ALBERT

Description: Introduction: Fludarabine (Flu)-based conditioning regimens, combined with either melphalan (Mel) or intravenous busulfan (Bu), are often utilized in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). While recent data supports that a myeloablative conditioning (MAC) strategy improves survival in patients who are able to tolerate this approach, the optimal regimen for patients elderly or unfit for MAC remains unclear. A single-center retrospective analysis was performed to evaluate outcomes in patients with AML or MDS deemed eligible only for reduced intensity regimens. Methods: Patients with AML and MDS who underwent peripheral blood mobilized allogeneic HCT at a single institution between January 2008 and December 2014 were identified. Of those, patients who received conditioning with either once-daily Bu (75-95 mg/m2) targeted to an area under the curve of 3500 µM*L/min and Flu 160 mg/m2 (Flu/Bu 3500) or Mel 140 mg/m2 plus Flu 120-160 mg/m2 (Flu/Mel) were evaluated and compared. All disease statuses (complete remission (CR), second CR, or with active disease) at time of HCT were included. Regimen toxicities, cumulative incidences of acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) were evaluated. Results: We identified 150 consecutive patients who received Flu/Bu 3500 (n=81) or Flu/Mel (n=69). Regimens were selected at physicians' discretion. The median ages for Flu/Bu 3500 and Flu/Mel were similar (66.9 (range, 48.2-75.9) and 65.8 (40.9-75.2) (p=0.14)). No differences were detected between the two groups with regard to recipient and donor gender, primary disease, donor type, recipient and donor cytomegalovirus (CMV) status, and Karnofsky performance status. Additionally, there were no differences between either groups in disease specific prognostic variables such as Disease Risk Index (Armand et al.), blast percentage at time of HCT, International Prognostic Scoring System (IPSS) and revised IPSS scoring in MDS patients, or AML cytogenetics at time of HCT. Patients receiving Flu/Mel had higher HCT-specific comorbidity index (HCT-CI, 〉3) when compared to Flu/Bu 3500 prior to transplantation (66.7% versus 46.9%, p=0.02). OS was similar between both arms (p=0.1) as was NRM (Hazard ratio (HR) 0.61 (CI, 0.34 - 1.1, p=0.1)) and PFS, HR 1.26 (CI, 0.83 - 1.94, p=0.2). However, CIR at 2 years post-allograft was significantly higher in the Flu/Bu 3500 arm, HR 2.54 (CI, 1.4 - 4.6, p=0.002) in comparison to Flu/Mel regimen (Figure 1). There was no difference detected in the cumulative incidences of either grades 2-4 acute GVHD, HR 1.00 (CI, 0.66 - 1.55, p=1.0), or grades 3-4 acute GVHD, HR 0.66 (CI, 0.27 - 1.57, p=0.3) between either conditioning regimen. The cumulative incidence of chronic GVHD was also similar, HR 1.27 (CI, 0.84 - 1.92, p=0.2). With regard to toxicity, diarrhea occurred more frequently in the Flu/Mel arm (p=0.0003) in the first 20 days following transplant. However, in the same period, mucositis occurred more frequently in the Flu/Bu 3500 arm (p=0.005). No differences were noted between the arms when assessing incidence of sinusoidal obstructive syndrome, diffuse alveolar hemorrhage, or thrombotic microangiopathy up to 90 days. Amongst patients receiving Flu/Mel, the most common cause of death was pneumonia or pulmonary failure (n=7) whereas the most common cause of death in the Flu/Bu 3500 arm was disease related (n=31). Conclusion: Flu/Mel resulted in a lower CIR at 2 years post-HCT compared to patients receiving Flu/Bu 3500 conditioning. Regarding toxicity, Flu/Mel produced more diarrhea but significantly less mucositis in comparison to Flu/Bu 3500; otherwise toxicity was comparable. Though there were no differences in OS and NRM between the two conditioning regimens, we speculate that the impact of the higher HCT-CI in the Flu/Mel arm may have contributed negatively to the lack of benefit in NRM and OS. Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding. Fernandez:Chimerix: Honoraria; Otsuka: Honoraria; Sanofi: Speakers Bureau.

Description: Background: Acute leukemias of ambiguous lineage (ALAL), including acute undifferentiated leukemia and mixed phenotype acute leukemia (MPAL), are rare hematologic malignancies, accounting for only 2-5% of cases of acute leukemia. Outcomes are generally poor, and retrospective studies have suggested that patients have better outcomes when treated with regimens used for acute lymphoblastic leukemia (ALL) rather than acute myeloid leukemia (AML). Due to heterogeneous definitions and rarity of these leukemias, no single ALL regimen has been studied extensively. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) is one of the most widely used adult ALL regimens in the United States. We retrospectively examined the effectiveness of this regimen as initial therapy in patients with ALAL. Methods: We retrospectively reviewed records from adult patients treated initially with hyperCVAD-based chemotherapy for ALAL as defined by the World Health Organization at five academic institutions. Only patients whose diagnosis was verified at a participating institution were examined. Philadelphia (Ph) chromosome-positive ALAL patients treated concurrently with tyrosine kinase inhibitors were included. The primary objective of the study was to determine the overall response rate (ORR) and median overall survival (OS). Descriptive statistics were used for baseline characteristics and responses, and Kaplan-Meier estimates were used to calculate all time-to-event outcomes. Results: Twenty-two patients were identified, and pre-treatment characteristics are shown in the Table. Median age was 50 years (range, 22-69), with an even distribution of male and female patients (50% each). The majority (77%) were Caucasian. Two patients (9%) had acute undifferentiated leukemia, 11 (50%) T/myeloid MPAL, 8 (36%) B/myeloid MPAL, and 1 (5%) B/T MPAL. Seven (32%) had a complex karyotype (at least 3 abnormalities), 6 (27%) had a normal karyotype, 3 (14%) were Ph-positive and were treated concurrently with dasatinib, and 1 (5%) had an 11q23 rearrangement. FLT3-ITD was detected in 5 of 8 patients (63%) with an available mutation panel. Three (15%) had central nervous system (CNS) involvement at presentation, and one additional patient developed CNS disease during the course of therapy. There were no deaths within the first 30 days, and the median number of cycles given was 4 (range, 1-8). The CR rate was 73% (n=16) and an additional 14% (n=3) had CR with incomplete count recovery (CRi), for an ORR rate of 86%. One patient had a partial response, and 2 patients had no response. Of the 19 patients achieving CR or CRi, median number of cycles to CR was 1.5, and 12 (63%) proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT). Of the 7 responders who did not receive alloHSCT, 3 relapsed shortly after initial CR and 4 are alive and in remission 77, 39, 37 and 10 months from treatment initiation. All 3 patients with Ph-positive disease achieved CR. Only 1 proceeded with alloHSCT and all 3 patients are alive and in remission at 51, 39, and 10 months. With a median follow up of 37 months, 14 (64%) patients were alive and in remission, including 11 who had undergone alloHSCT. Four of the 6 patients who died had a complex karyotype. Median overall survival for the entire cohort was not reached (Figure). Conclusions: HyperCVAD results in high remission rates in patients with ALAL, with low incidence of early mortality and high ability to proceed to allogeneic transplantation following response. HyperCVAD can be considered an effective front-line therapy for patients with ALAL. Additionally, hyperCVAD may be a backbone for incorporation of novel immunotherapies and targeted therapies, which may improve results in patients with appropriate targets. Disclosures Sweet: Astellas: Consultancy; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria; Phizer: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; BMS: Honoraria. Wang:Novartis: Speakers Bureau; Amgen: Consultancy; 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy. Al-Kali:Novartis: Research Funding.