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Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation.We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/mBetween May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4-51·3), and median follow-up was 24·3 months (IQR 12·1-29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation.Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (2·5 × 10US National Heart, Lung, and Blood Institute and US National Cancer Institute.

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).

The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single-agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 mg, 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.

Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). The National Marrow Donor Program® (NMDP) manages an IND under which 2456 patients (1499 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December, 2016. Median age was 31 years (

Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first‐in‐class, once‐daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra‐additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone), which was determined in phase 1. The primary efficacy endpoint was overall response rate (ORR). Fifty‐nine patients with RRMM received the RP2D (18 in phase 1 and 41 in phase 2b). These patients had received a median of three prior lines of therapy; 69% were refractory to bortezomib, and 90% were refractory to their last treatment. ORR in the RP2D population was 71% (stringent complete response and complete response: 3% each). Median duration of clinical benefit and median duration of response were both 6.5 months. Median progression‐free survival (PFS) was 7.4 months, and median overall survival (OS) was 35.9 months. High‐risk patients had comparable ORR and median PFS (67% and 7.7 months, respectively) to non–high‐risk patients, whose ORR was 73% and median PFS was 6.9 months, whereas median OS in high‐risk patients was 13.9 months and not reached in non–high‐risk patients. The most common grade ≥3 hematologic treatment‐emergent adverse events (TEAEs) were anemia and thrombocytopenia (17% each); the most common grade ≥3 non‐hematologic TEAE was hypertension (19%). In patients with RRMM treated with multiple previous lines of therapy, ibrutinib plus carfilzomib demonstrated anticancer activity within the expected efficacy range. No new safety signals were identified and the combination was well‐tolerated.

A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P = .64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients’ median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.

8025 Background: Intravenous (IV) isatuximab (Isa) + Pd is approved for the treatment of RRMM patients (pts). SC delivery would optimize convenience of administration. Prior results showed that SC Isa administered by syringe pump has efficacy and safety profiles comparable to IV Isa; the recommended Phase 2 dose (RP2D) was 1400 mg (IMW21 P-207). Methods: This multicenter Phase 1b study evaluated safety, PK and efficacy of SC vs IV Isa + Pd in RRMM pts after ≥2 prior treatment lines. Pts were randomized 2:1 to SC1000 mg or IV 10 mg/kg and to SC1400 mg or IV. An expansion cohort was later implemented with SC Isa administered at the RP2D via OBDS, a wearable bolus injector applied to the abdomen by a healthcare professional. Primary endpoints (EPs) were safety, including injection site reactions (ISRs), and PK. Main secondary EPs were overall response rate (ORR) and progression-free survival (PFS). Results: 56 pts were randomized and treated: 12 Isa IV, 12 Isa SC1000, 10 Isa SC1400 and 22 OBDS pts. At study entry, ISS stage II–III was 67% in IV, 33% in SC1000, 60% in SC1400 and 50% in OBDS pts. On Jan 20, 2022, 33% IV, 25% SC1000, 50% SC1400 and 86% OBDS pts remained on treatment. Due to sequential accrual, median follow-up (FU) was longer in IV (20.6 mo) and SC1000 (23.8 mo) than SC1400 (18.1 mo) and OBDS (6.5 mo) pts. Infusion reactions (IRs) were infrequent (≤10% in each cohort, all Grade [G] 2), only at first IV or SC infusion/injection, with no IRs in OBDS. Local tolerability of OBDS was very good, with 5 (22.7%) pts experiencing 7 ISR episodes, all G1, out of 305 administrations (2.3%): 5 injection site erythemas, 1 injection site hemorrhage, and 1 injection site induration. Median duration of OBDS injection was 10 min. Incidence of G4 neutropenia was lower in SC1000 (42%) vs the other cohorts (55–60%). The lower % of ≥G3 treatment-related AEs in OBDS (77%) vs the other cohorts (≥80%) may be due to shorter FU. Best overall responses are shown in table; longer FU is needed for OBDS pts. Median PFS was 22 mo in IV, 12.5 mo in SC1000 and not reached in SC1400 and OBDS pts. PK and CD38 receptor occupancy results in OBDS pts are consistent with those observed in SC1400 with pump. Conclusions: SC Isa administered by OBDS shows a safety profile consistent with IV administration with no IRs and excellent local tolerability. Efficacy in the SC cohorts was comparable to the Phase 3 ICARIA results. Isa SC administration by OBDS is well tolerated, requires a short duration of injection and provides a convenient hands-free option. Clinical trial information: NCT04045795. [Table: see text]

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Background Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients often require substantial but variable transfusion support. Study design and methods This single-center, retrospective study evaluated the red blood cell (RBC) and platelet (PLT) transfusion data of first-time allo-HSCT recipients transplanted in 2011 to 2017. Multivariate analyses were performed to assess the associations between patient and transplant-related factors and transfusion requirements. Results The study included 1762 patients who received peripheral blood stem cells (88.2%), marrow (7.0%), or umbilical cord (4.8%) from matched related (38.3%), unrelated (49.2%), or haploidentical (7.8%) donors. Almost all patients required RBCs (88.3%) or PLTs (97.4%) during the first 30 days, with medians of 3 (range, 1-37) RBC and 6 (range, 1-144) PLT units transfused. Fewer patients required RBC (43.8%) or PLT (27.3%) transfusions during Days 31 to 100, but the median (range) numbers of RBC and PLT units remained high at 3 (1-36) and 6 (1-116) among transfused patients. RBC and PLT transfusion independence was reached in medians of 24 (95% confidence interval [CI], 22-26) and 12 (95% CI, 11-12) days, respectively. Haploidentical donor, cord graft, and requiring RBC transfusions in the 10 days before HSCT were the most significant independent factors predictive of increased transfusion requirements. Advanced disease, diagnosis, ABO incompatibility, conditioning intensity, CD34+ cell dose, presence of severe acute graft-vs-host disease, and changes in recommended transfusion triggers were also shown to independently impact transfusion requirements. Conclusions This study provided for the first time quantitative and comparative transfusion data on a large contemporary cohort of HSCT recipients, including haploidentical and cord graft recipients, and identified factors predictive of increased transfusions.

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population.

Background Allogeneic hematopoietic cell transplant (allo-HCT) recipients often require substantial but variable transfusion support. Few studies have quantified their transfusion burden, or identified prognostic factors for increased transfusions to guide patient counseling or inventory management. Data on haploidentical HCT (Haplo-HCT) patients are especially scarce. Objectives To identify factors associated with increased RBC and platelet (PLT) transfusions, and provide for the first time data on a large cohort of Haplo-HCT patients. Methods We retrospectively evaluated 1803 consecutive first time adult allo-HCT patients transplanted at our center in 2011-17. Multivariate linear regression and Fine-Gray subdistribution hazards models were used to examine the associations between baseline characteristics (age, sex, disease stage, graft type, donor type, ABO compatibility and conditioning regimen) and log-transformed transfusion units in the first 30 days after HCT and time to reach transfusion independence respectively. Results The median age of the cohort was 53(18-78); 56.2% were male. Most common diagnoses were AML (38.8%), ALL (19.6%), and lymphoma (14.8%); 50.2% had advanced disease. Patients received nonmyeloablative/reduced intensity (58.9%) or myeloablative conditioning regimens (MAC, 41.1%), followed by peripheral blood stem cell (88.4%), bone marrow (6.9%) or umbilical (UC, 4.7%) HCT. Most grafts were from matched related (MRD, 38.7%) or unrelated (MUD, 49.1%) donors, and 7.6% were haploidentical. ABO incompatibility (Major 15.8%, minor 18.6%, bi-directional 8.5%) was present in 42.9% of the cases (Table 1). Most of the 1764 patients who survived 30+ days received RBC (88.2%) or PLT (97.2%) transfusions during the first 30 days, with a median of 3 (0-37) RBC and 5(0-144) apheresis PLT units. RBC and PLT transfusion independence was reached in 28 (95%CI: 26-31) and 12 (95%CI: 12-13) days respectively. Multivariate analyses showed that Haplo-HCT and UC graft were independently associated with more RBC and PLT transfusions, as were advanced disease, ABO incompatibility, older age, and MAC (P Conclusions We identified patient and transplant factors strongly associated with increased transfusions in the first 30 days after allo-HCT, and quantified the transfusion burden of Haplo-HCT relative to other types of HCT.

In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose-limiting. Per 3 + 3 phase I design, an additional three patients were enrolled to DL1, with no further dose-limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll three additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved ≥ partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥ stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.

Introduction: Intravenous (IV) isatuximab (Isa) + pomalidomide and dexamethasone (Pd) is an approved regimen for the treatment of adults with relapsed/refractory multiple myeloma (RRMM). Subcutaneous (SC) drug delivery would optimize convenience of administration. Methods: This multicenter, open-label, Phase 1b study evaluated the safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in patients (pts) with RRMM who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Pts were randomized 2:1 to Cohorts 1a (SC-1000 mg) or 1b (IV-10 mg/kg). After evaluation of Isa SC safety, PK and CD38 receptor occupancy (RO) in Cohort 1a, new pts were randomized to Cohorts 2a (SC-1400 mg) or 2b (IV-10 mg/kg). SC and IV Isa were administered once weekly for 4 weeks (Cycle 1) and then once every 2 weeks in subsequent cycles (QW/Q2W) in combination with Pd; SC Isa was delivered through a syringe pump. Primary endpoints assessed safety including dose-limiting toxicity (DLT), injection site reactions (ISR), and PK parameters. Main secondary endpoints were overall response rate (ORR), progression-free survival (PFS), CD38 RO, and patient-reported outcomes (PRO). Results: A total of 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. As of March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. Median time from initial MM diagnosis to first study treatment was ~5 years, and the median (range) number of prior lines of therapy was: 3.5 (2-7) in IV, 3.0 (2-6) in SC1000, and 2.5 (1-4) in SC1400 pts. At study entry, International Staging System (ISS) stage II-III was 58.4% in IV, 33.3% in SC1000 and 60% in SC1400 pts; median weight and beta-2 microglobulin rate tended to be higher in SC1400 compared to SC1000 pts, respectively (86.9 kg vs 70.3 kg and 3.55 mg/L vs 2.65 mg/L). Due to sequential accrual, the median follow-up was longer in IV (15.1 months [mos]) and SC1000 (14.8 mos) cohorts than SC1400 (8.8 mos). Infusion reactions (IR) were infrequent (≤10% across cohorts, all Grade [G] 2); in each cohort, 1 single episode of IR occurred in 1 patient each, only at first injection. Local tolerability of SC injection was very good with only a single episode of G2 ISR (erythema and pain) in SC1400 cohort. Similar occurrence of ≥G3 treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and neutropenia occurred across cohorts. There were no TEAEs leading to death, definitive treatment discontinuation, or premature discontinuation of Isa (Table 1). One DLT was reported in each SC cohort: G4 neutropenia (SC1000) and G3 pulmonary infection (SC1400); both pts resumed study treatment after corrective treatment and dose modification. No maximum tolerated dose was identified. ORR, ≥ very good partial response, and complete response were 66.7%, 33%, and 16.7% in the IV cohort; 66.7%, 41.7%, and 25% in the SC1000 cohort, and 80%, 40%, and 20% in the SC1400 cohort, respectively. At 8 mos, PFS-free rate was 73% in the IV and SC1000 cohorts, and 89% in the SC1400 cohort (Figure 1). After the first Isa administration, C max and AUC 1week of the SC1000 and SC1400 mg doses were comparable and lower than those after IV administration, in agreement with SC slower absorption. After the 4 weekly Isa administrations (Cycle 1), the exposures (C trough at 4 weeks) of SC1000 and SC1400 doses were comparable and higher than those after IV administration. The comparable exposure of the 2 SC cohorts despite the different doses (1000 mg and 1400 mg) was attributed to the unbalanced distribution of influential PK covariates, as beta-2 microglobulin and weight. High CD38 receptor saturation by Isa on bone marrow plasma cells was reached for both SC doses; mean (%) CD38 RO was 76 (68.2; 86.1) in IV, 80 (74.7; 84.2) in SC1000, and 81 (78.6; 83.2) in SC1400 cohorts with a smaller range at SC1400. Conclusions: The safety of Isa SC at 1000 mg and 1400 mg + Pd was consistent with the known safety profile associated with IV administration, with no new safety signals identified. IRs were infrequent, occurring only at first injection and local tolerability of Isa SC was very good. Efficacy results were comparable with the Phase 3 ICARIA study. Higher C trough at 4 weeks (PK best predictor of Isa efficacy) was achieved following SC administration compared with IV administration. Isa SC + Pd administration appears to be a promising and convenient option for pts with RRMM. Figure 1 Figure 1. Disclosures Moreau: Amgen: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria. Prince: Sanofi: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen China R&D: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Ocio: MSD: Honoraria; Karyopharm: Consultancy; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy; Secura-Bio: Consultancy. Madan: GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Speakers Bureau. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bories: Gilead: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Novartis: Honoraria; BMS: Honoraria. Delforge: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Semiond: Sanofi: Current Employment, Other: may hold shares and/ or stock options in the company. Jia: Sanofi: Current Employment, Other: may hold shares and/ or stock options in the company. Macé: Sanofi: Current Employment, Other: may hold shares and/ or stock options in the company. Suzan: Sanofi: Current Employment, Other: may hold shares and/ or stock options in the company. van de Velde: Sanofi: Current Employment, Other: may hold shares and/ or stock options in the company. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) is an approved regimen for an intravenous (IV) administration. This trial assesses the safety, pharmacokinetics and efficacy of subcutaneous (SC) administration of Isa-Pd.

BACKGROUND: Our group recently reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101 a randomized comparison between double umbilical cord blood (dUCB) and haploidentical bone marrow (haplo) with post-transplant cyclophosphamide (ptCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of overall survival (OS) in the haplo arm. In this secondary analysis we sought to investigate if transplant center experience with haplo and or cord blood HCT had an impact on outcomes. PATIENTS AND METHODS: All patient randomized in BMT CTN 1101 were included. In order to determine the transplant center experience with either haplo or dUCB we queried the Center for International Blood and Marrow Transplant Research (CIBMTR) for number of transplants with each platform in the year prior to initiation of the study. Centers were then grouped as dUCB center (> 10 dUCB, n=117, 10 centers), Haplo center (>10 haplo and ≤10 dUCB, n=110, 2 centers), and ≤10 haplo and ≤10 dUCB HCTs (other center, n=140, 21 centers). Further analysis considered the alternative cut-off for haplo (> 5 vs ≤ 5) experience, and considered the outcomes based on the donor experience vs. others (e.g. dUCB > 10 vs. ≤ 10; haplo > 5 vs. ≤ 5). RESULTS: The effect of center experience on HCT outcomes shown in Figure, below . After adjusting for age, Karnofsky performance score and, disease risk index we found that there was no difference in outcomes between haplo and dUCB for centers that were experienced with dUCB or had limited to no experience with either dUCB or haplo. In contrast, in centers that were primarily experienced with haplo had better outcomes with this donor type, as compared to dUCB. The higher risk of treatment failure (relapse or death) and overall mortality in dUCB in haplo experienced centers was driven by significantly higher risk of relapse. We then considered the transplant experience with each of the donor types separately. In transplant centers that had performed > 10 dUCB, there were similar outcomes for recipients of both dUCB and haplo. Similarly, centers that had ≤ 5 haplo HCTs had no difference in outcomes between donor types suggesting an overlap with centers that had performed > 10 dUCB HCTs. Overall mortality was higher among dUCB recipients in centers that had performed ≤ 10 dUCB. Notably, the hazard ratio of non-relapse mortality favored haplo in all four donor experience type of transplant center, albeit not statistically significant. CONCLUSION: Except for dUCB recipients in centers with < 10 dUCB/year had worse overall mortality, primarily driven by relapse, the transplant center experience in the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial. Figure 1 Figure 1. Disclosures Brunstein: NANT: Research Funding; FATE: Research Funding; GamidaCell: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria. Cutler: Deciphera: Consultancy; Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Horowitz: Sobi: Research Funding; Regeneron: Research Funding; Orca Biosystems: Research Funding; Tscan: Research Funding; Xenikos: Research Funding; Miltenyi Biotech: Research Funding; Stemcyte: Research Funding; Medac: Research Funding; Vor Biopharma: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Kiadis: Research Funding; Seattle Genetics: Research Funding; Mesoblast: Research Funding; GlaxoSmithKline: Research Funding; Sanofi: Research Funding; Pfizer, Inc: Research Funding; Omeros: Research Funding; Magenta: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; Vertex: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Shire: Research Funding; Gamida Cell: Research Funding; Daiicho Sankyo: Research Funding; CSL Behring: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding. Horwitz: Gamida Cell: Research Funding. McGuirk: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Vasu: Kiadis, Inc.: Research Funding; Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is the approach that offers the highest curative rate for acute myelogenous leukemia (AML) with intermediate or high-risk cytogenetics. Graft versus host disease (GvHD) has remained the main cause of post-transplantation mortality and morbidity, despite advances in prophylaxis and therapy, adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GvHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have developed a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy), to 1) reduce the possibly increased risk of relapse from PTCy, by using escalated radiation doses of TMLI, as increasing radiation doses has the potential to decrease the post-transplantation relapse rate (Blood, vol 76, pp. 1867-1871, 1990); and 2) reduce the risk of chronic GvHD by using PTCy. The major goal of this pilot study of TMLI and PTCy (clinicaltrials.gov: NCT03467386), was to thus improve GvHD-free/relapse-free survival (GRFS), reported to be 45% from total body irradiation (TBI) and tacrolimus/sirolimus prophylaxis (BBMT, vol 26(2), pp. 292-299, 2020), in patients with AML in remission. Patients and Methods: A total of 18 patients were enrolled and treated (see Table) between March 2018 and December 2019. Key criteria were ages 18 to 60, first or second CR, minimal residual disease negative by multi-color flow cytometry, and normal organ function. TMLI was administered on days -4 to 0 without addition of chemotherapy. The radiation dose for all patients (n=18) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Remaining organs were considered non-targeted. All patients received peripheral blood stem cells on day 0. Cyclophosphamide was given on days +3 and +4, 50 mg/kg each day for GVHD prevention. Tacrolimus, 1 mg continuous infusion adjusted to maintain levels from 5 to 10 ng/mL was given from day +5 to day +90, and G-CSF 5 µg/kg daily was administered at day +5 until recovery of neutrophil counts. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. A patient safety lead-in segment (n=6) was conducted to ensure that there were no unexpected toxicities, allowing for a dose de-escalation to 1800 cGy. GRFS was defined as grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurred first. Results: Bearman toxicity data are available for all patients. Among these patients, grade 2 toxicities were bladder toxicity and stomatitis. No grade 3-4 toxicities or toxicity-related deaths were observed. Acute GVHD (aGVHD) developed in 2 of patients (100-day Grade II-IV aGVHD: 11.1%, 95%CI: 1.7-30.4); of those, only 1 patient developed Grades III-IV (100-day Grade III-IV aGVHD: 5.6%, 95%CI: 0.3-23.1). Five patients developed mild chronic GVHD (1-year cGVHD rate: 28.6%, 95%CI: 7.5%-54.7%). The GRFS rate at 1 year was 59.3% (95% CI: 28.8-80.3) (Figure). The median follow up was 11.3 months (range 4.7 to 25.4) for surviving patients (n=17). All patients engrafted. Time to neutrophil and platelet recovery were 14 days (range 13-32 days) and 20 days (range 11-49 days), respectively. One-year estimates of OS and relapse-free survival were 100% and 80.8% (95% CI: 50.5-93.6), respectively (Figure). Disease relapse at 1 year was 19.2% (95% CI: 4.1-42.6). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusions: 1) This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe and feasible, with no NRM. 2) All patients achieved engraftment. 3) Participants with ≥1 year follow-up have discontinued immunosuppressive therapy, reducing financial burden and leading to improved quality of life. The preliminary results suggest an improved GRFS rate. A larger phase 2 trial is in preparation to corroborate these data. Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Ali:Incyte Corporation: Consultancy. Aribi:Seattle Genetics: Consultancy. Marcucci:Novartis: Speakers Bureau; Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Nakamura:Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees.

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 >5x106 cells/kg and of CD3 >2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

The use of post-transplant cyclophosphamide (PTCy) as graft-versus-host-disease (GvHD) prophylaxis after hematopoietic cell transplantation (HCT) has increased significantly over the past decade due to expansion of donor pool with haploidentical and mismatched unrelated donors. A recently completed phase 2 study, PROGRESS-2 (NCT02345850), has highlighted the efficacy of PTCy in the matched donor setting. Hemorrhagic cystitis (HC) is the most notable toxicity associated with high dose Cy. However, data specific to the incidence and severity of HC in the post HCT setting is sparse, with no consensus on best practices to prevent HC in patients receiving PTCy. Current strategies to prevent HC in PTCy setting have been adapted from data in pre-HCT Cy (conditioning setting), such as hyperhydration with forced diuresis, continuous bladder irrigation, mesna as an intermittent and continuous infusion, or a combination of these methods. The aim of our study was to describe the incidence and severity of HC in patients undergoing HCT with PTCy as GvHD prophylaxis, identifying potential risk factors and impact of HC on HCT outcomes. We retrospectively reviewed 194 consecutive patients who underwent their first HCT with PTCy from 2014 to 2018 at our center. More than half of the patients (53%) received myeloablative conditioning regimen with majority receiving peripheral blood stem cells (81%) from haploidentical donors (96%). GvHD prophylaxis was unified with PTCy (50 mg/kg on Days +3 and +4), in addition to MMF (1 gm 3x daily starting on Day +5) and tacrolimus (1 mg as a continuous infusion daily starting on Day +5). Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was based on physician documentation or presence of blood in urinalysis up to Day +100. To determine severity of HC, CTCAE 5.0 grading system was used. Median age of patients was 45 years (range: 2-73), with 60% of patients being male. KPS was ≥80% in 83% of patient and 40% had HCT-CI of ≥2. The most common diagnoses included: AML (41%), ALL (24%) and MDS/MPN (19%). There were 55 patients who received ≥3 lines of therapy, 116 patients received In conclusion, hyperhydration with forced diuresis added to aggressive mesna dosing is an effective strategy in preventing severe HC in HCT patients receiving PTCy as GvHD prophylaxis. Incidence of Grade 3 or 4 HC was low and transient and did not impact HCT outcomes. Viral HC had a significantly later onset than non-viral HC, suggesting a different pathophysiology. Older age and myeloablative conditioning were independent factors for higher incidence of HC in our cohort. Disclosures Ali: Incyte Corporation: Consultancy. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees. Aribi:Seattle Genetics: Consultancy. Pullarkat:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Marcucci:Merck: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Research Support (Investigation Initiated Clinical Trial). Nakamura:NapaJen Pharma: Consultancy; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Magenta Therapeutics: Other: Advisory board meeting; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy.

Introduction: CC-92480 is an oral novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent currently in phase 1/2 development in patients with relapsed/refractory multiple myeloma (RRMM). CC-92480 induces rapid degradation of the transcription factors Ikaros and Aiolos, leading to apoptosis of myeloma cells and immune-stimulatory effects. The innovative CC-92480-MM-001 phase 1 study design investigated the effects of a broad range of CC-92480 doses and schedules. The pharmacodynamic effects will be discussed in this analysis with a focus on modulation of immune cell subsets. Methods: An adaptive Bayesian dose-escalation design was used in the CC-92480-MM-001 study (NCT03374085) that allowed for evaluation of several dosing schedules. The continuous schedules included 10 days on followed by 4 days off × 2, and 21 days on followed by 7 days off in a 28-day cycle. The intensive schedules included 3 days on followed by 11 days off × 2, and 7 days on followed by 7 days off × 2. An intensive biomarker sampling program was included in the study to allow for characterization of pharmacodynamic changes. Peripheral blood and bone marrow aspirates (BMA) were obtained from patients enrolled in part 1 of the dose-escalation study for biomarker analysis. Samples were taken pre-dose and during treatment at multiple time points. Biomarker analyses included Ikaros and Aiolos levels in peripheral blood mononuclear cells by flow cytometry; CRBN, Aiolos, Ikaros, and ZFP91 expression by immunohistochemistry (IHC) in BMA; weekly levels of serum free light chain (sFLC) and soluble B-cell maturation antigen (sBCMA), and effects on immune cells in peripheral blood. CC-92480 plasma exposures were collected at several time points in Cycle 1. Results: CC-92480 1.0 mg, 21/28-days was selected as the recommended phase 2 dose (RP2D) based on tolerability, efficacy, and pharmacodynamic effects. Degradation of Ikaros and Aiolos was evident at all dose levels in bone marrow plasma cells independent of baseline CRBN staining intensity and prior treatment. In these heavily pretreated patients with RRMM, CC-92480 induced rapid and sustained decreases in sFLC (median 94%) and sBCMA (median 78%) in Cycle 1 at the RP2D. Ikaros and Aiolos degradation in peripheral blood T cells was dose-dependent and reached > 80% degradation at 0.6 mg and above. Substrate recovery occurred during drug holidays, with faster recovery at lower doses, and reached full recovery with ≥ 7-day breaks. Focusing on the immunomodulatory effects, dynamic and dose- and schedule-dependent changes were demonstrated in immune cell subtypes. B cells decreased with increasing dose and reached > 90% at 0.8 mg and above in the continuous schedules. Recovery was evident during drug holidays, especially at lower doses. T-cell proliferation by Ki-67 staining increased between 30% and 350% during treatment and returned toward baseline during drug holidays at lower doses and with longer breaks. NK-cell proliferation by Ki-67 staining was evident at all doses and peaked at approximately 1 week post dose regardless of schedule. T cells demonstrated a shift from naïve to effector phenotype at all doses and schedules, and showed an increase in activation markers, HLA-DR, CD38, and ICOS. Regulatory T cells increased by 90% and 130% at 0.8 mg and 1.0 mg, respectively. At the 1.0 mg dose (RP2D) and more continuous schedules (10/14 days × 2 and 21/28 days), higher percentages of proliferating CD3+CD4+ and CD3+CD8+ T cells associated with a clinical response. Conclusions: The novel study design and biomarker sampling have allowed us to understand how depth, duration, and recovery of Ikaros and Aiolos degradation lead to specific immune changes. CC-92480 pharmacodynamic activity was dose-dependent from 0.1 mg to 1.0 mg and recovery was dose- and schedule-dependent. These changes were also demonstrated in immune cell subsets. Dynamic changes of immune cell subsets in peripheral blood occurred in concert with Ikaros and Aiolos degradation and recovery, suggesting that immune profiles may be modified and optimized by dose and schedule. This new insight may be utilized to provide the rationale for dose and schedule for specific immune effects when combining with other immunotherapies, such as bispecific antibodies and CAR T cells. Disclosures Wong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Jiménez Nuñez:CITRE, a Bristol-Myers Squibb Company, Spain: Current Employment. Bauer:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Ramasamy:Takeda: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Trudel:Pfizer: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Takeda, Karyopharm, AstraZeneca, Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Mateos:EDOMundipharma: Consultancy; Adaptive: Consultancy; Pharmamar: Consultancy; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Rodriguez-Otero:Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Lonial:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Merck: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Takeda: Consultancy, Other: Personal fees, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; JUNO Therapeutics: Consultancy; Millennium: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Personal fees; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria. Popat:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Berdeja:Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Bluebird: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Vivolux: Research Funding; Kesios: Research Funding; Karyopharm: Consultancy; Glenmark: Research Funding; Genentech, Inc.: Research Funding; EMD Sorono: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Teva: Research Funding; Acetylon: Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Pierce:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Hematopoietic cell transplantation (HCT) is the only potential curative option for many advanced hematologic diseases. Pediatrics, adolescent and young adult (PAYA) patients overall have less pre-HCT comorbidity or organ toxicity and lower transplant related morbidity and mortality risk compared to older adults. As such, a higher percentage of patients in this age group tend to receive myeloablative conditioning (MAC) over non-myeloablative regimens. Current alternative donor sources when a matched sibling donor (MSD) is not available include matched unrelated (MUD), umbilical cord blood (UCB), and haploidentical (Haplo) donors. While there are accumulating data comparing the HCT outcomes between MUD vs. Haplo or UCB in adult patients, the data are sparse in PAYA patients. In this retrospective study, we reviewed 314 consecutive patients aged 1-39 years who underwent their first allogeneic HCT using MAC at City of Hope between 1/2005-7/2018. Patients who received HCT from a matched sibling donor were excluded. Patients received HCT from either an 8/8 HLA MUD (n=196 [BM= 27%, PBSC= 73%]), UCB (n=83 [single: n=30, double: n=53]) or Haplo (n=35) donor. The most used MAC regimens were fractionated total body irradiation-based (n=234, 74%). All Haplo recipients got post-HCT cyclophosphamide (PTCy) as GVHD prophylaxis. To adjust for the difference in transplant era between UCB (predominantly performed in earlier years) and Haplo (carried out predominantly in more recent years) the comparative analyses were focused on Haplo or UCB vs. MUD. Univariate and multivariable Cox regression models were used to assess the impact of patient, disease, and treatment factors on overall survival (OS), progression-free survival (PFS), relapse/progression (RP), and non-relapse mortality (NRM). Median age of patients at the time of HCT was 24 years (range: 0.7-39), with 55% of patients being male. KPS was ≥80% in 88% of the patients and 25% had HCT-CI ≥ 2. The most common diagnoses included: ALL (48%), AML (41%), and MDS/CML (11%). DRI was high/very high in 44% of patients. Groups were balanced in general but patients in the Haplo group had higher HCT-CI (median: 2, p Neutrophil engraftment was achieved at a median of 23 days (range: 10-94) in the UCB, 16 days (range: 12-32) in the Haplo and 15 days (range: 10-33) in the MUD (p In conclusion, our results indicated that in PAYA patients without a suitable MSD, outcomes of Haplo HCT are comparable to MUD HCT. By univariate analysis, UCB HCT was associated with a lower relapse rate compared to MUD. However, survival was worse in recipients of UCB HCT due to the higher NRM, possibly resulted from more infections and engraftment delays in these patients. Figure 1 Disclosures Ali: Incyte Corporation: Consultancy. Nakamura:Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Al Malki:Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy; Rigel Pharma: Consultancy.

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T-cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex vivo and in vivo. In support of Dara's immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

BACKGROUND While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor HCT (2005-2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range = 2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95% confidence interval [CI]: 43.0-52.0) and 43.6% (95% CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of nonrelapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% versus 50.7% at 5 y; P = 0.034), primarily due to greater risk of NRM (33.5% versus 21.7%; P = 0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% versus 12.8%; P = 0.022) and infection (33.0% versus 18.1%; P < 0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (hazard ratio [HR] = 2.21, 95% CI: 1.16-4.23; P < 0.01) and mMUD (HR = 1.55, 95% CI: 1.15-2.08; P = 0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.

Context: To reduce infusion duration, fixed-volume infusion of isatuximab (Isa), a CD38 monoclonal antibody, was confirmed to be feasible and safe in the primary analysis. Objective: Evaluate efficacy and safety of a fixed-volume infusion of Isa plus pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma (RRMM). Design: This two-part, Phase 1b study ( NCT02283775 ) enrolled RRMM patients who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, and who demonstrated disease progression. Part A was an Isa dose-escalation study. In Part B, Isa (10 mg/kg) was administered as a fixed infusion volume of 250 mL (mL/h infusion rate) with standard doses of Pd. The primary endpoint for Part B was incidence of Grade (Gr) ≥3 infusion reactions (IRs) during the first 6 Isa infusions. Secondary endpoints included duration of infusion, safety, efficacy, and immunogenicity. Results: Of 47 patients enrolled in Part B, 22 (47%) remained on treatment at data cut-off. Patients were heavily pretreated, with a median of 3 prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks (range, 1–77). IRs were reported in 19/47 (40%) patients, all Gr 2, and occurred only during first infusion. Median duration of the first, second and ≥3 infusions was 3.7, 1.8, and 1.2 hours, respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE). The most common non-hematologic TEAEs were fatigue (64%), IRs, cough, and upper respiratory tract infection (40% each); 6 patients (13%) died within 30 days of final study treatment. The overall response rate was 53% in all patients. Median time to first response was 0.95 months (range, 0.9–3.4). At a median duration of 9.9 months follow-up (range, 0–17.3), median duration of response, progression-free survival, and overall survival were not reached. Conclusions: Efficacy and safety findings were consistent with Part A of this study and the pivotal Phase 3 ICARIA study. Measurements of response were robust. There were no Gr ≥3 IRs, and all occurred during first infusion. These results confirm the safety, efficacy, and feasibility of Isa administered by a fixed infusion volume. Funding for this study was provided by Sanofi.

Multiple myeloma (MM), an incurable cancer of the bone marrow plasma cells, is a second most common hematological malignancy. While considerable progress has been made towards treatment of MM, the 5-year survival rate continues to hover around 50%. In this study, we aimed to evaluate the capacity of the Reconstructed Bone (r-Bone) model to predict clinical outcomes in patients with multiple myeloma. The r-Bone system incorporates cellular (hematopoietic and stromal) and extracellular (extracellular matrix and secretory factors) components, supports long-term survival (>30 days) and proliferation, and maintains cellular heterogeneity of the primary human bone marrow. The 1-to-1 reconstruction of the bone marrow architecture established by the r-Bone platform provides an ideal in vitro system to evaluate the efficacy of anti-myeloma agents to select those with highest probability of clinical success. Bone marrow aspirates collected from 21 patients with multiple myeloma were processed and set-up in r-Bone cultures. To establish the correct bone marrow architechture, cultures where grown for 5 days, after which the cells were treated according to the clinical regimen selected by the treating physician based on the orginal bone marrow aspirate. Subsequently, cells were isolated from the r-Bone and processed for flow cytometry. Plasma and non-plasma cell populations were evaluated post-treatment and the extent of cell death was correlated with the observed clinical response. r-Bone cultures correctly predicted the outcome of 19 out of 21 cases with 8 true positivies, 11 true negatives, and 2 false positives. This data demonstrate that the r-Bone system could be used for pipeline attrition management to select drug candidates with the highest probability of clinical success and can be developed into a prognostic tool for the selection of treatment regimen for patients with multiple myeloma. Citation Format: Julia Kirshner, Amrita Kirshnan, Nitya Nathwani, Myo Htut, Michael Rosenzweig, Chatchada Karanes, Sahebi Firoozeh, Steven Rosen. Reconstructed Bone (r-Bone): A patient-derived 3D culture platform for prediction of clinical outcomes in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 330.

This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.

8531 Background: CC-92480 is a novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a first-in-human phase 1 study (NCT03374085) in RRMM patients (pts). In preclinical studies, CC-92480 demonstrated efficient and sustained degradation of Ikaros/Aiolos leading to broad antiproliferative effects and induction of apoptosis in MM cell lines, and enhanced immune stimulatory effects. Methods: Eligible RRMM pts received escalating doses of CC-92480 + dexamethasone. Several dosing schedules were evaluated in parallel; more continuous with 4-day or 7-day breaks and intensive with longer breaks in a 28-day cycle. Peripheral blood and bone marrow aspirates (BMA) were taken before and during treatment at multiple time points. Levels of Ikaros/Aiolos in T cells, and effects on immunomodulation were assessed by flow cytometry. Weekly levels of free light chain (sFLC) and B-cell maturation antigen (sBCMA) were determined in serum during the first 2 cycles of treatment. BMA clots were analyzed by immunohistochemistry for CRBN, Ikaros, Aiolos, ZFP91, c-Myc, and IRF-4. Results: The rate and depth of Ikaros/Aiolos degradation in T cells increased with dose and reached maximal at ≥0.6 mg QD with sustained degradation over 24 hrs. Substrate recovery occurred during drug holidays with faster recovery at lower doses, and reached full recovery with ≥7-day break for all dose levels tested. B cells decreased with increasing dose, and T-cell proliferation was demonstrated at all doses/schedules. Substrate degradation was also evident in bone marrow plasma cells including in the setting of low CRBN levels. In these heavily pretreated, including triple-class-refractory, RRMM pts, CC-92480 dosing periods led to rapid and sustained decreases in sFLC and sBCMA. This was dose and schedule dependent and correlated with plasma exposure; the longer breaks in the intensive schedules led to rapid rebound of these markers, while the more continuous schedules maintained the depth of suppression. Conclusions: PD responses correlated with dose and schedule. PD samplings at multiple time points during treatment allowed dynamic changes and kinetics of each biomarker in all schedules to be followed and to inform next steps. Ikaros/Aiolos degradation and recovery, coupled with changes in sFLC and sBCMA, guided the adjustment of the dosing schedule during dose escalation in order to optimize efficacy and tolerability. The study is ongoing and selection of the recommended phase 2 dose is pending.

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .

Background/objectives Caregivers of older adults with cancer assist both with cancer care and other health issues, which may make them vulnerable to consequences of caregiving. Hospitalization may represent a time when a caregiver's ability to provide care at home is exceeded. We sought to characterize caregivers of hospitalized older adults with cancer, determine their quality of life (QOL), and identify factors associated with caregiver QOL. Methods Patients (n = 100), aged 65 years and older, with an unplanned hospitalization and their caregivers were included. Caregivers completed a questionnaire about their health, social support, caregiving relationship, QOL (Caregiver Quality of Life Index-Cancer [CQOLC] tool), and patient function. Patient medical history was obtained via chart review. The association between patient, caregiving, and caregiver factors and CQOLC was determined using multivariate linear regression. Results Most patients (73%) had metastatic/advanced disease, and 71% received treatment for their cancer within 30 days of hospitalization. Median Karnofsky Performance Status (KPS) was 60%, and 89% required help with instrumental activities of daily living, as reported by caregivers. Median caregiver age was 65 years (range = 29-84 years). The majority (60%) had no major comorbidities and rated their health as excellent/good (79%), though 22% reported worsening health due to caregiving. Caregivers had a median Mental Health Inventory-18 score of 70 (range = 0-97), a median Medical Outcomes Study (MOS)-social activity score of 56 (range = 0-87.5), and a median MOS-Social Support Survey score of 68 (range = 0-100). Caregivers provided a median of 35 hours of care per week (range = 0-168 hours of care per week). Mean CQOLC was 84.6 ± 23.5. Lower caregiver QOL was associated with poorer caregiver mental health, less social support, and poorer patient KPS (P Conclusion Caregivers of hospitalized older adults with cancer are older but generally in good health. Those with poorer mental health, less social support, and caring for patients with poorer performance status are more likely to experience lower QOL. J Am Geriatr Soc 67:978-986, 2019.

Background Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders, and expands transplant options for a racially/ethnically diverse population, who are often unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that all unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). Methods To allow continued access to unlicensed UCB units, the National Marrow Donor Program® (NMDP) manages a prospective distribution protocol for unlicensed UCB units, under an IND, 10-Cord Blood Access. This is an interim report of outcomes of 2466 US patients receiving unlicensed UCB units from 2011-2016. Of note, only 6% of available UCB units were licensed by December 2016. Results 1509 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December 2016. Median age was 31 years ( Conclusions Use of unlicensed UCB units is safe and effective, and provides an important graft source for a diverse population.

Summary Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80–96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51–76) and 36% (95%CI: 24–49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26–52), and the 3-year relapse incidence was 11% (95%CI: 4–21). With a median 37-month (range 23–71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37–63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

Introduction: 18Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and non-malignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with copper-64 via the chelator DOTA (64Cu-DOTA-Dara), led to improved sensitivity and specificity over that of FDG (Caserta et al, Blood 2018). Herein, we report the results of a Phase 1 trial (NCT#03311828) designed to 1) assess the safety and feasibility of 64Cu-DOTA-Dara PET/CT and 2) to evaluate and characterize the ability of 64Cu-DOTA-Dara to accurately detect or exclude MM lesions compared with FDG PET/CT. Methods: Patients with biopsy-proven MM and/or a plasmacytoma received an FDG PET/CT scan within 60 days of enrollment. On Day 0, patients were infused with unlabeled ("cold") Dara at one of four dose levels (0 mg, 10 mg, 45 mg, 95 mg) to optimize biodistribution of radioconjugated 64Cu-DOTA-Dara, especially in the liver and the spleen. Within 6 hours of unlabeled Dara administration, patients received 64Cu-DOTA-Dara at a dose of 13.63-16.68 mCi (~5 mg). Whole-body PET scans were obtained at 24 hours and at 48 hours (the latter scan encompassing known tumors). 64Cu-DOTA-Dara standardized uptake values (SUV) were evaluated in MM lesions and normal organs, which were then compared with values from standard FDG PET/CT. Biopsies were performed on accessible discordant lesions. Results: A total of 10 Dara-naïve patients were imaged. Patients were treated with 0 (n=3), 10 (n=3), 45 (n=3), or 95 mg (n=1) of unlabeled Dara. Four patients had newly diagnosed disease, one had biochemical relapse, one had a recurrent plasmacytoma by MRI, and four had possible recurrence by standard PET/CT. No significant adverse events were observed from either cold or 64Cu-DOTA-Dara. With the exception of the one patient with a recurrent plasmacytoma, radiolabeled antibody was eliminated from systemic circulation in subjects analyzed at the first three dose levels within 30 min post injection. In the patient with a recurrent plasmacytoma, the radiolabeled antibody was elevated in the blood for over two days. One newly diagnosed patient had extensive disease by FDG PET and had a biopsy-proven target lesion in the sternum, which had an SUVmax of 14.7 on 64Cu-DOTA-Dara PET/CT vs. 3.3 onFDG PET/CT. A second biopsy from the same patient was taken from a discordant iliac crest lesion (positive for 64Cu-DOTA-Dara but negative for FDG PET/CT) that showed 20-30% MM cell infiltration. In another patient, an iliac crest lesion was 64Cu-DOTA-Dara positive and FDG-negative; biopsy revealed 6% plasmacytosis in the bone. A third patient had an FDG PET/CT positive pleural lesion with an SUVmax of 8.98 and negative on 64Cu-DOTA-Dara (Figure 1A). The lesion did not show recurrence upon biopsy. Furthermore, 64Cu-DOTA-Dara PET/CT yielded superior imaging of bone lesions in the calvarium (Figure 1B). Escalating doses of unlabeled Dara decreased liver and spleen uptake by 64Cu-DOTA-Dara. Conclusions: In this ongoing study, 64Cu-DOTA-Dara PET/CT imaging is to date safe and provides whole body imaging of MM. Further dose escalation of cold Dara (145 mg, 195 mg) is planned to optimize background interference. This modality has the potential to improve sensitivity and specificity over FDG PET/CT scanning in early-stage MM as well as in recurrent disease. Disclosures Krishnan: Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau; Celgene, Z Predicta: Other: Stock Ownership; Takeda: Research Funding. Palmer:Gilead Sciences: Consultancy. Rosenzweig:Celgene, Takeda: Speakers Bureau. Wu:ImaginAb, Inc.: Consultancy, Other: Board Member.

Background: Based on pilot study data demonstrating safety and excellent survival [Blood 2014 124:46] in acute leukemia patients undergoing myeloablative cord blood transplant (CBT) plus infusion of an off-the-shelf non-HLA matched expanded CB unit (OTS) for bridging hematopoiesis, a randomized trial was conducted to determine whether myeloablative CBT with or without an OTS would confer more rapid neutrophil (ANC) engraftment and therefore a survival advantage. Methods: We conducted a multi-center, randomized controlled phase II trial (RCT) with a primary endpoint of ANC engraftment defined as the first of 2 consecutive days in which neutrophil count ≥ 500 cells/μL. Secondary endpoints included platelet engraftment, overall survival (OS), disease free-survival (DFS), acute/chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), and relapse. 160 patients were enrolled between February 2013 and June 2018. Patients were randomized to receive either a conventional single or double CBT (SOC group) (n=78) or SOC + OTS (OTS group) (n=82). Unmanipulated CB units had to be at least 4/6 HLA-matched to the patient (intermediate resolution for HLA-A, -B and allele-level for HLA-DRB1) with no HLA matching required for the OTS. Patient disease (AML=68, ALL=77, MDS=7, CML/other=8), disease risk, gender, age, race, ethnicity, CMV serology, performance score and HLA-match were balanced between the two study groups. Patients received conditioning with either FLU 75mg/m2, TBI 13.2 Gy, CY120 mg/kg or with FLU 150mg/m2, TBI 4Gy, CY 50 mg/kg and Thiotepa 10 mg/kg. Cyclosporin and MMF were used for GVHD prophylaxis in all patients (Table 1). Results: The median follow-up of surviving patients was 15 months. Approximately 30% of patients enrolled were Conclusion: In this multi-center RCT, no significant difference was observed in the primary or secondary endpoints. Importantly, while the median time to ANC recovery in the OTS group was unchanged (20 days) from our pilot study, the observed time to neutrophil recovery in the SOC group was 7 days quicker than expected based on previously observed outcomes following myeloablative CBT (median 26 days). During the 5 years that this study was open to accrual, the criteria for CB donor selection have improved, now regularly utilizing CD34+ cell content and high-resolution HLA-typing where available, as has the quality of the CB inventory. This RCT highlights that delayed engraftment should no longer be a barrier in the consideration of SOC CBT for patients with hematological malignancies. As expected, and observed consistently following CBT, both groups demonstrated low incidence of severe acute GVHD and relapse at 2 years. Interventions in CBT should focus on improving immune reconstitution and reducing the risk of NRM but must be easily adopted into SOC in order to be adopted clinically. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson & Johnson: Employment, Other: Brother is employed. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees.

We have previously reported that cytarabine/daunorubicin as well cytarabine/idarubicin can be safely combined with crenolanib at the full monotherapy dose (100mg TID) and administered throughout induction, consolidation and maintenance in newly diagnosed FLT3-mutated AML (Walter et al., EHA 2018). We hypothesize that crenolanib plasma levels might correlate with long term outcome in these patients. Methods: Twenty-seven newly diagnosed AML patients with FLT3 mutations, aged 18-60 years old enrolled in a phase II study of crenolanib combined with chemotherapy (NCT02283177) were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 90 mg/m2 (n=16) or idarubicin 12 mg/m2 (n=11) for 3 days. Crenolanib 100 mg TID was administered continuously starting 24-48 hours after induction until 72 hours prior to the next chemotherapy cycle. Consolidation could consist of up to four cycles of high-dose cytarabine (HiDAC): 3 g/m2 for < 60 years and 1 g/m2 for 60 years) q12 hours on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose in each cycle. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Crenolanib levels (total and free) were measured 2-4 hours following the first dose of crenolanib and after two weeks of continuous crenolanib administration. Crenolanib levels were also measured on first day of crenolanib treatment following HiDAC consolidation. Free crenolanib was measured by rapid equilibrium dialysis. Durability of clinical remissions were documented by routine follow up every 3-4 months (as per institutional practice). Results: As of July 2019, all patients have completed all protocol therapy (one patient has continued crenolanib maintenance for 25 months per patient request). Twenty-three of 27 patients (85%) achieved complete remission, all of whom required only 1 cycle of induction chemotherapy. Nineteen of 27 patients remain alive and free of disease with a median follow-up of 29.3 months (Figure 1). Three relapses have occurred, all within the first year of treatment and no relapses have occurred in patients who completed at least 1 cycle of crenolanib maintenance. Seven patients received HiDAC consolidation along with crenolanib but did not receive HSCT. Six of these patients remain in long term remission. While the number of patients is small, we observed similar overall survival and cumulative incidence of relapse in patients who underwent HSCT as compared to those who did not (Figure2). Pharmacokinetic studies demonstrate that despite increases in acute phase reactants and AGP levels, both total and free crenolanib rapidly achieve sufficient levels to provide the continuous inhibition required to eradicate FLT3-ITD, FLT3-D835, and other FLT3 mutations including FLT3-N841, A680, V592, V491, and D839. Total levels of crenolanib exceeded 500 nM at steady state, and the majority of patients showed clearance of FLT3 mutations after combination therapy. Summary/Conclusion: These pharmacokinetic data show that crenolanib when given with chemotherapy can achieve sufficient levels to inhibit multiple FLT3 mutations, despite rises in FLT3 ligand and acute phase reactants. These clinical data suggest that this combination might improve outcomes in younger patients with newly diagnosed FLT3-mutant AML. With 29 months median follow up, median overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) have not been reached. No relapses have been observed in patients after completing crenolanib maintenance. A phase III randomized multicenter trial has been initiated to compare the efficacy of crenolanib versus midostaurin combined with standard chemotherapy for newly diagnosed patients with FLT3-mutant AML (NCT03258931). Figure Disclosures Goldberg: Abbvie: Research Funding; ADC Therapeutics: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Arog Pharmaceuticals: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Research Funding; DAVA Oncology: Honoraria; Abbvie: Consultancy; Celgene: Consultancy. Coombs:Abbvie: Consultancy; Covance: Consultancy; Dedham Group: Consultancy; H3 Biomedicine: Honoraria; Cowen & Co.: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria; Loxo: Honoraria; Medscape: Honoraria. Wang:Kite: Other: Advisory role; Abbvie: Other: Advisory role; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Walter:Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. Messahel:Arog Pharmaceuticals: Employment. Stone:Astellas: Consultancy; Biolinerx: Consultancy; Arog: Consultancy, Research Funding; Trovagene: Consultancy; Macrogenics: Consultancy; Argenix: Other: DSMB; Argenix: Other: DSMB; Otsuka: Consultancy; Takeda: Other: DSMB; Trovagene: Consultancy; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Pfizer: Consultancy; Jazz: Consultancy; Roche: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Stemline: Consultancy; Biolinerx: Consultancy; Pfizer: Consultancy; Astra-Zeneca: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Biosight: Consultancy; Arog: Consultancy, Research Funding; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Roche: Consultancy; Argenix: Other: DSMB; Macrogenics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biosight: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Other: DSMB; Astellas: Consultancy; Agios: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Trovagene: Consultancy; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy.

CMVi leads to significant morbidity in R+ HCT and preemptive therapy (PET) has been the standard of care. LTV was FDA-approved in Nov. 2017 for CMVi prevention in R+ HCT. Besides the clinical trials, there is are real world data on LTV. Upon IRB approval, we retrospectively studied consecutive R+ HCT pts with their first HCT between 1/1/2017 and 6/30/2018. LTV group included pts with HCT between 2/20/18 and 6/30/2018, who had LTV Px started within 28 days of HCT (n=59), and R+ HCT between 1/1/2017 and 2/19/2018 (n=307) served as control (ctrl). We compared CMVi rates in first 100 days of HCT, and time to engraftment between the 2 groups. Risk stratification: high risk - haplo/cord HCT & ATG use, low risk - all others. CMVi was defined as viral load (VL) of 625 IU/ml to 1250 IU/ml or higher (CMV assay conversion factor of 1 genomic copy/ml = 2.5 IU/ml). CMV VL less than 625 IU/ml is reported negative, VL between 625 and 1250 IU/ml is qualitative positive but numeric value is provided only for VL ≥ 1250 IU/ml. PET was recommended for VL >1250 IU/ml (500 copies/ml) in high risk and > 3750 IU/ml (1500 copies/ml) in low risk HCT (including those on LTV requiring PET). Descriptive statistics was done for baseline characteristics. Cumulative incidence curves were generated for CMVi within 100 days post-HCT and Gray's test was used to compare the difference between the 2 groups. In both groups, median age was 54 years and HCT indications were similar. Donor type in LTV/ Ctrl groups: MRD (27 vs 36%), MUD (44 vs 47%), haplo (27 vs 15%), cord (1.7 vs 1.6%). PBMC was graft source in 90% of both groups. Myeloablative conditioning: 40.7% in LTV and 35% in Ctrl. GVHD Px: Cellcept (32 vs 25%), methotrexate (7 vs 9%), tacro/siro (58 vs 65), and others (3.4 vs 0.3%) in LTV & Ctrl respectively. A majority (n=36) received both intravenous & oral LTV formulation while 23 received oral only. Median time from HCT to LTV start was 13 days (range: 4-26). LTV group had significant reduction in CMVi rate (22.4% [95%CI: 12.7-34.0]) compared with ctrl group (41.1% [95%CI: 35.4-46.7], p=0.008, Fig 1). In a subgroup of high-risk HCT LTV was significantly reduced CMVi rate (22.2%) compared with ctrl (62.8%, p=0.004, Fig 2) while statistical difference was not reached in low-risk HCT pts (22.8% vs. 35.6%, p=0.11). In the LTV Px, clinically significant (CS)-CMVi requiring PET occurred in 8.4% (n=5) and on excluding 2 pts who were not on LTV at the time of CMVi, the rate was 5% (Fig 1). CMVi cleared without PET in 8/13 LTV pts and LTV was continued; all pts had VL LTV use in a real world setting is associated with significant reduction of CMVi and CS-CMVi without any discernible myelosuppression. The low level CMVi resolved spontaneously in majority with continued LTV Px and PET was not necessary. The high-risk HCT had most benefit with LTV Px.

Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.

Purpose: The goal of this study was to evaluate the feasibility, reliability, and validity of a computer-based geriatric assessment via two methods of electronic data capture ( SupportScreen and REDCap) compared with paper-and-pencil data capture among older adults with cancer. Methods: Eligible patients were ≥ 65 years old, had a cancer diagnosis, and were fluent in English. Patients were randomly assigned to one of four arms, in which they completed the geriatric assessment twice: (1) REDCap and paper and pencil in sessions 1 and 2; (2) REDCap in both sessions; (3) SupportScreen and paper and pencil in sessions 1 and 2; and (4) SupportScreen in both sessions. The feasibility, reliability, and validity of the computer-based geriatric assessment compared with paper and pencil were evaluated. Results: The median age of participants (N = 100) was 71 years (range, 65 to 91 years) and the diagnosis was solid tumor (82%) or hematologic malignancy (18%). For session 1, REDCap took significantly longer to complete than paper and pencil (median, 21 minutes [range, 11 to 44 minutes] v median, 15 minutes [range, 9 to 29 minutes], P < .01) or SupportScreen (median, 16 minutes [range, 6 to 38 minutes], P < .01). There were no significant differences in completion times between SupportScreen and paper and pencil ( P = .50). The computer-based geriatric assessment was feasible. Few participants (8%) needed help with completing the geriatric assessment (REDCap, n = 7 and SupportScreen, n = 1), 89% reported that the length was “just right,” and 67% preferred the computer-based geriatric assessment to paper and pencil. Test–retest reliability was high (Spearman correlation coefficient ≥ 0.79) for all scales except for social activity. Validity among similar scales was demonstrated. Conclusion: Delivering a computer-based geriatric assessment is feasible, reliable, and valid. SupportScreen methodology is preferred to REDCap.

We analysed the long-term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu-mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high-dose melphalan conditioning for autograft followed by low-dose total body irradiation conditioning for allogeneic HCT (auto-allo regimen). Donors included human-leucocyte-antigen-matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow-up of 9·8 years, 7-year overall survival (OS) and progression-free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft-versus-host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post-transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.

BACKGROUND: Unrelated cord blood (CB) is an important stem cell source for unrelated hematopoietic cell transplantation (HCT) of patients with nonmalignant disorders. Processing methods to prepare red blood cell–reduced CB units incur significant nucleated cell loss. In contrast, plasma depletion or reduction (PDR) processing of CB units entails the removal of only a portion of the plasma with minimal nucleated cell loss. However, there are relatively limited data regarding outcomes of CB transplants using units processed by PDR. STUDY DESIGN AND METHODS: A Center for International Blood and Marrow Transplant Research (CIBMTR)-audited analysis was performed on 120 pediatric patients with nonmalignant disorders transplanted between November 2001 and January 2008 at 29 US and 17 international centers using PDR CB units from two CB banks. RESULTS: Transplant characteristics were as follows: median age, 3.5 years (range, 0.1-14 years); median patient weight, 15 kg (range, 4-61 kg); 58% male; HLA matches (intermediate-resolution HLA-A and HLA-B and high-resolution HLA-DRB1) of the units used in these patients six of six in 26, five of six in 48, four of six in 47, and three of six or two of six in 6; median prefreeze total nucleated cell dose, 10.5 × 107/kg; median prefreeze CD34+ dose, 3.7 × 105/kg; and nonmyeloablative regimen in 24%. The median times to myeloid and platelet engraftment were 21 and 49 days, respectively. The cumulative incidence of reported Grade II to IV acute graft-versus-host disease (aGVHD) was 38 ± 5%, and 19 ± 4% had Grade III to IV aGVHD. The Kaplan-Meier estimates of 3-year transplant-related mortality, overall survival, and disease-free survival were 20 ± 4, 79 ± 4, and 70 ± 6%, respectively. CONCLUSION: These data demonstrate the effectiveness of PDR CB units for HCT.

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Purpose: To establish feasibility, maximum tolerated dose (MTD), and potential efficacy of ablative dose total marrow irradiation (TMI) delivered by helical tomotherapy in patients with multiple myeloma (MM). Experimental Design: Patients with responding or stable MM received tandem autologous stem cell transplants, first with melphalan 200 mg/m2, and 60 days or later with TMI. TMI doses were to be escalated from 1,000 cGy by increments of 200 cGy. All patients received thalidomide and dexamethasone maintenance. Results: Twenty-two of 25 enrolled patients (79%) received tandem autologous stem cell transplantation (TASCT): TMI was administered at a median of 63.5 days (44–119) after melphalan. Dose-limiting toxicities at level 5 (1,800 cGy) included reversible grade 3 pneumonitis, congestive heart failure, and enteritis (1), and grade 3 hypotension (1). The estimated median radiation dose to normal organs was 11% to 81% of the prescribed marrow dose. Late toxicities included reversible enteritis (1), and lower extremity deep venous thrombosis during maintenance therapy (2). The complete and very good partial response rates were 55% and 27% following TASCT and maintenance therapy. At a median of 35 months of follow-up (21–50+ months), progression-free and overall survival for all patients were 49% (95% CI, 0.27–0.71) and 82% (0.67–1.00). Conclusion: Ablative dose TMI as part of TASCT is feasible, and the complete response rate is encouraging. Careful monitoring of late toxicities is needed. Further assessment of this modality is justified at the 1,600 cGy MTD level in MM patients who are candidates for ASCT. Clin Cancer Res; 17(1); 174–82. ©2010 AACR.