In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/μl vs 910/μl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Immunomodulatory drugs are active agents in light-chain (AL) amyloidosis. However, previous studies could not show a survival advantage for patients with AL amyloidosis responding to salvage treatment with pomalidomide. In this phase 2 trial, we assessed the safety and efficacy of pomalidomide and dexamethasone (PDex) in patients with AL amyloidosis who were previously exposed to bortezomib, alkylators, and other immunomodulatory drugs. Twenty-eight patients were enrolled. Three patients received pomalidomide 2 mg/d with no dose-limiting toxicity. The remaining patients received 4 mg/d. Pomalidomide was administered continuously and dexamethasone was given once per week at a dose of 20 or 40 mg. Fifteen patients experienced grade 3 to 4 adverse events; the most common were fluid retention and infection. Hematologic response was observed in 68% of patients (very good partial response or complete response in 29%), as well as improved survival. Median time to response was 1 month. PDex is a rapidly active regimen and improves survival in responding, heavily pretreated patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT01510613.

In light of major advances in immunoglobulin light chain (AL) amyloidosis, we evaluated the trends in presentation, management, and outcome among 1551 newly diagnosed AL amyloidosis patients seen in our institution from 2000 to 2014. As compared with the 2 intervals 2000-2004 and 2005-2009, patients diagnosed in 2010-2014 were less likely to have >2 involved organs. Utilization of autologous stem cell transplant (ASCT) was similar across all periods, about one-third of patients, but there was an increase in the use of pre-ASCT bortezomib induction and of unattenuated melphalan conditioning in 2010-2014 compared with earlier periods. Non-ASCT first-line regimen changed with 65% of patients in 2010-2014 received bortezomib-based therapy, 79% of patients in 2005-2009 received melphalan-dexamethasone, and 64% of patients in 2000-2004 received melphalan-prednisone. The rate of better than very good partial response (VGPR) was higher in more recent periods (66% vs 58% vs 51%; P = .001), a change largely driven by improved VGPR rates in the non-ASCT population. Overall survival (OS) has improved, with inflection points for improvement differing for the ASCT and non-ASCT groups. In the ASCT population, the greatest gains were after 2010 (4-year OS, 91% compared with 73% and 65%). In the non-ASCT group, greatest gains were after 2005 (4-year OS, 38%, 32%, and 16%). Fewer patients died within 6 months of diagnosis in the 2 later periods (24% vs 25% vs 37%; P < .001). Overall, outcomes among patients with AL amyloidosis have improved with earlier diagnosis, higher rates of VGPR, lower early mortality, and improved OS.

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS, 35% ± 3 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ± 2 vs 22% ± 3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic risk AML (EFS, 26% ± 4 vs 40% ± 5 at 4 years; Cox P = .002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% ± 5 vs 40% ± 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.

Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.

The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors.

The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.

Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

In this phase 2 multicenter trial, we evaluated the efficacy of the combination of bortezomib, dexamethasone, and rituximab (BDR) in 59 previously untreated symptomatic patients with Waldenström macroglobulinemia (WM), most of which were of advanced age and with adverse prognostic factors. BDR consisted of a single 21-day cycle of bortezomib alone (1.3 mg/m2 IV on days 1, 4, 8, and 11), followed by weekly IV bortezomib (1.6 mg/m2 on days 1, 8, 15, and 22) for 4 additional 35-day cycles, with IV dexamethasone (40 mg) and IV rituximab (375 mg/m2) on cycles 2 and 5, for a total treatment duration of 23 weeks. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response). After a minimum follow-up of 6 years, median progression-free survival was 43 months and median duration of response for patients with at least partial response was 64.5 months. Overall survival at 7 years was 66%. No patient had developed secondary myelodysplasia, whereas transformation to high-grade lymphoma occurred in 3 patients who had received chemoimmunotherapy after BDR. Thus, BDR is a very active, fixed-duration, chemotherapy-free regimen, inducing durable responses and with a favorable long-term toxicity profile (www.ClinicalTrials.gov #NCT00981708).

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3-tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively.

A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P = .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.