The Phase 1/2 Intergroup study E4412 (NCT01896999; ClinicalTrials.gov) investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) in relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) while concurrently targeting CD30+ Hodgkin Reed Sternberg cells with the antibody-drug conjugate brentuximab vedotin (BV). 147 patients ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients are included in primary efficacy analysis. The primary endpoint, complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (one-sided p=0.29). The median survival follow-up is 38.0 months (interquartile range 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the two arms (HR=0.78, CI 0.39-1.57, one-sided p=0.24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, was similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared to BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned post-hoc comparison; 58 patients received SCT; 36-month PFS (from SCT) was greater than 90% for both arms. Sixty-six patients were alive and progression free after the first scan (disease evaluation) and did not undergo SCT. The 36-month PFS (from first scan) was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared to 45.8% (26.3, 63.4) for BV/Nivo (HR=0.45, CI 0.19-1.08, one-sided p=0.03). The study did not meet its primary endpoint of superior CR rate for the triplet, but it supports the use of checkpoint-ADC induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT for the triplet of BV/Ipi/Nivo.

6555 Background: TBI/Cy is a commonly used conditioning regimen prior to allogeneic stem cell transplant (SCT). Chemotherapy only regimens, mostly containing busulfan, have been shown to be effective and less toxic in patients with myeloid malignancies. Here, we present the largest reported experience with a non-busulfan myeloablative chemotherapy regimen of TT/Cy in myeloid malignancy patients undergoing allogeneic SCT and compare outcomes with TBI/Cy. Methods: Patients with myeloid malignancies receiving allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,046 (range 816-5,572) days. Results: 225 patients with AML (n=160), CML (n=45), and MDS (n=30) of median age 44 (range 19-59 years) received conditioning with TT/Cy (n=159) or TBI/Cy (n=66). Baseline characteristics were similar. For TT/Cy patients, the median OS was not reached, and 4-year OS was 57.2% (95% confidence interval [CI], 49.2-65.2%), which was significantly better than with TBI/Cy, with median OS 373 days and 4-year OS 33.9% (95% CI, 22.3-45.5%; p<.001). Similarly, for TT/Cy patients, the median RFS was not reached and 4-year RFS was 59.2% (95% CI, 52-67.2%), significantly better than median RFS of 341 days and 4-year RFS 35.2% (95% CI, 23.7-46.9%; p<.001) for recipients of TBI/Cy. On multivariable analysis adjusting for age, sex, diagnosis, disease risk, comorbidity index (HCI), and degree of stem cell source, TT/Cy had significantly lower risk of death (HR 0.44, 95% CI, 0.30-0.65; p<.001) together with female sex (p=.03) and lower HCI (p=.046). As shown in the Table summarizing secondary endpoints, TBI/Cy was associated with significantly higher rates of mucositis, sinusoidal obstruction syndrome (SOS), TPN usage, multiorgan failure, and length of stay of primary admission. Conclusions: TT/Cy is an efficacious regimen for patients with myeloid malignancies undergoing myeloablative allogeneic SCT with less toxicity and improved RFS and OS compared with TBI/Cy. TT/Cy should be compared to other non-TBI containing busulfan-based regimens. [Table: see text]

6556 Background: Total body irradiation (TBI)-based preparative regimens have been standard for patients with ALL undergoing allogeneic stem cell transplant (SCT). It is unclear if chemotherapy-only regimens are equally efficacious. Here, we present the largest reported experience with myeloablative TT/Cy in patients with ALL undergoing allogeneic SCT and compare outcomes with TBI-based regimens. Methods: Patients with ALL receiving myeloablative allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m2 or etoposide 60 mg/kg. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,532 (range 599-4,762) days. Results: 80 patients with ALL of median age 40 (range 22-59 years) received conditioning with TT/Cy (n=25) versus TBI/Cy or TBI/etoposide (n=55). Baseline characteristics were similar. For patients receiving TT/Cy, the median OS was not reached, and the 4-year OS was 54.5% (95% confidence interval [CI], 34.3-74.7%), compared with a median OS of 1,491 days and a 4-year OS of 50.9% (95% CI, 37.8-64.2%) for those receiving TBI-based conditioning (p=.75). Similarly, for TT/Cy patients, the median RFS was 847 days and 4-year RFS was 43.2% (95% CI, 23.4-63%), not significantly different from median RFS of 1491 days and 4-year RFS 50.2% (95% CI 36.9-63.5; p=.232) for recipients of TBI regimens. On multivariable analysis, only a higher disease risk index was associated with significantly worse OS (p<.001), while conditioning regimen was not predictive of OS. Similarly, there was no significant difference in RFS between TT/Cy and TBI-based regimens on either univariable or multivariable analysis. Secondary endpoints are summarized in the table. As shown, TT/Cy was associated with significantly lower incidence of mucositis, TPN usage, bacterial infection, sinusoidal obstruction syndrome (SOS), and longer length of stay of primary transplant admission. Conclusions: While there was no significant difference in OS or RFS for patients receiving either TT/Cy or TBI-based conditioning, TBI was associated with greater toxicity. Our data suggests that TT/Cy is an acceptable alternative to TBI-based conditioning for ALL patients undergoing myeloablative allogeneic SCT. [Table: see text]

Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population.

Background Mantle cell lymphoma (MCL) is an incurable form of aggressive non-Hodgkin lymphoma. Treatment choice at diagnosis is based on tolerability of cytarabine and high-dose chemotherapy. With a median age of 60-70 years, many patients are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a reasonable treatment option (E1411, Smith MR et al. ASH 2022) for this patient population and venetoclax (VEN) has shown pre-clinical evidence of synergy with chemoimmunotherapy. PrECOG 0405 was designed to evaluate the addition of VEN to BR in previously untreated patients with MCL aged over 60 years. Methods Eligible patients included those that were previously untreated and diagnosed with MCL as defined as the presence of t(11;14) by FISH or cyclin D1 expression by IHC. Patients must have been at least 60 years of age or older on D1C1 of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance of ≥ 40 mL/min. Treatment administration is summarized in Figure 1. Dose of bendamustine was either 90mg/m 2 D1&2; or, for subjects over the age of 75 years, 70mg/m 2 was allowed per investigator discretion. VEN was dose escalated during Cycle 1 to 200mg. At the time of C2, BR was repeated and VEN was also escalated to 400mg. With C2-6, VEN 400mg PO daily was given D1-10 only. Primary endpoint was PET-negative complete response (CR) rate at end of treatment (EOT) by Lugano Criteria. A negative bone marrow biopsy was required to confirm CR if involved at screening. Minimal residual disease (MRD) by next-generation sequencing was performed at the EOT. Maintenance rituximab was encouraged per investigator discretion. This was a single arm study with an original accrual goal of 53 subjects to detect a 15% improvement in CR rate compared to historical data. However, due to slow study accrual during COVID pandemic and preliminary efficacy data from E1411 study, the statistical parameters were updated after 25 subjects had been accrued. The revised accrual goal was 33 patients to obtain 32 eligible and treated patients, which provided 81.8% statistical power to detect a 17% difference in CR rate (from 60% [E1411 data] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. This combination regimen will be considered promising if 23 or more (out of 32) patients attain CR. Results From January 2020 to March 2022, 33 subjects enrolled and were treated on study. Subject characteristics are listed in Table 1. Seven (21%) unique subjects were treated with 70mg/m 2 of bendamustine during induction cycles. Laboratory tumor lysis syndrome (TLS) was seen in 2/33 during C1 only; clinical TLS was not seen. Treatment was generally well tolerated with treatment-related adverse events (TRAE) of Grade ≥3 and occurring in >10% of subjects being neutropenia (n=5, 15%), thrombocytopenia (n=5, 15%) and lymphopenia (n=9, 27%). Other common non-hematologic TRAE of all grades were nausea/vomiting (n=26, 79%), diarrhea (n=10, 30%), and fatigue (n=17, 52%). There were 4 (12%) instances of COVID-19/COVID-19 pneumonia considered treatment related. Dose adjustments and delays for any drug occurred in 36% and 67% of subjects respectively. 22/33 (66.7%) subjects completed 6 cycles of BR-VEN. Maintenance rituximab was administered in 19/33 (57.6%) of subjects. Overall response rate was 97% (32/33) and PET-negative bone marrow biopsy confirmed CR Rate at EOT was 85% (28/33), achieving the primary endpoint (≥23 CRs). MRD at EOT is under analysis. With a median survival follow up of 21.5 months (mo), Median PFS and OS were not reached; estimated 2-year PFS and OS was 69.7% and 81.1% respectively. During follow up, there have been 6 deaths, 4 from COVID-19 (all in remission), one from influenza A (in remission), and one from disease progression (non-responding pt). There have been 2 other progression events who are alive. Conclusions BR-VEN was generally well-tolerated in this older patient population though GI toxicities were common. With a PET-negative CR rate of 85%, the combination is promising but longer follow-up is needed. There was a competing risk of death related to upper respiratory viruses identified, mostly COVID-19, as has been seen in other BR-based protocols during the COVID-19 pandemic. MRD analysis and survival data will be updated.

Cytokines regulate both the innate and adaptive immune responses to cancer. Although antitumor activity has been seen for several cytokines in preclinical models, they have had limited success as single therapeutic agents in clinical trials of cancer immunotherapy. However, the possible combinations of cytokines with other immune therapeutics and the advancement in genetic engineering, synthetic biology and cellular and immune therapy has led to the revival of interest in cytokines as anticancer agents. This article will review several immunostimulatory cytokines with anticancer activity, focusing on the those that have been studied in treatment of lymphoma and highlighting recent advances of potential clinical relevance.

Figure 1: E4412 Response: DOR (A), PFS (B), OS (C) Background: E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of brentuximab (BV), nivolumab (N), and ipilimumab (I) in patients with R/R HL. Here we present the long-term safety and response data on the full cohort of patients treated in Phase 1 (Arms A-I). Methods: Patients with confirmed R/R HL were treated in sequential dose escalation cohorts using 3 + 3 design. Additional patients were enrolled in expansion cohorts. Dose limiting toxicity (DLT) was evaluated within the first cycle of therapy. Results: Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; 3 patients were excluded due to ineligibility after enrolment. Thirty-five patients (57%) were refractory to their prior therapy; twenty-one (34%) had autologous stem cell transplant (SCT), 4 (6%) had prior alloSCT. Eight patients (13%) had prior BV. Safety: All 64 enrolled patients are included in the safety analysis. The most common (>30%) treatment-related grade 1–2 AEs were: nausea, peripheral sensory neuropathy, diarrhea, fatigue, elevated liver transaminases, anemia, and rash. Grade 3+ rash was more common in BV-I, in 22% of 23 patients compared with 7% of 41 patients in the other groups. Grade 3–4 events occurred in ten (43%) patients on BV-I, three (16%) patients on BV-N, and 12 (55%) patients in the triplet group. Two (3%) patients had treatment related death, one on BV-N (pneumonitis) and one in the BV-N-I group (dyspnea). Response: The overall response rate (ORR) was 76% for BV-I, with a complete remission (CR) rate of 57%, for BV-N the ORR was 89% with a CR rate of 61% and for BV-N-I the ORR was 82% with a CR rate of 73%. The median follow-up (Q1, Q3) for PFS and OS is 2.24 (1.67, 2.72) years and 2.98 (2.83, 3.04) years. Duration of response (DOR) is 1.32 years for BV-I responders, not reached for BV-N and BV-N-I responders (Figure 1A). The median PFS is 1.1 years, NR, and 2.49 years for BV-I, BV-N and BV-N-I respectively (Figure 1B). The median OS has not been reached for any of the arms (Figure 1C). Conclusion: Long term data from the Phase 1 component of E4412 shows no late safety concerns, and significant durability of response in both N containing arms with median follow-up of nearly 3 years. Analysis of the impact of transplant and depth of response will be updated by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-N to the triplet of BV-N-I.

Peripheral T cell lymphomas (PTCL) comprise a diverse group of aggressive T-cell and NK-cell lymphomas with many subtypes sharing same treatment algorithms despite having different pathobiology and responses to treatment. The molecular advances made in discovery of genetic mutations that disrupt epigenetic modulation in some subtypes of PTCL such as angioimmunoblastic T cell lymphoma and PTCL-not otherwise specified (NOS) may explain the poor outcomes and unsatisfactory responses to frontline line CHOP and CHOP-like therapy seen in this group of lymphomas. In this article, we address the main genetic mutations such as IDH2, TET2 and DNMT3A seen in PTCL and that disrupt the epigenetic modulation pathways, focusing on acetylation, deacetylation and methylation. Since therapeutic agents that target the disrupted epigenetic modulation pathways in PTCL may change treatment landscape in the near future, we will highlight the ones approved for treatment of refractory and/or relapsed PTCL and also the pivotal regimens being evaluated in clinical trials for treatment of frontline and refractory relapsed disease. We stress the importance of determining whether there is an association between the discussed genetic mutations and responses to the highlighted therapeutic agents such that treatments could be better tailored in patients with this kind of lymphoma with unmet needs.

Prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Immune-based therapeutic treatments such as CD19 Chimeric Antigen Receptor (CAR) T cell therapies have dramatically changed the treatment landscape for R/R DLBCL leading to durable remissions in ~ 50% of patients. However, there remains an unmet need for developing novel therapies to improve clinical outcomes of patients not responding or relapsing after CAR T cell therapies. Lack of suitable immunotherapeutic targets and disease heterogeneity represent the foremost challenges in this emerging field. In this review, we discuss the recently approved and emerging novel immunotherapies for patients with R/R DLBCL in the post-CAR T era and the cell surface targets currently used.

The improvement in outcomes seen with the introduction of rituximab, a CD20 monoclonal antibody in combination with chemotherapy or as a single agent in the treatment of indolent non-Hodgkin lymphomas has paved the way for development of various forms of monoclonal antibodies that act in different ways against non-Hodgkin lymphoma tumor cells. These could directly target a single surface antigen resulting in various ways of tumor cells toxicity and killing. Other forms of monoclonal antibodies include antibody-drug conjugates and bispecific antibodies. The role of therapeutic monoclonal antibodies in the treatment of lymphoma will be reviewed, highlighting their mode of action, clinical efficacy, and side effects.

BACKGROUND:Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.METHODS:We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.RESULTS:A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.CONCLUSIONS:In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

IntroductionDPP-IV is a homodimeric type II transmembrane receptor identical to the leucocyte surface antigen CD26. The interaction of CD26/DPP-IV on T cells with its ligand caveolin-1 on antigen-presenting cells (APC) enhances T cell activation, proliferation, and cytokine production. It also upregulates CD86 on APC resulting in co-stimulation. In a xenograft mouse model, reducing CD26 expression by a monoclonal antibody prevented aGVHD and preserved graft-versus-tumor effects (Hatano et al. BJH 2013). In a pilot trial testing sitagliptin for enhancement of cord blood engraftment, we observed a lower than expected rate of aGVHD (Farag et al. Stem Cell Dev 2013) and hypothesized that CD26/DPP-IV inhibition with sitagliptin may prevent aGVHD following allogeneic PBSC transplants.ObjectiveConduct a prospective phase II trial to test if sitagliptin can reduce the rate of grade II-IV aGVHD by day +100 following myeloablative allogeneic PBSC transplants (ClinicalTrials.gov, NCT02683525). The primary endpoint was grade II-IV aGVHD by day +100.MethodsPatients received thiotepa (15 mg/kg) and cyclophosphamide (120 mg/kg), followed by G-CSF mobilized PBSC from matched related (6/6 HLA match) or unrelated (10/10 HLA match) donors. Sitagliptin (600 mg q12 hours) was given on days -1 to day +14, together with tacrolimus and sirolimus through day +100, then tapering until day +180. In a Simon two-stage design, <8 of a total of 36 patients developing grade II-IV aGVHD by day +100 would demonstrate a reduction of aGVHD from a historical rate of 30% to <15% with 80% power and type 1 error = 0.1.ResultsThirty-six (17 M; 19 F) patients of median age 46 (20-59) years were enrolled. Patients had AML (n=19), ALL (n=9), MDS (n=4), and CML (n=4). Transplants were from matched related (13 patients) or unrelated (23 patients) donors. Acute GVHD occurred in 2 of 36 patients by day +100 (1 grade II; 1 grade IV), for cumulative incidences of 5.6% (95% confidence interval [CI], 0% - 13.2%) and 2.8% (95% CI, 0% - 8.2%) for grade II-IV aGVHD and grade III-IV aGVHD at day +100, respectively (Fig 1). An additional patient developed late-onset grade II aGVHD at day +140 following abrupt stopping of immunosuppression on day +100 for low donor chimerism in absence of relapse. Significant toxicities though day +30 included grades III-IV mucositis (n=15), acute kidney injury (4 with high tacrolimus levels, 1 sepsis), viral reactivation/infection (4 CMV, 2 BK, 1 EBV, 1 HHV6), and passenger lymphocyte syndrome (n=2). Non-relapse mortality was 0% at 12 months. With median follow-up of 699 (118-1312) days, the relapse-free survival was 77.2% (95% CI, 63.2% - 91.1%) and overall survival was 94.3% (95% CI, 86.7% - 100%) at 12 months (Fig 2a-b).ConclusionCD26/DPP-IV inhibition with sitagliptin is well-tolerated and significantly reduced the rate of aGVHD by day +100 in patients undergoing myeloablative allogeneic PBSCT transplantation.

Background Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma. Methods In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1.8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentwciinab vedotin 1.2 mg/kg (cohort D) or 1.8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1.2 mg/kg (cohort G) or 1.8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipiliinuinab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01896999. The phase 2, randomised portion of the trial is still enrolling. Findings Between March 7,2014, and Dec 28,2017,64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were exduded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3-4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11(50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53-92) in the ipilimumab group, 89% (65-99) in the nivolumab group, and 82% (60-95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34-78%) in the ipilimumab group, 61% (36-83%) in the nivolumab group, and 73% (50-89%) in the triplet therapy group. With a median follow-up of 2.6 years (IQR 1.8-2.9) in the ipilimumab group, 2.4 years (2.2-2.6) in the nivolumab group, and 1.7 years (1.6-1.9) in the triplet therapy group, median progression-free survival is 1.2 years (95% CI 1.7-not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups. Interpretation There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial (NCT01896999). Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12–58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21–30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57–8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

Corticosteroids are considered the standard first-line treatment for moderate/severe acute graft versus host disease (aGVHD), yet there is no consensus on the optimal management of patients that are steroid-refractory (SR). Infliximab is a chimeric monoclonal antibody with anti-TNF-α activity that has previously demonstrated efficacy in SR-aGVHD.We performed a retrospective review of 59 patients at Indiana University who underwent allogeneic stem cell transplantation and developed SR grade III-IV aGVHD from January 2007 to August 2018. Infliximab was administered 10 mg/kg weekly intravenously. Response criteria was in accordance with Martin et al (BBMT 2009; 12:777-784).Median age of treated patients was 49.5 years (range, 34.5-60) and median time from transplant to diagnosis of aGVHD was 106 days (range, 42-185) Patients received a median of 12 days (range, 8-20) of systemic steroids prior to infliximab. At the start of infliximab, 52 (88%) patients were on non-steroidal immunosupressants and 39 (66%) on non-absorbable steroids concurrently with systemic steroids. Patients received a median of 3 doses of infliximab with 37 (62.7%) patients receiving <4 doses. At 28 days after first infliximab dose, overall response was seen in 16 (27.1%) patients, with 8 patients achieving a complete response and 8 with a very good partial response. From the start of infliximab, the median overall survival was 104 days with 76.3% (n=45) non-relapse mortality and 5% (n=3) relapse mortality. Bacterial infections were seen in 41 (66%) patients treated with infliximab with median time to onset of 13 days (range, 6-24), and viral infections were seen in 31 (50%) of patients with median time to onset of 16 days (range, 9-43).There was no significant difference between responders (n=16) and non-responders (n=43) in baseline demographic, transplant-related characteristics, initial GVHD prophylaxis regimen, number of non-steroidal systemic immunosuppressants at time of aGVHD diagnosis, or use of non-absorbable steroids. There was no difference in time from diagnosis of aGVHD to start of infliximab (median 16 vs. 11 days, P=0.06). Responders were less likely to have liver aGVHD involvement vs. non-responders (18% vs. 53%, P=0.016) and had slower tapering of systemic steroids, both at median time to 50% steroid dose (18 vs. 12 days, P=0.02) and 25% steroid dose (36 vs. 24 days, P=0.01). Responders had lower incidence of bacterial infection (44% vs. 74%, P=0.04), but not viral infections (56% vs. 47%, P=0.57). Responders had a longer overall survival (median 20.3 vs. 2.8 months, P=0.01).Our single center report of 59 patients with SR-aGVHD treated with infliximab is among the largest reported. The outcomes of response to SR-aGVHD are poor and there is an unmet need for better agents. Additional studies with greater patient numbers are needed to identify factors associated with improved response to infliximab.

BackgroundTT/Cy has been reported as a well-tolerated conditioning regimen in patients with a variety of advanced leukemias undergoing allogeneic HCT (Blood 1996, 88:353-7). While other TT-containing regimens have been investigated, outcomes with TT/Cy, specifically, in a more uniform population have not been reported. Here, we report the outcome of TT/Cy in patients with myeloid malignancies undergoing allogeneic HCT, and compare the results with TBI/Cy.MethodsWe retrospectively analyzed 149 consecutive patients with AML (n=101), advanced CML (n=29), and high-grade MDS with >5% blasts (n=19) who received either TBI/Cy (TBI >13.5 Gy; Cy 120 mg/kg) or TT/Cy (TT 15 mg/kg; Cy 120 mg/kg) and allogeneic HCT from HLA-matched sibling or 10/10 or 9/10 HLA-matched volunteer unrelated donors (VUD) between 2007-2016 at Indiana University.ResultsSixty-seven patients received TBI/Cy and 82 received TT/Cy. Baseline characteristics were not significantly different. TBI/Cy resulted in significantly higher grades 3-4 toxicity, including mucositis (64% vs. 48%, P=0.048), acute respiratory failure (22% vs. 10%, P=0.04), transaminase elevation (24% vs. 9%, P=0.01), acute renal failure (16% vs. 5%, P=0.02), and sinusoidal obstruction syndrome (16% vs. 0%, P=0.0001). Cumulative incidence of 100-day grades 2-4 acute GVHD (TBI/Cy 15.0% ± 4.4%, TT/Cy 20.7% ± 4.5%; P=0.15) and extensive stage chronic GVHD at 1-year (TBI/Cy 35.3% ± 6%, TT/Cy 43.6% ± 5.6%; P=0.27) were not significantly different. The cumulative incidence (CI) of non-relapse mortality (NRM) was higher following TBI/Cy (Fig 1A, P<0.001); at 1 year NRM was 31.5% ± 5.8% for TBI/Cy and 12.2% ± 3.6% for TT/Cy. There was no significant difference in the CI of relapse (CIR) (Fig 1B, P=0.49); the 3-year CIR was 21.2% ± 5.1% with TBI/Cy and 28.7% ± 5.6% with TT/Cy. The overall survival (OS) was significantly higher with TT/Cy compared with TBI/Cy at 1 year (79.3% ± 4.5% versus 52.2% ± 6.1%) and 3 years (57.3% ± 5.9% versus 35% ± 5.9%) (Fig 1C, P=0.001). On multivariable analysis, TT/Cy was associated with a significantly lower risk of death (HR 0.42; 95% CI: 0.27-0.68, P<0.001), while 9/10 HLA-matched VUD and Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) >5 were both associated with a higher hazard of death (P=0.02 and P=0.004).ConclusionTT/Cy is an effective conditioning regimen in patients with myeloid malignancies undergoing allogeneic HCT and is associated with lower NRM compared with TBI/Cy. Future studies should assess whether addition of other agents to TT and Cy improve outcomes or simply increase toxicity. TT/Cy has been reported as a well-tolerated conditioning regimen in patients with a variety of advanced leukemias undergoing allogeneic HCT (Blood 1996, 88:353-7). While other TT-containing regimens have been investigated, outcomes with TT/Cy, specifically, in a more uniform population have not been reported. Here, we report the outcome of TT/Cy in patients with myeloid malignancies undergoing allogeneic HCT, and compare the results with TBI/Cy. We retrospectively analyzed 149 consecutive patients with AML (n=101), advanced CML (n=29), and high-grade MDS with >5% blasts (n=19) who received either TBI/Cy (TBI >13.5 Gy; Cy 120 mg/kg) or TT/Cy (TT 15 mg/kg; Cy 120 mg/kg) and allogeneic HCT from HLA-matched sibling or 10/10 or 9/10 HLA-matched volunteer unrelated donors (VUD) between 2007-2016 at Indiana University. Sixty-seven patients received TBI/Cy and 82 received TT/Cy. Baseline characteristics were not significantly different. TBI/Cy resulted in significantly higher grades 3-4 toxicity, including mucositis (64% vs. 48%, P=0.048), acute respiratory failure (22% vs. 10%, P=0.04), transaminase elevation (24% vs. 9%, P=0.01), acute renal failure (16% vs. 5%, P=0.02), and sinusoidal obstruction syndrome (16% vs. 0%, P=0.0001). Cumulative incidence of 100-day grades 2-4 acute GVHD (TBI/Cy 15.0% ± 4.4%, TT/Cy 20.7% ± 4.5%; P=0.15) and extensive stage chronic GVHD at 1-year (TBI/Cy 35.3% ± 6%, TT/Cy 43.6% ± 5.6%; P=0.27) were not significantly different. The cumulative incidence (CI) of non-relapse mortality (NRM) was higher following TBI/Cy (Fig 1A, P<0.001); at 1 year NRM was 31.5% ± 5.8% for TBI/Cy and 12.2% ± 3.6% for TT/Cy. There was no significant difference in the CI of relapse (CIR) (Fig 1B, P=0.49); the 3-year CIR was 21.2% ± 5.1% with TBI/Cy and 28.7% ± 5.6% with TT/Cy. The overall survival (OS) was significantly higher with TT/Cy compared with TBI/Cy at 1 year (79.3% ± 4.5% versus 52.2% ± 6.1%) and 3 years (57.3% ± 5.9% versus 35% ± 5.9%) (Fig 1C, P=0.001). On multivariable analysis, TT/Cy was associated with a significantly lower risk of death (HR 0.42; 95% CI: 0.27-0.68, P<0.001), while 9/10 HLA-matched VUD and Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) >5 were both associated with a higher hazard of death (P=0.02 and P=0.004). TT/Cy is an effective conditioning regimen in patients with myeloid malignancies undergoing allogeneic HCT and is associated with lower NRM compared with TBI/Cy. Future studies should assess whether addition of other agents to TT and Cy improve outcomes or simply increase toxicity.

7538 Background: Emerging data suggests that checkpoint blockade therapy (CBT) subsequent to stem cell transplant (SCT) may cause significant immune-related toxicity. We evaluated whether increased patterns of immune toxicity were seen in post SCT patients treated on Arms A-F of E4412: A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma Methods: Transplant status of patients treated with brentuximab vedotin (BV) + ipilimumab (Ipi) (Arms A-C) or BV + nivolumab (Nivo) (Arms D-F) was recorded at study entry. Toxicity was graded according to CTCAE v4.0. Results: Eighteen of 42 patients enrolled on Arms A-F were post SCT; 15 autologous (ASCT) and 3 allogeneic (AlloSCT). There were no demographic differences between the SCT and all patients. No patients had active GVHD. In Arms A-C grade 3 toxicities (rash and allergic reaction), occurred in 20% (2/10) of SCT patients (8 ASCT, 1 AlloSCT) compared with 39% (9/23) of all patients; there were no grade 4 toxicities in SCT patients compared to 4% (1/23) of all patients. A higher incidence of grade-1-2 rash was noted in ASCT patients 70% vs 39% all patients; however there was no increase in diarrhea, arthritis, or uveitis. In Arms D-F there were no significant differences in high grade toxicities in ASCT 16% (1/6) vs. 21% (4/19) all patients; 50% (1/2) AlloSCT patients experienced grade 3 toxicity (pneumonitis, typhlitis). A second pneumonitis, grade 5, occurred in the non SCT population. There remainder of toxicities were grade 1-2 and were not significantly increased in the SCT patients. A transient and clinically insignificant elevation in transaminases was not increased in SCT 16% (3/19) compared to all patients 47% (9/19). Conclusions: CBT in combination with BV was well tolerated in the ASCT population, however larger studies are required to confirm this finding for AlloSCT patients. Investigation of dual CBT (Ipi + Nivo) in combination with BV in this population continues. Evaluation of the safety of CBT + BV in E4412 in the pre SCT setting is ongoing and will be combined with this data by the ASCO meeting. Clinical trial information: NCT01896999.

Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo. Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.