Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.

Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial.

Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n = 42) or placebo (n = 18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P = .046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation.

PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.

Single Center Outcomes of Carotid Artery Stenting in Veterans with Prior Head and Neck Cancer.

BACKGROUND: Patients meeting criteria for intervention of carotid stenosis with a history of prior cervical radiation or neck dissection are considered "high risk" for carotid endarterectomy. This is a well-established indication for carotid artery stenting (CAS). The long-term outcomes of CAS in this population are less frequently published in the literature but are poor. The purpose of this study was to review long-term results of CAS in veteran patients with a prior history of treatment for head and/or neck cancer. METHODS: This is a retrospective review of a veteran patient population from 1998 to 2016. All patients at our institution with a prior history of treatment for head and/or neck cancer who underwent CAS were included in the analysis. During this time period, 44 patients met inclusion criteria and were treated with 57 carotid stenting interventions. The Kaplan-Meier analysis was used to determine survival and primary patency. The secondary aims were to analyze early outcomes and to identify predictive risk factors for mortality and reintervention. RESULTS: The mean follow-up was 42.9 ± 36.6 months. The cumulative survival at 1, 5, and 10 years was 91%, 67%, and 48%, respectively. The primary patency at 1, 5, and 10 years was 95%, 86%, and 86%, respectively. The reintervention rate was 11% (n = 6) with an assisted primary patency rate of 100%. No neurologic events occurred within 30 days. There were 3 strokes in late follow-up and no stroke-related deaths. Eighteen patients (41%) died during the follow-up period, 15 of whom died during the first 5 years of follow-up. Ten (66%) of those patients died of recurrent or active index cancer. On univariate analysis, tumor, node, metastasis stage IV was significantly associated with death (P = 0.02). Multivariate models were not statistically significant for predicting mortality or reintervention CONCLUSIONS: On the basis of the results in this series, CAS can be performed in these patients with low long-term rates of neurologic events and need for reintervention. However, the survival of patients with head and neck cancer undergoing CAS in this cohort is poor, which is consistent with other published series of patients undergoing CAS for head/neck cancer with at least 5-year follow-up. In this specific patient population, a more critical analysis of the patient's overall prognosis, especially as related to cancer, should be undertaken before offering CAS.

Development and validation of a risk assessment tool for BKPyV Replication in allogeneic stem cell transplant recipients.

BACKGROUND: BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS: In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS: The total risk score was significantly associated with BKPyV replication (P < .0001). At 30 days after transplantation, the low-risk (score ≤ 0) patients had a 9% chance of developing symptomatic BKPyV replication, while the high-risk (score ≥ 8) of the population had 56% of developing BKPyV replication. We validated the risk score using a separate cohort of 1478 patients. The AUC of the ROC of the risk-score-only model was 0.59. Both the total risk score and 3-level risk variable were significantly associated with BKPyV replication in this cohort (P < .0001). CONCLUSIONS: This grading system for the risk of symptomatic BKPyV replication may help in early monitoring and intervention to prevent BKPyV-associated morbidity, mortality, and kidney function decline.

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 µmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.

Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS.

Conditioning regimens contribute significantly to outcomes following allogeneic stem cell transplantation (allo-SCT). Reduced-intensity conditioning (RIC) regimens provide lower toxicity at the cost of reduced efficacy compared with myeloablative conditioning (MAC) regimens. However, because pre-transplant prognostic variables often determine the conditioning regimen, studies of RIC vs. MAC have been inconclusive. We present a retrospective analysis of 242 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients, 112 of whom were in 56 pairs matched using propensity scores, to account for variation that may confound clinical outcomes. The uniform conditioning regimens consisted of fludarabine with pharmacokinetic (PK)-guided intravenous busulfan (Bu). The RIC and MAC regimens were dosed at the average daily area under the concentration-vs-time curve (AUC) of 4000 µMol min and 5000-6000 µMol min, or total course AUC of 16,000 µMol min and 20,000-24,000 µMol min, respectively; PK-guided dosing removes overlap in systemic Bu exposure. When patients' data were propensity-matched, there was a trend toward significantly increased full donor chimerism and decreased chronic graft vs. host disease in RIC, and no significant differences in progression free survival and overall survival between RIC and MAC. Our results also elucidate the efficacy of PK-guided-dosing in the setting of allo-SCT for AML and MDS.

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial.

BACKGROUND: Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities. METHODS: This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 µmol/min (16K group) or 20 000 µmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662. FINDINGS: Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group. INTERPRETATION: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse. FUNDING: Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).

Phase II Trial of High-Dose Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell Transplantation for Primary Refractory or Poor-Risk Relapsed Hodgkin Lymphoma.

We conducted a prospective phase 2 trial of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) with autologous stem cell transplantation (ASCT) in patients with primary refractory or poor-risk relapsed Hodgkin lymphoma (HL) (ie, extranodal relapse or within 1 year of frontline therapy). The trial was powered to detect an improvement in 2-year progression-free survival (PFS) from a historical 50% using a BEAM regimen (carmustine/etoposide/cytarabine/melphalan) to 65%. We compared the study population with all other concurrent patients who were eligible for the trial but instead received the BEAM regimen at our center. No patient received post-ASCT maintenance therapy. The Gem/Bu/Mel trial enrolled 80 patients with a median age of 31 years, 41% with primary refractory HL and 59% with relapsed HL (36% extranodal relapses), and 30% with positron emission tomography (PET)-positive lesions at ASCT. The concurrent BEAM (n = 45) and Gem/Bu/Mel cohorts were well balanced except for higher rates of bulky relapse and PET-positive tumors in the Gem/Bu/Mel cohort. There were no transplantation-related deaths in either cohort. At a median follow-up of 34.5 months (range, 26 to 72 months), Gem/Bu/Mel was associated with better 2-year PFS (65% versus 51%; P = .008) and overall survival (89% versus 73%; P = .0003). In conclusion, our data show that Gem/Bu/Mel is safe, in this nonrandomized comparison yielding improved outcomes compared with a concurrently treated and prognostically matched cohort of patients with primary refractory or poor-risk relapsed HL receiving BEAM.

Stem Cell Transplantation and Informatics: Current Considerations.

Informatics strategies and applications available to stem cell transplant (SCT) programs are diverse and changing rapidly. Although most hospitals have electronic medical records (EMRs), few are equipped with specialized SCT applications. Most EMRs do not contain critical elements to support SCT practice and research. Strategies to optimize information technology resources to support SCT programs are reviewed and technical and workflow support discussed. Guidance and rationale for the use of both SCT applications and EMRs are emphasized.

A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results.

High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m2 ) (n = 42) or SD-R (375 mg/m2 ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7·92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08-2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13-3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan.

BACKGROUND: High-dose melphalan is of little benefit as a regimen for patients with relapsed or refractory myeloma undergoing an autologous stem-cell transplant (ASCT). The poor performance of single-agent melphalan in this setting prompted us to study a new high-dose combination of infused gemcitabine, busulfan, and melphalan. METHODS: We did a phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). We enrolled patients with primary refractory or relapsed myeloma who had received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT. Gemcitabine was infused at 1875 mg/m2 for 3 h for 2 days, followed by busulfan (target area under the curve 4000 µmol/L per min per day for 4 days) and melphalan (60 mg/m2 per day for 2 days). The primary endpoint of this trial was to establish the proportion of patients with measurable disease at ASCT receiving gemcitabine, busulfan, and melphalan who achieved stringent complete remission in accordance with the International Myeloma Working Group criteria. We then retrospectively compared the patients in this study with all other concurrent patients at the MD Anderson Cancer Center who were eligible for this trial but declined to participate or had no financial coverage for ASCT in a clinical trial and instead received melphalan at 200 mg/m2 intravenously over 30 min on 1 day, followed by ASCT (control group). To compare survival outcomes, we used a statistical algorithm to select a subset of patients from this control cohort who were matched in a 1-2:1 ratio with the patients in the gemcitabine, busulfan, and melphalan group by sex, age, disease status, refractory to both proteasome inhibitors and immunomodulatory imide drugs, time from diagnosis to ASCT, and cytogenetic risk. All analyses were per protocol. This is the final analysis of the clinical trial, which is registered at ClinicalTrials.gov, number NCT01237951. FINDINGS: Between Nov 30, 2010, and Dec 11, 2013, we enrolled 74 patients into the gemcitabine, busulfan, and melphalan trial. In these patients, median age was 58 years (IQR 51-62), median number of previous lines of therapy was two (2-5), 38 patients had high-risk cytogenetics, 17 were unresponsive to all previous treatments, and 32 were receiving a salvage ASCT. We identified 184 patients for the concurrent control cohort. The study patients and the concurrent controls received similar post-ASCT maintenance. Among patients with measurable disease at ASCT, 16 of 65 patients (24·6%, 95% CI 14·2-35·0) in the gemcitabine, busulfan, and melphalan group had stringent complete remission compared with 22 of 174 patients (12·6%, 10·1-15·1) in the concurrent control group (p=0·040). Median follow-up time was 36 months (IQR 30-46) in the patients receiving gemcitabine, busulfan, and melphalan and 34 months (25-53) in the matched control subset (n=111). With respect to the secondary survival endpoints, the gemcitabine, busulfan, and melphalan cohort had significantly longer median progression-free survival than the matched control cohort (15·1 months [95% CI 8·7-22·1] vs 9·3 months [8·0-10·7]) with a significantly reduced risk of progression or death (HR 0·55, 95% CI 0·38-0·81, log-rank p=0·030), as well as significantly longer median overall survival (37·5 months [26-not reached] vs 23·0 months [16·6-30·5]) and a lower risk of death (HR 0·60, 0·34-0·84, log-rank p=0·0092). For only the patients treated with gemcitabine, busulfan, and melphalan, grade 3 or worse adverse events included grade 3 mucositis (12 patients), grade 3 dermatitis (five patients), grade 3 aminotransferase elevation (seven patients), grade 3 diarrhoea (two patients), and three treatment-related deaths. One death was cardiac sudden death and two were due to sepsis. INTERPRETATION: Gemcitabine, busulfan, and melphalan is a comparatively safe and active regimen for ASCT in patients with refractory or relapsed myeloma. Better outcomes were achieved in patients who received this regimen than in a concurrent matched cohort receiving melphalan, although this will need to be confirmed in a prospective, randomised trial. FUNDING: Otsuka Pharmaceutical Development & Commercialization and US National Cancer Institute.

Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results.

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

Poor immune reconstitution is associated with symptomatic BK polyomavirus viruria in allogeneic stem cell transplant recipients.

BACKGROUND: BK polyomavirus (BKPyV) infections are known indicators of immune suppression in hematopoietic stem cell transplant (HSCT) recipients; they can lead to hemorrhagic cystitis, ureteral stenosis, renal dysfunction, and prolonged hospital stays. In this study, we determined transplant-associated variables and immune parameters that can predict for the risk of BKPyV viruria. We hypothesized that BKPyV infection is a marker of poor immune recovery. METHODS: We analyzed all engrafted patients undergoing first allogeneic HSCT at MD Anderson Cancer Center in Houston between January 2004 and December 2012. We evaluated their immune parameters and their transplant-associated factors. BKPyV positivity was defined as BKPyV detection in urine by polymerase chain reaction testing. Cox proportional hazards model, as well as competing risk analysis method using subdistribution hazard models with death as competing risk, were applied to assess risk of BKPyV viruria. RESULTS: We identified a total of 2477 patients with a median age of 52 years. BKPyV viruria was manifest in 25% (n=629) of the patients. The median time from transplantation to BKPyV viruria development was 42 days among the patients who had BKPyV viruria. On multivariate analysis, tumor type, acute GVHD, chronic GVHD, myeloablative conditioning regimen, cord blood as the graft source, CD3+ , CD4+ , CD8+ , CD56+ , NK counts, and low platelet count were shown to be significantly associated with BKPyV infection. These finding were further confirmed when models incorporating the competing risk of death yielded similar findings. CONCLUSION: In this study, we report significant associations between BKPyV reactivation following allogeneic HSCT and suppressed immune variables. In addition, this study provides valuable information on the immune status of HSCT recipients as a predictor of BKPyV infections that may in turn help us formulate plans for more effective prevention and treatment of this infection.

IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation.

Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naive and transitional B-cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40L signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10-producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4(+) T cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Bregs and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this posttransplant complication.

Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.

Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group.

Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation.

The ability of cord blood transplantation (CBT) to prevent relapse depends partly on donor natural killer (NK) cell alloreactivity. NK effector function depends on specific killer-cell immunoglobulin-like receptors (KIR) and HLA interactions. Thus, it is important to identify optimal combinations of KIR-HLA genotypes in donors and recipients that could improve CBT outcome. We studied clinical data, KIR and HLA genotypes, and NK-cell reconstitution in CBT patients (n = 110). Results were validated in an independent cohort (n = 94). HLA-KIR genotyping of recipient germline and transplanted cord blood (CB) grafts predicted for large differences in outcome. Patients homozygous for HLA-C2 group alleles had higher 1-year relapse rate and worse survival after CBT than did HLA-C1/C1 or HLA-C1/C2 (HLA-C1/x) patients: 67.8% vs 26.0% and 15.0% vs 52.9%, respectively. This inferior outcome was associated with delayed posttransplant recovery of NK cells expressing the HLA-C2-specific KIR2DL1/S1 receptors. HLA-C1/x patients receiving a CB graft with the combined HLA-C1-KIR2DL2/L3/S2 genotype had lower 1-year relapse rate (6.7% vs 40.1%) and superior survival (74.2% vs 41.3%) compared with recipients of grafts lacking KIR2DS2 or HLA-C1 HLA-C2/C2 patients had lower relapse rate (44.7% vs 93.4%) and better survival (30.1% vs 0%) if they received a graft with the combined HLA-C2-KIR2DL1/S1 genotype. Relapsed/refractory disease at CBT, recipient HLA-C2/C2 genotype, and donor HLA-KIR genotype were independent predictors of outcome. Thus, we propose the inclusion of KIR genotyping in graft selection criteria for CBT. HLA-C1/x patients should receive an HLA-C1-KIR2DL2/L3/S2 CB graft, while HLA-C2/C2 patients may benefit from an HLA-C2-KIR2DL1/S1 graft.

Double epigenetic modulation of high-dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor-risk relapsed lymphoma.

BACKGROUND: More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel. METHODS: Patients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days -11 through -3 at doses from 15 to 35 mg/m(2) daily (dose levels 1-3), followed by oral vorinostat (1000 mg once daily on days -11 through -3), gemcitabine (2775 mg/m(2) over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m(2) × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day -9. RESULTS: In total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16-65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2-7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m(2) daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8-27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma. CONCLUSIONS: Double epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2680-2688. © 2016 American Cancer Society.

Pure Red Cell Aplasia in Major ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Severe Pancytopenia.

In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/µL or requiring granulocyte colony-stimulating factor, platelets < 50 K/µL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients.