Allogeneic hematopoietic cell transplant (HCT) remains the best option for a cure for many patients with hematologic malignancies, but is associated with significant morbidity and mortality, particularly for older patients. In the absence of a matched related or unrelated donor, a mismatched unrelated donor (MMUD) increases donor options, particularly for Black and Latinx patients. MMUD HCTs have historically been associated with an increased risk of severe acute graft-versus-host-disease (aGVHD), resulting in increased transplant related mortality (TRM) and decreased overall survival (OS) when compared with matched related or unrelated donor HCTs [1–4]. Abatacept, cytotoxic T-cell lymphocyte-4-immunoglobulin (CTLA4-Ig), is a T-cell co-stimulation blockade agent [5] that was granted FDA approval for the prevention of aGVHD in patients receiving unrelated donor HCT in part based on results of the Abatacept 2 trial (ABA2, NCT01743131). ABA2 was a multicenter phase II trial that evaluated abatacept in addition to standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate (CNI/MTX) for GVHD prevention in 8/8 HLA-matched unrelated donor (MUD) HCT and 7/8 MMUD HCT. Patients in the 7/8 MMUD cohort were assigned to a single arm open label stratum compared to a prespecified Center for International Blood and Marrow Transplant Research (CIBMTR) cohort and demonstrated a significant reduction in grade 3–4 aGVHD compared with the CIBMTR cohort receiving CNI/MTX alone. The lower rates of grade 3–4 aGVHD translated into significant improvement in TRM and OS at 2 years for patients receiving abatacept [6]. The ABA2 trial enrolled patients 6–76 years of age in the 7/8 MMUD analysis, but outcomes were not reported separately for patients over 60 years of age. This age group is at increased risk of TRM [7, 8] that is further compounded by a MMUD HCT and the epidemiology of myeloid malignancies. Therefore, the goal of this analysis was to evaluate outcomes in patients 60 years and older undergoing MMUD HCT for hematologic malignancies.

Allogeneic hematopoietic cell transplant (HCT) offers a chance for cure in children with hematologic malignancies but is associated with significant morbidity. In the absence of a matched related or unrelated donor, a mismatched unrelated donor (MMUD) increases donor options, particularly for black, indigenous and people of color (BIPOC) patients, who have a less than 25% chance of having a matched unrelated donor (MUD) in the registry [1]. However, historically, MMUD HCTs have an increased risk for severe acute graft-versus-host-disease (aGVHD) resulting in increased treatment related mortality (TRM) and decreased overall survival (OS) when compared to matched related or unrelated donor HCTs [2–5] contributing to the lower survival of BIPOC patients receiving HCT [6]. Abatacept is a T-cell co-stimulation blockade agent [7] that was granted FDA approval for the prevention of aGVHD in patients receiving an unrelated donor (URD) HCT in part based on results from the “Abatacept 2” trial (ABA2, clinicaltrial.gov NCT01743131), a phase II trial that evaluated abatacept in addition to standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate (CNI/MTX) for GVHD prevention in 8/8 MUD HCT and 7/8 MMUD HCT. In the ABA2 7/8 MMUD cohort, abatacept was associated with a significant reduction in grade 3-4 aGVHD compared with the matched CIBMTR cohort receiving CNI/MTX alone. The lower rates of grade 3-4 aGVHD translated into significant improvement in TRM and OS at 2 years [8]. The ABA2 trial and subsequent FDA approval paved the way for real world data that could validate these results and provide additional data on the potential benefit of abatacept. The ABA2 trial enrolled pediatric patients in the analysis, but outcomes were not reported separately for these patients. Given the lower risk of acute and chronic GVHD in pediatric patients [9], the translatability of the ABA2 results to this population would benefit from a focused analysis. Furthermore, patients treated on clinical trials may benefit from selection bias that can lead to improved outcomes compared to patients treated off study [10, 11]. The objective of this analysis was to explore the real-world impact of abatacept + CNI/MTX in pediatric patients not enrolled on ABA2.

Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker–based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.

TO THE EDITOR: Allogeneic hematopoietic cell transplantation (HCT) is paramount to the treatment of relapsed refractory hematologic malignancies. In the absence of a matched related or unrelated donor, a mismatched unrelated donor (MMUD) increases the donor options, particularly for patients from ethnic minorities. However, MMUD HCTs have historically conveyed an increased risk of severe (grade 3-4) acute graft-versus-host disease (aGVHD) and treatment-related mortality (TRM).

More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day −7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P =.01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P =.02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P =.005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P =.054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.

Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1·6 mg/m2) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1·5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48·7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL.

Dr. Mangaonkar’s last name was mistakenly spelled in this article: DOI:10.4081/hr.2017.7083 Acute promyelocytic leukemia (APL) is a hyper-acute leukemia and presents with cytopenias and disseminated intravascular coagulation. Jehovah’s Witnesses with APL offer a unique challenge during induction by refusing transfusion and pose a difficult challenge in this curable disease. Our focus over the last 8 years has been decreasing early deaths in APL in both academic and community centers. As a result we have extensive experience in APL induction with a proven improvement in early deaths. Three patients with APL belonging to the Jehovah’s Witness congregation were treated in our practice and published literature in treating Witnesses with APL was reviewed. It is highly imperative to prevent induction mortality in this patient population. The goal of treatment among the Witnesses is to prevent death during induction and subsequently cure them. We discuss the management and proactive measures to prevent induction mortality in this most curable blood cancer.

Acute promyelocytic leukemia (APL) is a hyper-acute leukemia and presents with cytopenias and disseminated intravascular coagulation. Jehovah’s Witnesses with APL offer a unique challenge during induction by refusing transfusion and pose a difficult challenge in this curable disease. Our focus over the last 8 years has been decreasing early deaths in APL in both academic and community centers. As a result we have extensive experience in APL induction with a proven improvement in early deaths. Three patients with APL belonging to the Jehovah’s Witness congregation were treated in our practice and published literature in treating Witnesses with APL was reviewed. It is highly imperative to prevent induction mortality in this patient population. The goal of treatment among the Witnesses is to prevent death during induction and subsequently cure them. We discuss the management and proactive measures to prevent induction mortality in this most curable blood cancer.

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of > 500 and > 700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of < 250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for ≥2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. © 2017 American Cancer Society.