Basem M. William

Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

PURPOSEnTo develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS).nnnPATIENTS AND METHODSnWe examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT.nnnRESULTSnBlood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort.nnnCONCLUSIONnThe proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis

Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; Pu2009=u2009.16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; nu2009=u2009123) had higher 5-year OS than those without autoHCT (73% versus 60%, Pu2009=u2009.05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; Pu2009=u2009.02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60u2009mL/min), N=1240, moderate (30–59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200u2009mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140u2009mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31–38)%, 40 (31–49)% and 27 (15–40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65–71)%, 68 (60–76)% and 60 (46–74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140u2009mg/m2 was 18 (6–35)% and for Mel 200 was 46 (36–57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11–41) % and for Mel 200 was 32 (11–58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Bortezomib for the treatment of mantle cell lymphoma: an update.

Bortezomib is a first in class proteasome inhibitor, initially approved by the US Food and Drug Administration for the treatment of plasma cell myeloma. Bortezomib has been approved for the treatment of relapsed and refractory mantle cell lymphoma (MCL) and, more recently, in the upfront setting as well. Treatment algorithms for MCL have rapidly evolved over the past two decades, and the optimal regimen remains to be defined. The choice of treatment regimen is based on disease risk stratification models, the expected toxicity of antineoplastic agents, the perceived patient ability to tolerate the planned treatments and the availability of novel agents. As new drugs with novel mechanisms of action and variable toxicity profiles come into use, treatment decisions for a given patient have become increasingly complex. This article provides an overview of the evolving use of bortezomib in the rapidly changing management landscape of MCL

Psychosocial risk predicts high readmission rates for hematopoietic cell transplant recipients

Hematopoietic cell transplantation (HCT) is an intensive treatment resulting in disease control however subsequent psychosocial distress is common. Screening for psychosocial risk factors that contribute to morbidity is underutilized; moreover, the value in screening is uncertain. We performed a retrospective study of 395 HCT patients who were screened for psychosocial risk using the Transplant Evaluation Rating Scale (TERS). Patients were classified by psychosocial risk as no-risk (TERSu2009=u200926.5, 52%) vs. at-risk (TERSu2009>u200926.5, 48%), with at-risk patients stratified by cumulative deficits into mild risk (TERSu2009=u200927–35.5, 39%) and moderate risk (TERSu2009>u200935.5, 9%). At-risk patients were more likely to be readmitted within 90 days (mild risk HRu2009=u20091.62, pu2009=u20090.02; moderate risk HRu2009=u20092.50, pu2009=u20090.002). Prior psychiatric history (HRu2009=u20091.81, pu2009=u20090.002) and poor coping skills (HRu2009=u20091.64, pu2009=u20090.04) also influenced readmission. At-risk patients were more likely to be readmitted for infection (no-risku2009=u200912% vs. at-risku2009=u200925%, pu2009=u20090.002). Pre-HCT screening with the TERS did not predict survival or length of stay although at-risk patients are at a heighted risk of readmission. Implementing strategies to reduce readmission in higher risk patients is warranted.

Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma

MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4+ T cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells. Patient cells and miR-29b-/- mouse cells revealed an inverse relationship between miR-29b and BRD4, the latter of which is overexpressed in these cells. Chromatin immunoprecipitation and sequencing analysis revealed increased genome-wide BRD4 occupancy at promoter and enhancer regions in CD4+ T cells from CTCL patients. The cumulative result of BRD4 binding was increased expression of tumor-associated genes such as NOTCH1 and RBPJ, as well as the interleukin-15 (IL-15) receptor complex, the latter enhancing IL-15 autocrine signaling. Furthermore, we confirm the in vivo relevance of this pathway in our IL-15 transgenic mouse model of CTCL by showing that interference with BRD4-mediated pathogenesis, either by restoring miR-29b levels via bortezomib treatment or by directly inhibiting BRD4 binding via JQ1 treatment, prevents progression of CTCL. We describe a novel oncogenic pathway featuring IL-15, miR-29b, and BRD4 in CTCL and suggest targeting of these components as a potentially effective therapy for CTCL patients.

T-Cell Lymphomas, Version 2.2018 Featured Updates to the NCCN Guidelines

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkins lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Phase I clinical trial of the base excision repair inhibitor methoxyamine in combination with fludarabine for patients with advanced hematologic malignancies

Purpose We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine. Materials and Methods This was a phase I study with intravenous fludarabine (25 mg/m2, days 1–5), and methoxyamine (15 mg/m2–120 mg/m2, once). A maximum of six cycles were given. Adult patients with relapsed/refractory hematologic malignancies, excluding acute myeloid leukemia, were eligible. Results Twenty patients were treated; diagnoses included CLL/SLL (n = 10), follicular lymphoma (n = 3), DLBCL (n = 3), mantle cell lymphoma (n = 1), anaplastic large cell lymphoma (n = 1) and plasma cell myeloma (n = 2). No DLTs were observed and dose escalation reached the maximum planned dose. Hematologic toxicity was frequent; most common grade 3–4 toxicities were lymphopenia (70%), neutropenia (60%), leukopenia (50%) and anemia (40%). Four patients achieved a partial remission and 8 achieved stable disease. The drug combination resulted in increased DNA damage measured with the Comet assay. Conclusions Methoxyamine combined with fludarabine was safe and well tolerated. Hematologic toxicity was comparable to single agent fludarabine. Activity appears to correlate with increased levels of DNA damage. Further studies will examine use of this combination of as part conditioning regimens of stem cell transplant and use of methoxyamine as fludarabine dose-sparing agent.

Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma

BACKGROUNDnExposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).nnnMETHODSn9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; nu2009=u2009916), non-Hodgkin lymphoma (NHL; nu2009=u20093546) and plasma cell myeloma (PCM; nu2009=u20094566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.nnnRESULTSn335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HRu2009=u20094.0; 95% confidence interval [1.4, 11.6]) and NHL (HRu2009=u20092.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HRu2009=u20091.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HRu2009=u20092.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.nnnCONCLUSIONSnThere are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Marginal Zone Lymphoma: Clinicopathologic Variations and Approaches to Therapy

Purpose of ReviewThe purpose of the study is to summarize the current conundrums in the management of marginal zone lymphomas (MZL).Recent FindingsIn 2017, the US Food and Drug Administration (FDA) approved ibrutinib, a first in class Bruton Tyrosine Kinase inhibitor, for the treatment of relapsed/refractory MZL based on pivotal open-label phase II trial demonstrating an overall response rates of 48%. Clinical trials design utilizing chemotherapy-free regimens for relapsed/refractory disease are gaining popularity. Recent studies have identified multiple genetic biomarkers that helped characterize and prognosticate different subtypes of MZL.SummaryMZLs are heterogeneous, mostly indolent, malignancies derived from B lymphocytes. Three disease subtypes are recognized, extranodal, nodal, and splenic. The disease characteristics, clinical picture, and treatment algorithms vary considerably based on subtype and site of involvement. Recent discoveries have enhanced our knowledge of the pathogenesis of MZLs leading to development of more accurate prognostic models as well as novel targeted systemic therapies.