A Phase I Study of Pelabresib (CPI-0610), a Small-Molecule Inhibitor of BET Proteins, in Patients with Relapsed or Refractory Lymphoma.

Purpose: NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883). Experimental Design: Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule. Results: The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease. Conclusions/Discussion: Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily. Significance: BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis.

Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene. METHODS: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS. RESULTS: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%). CONCLUSIONS: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.

Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience.

Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy.

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.

Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia.

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.

Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial.

BACKGROUND: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting. METHODS: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412. FINDINGS: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary. INTERPRETATION: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center. FUNDING: National Institutes of Health.

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia.

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Long-term sustained disease control in patients with mantle cell lymphoma with or without active disease after treatment with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

BACKGROUND: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL). METHODS: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%). RESULTS: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03). CONCLUSIONS: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses.

Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation.

The haematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed in a single centre as a weighted scoring system to predict risks of non-relapse mortality (NRM) following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT-CI in multi-centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen-matched grafts from five different US institutions were analysed. Among all patients, HCT-CI scores of 0 vs. 1-2 vs. ≥3 were associated with 2-year NRM rates of 14%, 23% and 39% (P < 0·0001), respectively, and 2-year overall survival (OS) rates of 74%, 61% and 39%, respectively (P < 0·0001). Using regression models, increasing HCT-CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT-CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C-statistic estimates for the prognostic power of the HCT-CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT-CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions.

REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia.

This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2)  d 1, 8, 15; B: 72 mg/m(2)  d 1, 8; C: 72 mg/m(2) or 90 mg/m(2)  d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2)  d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia.

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation.

PURPOSE: Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown. PATIENTS AND METHODS: Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models. RESULTS: In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens. CONCLUSION: Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT.

Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality.

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials.

Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation.

PURPOSE: We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. PATIENTS AND METHODS: Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). RESULTS: Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. CONCLUSION: Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.