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Primary immunodeficiency diseases are associated with an increased tendency for noninfectious complications of autoimmunity and malignancy, particularly leukemia and lymphoma. The mechanisms of immune dysregulation have been linked to the combination of dysregulated immune cells and environmental factors such as infections. In particular, dysfunction in T-cell subsets and Epstein-Barr virus contributes to the development of autoimmunity and lymphoproliferative disease in primary immunodeficiency diseases. There are scant reports of patients with partial DiGeorge syndrome and Epstein-Barr virus-driven lymphoma. We report 1 patients with partial DiGeorge syndrome who developed lymphoma, and review reported cases in the literature.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P= .01; HR, 1.71; P< .001, respectively). Leukemia-free survival was similar for patients with KMT2Arearrangement or adverse risk (HR, 1.26; P= .002, and HR, 1.47; P< .001), as was overall survival (HR, 1.32; P< .001, and HR, 1.45; P< .001). No differences in outcome were detected when patients were stratified by KMT2Afusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD.  This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day −5 (5 mg orally 3 times a week) with tacrolimus initiated on day −3 plus sirolimus on day −1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8–matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor–stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.govas #NCT02588339.

Our phase I graft-versus-host disease (GVHD) prevention trial of pacritinib (recommended phase II dose: 100mg po BID day 0 to +70, dose level 2) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits JAK2-cytokines (IL-6, IL-12, and IL-23) and pathogenic Th1/Th17 differentiation. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT.

Human herpesvirus 6 (HHV-6) frequently reactivates following allogeneic hematopoietic stem cell transplant (alloHCT) with spontaneous resolution in most patients. HHV-6 related encephalitis may occur; however, other clinical syndromes are less well defined. Previous antiviral pre-emptive and prophylactic studies have not demonstrated clinical efficacy in preventing HHV-6 related encephalitis or improving transplant related outcomes and is not routinely recommended by clinical guidelines. Less is known about the clinical impact of HHV-6 reactivation and antiviral treatment following haploidentical alloHCT.

•MMF is commonly included with haploidentical transplant with PTCy.•Dosing of MMF with this platform is not well studied.•In this study, lower MMF dose/kg was associated with improved relapse and PFS.•MMF dose/kg was not associated with risks of graft failure or graft-versus-host disease.•For haploidentical transplant with PTCy, lower dosing of MMF may improve outcomes.

•Autologous and allogeneic hematopoietic cell transplantation are both effective consolidative strategies in patients with Hepatosplenic T Cell Lymphoma.•Median overall survival and progression free survival for the entire cohort were 78.5 months (95% CI: 25-NR) and 54 months (95% CI: 18 to 75), respectively.•No significant differences in OS or PFS we seen when comparing autologous and allogeneic HCT groups.•Pts with less than CR at time of transplant had better median overall survival with allogeneic hematopoietic cell transplantation compared to autologous hematopoietic cell transplantation (65 mo versus 7 mo, P< .001).

•JAK2/mTOR inhibition decreases the differentiation of donor Th1 and Th17 cells after allogeneic hematopoietic cell transplantation.•Adding pacritinib (JAK2 inhibitor) to sirolimus and tacrolimus fails to improve graft-versus-host disease prevention in a phase II trial.

Nodal peripheral T-cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-SCT) as a consolidation strategy following initial chemotherapy response remains uncertain.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype–incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.

In patients with lymphoma, third-space fluid accumulations may develop or worsen during cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T cell therapy. Pre-existing symptomatic pleural effusions were excluded by the ZUMA-1 trial of axicabtagene ciloleucel for large B cell lymphoma (LBCL) and variants. The incidence and management of effusions during CAR T cell therapy for LBCL are unknown. We performed a single-center retrospective study evaluating 148 patients receiving CD19-directed CAR T cell therapy for LBCL between May 2015 and September 2019. We retrospectively identified patients who had radiographic pleural, pericardial, or peritoneal effusions that were present prior to the time of CAR T infusion (pre-CAR T) or that newly developed during the first 30 days after CAR T-cell infusion (post-CAR T). Of 148 patients, 19 patients had a pre-CAR T effusion, 17 patients without pre-existing effusion developed a new infusion after CAR T, and 112 patients had no effusions. Comparing pre-CAR T effusions to new effusions post-CAR T, pre-CAR T effusions were more often malignant (84% versus 12%), persistent beyond 30 days (95% versus 18%), and required interventional drainage after CAR T infusion (79% versus 0%). Compared to patients with no effusion, patients with pre-CAR T therapy effusions had a higher frequency of high-risk baseline characteristics, such as bulky disease and high International Prognostic Index. Similarly, patients with pre-CAR T therapy effusions had a higher rate of toxicity with grade 3 or higher CRS occurring in 32% of patients. On multivariate analysis adjusting for age, Eastern Cooperative Oncology Group status, bulky disease, albumin, and lactate dehydrogenase, a pre-CAR T therapy effusion was associated with reduced overall survival (hazard ratio, 2.34; 95% confidence interval, 1.09 to 5.03; P = .03). Moreover, there was higher non-relapse mortality (11% versus 1%; P = .005). Post-CAR T effusions were not associated with significant difference in survival. Effusions commonly complicate CAR T cell therapy for lymphoma. Malignant effusions that occur prior to CAR T therapy are frequently persistent and require therapeutic intervention, and patients have a higher rate of toxicity and death. Effusions that newly occur after CAR T therapy can generally be managed medically and tend not to persist.

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P< .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P< .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P< .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.

Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) is associated with improved overall survival. As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the effect of cell dose on outcomes with this platform also requires elucidation. We retrospectively evaluated 144 consecutive adult patients who received allogeneic T-cell replete PBSCT with PTCy-based graft-versus-host disease (GVHD) prophylaxis for a hematologic malignancy from 2012–2018. The infused CD34+ cell dose was stratified into low (<5 × 106/kg), intermediate (5–10 × 106/kg) and high (>10 × 106/kg) dose level groups. In multivariate analysis, the low CD34+ cell dose group had worse non-relapse mortality (HR = 4.51, 95% CI: 1.92–10.58, p< 0.001), progression- free survival (HR = 4.11, 95% CI: 2.07–8.15, p< 0.001), and overall survival (HR = 4.06, 95% CI: 2.00–8.25, p≤ 0.001) compared to the intermediate group. Clinical outcomes between the intermediate and high CD34+ cell dose groups were similar. TNC and CD3+ cell dose had no significant impacts on outcomes. These findings suggest that, in patients receiving allogeneic PBSCT with PTCy, infused CD34+ cell doses >5 × 106cells/kg may result in improved survival. Thus, this study supports targeting a CD34+ cell dose of >5 × 106cells/kg for allogeneic PBSCT with PTCy.

High metabolic tumor volume (MTV) predicts worse outcomes in lymphoma treated with chemotherapy. However, it is unknown if this holds for patients treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 targeted chimeric antigen receptor T-cell therapy. The primary objective of this retrospective study was to investigate the relationship between MTV and survival (overall survival [OS] and progression-free survival [PFS]) in patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axi-cel. Secondary objectives included finding the association of MTV with response rates and toxicity. The MTV values on baseline positron emission tomography of 96 patients were calculated via manual methodology using commercial software. Based on a median MTV cutoff value of 147.5 mL in the first cohort (n = 48), patients were divided into high and low MTV groups. Median follow-up for survivors was 24.98 months (range, 10.59-51.02 months). Patients with low MTV had significantly superior OS (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.10-0.66) and PFS (HR, 0.40; 95% CI, 0.18-0.89). Results were successfully validated in a second cohort of 48 patients with a median follow-up for survivors of 12.03 months (range, 0.89-25.74 months). Patients with low MTV were found to have superior OS (HR, 0.14; 95% CI, 0.05-0.42) and PFS (HR, 0.29; 95% CI, 0.12-0.69). In conclusion, baseline MTV is associated with OS and PFS in axi-cel recipients with LBCL.

Background:Secondary hematologic malignancies are increasingly recognized due to the rising number of cancer survivors. While therapy related myeloid malignancies have distinct genetic profiles and inferior allogeneic stem cell transplantation (alloHCT) outcomes, there is limited data regarding secondary acute lymphoblastic leukemia (sALL). In one report, patients with therapy related ALL had an inferior OS of 23 months after alloHCT compared to primary (pALL) where OS was not reached [Saygin et al. 2019]. In the past decade, several novel therapies have been FDA approved for adults with B-ALL allowing more patients to achieve molecular remissions prior to alloHCT, therefore, we aimed to examine the role of alloHCT for adults with sALL compared to adults with pALL in a contemporary era.

Introduction:Our phase I graft-versus-host disease (GVHD) prevention trial of pacritinib (recommended phase II dose: 100mg po BID day 0 to +70, dose level 2) plus sirolimus (8-14ng/ml) and tacrolimus (3-7ng/ml) (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits JAK2 with no activity against JAK1, avoiding off-target suppression of IL-2 required by Tregs. JAK2/STAT3 activity mediates IL-6, IL-12, and IL-23 receptor signaling and subsequent pathogenic Th1 and Th17 differentiation. JAK2/mTOR blockade supports Treg potency, providing further rationale for the PAC/SIR/TAC combination. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT.

Background: