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Abstract: Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ≥400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated. [Copyright &y& Elsevier]

With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m2, a substantial increase from the usual dose of 140 mg/m2 in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned. [Copyright &y& Elsevier]

Abstract: We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2mg/m2 with once weekly idarubicin 10mg/m2 for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61–83) and 7 relapsed (median age 58, range 40–77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8mg/m2 and idarubicin 10mg/m2); idarubicin was reduced to 8mg/m2 without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2mg/m2 and idarubicin 8mg/m2. Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954. [Copyright &y& Elsevier]

Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO grading scales, other scales included in the studies were Oral Mucositis Index, the Southwest Oncology Group Criteria, and Eastern Cooperative Oncology Group scale. To our knowledge, this is the first analysis on OM in allogeneic HSCT patients with respect to conditioning regimens, and we observed that RIC regimens led to a high incidence of OM similar to that of MA regimens. Clinical trials on treatment of OM are lacking, emphasizing the essential need for prospective studies in this arena. A significant variance in the criteria for grading OM underscores the importance of establishing a standard grading system for OM measurement in future allogeneic HSCT clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: A phase I study utilizing decitabine (DAC) followed by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, in patients with relapsed/refractory adult AML was undertaken to assess safety and feasibility. Patients received DAC 20mg/m2 intravenously daily for 5 days followed by rapamycin from day 6 to day 25 at doses of 2mg, 4mg, and 6mg/day in a standard 3+3 dose escalation design. Twelve patients completed treatment for safety evaluation. Maximum tolerated dose (MTD) was not reached, and except for grade 3 mucositis in 4 patients, no other significant unexpected non-hematologic toxicities have occurred indicating safety of this regimen. This trial is registered at clinical trials.gov as NCT00861874. [Copyright &y& Elsevier]

Abstract: Hematopoietic-cell-transplantation-specific-comorbidity-index (HCT-CI) has been reported as a predictor of survival in allogeneic-transplant recipients; however its validity has recently been challenged. We evaluated the association of HCT-CI with survival of transplant recipients who underwent reduced-intensity-conditioning (RIC) with photopheresis, pentostatin, and total-body-irradiation. Median age of 103 patients selected was 55 years. Most patients (58.3%) had high (≥3) HCT-CI. Median OS was 298 days. Age, disease-type, disease-status, HCT-CI correlated with survival on bivariate analysis. On multivariate analysis, only HCT-CI was significantly associated with OS (low HCT-CI HR=0.29, CI 0.091–0.886; intermediate HCT-CI HR=0.41, CI 0.226–0.752). Our findings suggest HCT-CI as an independent predictor of survival in the setting of RIC transplants. [Copyright &y& Elsevier]

Abstract: Background and purpose: Patients with recurrent or primary refractory Hodgkin lymphoma (HL) treated with high dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) commonly relapse post-ASCT in previous disease sites. We sought to evaluate involved field radiation therapy (IFRT) following ASCT and patterns of recurrence, overall survival (OS), and disease specific survival (DSS). Methods and materials: Between May 1993 and October 2003, 62 (n =66) evaluable patients with refractory/relapsed HL underwent HDT followed by ASCT. Thirty-two (52%) patients received IFRT following transplant. Survival was calculated from the day of hematopoietic stem cell infusion. Results: Median follow-up was 2.3years (range 0.03–11.56). Estimated 3-year OS (p =0.05) and DSS (p =0.08) were 69.6% and 82.1% with IFRT and 40% and 57.6% without IFRT on univariate analysis. B-symptoms were adverse on univariate (p =0.007) and multivariate (p =0.01) analysis. HL patients who received IFRT following ASCT had improved local control in areas of previously recurrent disease (p =0.03). Conclusion: OS and DSS showed marginal benefit at 3years. Given the retrospective nature of our study and attendant selection bias that can be both positive and negative, a future prospective study is warranted to better understand the value of IFRT in the transplant setting. [Copyright &y& Elsevier]

Purpose: To evaluate the patterns and timing of initial recurrence in patients with Hodgkin''s lymphoma (HL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplantation to enhance our understanding of the natural history of this disease and its modern treatment strategies and to direct approaches to disease surveillance. Methods and Materials: The records of 69 patients with HL who had undergone high-dose chemotherapy with autologous stem cell transplantation in our center between May 1992 and June 2006 were analyzed. The initial diagnosis had been made between April 1982 and January 2005 at a median patient age of 33 years (range, 19–65). The patients were segregated according to the initial stage (Stage I-II vs. III-IV). Results: Early-stage HL patients developed a relapse at a median of 2.1 years (range, 0.5–10.3), with 91% of relapses at the initial disease site, 71% of which (65% overall) were only in previously involved sites. Advanced-stage HL patients developed a relapse at a median of 1.5 years (range, 0.6-10.5), with 97% at the initial site, 71% of which (69% overall) were only in previously involved sites. Single-site relapses occurred in 47% of early- vs. 26% of advanced-stage patients, and extranodal relapses occurred in 12% of early- vs. 31% of advanced-stage patients. Conclusions: Almost all patients with HL who develop relapse and subsequently undergo high-dose chemotherapy with autologous stem cell transplantation initially developed recurrence in previously involved disease sites. Early-stage HL relapses often occurred in single sites, and advanced-stage disease relapses were more likely in multiple and extranodal sites. The interval to recurrence was brief, suggesting that the frequency of screening should be the greatest in the early post-therapy years. [Copyright &y& Elsevier]