Jethava, Yogesh S.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Introduction: Front-line immunochemotherapy (IC) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is expected to cure 60-70% of newly diagnosed DLBCL. Up to one third of newly diagnosed DLBCL patients will have relapsed or refractory (r/r) disease.1 Current standard of care for these patients is salvage chemotherapy and, if chemosensitive, to be followed by high dose chemotherapy with hematopoietic cell rescue (autoHCT).2,3 Event-free survival at 24 months (EFS24) after frontline IC is associated with excellent long-term outcomes with overall survival (OS) similar to that of age- and sex-matched controls.4 In comparison, those achieving EFS24 following autoHCT for relapsed or refractory disease may have increased risk for late-mortality compared to the general population with advanced age and intensive salvage therapy contributing to the risk of late complications.5 We sought to better characterize EFS24 after autoHCT to determine the utility of this end-point for informed clinical decisions, patient management, and future clinical trials. Methods: Patients were prospectively enrolled onto the Molecular Epidemiology Resource (MER) of the University of Iowa/ Mayo Clinic Specialized Program of Research Excellence (SPORE). Patients were followed for relapse, retreatment, and death; all events were validated by medical record review. For this analysis patients were included if they were consented within 9 months of initial diagnosis of DLBCL between 2002-2012, had received anthracycline-based IC (R-CHOP, or similar), and eventually had undergone autoHCT for r/r DLBCL. Patients with primary central nervous system (CNS) lymphoma or post-transplant lymphoproliferative disorders (PTLD) were excluded. Overall survival (OS) was defined as time from autoHCT until death due to any cause. Event-free survival (EFS) was defined as time from autoHCT until progression, relapse, retreatment, or death due to any cause. OS from achieving EFS24 after autoHCT was compared to age- and sex-matched general US population. Results: 108 patients underwent autoHCT for relapsed DLBCL between 2002 and 2017. Median age at autoHCT of the patients was 60 years (range 20-78) and 72 (67%) were male. The most common transplant conditioning regimen was BEAM (82%). At a median follow-up after autoHCT of 85 months (range 1-171), 72 patients (67%) had an event and 64 patients (59%) had died. Kaplan-Meier estimates for EFS and OS at 24 months from the time of autoHCT were 49% (95% CI: 40-59) and 61% (95% CI: 52-71), respectively. 52 patients had a progression within 24 months of autoHCT; OS from progression was poor (median OS=2.8 months, 95% CI: 1.8-6.0; 5 year OS = 9%, 95% CI: 2-22). 48 patients achieved EFS24 after autoHCT; median OS from achieving EFS24 was 136 months (95% CI: 92-NE) and 5 year OS was 79% (95% CI: 68-93). This was inferior to the background population (Figure 1, SMR=3.64, 95% CI: 2.11-6.27, p<0.0001). Eight patients had a progression after achieving EFS24 from autoHCT. OS from progression in these 8 patients (median OS=27.3 months, 95% CI: 14.4-NE; 5 year OS = 16%, 95% CI: 3-93) was improved compared to progression within 24 months of autoHCT (p=0.072, figure B). Cause of death (COD) in EFS24 achievers was progression of lymphoma (n=6), infection (n=1), secondary malignancy related to therapy (n=3), heart disease (n=1), and unknown (n=1). Conclusions: Patients achieving EFS24 after salvage chemotherapy and autoHCT have a favorable long-term prognosis; however, overall survival remained inferior to the general population. Most common COD after achieving EFS24 was progression of lymphoma. In spite of this, EFS24 remains a valuable end-point for informed clinical decisions, patient management, and future clinical trials. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Nanostring: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding.

Introduction: Allogeneic hematopoietic stem cell transplant is curative in several benign and malignant hematological disorders with predominant complications of graft versus host disease (GVHD) and infections. Antithymocyte globulin (ATG) has been shown in a number of prospective trials to be effective in decreasing acute and chronic GVHD. Recently, it has been suggested that recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration interacts with the dose of ATG administered and predicts transplantation outcomes. This interaction may depend on the preparative regimen and the dose of ATG used. We sought to determine if ALC at time of administration of ATG could impact clinical outcomes in a population treated with busulfan fludarabine myeloablative regimen and a fixed dose of 4mg/kg of ATG. Methods: Seventy consecutive pts who underwent a matched unrelated donor transplant with ATG at the University of Iowa were retrospectively analyzed. All pts received rabbit ATG (Thymoglobulin®) at 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2 mg/kg on day -3 in addition to tacrolimus and methotrexate. All received a myeloablative preparative regimen with busulfan (130 mg/m2 days -6 to -3) and fludarabine (40 mg/m2 daily for 4 days). All but one pt received peripheral blood as graft source. The effect of patient, disease, and transplant characteristics on 2-year outcomes was evaluated using Cox and Fine and Gray regression models. For relapse, GVHD, and infections, death was considered a competing risk. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. Results: Median age was 59 years (range 20-68). Underlying diagnoses were AML (n=47), MDS (n=20) and CML (n=3). Disease Risk index showed 25 high risk, 24 intermediate risk and 21 low risk patients in this study. The median peripheral blood ALC on day -3 was 100 × 102/µL (range 0-1144 × 102/µL). Univariate analysis showed no significant impact of ALC (100+ vs <100) on 2-year risk of developing GVHD (HR 1.49, 95%CI: 0.77 - 2.86), 2-year overall infection risk (HR 0.86, 95%CI: 0.51-1.46), 2-year bacterial (HR 0.78, 95%CI: 0.43-1.42), viral (HR 0.81, 95%CI: 0.41-1.60) and fungal (HR 0.63, 95% CI: 0.17-2.33) infections. Univariate analysis also showed no significant influence on 2-year relapse-free survival (HR 0.67, 95%CI: 0.21-2.14) and overall survival (HR 0.84, 95%CI: 0.34-2.06). Significantly worse survival is seen in MDS in comparison to leukemic pts, and high disease risk in comparison to low disease risk. Conclusion: Our single center experience using busulfan and fludarabine myeloablative regimen and rabbit ATG dosed at 4 mg/kg showed no interaction between the recipient peripheral blood ALC and ATG to predict GVHD, infections, overall and relapse free survival. Disclosures Farooq: Celgene: Honoraria; Kite Pharma: Research Funding.

Conventional therapies to multiple myeloma (MM) are not aimed at specific molecular targets leading ultimately to treatment resistance. Recent reports have shown that iron is instrumental in cancer development and progression and that high intracellular iron levels are associated with poor prognosis. We have demonstrated that MM cells exhibit dysregulated iron homeostasis and that limitation of cytosolic iron inhibits MM cell growth both in vitro and in vivo. The potential therapeutic role of iron should be further investigated to better understand how targeting high-iron MM cells could prevent or delay MM development and recurrence. Our study will provide crucial insights into the iron biology of MM pathogenesis and may lead to novel MM therapy. In this study, two mouse models, young Vk*MYC and old KaLwRij mice, were injected with iron dextran (1.25 mg/kg, IP, once a week). Tumor burden was monitored by serial Serum Protein Electrophoresis (SPEP) tests, flow cytometry, and immunohistochemistry. In vitro co-culturing of ARP1 MM cells with macrophages was employed to determine iron transfer. To determine iron's roles in MM evolution, we injected iron dextran into Vk*MYC mice at 8-week age. Vk*MYC mice develop MGUS around 40-50 weeks with plasma cell (PC) bone marrow infiltration and kidney damage etc. Iron-dextran was used because it is primarily taken up by macrophages. After 14-16 weeks of iron injection, M spike was detected in the injected Vk*MYC mice. The percentage of bone marrow plasma cells (CD138+) were significantly increased to 9% in the Vk*MYC mice injected with iron compared to control mice injected with vehicle by flow cytometry and immunohistochemistry. The acceleration of disease progression via iron injection was also tested in KaLwRij mice, which also spontaneously develops MGUS in old age. M protein was detected in 12 of 15 mice (80%) injected with iron dextran for 10 weeks and 1 of 5 KaLwRij (20%) control mice at 18-months of age. CD138+ B220- plasma cells were determined by flow cytometry. A significant increase of CD138+B220- plasma cells in iron treated mice (4% versus 2%) was observed compared to vehicle control mice. Deparaffined sections of bone marrow from the above mice were stained with Prussian blue and confirmed positive staining of macrophages from iron administrated mice. These results indicate that iron accelerates MGUS development in vivo. We next evaluated whether MM cells accumulate iron from the microenvironment. ARP1 MM cells were co-cultured with primary macrophages derived from mouse bone marrow to mimic disease environment in vitro. Under these conditions, MM cells induced macrophage polarization from M0 to M1 and M2. Furthermore, increased macrophage polarization was confirmed in vivo from the KaLwRij mice injected with 5TGM1 MM cells. To confirm that MM cells uptake iron from macrophages, increased intracellular ferritin levels were observed by western blot in ARP1 MM cells following co-culture with iron-loaded macrophages. We observed that this increase in intracellular ferritin was mediated via the transferrin receptor. This iron mobilization was prevented by iron chelation. Additionally, we confirmed that ferritin levels were higher in CD138+ primary human MM cells compared to CD138- non-MM cells by western blot. Our data indicate that MM cells promote macrophage polarization resulting in the transferring of iron into MM cells. The blockade of iron trafficking between MM cells and macrophages might hold a promise for the prevention and therapy in MM. Disclosures Bergsagel: Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Zhan:BIPHARM LLC: Consultancy, Other: % Allocation of Profit.

Abstract Background: In the past several years, biology of CLL is being unleashed which had led to discovery of novel treatments, including ofatumumab and obinutuzumab, CD20 monoclonal antibodies (mAb), and ibrutinib, a Bruton tyrosine kinase inhibitor, which exhibited a paradigm shift in CLL. Available clinical trials provided direct comparison with chlorambucil, with no head-to-head trials to compare them. We conducted a network meta-analysis (NMA) to summarize the evidence on first-line treatments of CLL. Methods: We included randomized controlled trials (RCTs) that evaluated the efficacy of ofatumumab, obinutuzumab, ibrutinib, rituximab, bendamustin or alemtuzumab, in patients with previously untreated CLL. Efficacy outcome measures included progression-free survival (PFS) at 18 months and best overall response rate (ORR), which consists of both complete and partial response rates. Bayesian NMA method was used to conduct this NMA that pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments used. Results: Five trials were identified, enrolling 2,113 newly diagnosed CLL patients with a median age ranging from 60 to 73. NMA demonstrated superiority of obinutuzumab plus chlorambucil over other mAb combinations and ibrutinib, and had the highest probability of achieving PFS at 18 months when compared to ibrutinib with risk ratio (RR) of 2.41 (credible interval [CrI] 0.89 to 5.29) and ofatumumab plus chlorambucil with RR of 7.11 (CrI 3.31 to 13.8). Table-1 depicts the results of NMA for PFS at 18 months. It also had the highest probability of achieving ORR, followed by ibrutinib ranking the second. Conclusion: Obinutuzumab plus chlorambucil has higher probability of achieving efficacy compared to other mAb combinations or ibrutinib, in terms of better ORR and better PFS rates, followed by ibrutinib. The certainty in the evidence is low because of indirectness, which is a limitation in this NMA, however our results parallel the evidence based practice. Although no head to head clinical trials compared first-line treatments for CLL, our NMA showed that obinutuzumab plus chlorambucil and ibrutinib had better efficacy profile. NMA is not a substitute for well conducted RCTs investigating direct comparisons. Abbreviations: CrI, credible intervals; PFS, progression free survival. *Treatments are ranked according to their probability of achieving comparative effectiveness. Disclosures No relevant conflicts of interest to declare.