Citations

Abstract Introduction Transformation of chronic lymphocytic leukemia (CLL) into Hodgkin lymphoma (HL) is a rare, but recognized complication of CLL. The prognosis of CLL with HL Transformation (HT) appears significantly worse than de novo HL, but most series are small and there are limited published data. These reports have prompted several groups to recommend aggressive therapy with stem cell transplantation (SCT) in first complete remission (CR1). We describe the largest reported series of HT patients (pts) with analyses of the clinicobiologic characteristics, treatment patterns, and clinical outcomes based upon our multi-institutional clinical experience. Methods Pts diagnosed with HT from 01/2000 - 01/2018 were retrospectively identified in 13 tertiary cancer centers. Clinicobiologic characteristics, treatment type, and survival outcomes for each pt were analyzed. Overall survival (OS) was measured from the time of HT diagnosis until time of death. OS estimates were calculated using the Kaplan-Meier method. The log-rank test was used to calculate differences in survival. Results Ninety-four pts with HT were identified. Median age at HT was 67 years (yrs; range, 38-85) and 81% of the pts were male. Median time from CLL diagnosis to HT was 5.5 yrs (range, 0-20.2; 7 pts with simultaneous diagnosis of CLL and HL). At initial CLL diagnosis, 31%, 34%, 21%, 10%, and 4% were Rai Stage 0, 1, 2, 3, and 4, respectively. At CLL diagnosis, 67% (25/37) had an un-mutated IgVH gene, 36% (21/59) had del(13q), 32% (14/44) had trisomy 12, 24% (14/59) had del(11q), and 15% (9/61) had del(17p). Prior to HT diagnosis, pts had a median of 2 (range, 0-12) therapies for CLL. Seventeen (18%) had no prior CLL treatments. Forty-three (46%) and 25 (27%) patients had received purine analogue- and ibrutinib-based therapy prior to HT, respectively. Baseline characteristics at HT are described in Table 1. As initial therapy for HL, the majority of pts (61%, n = 62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine) at full (n = 48) or reduced (n = 14) doses. Of these, CD20 monoclonal antibody was added in 6 and Bruton-tyrosine kinase inhibitor was added in 2. Ten (11%) received a brentuximab-based regimen. Seven (7%) received an RCHOP-based regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Six patients (6%) received no therapy for HT due to frailty. Subsequent therapy included autologous SCT and allogeneic SCT in 7 (7%) and 11 (12%) of patients, respectively. Two (2%) and 5 (5%) pts received their autologous and allogeneic SCT while in CR1, respectively. The median number of treatments for HT per pt was 1 (range, 0-5) with 59 (61%) pts only receiving one line of therapy. After HT diagnosis, pts had a median follow-up of 1.6 yrs (range, 0.0 - 15.1). Two-yr OS after HT diagnosis was 72% (95%CI 62 - 83%). The pts who received any CLL directed therapy (n = 80) prior to HT had a significantly lower estimated 2-yr OS of 69% (95%CI 58 - 82%) compared with pts who did not receive any prior CLL-directed therapy (n = 17; 93%; 95%CI 82-100%; p 0.02; Figure 1). Pts who received purine-analogue-based therapy for their CLL prior to HT had a significantly lower estimated 2-yr OS of 60% (95%CI 46 - 79%) compared with pts who did not receive purine-analogue-based CLL-directed therapy prior to HT (n = 51; 83%; 95%CI 73 - 96%; p 0.009; Figure 2). Although limited by small sample size, the pts who underwent SCT for HT in CR1 had a similar 2-yr OS (n = 7; 67%; 95%CI 38-100%) to pts who did not undergo SCT for HT in CR1 (n = 87; 72%; 95%CI 63 - 84%; p 0.46; Figure 3). Conclusions In this retrospective analysis, we describe the largest reported series of pts with HT from CLL. Two-yr survival in pts with HT was shorter than what is historically expected in patients with de novo HL, but longer than what is expected in CLL pts who transform to diffuse large B-cell lymphoma. Pts with HT who have received prior CLL-directed therapies (specifically purine-analogue-based treatments) are estimated to have a shorter 2-yr OS, likely due to underlying immunosuppression. The majority of pts (61%) only received 1 line of HL therapy and only 20% went on to receive SCT (7% while in CR1), indicating that these patients can have prolonged OS after achieving response to first-line therapy for HT and may not require SCT in CR1. Further study of this rare population is required to determine optimum management. Disclosures Kander: AstraZeneca: Consultancy. Parikh:Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Shadman:Acerta Pharma: Research Funding; Verastem: Consultancy; Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mato:Portola: Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Celgene: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Johnson & Johnson: Consultancy; AbbVie: Consultancy, Research Funding. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov:Verastem: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding. Phillips:Abbvie: Research Funding; Bayer: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Smith:BMS: Consultancy; Portola: Honoraria. Davids:Surface Oncology: Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MEI Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Celgene: Consultancy; BMS: Research Funding; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding.

Abstract Background: Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (R/R AML) who have failed standard induction therapies most often receive salvage therapy with a wide variety of agents, but very few achieve remission. These patients do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to lack of efficacy using a standard HCT approach. The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial designed to address this significant unmet need in R/R AML. This trial compares Iomab-B, an 131I-radiolabeled anti-CD45 antibody as targeted conditioning prior to HCT against standard conventional care therapies with an accrual goal of 150 patients. We have performed a preliminary safety analysis, validating the initial feasibility of this multi-center trial. Methods: Eligible patients are ≥ 55 years of age with active, R/R AML, adequate organ function, and related/unrelated matched donor. Patients are randomized (1:1 ratio) to receive dosimetry directed Iomab-B followed 12 days later by HCT with fludarabine 30 mg/m2 x 3 days and 2 Gy of total body irradiation as transplant conditioning, or to a Conventional Care (CC) arm. Patients randomized to CC, may receive investigator's choice of salvage induction chemotherapy including approved targeted agents as well as Venetoclax (in combination with a hypomethylating agent) and proceed to standard HCT if they achieve complete remission (CR). If patients do not achieve CR, the study allows optional cross-over to the Iomab-B arm, evaluated between days 28-42 after CC therapy. The primary efficacy endpoint for the study is durable complete remission (dCR) of 6 months. The secondary efficacy objective is to evaluate overall survival at 1 year. Results: Forty patients have been enrolled to date and data are available for 38 patients (19 = Iomab-B, 19 = CC) as of July 5th, 2018. The median age was 63 years (range: 55-76). All patients had active disease at the time of enrollment with median bone marrow (BM) blasts of 30% in the Iomab-B arm and 47% in the crossover arm prior to receiving Iomab-B (Table 1). Of the patients in the CC arm, 88% did not achieve a CR and 65% of those crossed-over to receive Iomab-B. The most common reason preventing crossover was declining performance status. Time to HCT was not increased in the crossover patients receiving Iomab-B compared to those that underwent a standard of care transplant after achieving CR (median 65 vs 75 days), while the Iomab-B arm patients were transplanted at a median of 27 days after randomization. Iomab-B therapy was well-tolerated with no grade 3 or 4 infusion-related reactions reported. The median activity of Iomab-B was 626 mCi (range: 397-1027). All patients randomized to Iomab-B (N=13) engrafted, with median days to engraftment of ANC at 13 (range: 9-22) and platelets at 17 (range: 13-26). All patients who received Iomab-B after crossover (N=9) also engrafted with time to engraftment similar to patients initially randomized to the Iomab-B arm (Table 1). Donor chimerism (≥95%), within 100 days after HCT, was found in 9 of 10 patients in the Iomab-B arm and 8 of 9 patients in those that crossed over to receive Iomab-B, with two patient exceptions having mixed donor chimerism at day 28. A preliminary safety analysis for all randomized patients on either study arm showed the most frequent non-hematologic adverse events ≥ grade 3 occurring in >10% patients were febrile neutropenia (34.2%), stomatitis (15.8%), malnutrition (13.2%), epistaxis, sepsis, hypotension, hypobilirubinemia and fatigue (all 10.5%). There were no Iomab-B-related deaths. Interpretation: Preliminary safety analysis demonstrates the feasibility of delivering targeted conditioning with Iomab- B for HCT in R/R AML patients who have active disease and a high BM blast burden (median: ≥ 30%) prior to transplantation. All patients who received Iomab-B, including those crossed over after failing to achieve CR on CC salvage therapy, engrafted ANC within 13 days, despite active disease prior to transplant. In addition, the time to HCT from randomization was not increased in patients receiving Iomab-B after cross-over compared to those who underwent standard of care HCT after achieving CR on the CC arm. This study is currently enrolling and for full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Tomlinson: Foundation Medicine: Consultancy. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Chen:Bellicum Pharmaceuticals: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Lazarus:Pluristem Ltd.: Consultancy. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Abstract Background: A majority of younger pts with AML receive initial therapy with a 7+3 scheme. Escalated doses of daunorubicin (dauno) in combination with standard doses of ara-C may lead to improved outcomes (Fernandez; NEJM 2009). A phase II trial of idarubicin and high-dose ara-C (IA) in combination with the histone deacetylase inhibitor vorinostat (IA+V) resulted in historically high response rates compared to IA or 7+3 (Garcia-Manero; JCO 2011). SWOG 1203 tested whether a high-dose ara-C induction with or without vorinostat could result in improved outcomes for younger AML pts compared to 7+3. Methods: The primary endpoints were comparison of event-free survival (EFS) of 7+3 vs IA vs IA+V and evaluating the frequency of allogeneic hematopoietic cell transplantation. Secondary endpoints included toxicity, remission rate, relapse-free survival (RFS), and overall survival (OS) according to treatment arm, and by cytogenetic and molecular subgroups. Because of the historical trend of cured pts in S0106, EFS was modeled with an exponential cure model, and it was assumed IA or IA+vorinostat increased the proportion of pts cured from 35% to 45% and increased median EFS among those not cured from 4.7 months to 7.1 months. Main inclusion criteria included a diagnosis of previously untreated non-APL AML by WHO criteria, age 15 to 60 years, and preserved cardiac function but no severe comorbidities. Pts with known CBF rearranged or FLT3 mutant leukemias were eligible if no other alternative clinical trials existed. Treatment was as follows: Induction: 7+3 arm: dauno 90 mg/m2 IV QD x 3 on days 1-3 with ara-C CI 100 mg/m2 QD x 7 days on days 1 to 7. IA arm: ida 12 mg/m2 QD x 3 on days 1 to 3 with 24 hours CI ara-C 1.5 gm/m2 QD for 4 days on days 1 to 4. IA+vorinostat was as IA but with vorinostat 500 mg orally TID for 3 days on days 1 to 3. Consolidation: 7+3 arm: standard high-dose ara-c at 3 gm/m2 over 3 hrs q12 hours x 6 doses for 1 to 4 cycles depending on transplant availability. IA arm: idarubicin 8 mg/m2 IV QD x 2 days on days 1 to 2 with ara-C 0.75 gm/m2 CI for 3 days on days 1 to 3 for 4 cycles. The number of consolidation cycles depended on transplant indication; a secondary aim of the study was to transplant all cytogenetically-determined high risk pts (presented in a different abstract). Results: Of 754 pts randomized, 738 were eligible (261 to 7+3, 261 to IA, and 216 to IA+V). Baseline characteristics were well balanced among all three groups. Most (75%) pts were between 40 and 60 years, 51% were male, median (range) WBC and platelets were 10.8 (0.3-800) and 49 (3-3900), respectively; marrow blast percentage was 60% (0%-100%); cytogenetics were favorable in 13% of pts, intermediate in 63%, and high-risk in 22%; FLT-3 was mutated in 21% and unknown in 31%; NPM1 was mutated in 20% and was unknown in 37%. Complete remission (CR) rates were 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). Significantly more pts received reinduction with 7+3 (24%) versus 11% with IA and 9% with IA+V (p=0.001). 48% of intermediate and unfavorable risk pts received transplant in CR1, with no significant differences among arms (p=0.44). There were no significant differences in EFS, RFS or OS among all three arms (Figure 1, all p>0.5). By cytogenetic or molecular group, there were no differences in outcome for any standard risk subset (FLT-3, NPM1, or CEBPα or cytogenetic subset), although pts with favorable cytogenetics had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (Figure 2, all p≤0.015). 30% of pts received 1 consolidation cycle, 18% 2, 16% 3, and 37% 4 cycles. Grade 5 induction toxicity rates were 4% (7+3), 8% (IA), and 9% (IA+V) by arm (p=0.07), and for toxicities related to therapy, 2%, 7%, 8%, respectively (p=0.01). Grade 4 induction toxicity rates were similar across arms (p=0.38). Conclusion: Treatment with IA is not more effective than 7+3 in younger pts with AML. Outcomes with IA or IA plus vorinostat are similar. In pts with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation. Clinical Trials Registry: NCT #0180233 Support: NIH/NCI grants CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI grant #021039 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy; BMS: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; Baxalta: Consultancy; Cyclacel: Research Funding; Celator: Research Funding; Abbvie: Research Funding; Ambit: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Lundbeck: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Ariad: Consultancy; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Agios: Research Funding; Jannsen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Agios: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Ariad: Consultancy; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB.