Outcomes of patients with myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation from matched unrelated donors compared with one human leukocyte antigen mismatched related donors using HLA typing at 10 loci.

Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.

Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease.

The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).

Resolved hepatitis B virus infection is not associated with worse outcome after allogeneic hematopoietic stem cell transplantation.

Serologic evidence of resolved hepatitis B virus (HBV) infection has been associated with reactivation of hepatitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the true impact of this finding is unknown. We conducted a retrospective matched-control analysis of the outcomes of 76 patients with positive HBV core antibody (HBcAb) and negative HBV surface antigen (HBsAg) at the time of allo-HSCT for hematologic or solid malignancies. Control patients (matched controls), with negative serology for HBV and other viral hepatitides, were matched by age, diagnosis, disease risk, intensity of conditioning regimen, and donor type. In addition, the HBcAb-positive patients and all seronegative patients (all controls, n = 1858) undergoing transplantation during the same period were compared to adjust for other confounding effects. Patient characteristics and baseline hepatic function studies were similar in the HBcAb-positive and matched control groups. The cumulative incidence of hepatitis B reactivation (defined as the emergence of HBsAg in serum) was 11.6% at 3 years. There were no significant differences in overall survival, relapse, nonrelapse mortality, and incidence of acute graft-versus-host disease between the HBcAb-positive and control groups. Our data suggest that seropositivity for HBcAb and seronegativity for HBsAg at the time of transplantation does not seem to adversely affect outcome after allo-HSCT.

Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type.

BACKGROUND: Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis. DESIGN AND METHODS: To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19-71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8). RESULTS: Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, P<0.001). CONCLUSIONS: Hemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.

Immune-mediated pancytopenia induced by oxaliplatin: a case report.

BACKGROUND: Drug-induced immune pancytopenia is considered an uncommon disorder. CASE REPORT: A 76-year-old woman with metastatic gastric adenocarcinoma received 15 cycles of FOLFOX-6 (oxaliplatin/folinic acid/fluorouracil) with a complete response. Upon disease progression, she was restarted on FOLFOX; during the seventh cycle of treatment, 1 hour after completing her oxaliplatin infusion, she presented oral bleeding, petechiae and generalized hematomas. Her platelet (PLT) count decreased from 164 x 10(9)/L to less than 5 x 10(9)/L within a 3-hour period and her white blood cells (WBCs) decreased from 5 x 10(9) to 1.5 x 10(9)/L. One day later she presented a decrease in hemoglobin level (from 11.4 to 10 g/dL, reaching 8.9 g/dL after 5 days). The patient's PLT and lymphocyte count started to recover after 3 days of immunosuppressive treatment. STUDY DESIGN AND METHODS: PLT, red blood cell (RBC), and WBC antibody detection tests were performed in the presence and absence of oxaliplatin. PLT-associated antibodies were evaluated by monoclonal antibody immobilization of PLT antigen assay and flow cytometry; WBC antibodies were tested by flow cytometry; and RBC antibodies were evaluated by gel and indirect antiglobulin test tube testing drug-treated RBCs and untreated RBCs in the presence of drug. RESULTS: Positive reactions were obtained only in the presence of the drug (1 mg/mL) for all tests performed (PLTs, RBCs, and WBCs). CONCLUSIONS: Our case convincingly demonstrates that oxaliplatin led to the production of drug-dependent PLT, RBC, and WBC antibodies inducing pancytopenia in the patient. The oxaliplatin was discontinued and patient's hematologic values recovered to normal levels.

Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor-Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors: A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial.

IMPORTANCE: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. OBJECTIVE: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. DESIGN, SETTING, AND PARTICIPANTS: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. INTERVENTIONS: The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. MAIN OUTCOMES AND MEASURES: The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. RESULTS: With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. CONCLUSIONS AND RELEVANCE: Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02598960.

Moderate renal function impairment does not affect outcomes of reduced-intensity conditioning with fludarabine and melphalan for allogeneic hematopoietic stem cell transplantation.

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

Impact of hepatitis C virus seropositivity on survival after allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

BACKGROUND: Because hepatitis C virus infection causes hepatic and immunological dysfunction, we hypothesized that seropositivity for this virus could be associated with increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation. DESIGN AND METHODS: We performed a case-control study of the outcomes of patients who were hepatitis C virus seropositive at the time of allogeneic hematopoietic stem cell transplantation (N=31). Patients positive for hepatitis C virus were considered candidates for stem cell transplantation only if they had no significant evidence of hepatic dysfunction. Matched controls (N=31) were seronegative for viral hepatitides and were paired according to age, diagnosis, disease stage, conditioning regimen and donor type. We also compared the hepatitis C virus seropositive patients to all seronegative patients (all controls, N=1800) transplanted during the same period, to adjust for other confounding effects. RESULTS: The median age of the seropositive patients was 49 (range 26-72); 15 had acute myeloid leukemia/myelodysplastic syndrome, 6 had chronic myeloid leukemia/myeloproliferative disease, 6 non-Hodgkin's lymphoma, 2 myeloma, 1 acute lymphocytic leukemia and 1 Hodgkin's lymphoma; 61% had poor risk disease; 68% had related donors; 68% received reduced intensity conditioning; 7 patients had mildly abnormal alanine transaminase levels (all less than three times the upper limit of normal) and 1 patient had minimally elevated bilirubin. These characteristics were similar to those of the matched control group. Median overall survival was 3, 18 and 20 months, and 1-year survival was 29%, 56% and 56%, in the hepatitis C virus, matched and all controls groups, respectively (hazard ratio for death 3.1, 95% confidence interval 1.9-5.6, p<0.001 in multivariate analysis). Non-relapse mortality at 1 year was 43%, 24% and 23%, respectively (hazard ratio 3.3, 95% confidence interval 1.8-7.1, p<0.01). Disease progression and graft-versus-host disease rates were comparable. CONCLUSIONS: Hepatitis C virus seropositivity is a significant risk factor for non-relapse mortality after allogeneic hematopoietic stem cell transplantation even in patients with normal or minimally abnormal liver function tests.

The role of transplantation in diffuse large B-cell lymphoma: the impact of rituximab plus chemotherapy in first-line and relapsed settings.

Rituximab has improved the prognosis of patients with diffuse large B-cell lymphoma, but a high proportion of patients with advanced disease will relapse or will fail to achieve a remission with front-line treatment. Salvage chemotherapy, followed by high-dose chemotherapy or radiation therapy and autologous stem cell transplantation, remains the best treatment option for such patients, especially those who retain chemosensitivity. Allogeneic transplantation is under investigation in this setting, often as a treatment for relapse after autologous transplantation. Treatment-related mortality due to graft-versus-host disease, preparative regimen toxicity, and poor immune recovery often limits its benefits. This article reviews the role of hematopoietic stem cell transplantation in the treatment of diffuse large B-cell lymphoma, the incorporation of rituximab, and avenues of clinical investigation in this rapidly evolving field.