Annie Oh

Melphalan 200 mg/m 2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival

Data on the effectiveness and toxicity of high-dose melphalan in patients with renal impairment (RI) are lacking. We evaluated the impact of RI on outcomes of patients with multiple myeloma treated with melphalan 200u2009mg/m2 (Mel200) and autologous stem cell transplantation. Similar baseline characteristics were seen among 46 patients with creatinine clearance (CrCl) <60u2009mL/min (median 50u2009mL/min, range 20–59) and 103 patients with CrCl ⩾60u2009mL/min (median 83u2009mL/min, range 60–128). Patients with CrCl <60u2009mL/min had longer time to neutrophil (P=0.008) and platelet engraftment (P<0.001). Diarrhea, duration of total parenteral nutrition use and infection were significantly higher in the CrCl <60u2009mL/min group. With a median follow-up of 35 months (range 2–132) in the CrCl <60u2009mL/min group and 47 months (range 1–45) in the CrCl ⩾60u2009mL/min group, overall survival was comparable between the two groups. Median treatment-free survival was longer in the RI group (37 vs 17 months, P=0.0025). Multivariate analysis showed CrCl <60u2009mL/min (hazard ratio (HR) 3.5), and prior proteasome inhibitor therapy (HR 2.441) both predicted longer treatment-free survival. We consider Mel200 safe and effective in patients with CrCl between 30 and 60u2009mL/min.

Decreased pulmonary function in asymptomatic long-term survivors after allogeneic hematopoietic stem cell transplant

Decreased pulmonary function in asymptomatic long-term survivors after allogeneic hematopoietic stem cell transplant

A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL.Significance: A new l-asparaginase-based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes Cancer Res; 78(6); 1549-60. ©2018 AACR.

A prospective study of intravenous pentamidine for PJP prophylaxis in adult patients undergoing intensive chemotherapy or hematopoietic stem cell transplant

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is recommended for patients undergoing hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy. Trimethoprim–sulfamethoxazole and inhaled pentamidine are used frequently, but are limited, by their tolerability and therefore compliance. Intravenous (IV) pentamidine is a potential alternative agent. Here we conducted the first prospective study of the safety and efficacy of IV pentamidine for PJP prophylaxis in adult patients undergoing HSCT or intensive chemotherapy (clinicaltrials.gov NCT02669706). Fifty patients requiring PJP prophylaxis were enrolled and received monthly IV pentamidine at 4u2009mg/kg (maximum 300u2009mg) while undergoing intensive chemotherapy or HSCT. Patients were followed for the occurrence of PJP pneumonia and for adverse events. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. There were no grade 3/4 events. The TSQM questionnaire indicated that the majority of patients were satisfied with the administration of IV pentamidine (nu2009=u200943, 86%, pu2009u2009=u20090.01). There were no cases of PJP during the 24 month follow-up period. Our study illustrates the safety, feasibility, and high degree of patient satisfaction when using IV pentamidine for PJP prophylaxis.

Similar survival but increased toxicity with a sequential versus concurrent FluBu4 regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) using myeloablative-conditioning results in a reduced risk of relapse compared to reduced intensity regimens [1–3]. Fludarabine and intravenous (i.v.) busulfan (FluBu4) has been adopted as a myeloablative but limited toxicity conditioning regimen [4–6]. It has previously been shown that combined in vitro treatment with fludarabine and busulfan leads to synergistic cytotoxicity with maximal synergy being achieved when fludarabine is administered immediately prior to busulfan [5–10]. However, FluBu4 may be administered both as either a concurrent 5-day regimen or a 9-day sequential, non-overlapping schedule [4–6]. Clinical data suggest that sequential regimens have increased antileukemia activity as well as decreased toxicity which allows for application in elderly, co-morbid patients [11, 12]. Because the clinical impact of sequence and schedule of administration of FluBu4 conditioning on toxicity and transplant outcomes is unknown, we sought to compare toxicity, survival and relapse outcomes between patients receiving HSCT with a concurrent 5-day versus a sequential 9-day FluBu4 regimen. At our institution, we initially administered FluBu4 in a sequential fashion over 9 days and subsequently shortened it to 5 days based on studies predominantly administering in a concurrent fashion [13]. We retrospectively analyzed consecutive adult patients who underwent FluBu4 and HSCT between January 2003 and December 2016. Approval of the University of Illinois at Chicago Institutional Review Board was obtained before study commencement. One-hundred and two patients who received FluBu4 prior to HSCT were included in the final analysis. Supportive care measures and graft versus host disease (GVHD) prophylaxis were as previously published. Briefly, GVHD prophylaxis consisted of standard tacrolimus and methotrexate. Patients undergoing HSCT from an unrelated donor additionally received rabbit anti-thymocyte globulin 4.5 mg/kg. For all patients, anti-microbial prophylaxis consisted of levofloxacin during neutropenia, fluconazole until Day+ 90 and acyclovir until Day+ 180. In addition, patients received Pneumocystis jiroveci prophylaxis with either sulfamethoxazoletrimethoprim or monthly pentamidine until day+ 180. Acute and chronic GVHD were graded using standard criteria [14, 15]. Mucositis was graded according to the NCI-CTCAE version 4.0 criteria. In patients experiencing mucositis, specific attention was paid to methotrexate dose reductions and omissions. Categorical data were analyzed by chi-square test and Fisher’s exact test with cells < 5. Comparison of means and medians for continuous data were analyzed by the student’s t-test and Wilcoxon rank-sum test respectively. Equality of survivor functions for GVHD-free, relapse-free survival (GRFS), overall survival (OS), progression free survival (PFS), and cumulative incidence of aGVHD and relapse were assessed using the Kaplan–Meier method and log-rank test. In timedependent Cox proportional hazards model, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between a 9-day regimen and overall and progression-free survival. We assessed proportional hazards by testing for interaction between regimen and person time at risk for each of the outcomes and found no evidence suggesting violation of the proportionality assumption. Analyses were performed using GraphPad Prism (GraphPad, La Jolla, CA, USA) or SAS (SAS Institute, Cary, NC, USA). Thirty-seven (36%) patients received the 5-day regimen, which consisted of fludarabine 40 mg/m and intravenous * Karen Sweiss ksweis2@uic.edu

Non-myeloablative allogeneic stem cell transplant with post-transplant cyclophosphamide cures the first adult patient with congenital dyserythropoietic anemia.

Non-myeloablative allogeneic stem cell transplant with post-transplant cyclophosphamide cures the first adult patient with congenital dyserythropoietic anemia