Progression , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Tumor Effect , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Remission Induction , Treatment OutcomeABSTRACT
BACKGROUND: High-dose chemotherapy with autologous hematopoietic cell transplant (auto-HCT) has been shown to improve survival in patients with newly diagnosed multiple myeloma. However, the role of salvage auto-HCT for relapsed patients, particularly in the era of novel therapeutics, is not well defined. METHODS: The authors performed a retrospective analysis of all 44 myeloma patients (24 men, 20 women) who received a second auto-HCT as salvage between January 3, 1992 and November 4, 2008 at The University of Texas MD Anderson Cancer Center. RESULTS: Median interval between the first and salvage auto-HCT was 30 months (range, 2-78 months). Median age at salvage HCT was 54 years (range, 38-73 years), and median number of salvage treatment regimens was 2 (range, 0-5). Eleven (25%) patients had high-risk chromosomal abnormalities on conventional cytogenetic studies between diagnosis and salvage auto-HCT. Ten patients (23%) experienced grade 3 or higher nonhematologic toxicity after the salvage auto-HCT. One patient died within 100 days, for a treatment-related mortality of 2%. Best responses after salvage chemotherapy + salvage auto-HCT were as follows: complete response (CR) + near CR, 11%; partial response, 79%; overall response rate, 90%. Eighteen (41%) patients received post auto-HCT maintenance therapy. Median follow-up from salvage HCT was 41 months. Kaplan-Meier estimates of median progression-free survival (PFS) and overall survival (OS) from time of salvage auto-HCT were 12.3 and 31.7 months, respectively. Median OS from the time of diagnosis was 75 months. In a fitted Bayesian multivariate model, shorter time to progression after first auto-HCT, greater number of prior therapies, African American race, and immunoglobulin G subtype were significantly associated with worse OS. CONCLUSIONS: In selected myeloma patients, a second auto-HCT for salvage therapy is well tolerated, with acceptable toxicity. The overall response rate and PFS are comparable to other salvage regimens.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Adult , Aged , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Prognosis , Recurrence , Remission Induction , Retreatment , Salvage Therapy , Transplantation, AutologousABSTRACT
Abstract We retrospectively analyzed the outcomes of all consecutive patients with myeloma (n = 84) aged ≥70 years who had received autologous hematopoietic stem cell transplant (auto HCT) between July 1999 and June 2010 at our institution. The median age at auto HCT was 72 years, the median number of prior therapies was 2.5 and the median time from diagnosis to auto HCT was 10.2 months. The conditioning regimen consisted of melphalan at 140 mg/m(2) in 10%, 180 mg/m(2) in 25% and 200 mg/m(2) in 65% of patients. The day-100 non-relapse mortality was 3%. The overall response rate at day 100 was 85% (complete response 18%, very good partial response 12%, partial response 55%). After a median follow-up of 25 months among surviving patients, the estimated progression-free survival and overall survival at 5 years were 27% and 67%, respectively. The incidence of grade II-IV toxicity, response rate and survival were similar across three melphalan dose levels. These results indicate that high-dose melphalan plus auto HCT is safe and feasible for patients with multiple myeloma aged ≥70 years and age alone should not be an exclusion criterion for auto HCT.