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7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.

7024 Background: Mutations in the FLT3 tyrosine kinase are the most frequent ones that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3/8 IDHm patients (pts) responded. Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 pts with R/R IDHm AML. Methods: Pts with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety; adverse events (AEs) were graded according to NCI-CTCAE v4.03. The secondary endpoint was anti-leukemic activity including overall response rates (ORR). Results: As of 10 Jan 2022, 14 pts were enrolled in the IDHm cohort. Median age was 68 years (range 37-79). Four pts had AML secondary to myelodysplastic syndrome and 7 pts had intermediate cytogenetic risk. The median number of prior lines was 2 (range 1-3). Seven pts had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3/ITD were detected in 2 pts. Median duration of treatment was 2 cycles (range 1-8). Safety data (N = 12) showed that serious treatment-emergent AEs (TEAEs; ≥5%) were pneumonia (33%), and skin infection and gastroenteritis clostridial (8% each). These were all unrelated to study drug. Drug-related TEAEs were liver injury, overdose, and hyponatremia (8% each). The drug-related liver injury occurred in a pt who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10%) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 pts who completed ≥1 treatment cycle and had ≥1 post-baseline assessment or clear disease progression, ORR was 28.6%; 1 pt achieved CRi at cycle (C) 3 and underwent hematopoietic stem cell transplant, 1 pt had PR at C4 (confirmed at C7 and still on treatment), 4 had disease progression, 1 discontinued for AE not drug-related. Among the 7 remaining pts, 3 discontinued before completion of C1 without progression or response, while 4 pts were ongoing and have not yet had any post-baseline assessment. Conclusions: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first in class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in pts with R/R IDHm AML. Updated results will be presented at the congress. Clinical trial information: NCT03008187.

Acute myeloid leukemia (AML) is a heterogeneous disease with variable clinical outcomes. Cytogenetic analysis reveals which patients may have favorable risk disease, but 5-year survival in this category is only approximately 60%, with intermediate and poor risk groups faring far worse. Advances in our understanding of the biology of leukemia pathogenesis and prognosis have not been matched with clinical improvements. Unsatisfactory outcomes persist for the majority of patients with AML, particularly the elderly. Novel agents and treatment approaches are needed in the induction, post-remission and relapsed settings. The additions of clofarabine for relapsed or refractory disease and the hypomethylating agents represent recent advances. Clinical trials of FLT3 inhibitors have yielded disappointing results to date, with ongoing collaborations attempting to identify the optimal role for these agents. Potential leukemia stem cell targeted therapies and treatments in the setting of minimal residual disease are also under investigation. In this review, we will discuss recent advances in AML treatment and novel therapeutic strategies.

Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.

Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. However, the risk of VTE among patients undergoing hematopoietic stem cell transplantation (HSCT) is unclear. We examined the incidence and risk factors for VTE and bleeding among 1514 patients undergoing in-patient HSCT. No protocolized VTE prophylaxis was used. By HSCT day 180, 75 symptomatic VTE occurred in 70 patients (4.6%; 95% confidence interval [CI], 3.6%-5.8%). Fifty-five (3.6%) were catheter-associated, 11 (0.7%) were non–catheter-associated deep venous thromboses, and 9 (0.6%) were pulmonary emboli. Thirty-four percent of VTE occurred at a platelet count less than 50 ×109/L; 13% occurred at a platelet count less than 20 ×109/L. In multivariate analysis, VTE was associated with prior VTE (odds ratio [OR], 2.9; 95% CI, 1.3-6.6) and with graft-versus-host disease (GVHD; OR, 2.4; 95% CI, 1.4-4.0). Clinically significant bleeding occurred in 230 patients (15.2%; 95% CI, 13.4%-17.1%); 55 patients (3.6%; 95% CI, 2.7%-4.7%) had fatal bleeding. Bleeding was associated with anticoagulation (OR, 3.1; 95% CI, 1.8-5.5), GVHD (OR, 2.4; 95% CI, 1.8-3.3), and veno-occlusive disease (OR, 2.2; 95% CI, 1.4-3.6). In HSCT patients, VTE is primarily catheter-related and 3-fold less common than clinically significant bleeding. These findings warrant consideration when selecting VTE prophylaxis in HSCT patients.

7002 Background: Serial studies have demonstrated that induction therapy with flavopiridol (50 mg/m2 days 1-3), a multi-serine-threonine cyclin-dependent kinase inhibitor, followed by cytarabine (6...

Introduction: Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. It is unclear whether patients undergoing hematopoietic stem cell transplantation (HSCT) are at risk for VTE. We aimed to describe the incidence of VTE and risk factors among patients undergoing HSCT. Methods: Using ICD-9 procedure codes in a discharge database, we identified all patients undergoing inpatient HSCT at Johns Hopkins between July 1, 1993, and June 30, 2005. We reviewed electronic medical records for each patient to identify VTE and bleeding. The associations between VTE and clinical characteristics were tested using parametric and non-parametric statistical tests and survival analysis methods. Results: 1,570 patients had 3,425 person-years of follow-up. Median age was 46 years and 51% of patients were male. All patients had indwelling central venous catheters; pharmacological VTE prophylaxis was not used for any patient but ambulation was encouraged. Between admission and 180 days after HSCT, 75 VTE occurred in 70 patients (4.5%; 95% CI, 3.5–5.6%). VTE included 55 (73%) catheter-associated and 11 (15%) non-catheter-associated deep venous thromboses (DVT), and 9 (12%) pulmonary emboli (PE). Median platelet count at time of VTE was 77 K/mm3 (interquartile range [IQR] 42–159 K/mm3), and platelet count was < 50 K/mm3 at the time of VTE in 31% of cases. In multivariate analyses, VTE was associated with a history of prior VTE (OR 2.86; 95% CI, 1.25–6.55) and with graft-versus-host-disease (GVHD) (OR 2.36; 95% CI, 1.38–4.04). 86% of patients received anticoagulation for treatment. Clinically significant bleeding occurred in 238 patients after HSCT (15%), of whom 56 patients had fatal bleeding. Bleeding was associated with GVHD (OR 2.32; 95% CI, 1.71–3.16) and with initiation of anticoagulation for VTE diagnosed after HSCT (OR=3.00; 95% CI, 1.73–5.21). Bleeding was not associated with the continuation of anticoagulation initiated prior to admission (OR=1.13; 95% CI, 0.54–2.35). Conclusions: VTE occurs relatively infrequently among patients undergoing HSCT and primarily in association with central venous catheter use. In contrast, clinically significant bleeding is a relatively common complication of HSCT, even in the absence of pharmacologic VTE prophylaxis. The unique hemostatic milieu associated with HSCT should be carefully considered when contemplating routine VTE prophylaxis in this patient population. The low risk of VTE associated with the high risk of bleeding makes pharmacologic VTE prophylaxis in this population both unnecessary and hazardous.

Cytomegalovirus (CMV) disease remains an important complication of allogeneic stem cell transplantation (SCT). A major goal has been to develop bone marrow transplant (BMT) preparative regimens that minimize the duration of post-transplantation immunosuppression, and thus the risk of severe infectious complications. Previously, we reported a low rate of CMV reactivation (17.6%, 6/34 eligible patient-donor pairs) among hematologic malignancies patients receiving partially HLA-mismatched (haploidentical) BMT after non-myeloablative conditioning including high dose, post-transplantation Cy (50 mg/kg IV on days 3 and 4). Here, we have retrospectively analyzed an additional 99 recipients of post-transplantation Cy after fludarabine/200 cGy TBI-based nonmyeloablative conditioning and haploidentical BMT (n=44) or busulfan/Cy-based myeloablative conditioning and HLA-matched BMT (n=55). After high-dose Cy, patients undergoing haploidentical BMT received mycophenolate mofetil and tacrolimus, while recipients of HLA-matched grafts received no further graft-versus-host disease (GVHD) prophylaxis. Patients did not receive CMV prophylaxis. CMV reactivation, measured weekly by quantitative PCR, occurred in 38.7% (12/31 eligible donor-patient pairs) in the mini-haploBMT trial and 31% (13/42 eligible patient donor pairs) in the myeloablative trial. CMV reactivation occurred twice in two patients in each trial. CMV disease occurred in two patients in the haploidentical BMT trial (1 retinitis, 1 pneumonia) but in no recipients of HLA-matched grafts. No deaths have been attributed to CMV infection on either trial. In the mini-haplo BMT patients, 58.3% (7/12) of those with CMV reactivation were considered high-risk (recipient CMV IgG positive, donor CMV IgG positive or negative) and 25% (3/12) were considered to be at intermediate risk (recipient CMV IgG negative and donor CMV IgG positive). Of the myeloablative BMT patients, 100% (13/13) of patients with CMV reactivation were part of the high-risk group. In addition to recipient CMV positivity, the presence of graft-versus-host disease (GVHD) was a risk factor for CMV reactivation on the myeloablative trial as 77% (10/13) of patients who reactivated their CMV had GVHD, but not on the “mini-haploBMT” trial where only 41.7% (5/12) had GVHD. The median number of days post-transplant to CMV reactivation was 49 (range 19–197) in the “mini-haploBMT” patients and 56 (range 19–140) in the myeloablative group. The median number of weeks to clear detectable CMV was 1 (range 1–11 in the mini-haploBMT group and 1–4 in the myeloablative group). These rates of CMV reactivation and infection compare favorably to the rates seen in patients receiving haploidentical and HLA-matched grafts following myeloablative conditioning without post-transplantation Cy. The low rates of CMV reactivation may be secondary to low rates of Grade 3–4 GVHD (9.1%, 4/44 “mini-haploBMT patients”; 7.3%, 4/55 myeloablative patients) and rapid immunologic recovery facilitated by the absence of prolonged pharmacologic immunosuppression, especially among recipients of HLA-matched grafts.

Donor vs. recipient natural killer (NK) cell alloreactivity in mismatched (haploidentical) bone marrow transplantation (BMT) has been defined as a mismatch between killer inhibitory receptors (KIR) on donor NK cells and their inhibitory HLA class I ligands on recipient cells. Data reporting the impact of KIR incompatibility in the haploidentical BMT setting have been controversial. Here, we examine the effect of KIR ligand mismatches in 60 patients with advanced hematologic malignancies who were enrolled in a clinical trial of nonmyeloablative haploidentical BMT (“mini-haploBMT”). All patients were conditioned prior to transplantation with fludarabine, low dose cyclophosphamide (Cy), and 200 cGy TBI, and after transplantation received high dose Cy, mycophenolate mofetil (MMF) and tacrolimus. The median age of transplant recipients was 48 years (range, 1–71years). Patients received a median of 1.27x 108/kg mononuclear cells/kg and a median of 3.9 x 106 CD34+ cells/kg. Donor-recipient pairs had an average of 3 out of 8 HLA antigen mismatches in both the host-vs.-graft (HVG) and graft-vs.-host (GVH) directions. Graft failure occurred in 12/58 (21%) evaluable patients, and grade 3–4 GVHD occurred in 7/60 patients (11.7%). Median time to disease progression was 222 days and median overall survival was 255 days. The median follow-up at the time of this analysis was 251 days (range 41–1715 days). KIR mismatches were identified via KIR genotyping (KIR genes determined by SSP from genomic DNA extracts) as well as via the previously described receptor:ligand model which identifies the presence of inhibitory KIR on donor cells, with absence of HLA ligand on host cells. Utilizing the receptor:ligand model, our results demonstrate an improvement in time to relapse (TTR) in patients with ≥1 inhibitory KIR mismatches (32 patients, median TTR 359 days) versus no mismatches (27 patients, median TTR 185 days) (p=0.036) and an improved overall survival (OS) in patients with ≥1 inhibitory KIR mismatches (32 patients, median OS 622 days) versus no mismatches (27 patients, median OS 208 days) (p=0.008). No significant difference in OS or TTR was found when patients were separated by disease type (myeloid versus lymphoid; OS p= 0.095 vs. p=0.1 and TTR p=0.2 vs. 0.1). There were also no significant differences in TTR or OS when using the KIR genotyping method of identifying mismatches. No differences in Grades 2–4 graft-versus-host disease (GVHD) or engraftment were found based on the presence of inhibitory or stimulatory KIR mismatches, although the small numbers of patients with GVHD or engraftment failure prevent a definitive analysis. KIR ligand incompatibility in the GVH direction is associated with a prolonged time to relapse and improved overall survival after nonmyeloablative haploidentical BMT. These findings may warrant the selection of donors based upon KIR ligand incompatibility.

Graft rejection, severe graft-versus-host disease (GVHD), and prolonged immunosuppression are major complications of partially HLA-mismatched, or haploidentical, stem cell transplantation in humans. Intensive conditioning of the recipient and rigorous T cell depletion of the donor graft reduces the risk of the first two complications, but may prolong or intensify post-transplantation immunodeficiency, increasing the patient’s susceptibility to opportunistic infection. In contrast, alloreactive T cells may be selectively eliminated in vivo by the early post-transplantation administration of high dose cyclophosphamide (Cy), leaving virus or other pathogen specific resting memory T cells relatively unharmed. To test this hypothesis, we have analyzed the infectious complications in 60 patients who were enrolled in a clinical trial of nonmyeloablative haploidentical bone marrow transplantation (“mini-haploBMT”) incorporating post-transplantation Cy. All patients received fludarabine 30mg/m2/dose on days -6 to -2, Cy on day -2, and 200 cGy total body irradiation (TBI) on day -1. The first 20 patients received a single dose of 50 mg/kg Cy IV on day 3, whereas the final 40 patients received the same dose of Cy on day 3 and 4. The median age of transplant recipients was 48years (1-71years), 12 patients had 13 prior autologous transplants prior to enrollment, and patients had an average of 2.7 treatment regimens prior to transplant (0–8). Patients received a median of 1.27x 108/kg mononuclear cells/kg with 3.9 x 106 CD34+ cells/kg. The median follow-up at the time of this analysis was 245.5 days (41–1550 days). An ANC >500/mm3 was achieved a median of day 16 (12–208). Only 5 patients (8.3%) died from infectious related causes. Of these, 3 were known to have relapsed disease. There were 34 patient/donor pairs (56.6%) at risk for CMV reactivation. In these pairs, only 6 patients developed CMV reactivation (17.6%), and 2 patients developed CMV infection. 3 patients with CMV reactivation received one dose of post-transplant Cy, and 3 patients received two. Both patients who developed CMV infections received only dose of post transplant Cy. 23% (14/60) of patients developed an invasive fungal infection, of which 21.4% (3/14) developed in the first 30 days post transplant, 14.3% (2/14) developed between days 31–60, 14.3% (2/60) developed between days 61–100, and 50% (7/14) occurred more then 100 days post transplant. 15% (9/60) had at least one systemic viral infection (other then CMV), of which 22.2% (2/9) developed in the first 30 days post-transplant and 77.8% (7/9) developed more then 90 days post transplant. No patients developed viral infections between days 31–100. These rates of infection compare favorably to the rates of infection seen in patients receiving haploidentical grafts following myeloablative conditioning without post-transplantation Cy. We propose that the very low numbers of patients with CMV reactivation, fungal or viral infections, and infectious related mortality is secondary to early engraftment, low rates of Grade 3–4 GVHD (7/60 patients, 11.7%; 5/7 patients received one dose of post-transplant Cy, 2 received two) or prolonged immunosuppression, and an intact host B cell and memory T cell function preserved with this novel prep regimen and T cell replete graft.