Antecedent Hematologic Malignancy Research Articles

Outcomes of Patients Treated with CPX-351 As First Line Therapy for AML Based on Their Antecedent History of Myeloid Malignancy

Outcomes of Patients Treated with CPX-351 As First Line Therapy for AML Based on Their Antecedent History of Myeloid Malignancy

Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven)

Background:The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML.Methods:Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression.Results:82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS.There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10).Conclusions:Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. [Display omitted] DisclosuresMannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Azacitidine, Venetoclax and Pevonedistat As Frontline Therapy for Patients with Secondary Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Results from a Phase I/II Study

Azacitidine, Venetoclax and Pevonedistat As Frontline Therapy for Patients with Secondary Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Results from a Phase I/II Study

Bone Marrow Cellularity and Recovery of Blood Counts after Venetoclax and Azacitidine in Elderly Acute Myeloid Leukemia Patients Unfit for Induction Chemotherapy

Introduction: Cytotoxic chemotherapy is frequently employed in the treatment of aggressive malignancies such as acute myeloid leukemia (AML). Patients (pts) who respond to this therapy universally experience significant cytopenias after a period of bone marrow hypocellularity that is the result of toxicity to normal hematopoietic cells. Older pts with AML poorly tolerate cytotoxic chemotherapy, largely due to these cytopenias, and novel therapies that spare this toxicity are needed. In the setting of a multi-center phase 1b dose escalation/expansion study (NCT02203773), we explored the combination of the BCL-2 inhibitor venetoclax (ven) with azacitidine (aza) for elderly AML pts unfit for induction chemotherapy. We noted distinctive post treatment morphologic appearances of some pts' bone marrow biopsies that could be grouped based on cellularity. This observation, coupled with a high overall response rate that included some pts who did not achieve full count recovery, led to a hypothesis that bone marrow cellularity, either at baseline or after 1 treatment cycle, might predict full vs. incomplete count recovery in the context of this novel therapy.Methods: We enrolled 33 pts at our institution into this dose escalation/expansion study involving the sequential administration of aza at the standard dose and schedule with daily ven; 23 received 400 mg venetoclax, 9 received 800 mg and 1 received 1200 mg. Cycles lasted 28 days and were repeated indefinitely in the absence of progression or limiting toxicity. Baseline and post cycle 1 bone marrow biopsies were assessed as hypercellular (>80% cellularity) or hypocellular (<20% cellularity) (Figure 1). Univariate logistic regression analysis was used to determine whether these features predicted the ability to achieve a complete remission (CR) versus CR with incomplete count recovery (CRi) or morphological leukemia free state (MLFS), and McNemar's test for paired samples was used to predict whether pre-treatment cellularity predicted post-treatment cellularity.Results: 17 pts at baseline met pre-defined criteria for hypercellularity and 2 were hypocellular. 10/33 pts had AML with myelodysplasia related changes; of these, 6 were hypercellular and none were hypocellular at baseline. After 1 cycle, 2 pts met criteria for hypercellularity and 9 were hypocellular. Hypercellularity at baseline predicted post treatment hypercellularity (P=0.0001) and hypocellularity at baseline predicted post treatment hypocellularity (P=0.0196) (Table 1). Median time to platelet and neutrophil recovery was 25 and 42 days, respectively. Hypercellularity at baseline was significantly associated with a reduced ability to recover blood counts (OR to achieve CR vs. CRi/MLFS was 0.15, 95% CI 0.02-0.89, P=0.0369). Hypocellularity at baseline was not associated with failure to recover blood counts (P=0.9618). Hyper or hypocellularity after cycle 1 did not predict ability to recover counts (p=0.9403 and 0.1593, respectively) (Table 2).Conclusion: Novel therapies that spare elderly pts long periods of cytopenias are necessary. Ven with aza is an active combination in this population. Although nearly all pts in our cohort achieved an International Working Group defined overall response, several had a CRi or MLFS. After cycle 1 of treatment, some pts achieved a remission without an apparent period of hypocellularity. Surprisingly, hypercellularity at baseline was associated with a lower likelihood of achieving full count recovery after treatment. Patients that were hypercellular after cycle 1 were more likely to have been hypercellular at baseline, however, hypercellularity after cycle 1 was not associated with delayed count recovery. Neither baseline nor post treatment hypocellularity had a higher association with poor count recovery. These observations will need to be tested in a larger sample set, but they suggest that marrow recovery may not be linked to morphologic features like baseline cellularity. In the setting of non-intensive therapies other features may predict inferior count recovery, such as the presence or duration of an antecedent hematologic malignancy like MDS. [Display omitted] DisclosuresPollyea:Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding.

A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia

Background: Older patients (pts) with acute myeloid leukemia (AML) are often not candidates for intensive cytotoxic chemotherapy due to frailty or comorbidities, and decitabine has been shown to improve their survival compared to supportive care or low-dose cytarabine. However, the optimal dosing schedule of decitabine in this setting is not well-established. This phase II randomized study was conducted to evaluate relative safety and efficacy of two different schedules of decitabine in this population.Methods: Adult pts ≥60 years of age with newly diagnosed AML were randomized using a Bayesian adaptive design to receive decitabine at a dose of 20 mg/m2 IV daily for either 5 or 10 consecutive days. Pts <60 years of age were also eligible if deemed not to be suitable candidates for intensive cytotoxic chemotherapy. Pts were required to have a performance status of ≤3, total bilirubin <2 mg/dl and creatinine <2.5 mg/dl. Pts who had received prior hypomethylating agents for an antecedent hematologic malignancy were ineligible. Pts could receive up to 3 consecutive cycles of induction at the randomly assigned dose at approximately monthly intervals. Responding pts received additional consolidation cycles every 4-8 weeks for up to 24 total cycles. The primary endpoint was to compare the response rates of decitabine x 5 days versus decitabine x 10 days. Secondary endpoints included the response duration, survival and the safety of the 2 schedules.Results: Between 2/2013 and 3/2017, 63 pts have been randomized to receive decitabine for either 5 days (n=24) or 10 days (n=39). Baseline characteristics of the 2 arms were well-balanced and are shown in Table 1. Among the total cohort (both arms), the median age was 77 years (range, 57-90 years); 49% had poor-risk cytogenetics, 43% had therapy-related or secondary AML and 35% had a TP53 mutation. The overall response rate (CR + CRi + PR) was 46% for the 5-day arm and 38% for the 10-day arm (P=0.56). The CR rates were 29% and 28%, respectively (P=0.94). No baseline characteristics were observed that predicted for superior response to either of the treatment arms. The median number of cycles to best response in both arms was 2 (range, 1 to 5 cycles for both arms). Early mortality was similar with both dosing schedules. The 30-day mortality rates for the 5-day and 10-day arms were 4% and 8%, respectively (P=0.58), and the 60-day mortality rates were 21% and 26%, respectively (P=0.66).The median duration of follow-up was 34 months. Among the 11 responding pts in the 5-day arm and the 15 responding pts in the 10-day arm, the median remission durations were 9.4 and 6.4 months, and the 1-year continued remission rates were 25% and 27%, respectively (P=0.56). No pts in either arm underwent subsequent allogeneic stem cell transplantation. Survival outcomes did not differ between the 2 arms. The median EFS was 3.0 months for the 5-day regimen and 3.4 months for the 10-day regimen; 1-year EFS rates were 14% and 13%, respectively (P=0.83; Figure 1A). The median OS was 4.9 and 7.1 months, respectively; 1-year OS rates were 26% and 24%, respectively (P=0.62; Figure 1B). There was no difference in survival by treatment arms when pts were stratified by TP53 mutation status.Conclusions: In this relatively poor-risk cohort of older adults with newly diagnosed AML, decitabine given for either 5 or 10 consecutive days resulted in similar response rates, early mortality and survival. [Display omitted] DisclosuresKantarjian:Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Daver:Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Kiromic: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Daiichi-Sankyo: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Immunogen: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding. DiNardo:Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Wierda:Juno: Research Funding; Merck: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Kite: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Karyopharm: Research Funding; Genzyme: Consultancy, Honoraria; Acerta: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Bose:Incyte Corporation: Honoraria. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding.

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

The use of venetoclax‐based salvage therapy for post‐hematopoietic cell transplantation relapse of acute myeloid leukemia

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.

Efficacy and Safety of CPX-351 Versus 7+3 in a Phase 3 Exploratory Analysis in Patients with High-Risk/Secondary Acute Myeloid Leukemia (sAML) with Prior Hypomethylating Agent (HMA) Exposure Who Achieved Remission

Introduction Patients (pts) with newly diagnosed sAML may have previously received HMA therapy for an antecedent hematologic malignancy (eg, myelodysplastic syndrome [MDS]). Outcomes for pts with MDS who progress following HMA therapy are typically poor, with remission rates Objective An exploratory subgroup analysis of the phase 3 study was performed to compare outcomes in pts with any prior HMA exposure who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi). Methods Pts were randomized 1:1 to receive 1-2 induction cycles with CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR+CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the physician's discretion. Results Of 309 pts enrolled, 133 (43%) had received prior HMAs; Of these, 23/62 (37%) receiving CPX-351 and 20/71 (28%) receiving 7+3 achieved CR+CRi (odds ratio [OR] = 1.50 [95% CI: 0.73-3.12]) and were included in this analysis. Baseline characteristics were balanced between treatment arms. In pts with prior HMAs who achieved CR+CRi, median OS was longer with CPX-351 (Figure 1). Of note, median OS was also longer with CPX-351 (26.32 vs 10.43 months) in pts without prior HMAs. More pts with prior HMAs who achieved CR+CRi with CPX-351 vs 7+3 underwent HCT (57% vs 35%; relative risk = 1.39 [95% CI: 0.73-2.67]), and OS landmarked from the HCT date was longer with CPX-351 vs 7+3 (Figure 2). The safety profile was generally comparable between treatment arms in pts with prior HMAs who achieved CR+CRi. The most common serious treatment-emergent adverse events were febrile neutropenia (CPX-351: 13%; 7+3: 10%), ejection fraction decreased (9%; 10%), and subdural hemorrhage (0%; 10%). There was no early mortality by Day 60 in either arm. Conclusions Among pts who had prior HMA exposure and achieved CR+CRi, CPX-351 improved median OS, the rate of HCT, and median OS landmarked from the HCT date vs 7+3. The CPX-351 safety profile in this subgroup was consistent with the overall study population and the known profile of 7+3.

Venetoclax-Based Salvage Therapy for Post-Hematopoietic Cell Transplantation Relapse in Acute Myeloid Leukemia

Venetoclax-Based Salvage Therapy for Post-Hematopoietic Cell Transplantation Relapse in Acute Myeloid Leukemia

Efficacy and Safety of CPX-351 Versus 7+3 in a Phase 3 Exploratory Analysis in Patients with High-Risk/Secondary Acute Myeloid Leukemia (AML) with Prior Hypomethylating Agent Exposure Who Achieved Remission

Efficacy and Safety of CPX-351 Versus 7+3 in a Phase 3 Exploratory Analysis in Patients with High-Risk/Secondary Acute Myeloid Leukemia (AML) with Prior Hypomethylating Agent Exposure Who Achieved Remission

Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy

Myeloid Sarcoma: The Mayo Clinic Experience of Ninety Six Case Series

Background: Myeloid sarcoma is a tumor mass consisting of myeloid blasts occurring at anatomical site other than the bone marrow (Arber et al. Blood 2016;127(20):2391-2405). It is a subgroup of acute myeloid leukemia, which can be localized or disseminated and may involve multiple organs. It can present with or without a positive bone marrow. It may precede or follow bone marrow involvement. It may be identified at diagnosis or relapse, and is not uncommon after stem cell transplantation (Koc et al. Cancer 1999;85(3):608-615; Yoshihara et al. Biol. Blood Marrow Transplant 2012;18(12):1800-1807).Objective: To describe the clinical characteristics, cytogenetics, prognosis and outcome of patients with myeloid sarcoma with or without bone marrow involvement.Methods: The Mayo Clinic database was interrogated using the ICD-9 codes 205.0, 205.2, 205.3, as well as terms "myeloid sarcoma," "chloroma," and "extramedullary sarcoma" in clinical notes and pathology reports. Patients' follow up information was collected until July 2016.Results: Ninety six patients with a diagnosis myeloid sarcoma were identified. The diagnosis was based on biopsy results and in some cases imaging studies in addition to bone marrow biopsy. The median age was 53 (range 17-83) years, and 64 (67%) patients were males. Myeloid sarcoma with de novo (primary) and secondary acute myeloid leukemia (with antecedent hematologic malignancy and therapy related) accounted for 64% (61) and 36% of the cases respectively.The sites involved based on their frequency of occurrence included integumentary system (skin and soft tissues) in 37 (38%), lymphatic system in 17 (18%), the gastrointestinal and genitourinary system in 14 (15%), the nervous system in 9 (9%), the breast in 3 (3%) and multiple and other single sites in 16 (17 %). Bone marrow cytogenetics findings were documented in 74 (77%) patients; favorable, intermediate, and poor cytogenetic abnormalities account for 7 (9%), 45 (61%), and 22 (30%) cases respectively. After a median follow up of 135 weeks, 57 (59%) patients died. The median survival of primary and secondary acute myeloid leukemia with myeloid sarcoma was 52 and 11.5 months (P<0.0001); and that of favorable, intermediate and unfavorable cytogenetics abnormalities was 169, 52 and 17.5 months (P=0.04) respectively.Twenty six (27%) patients had no bone marrow involvement; and 18 (69%) of them were primary myeloid sarcoma (without antecedent malignancy or therapy). The median (range) age of those with and without bone marrow involvement was 53 (17-83) and 56 (17-81) years (P=0.6). At diagnosis patients with and without bone marrow involvement have a median (range) hemoglobin (gm/dL) (10.3 (6.2-15.4) vs 13.1 (9.9-15.2) P=0.0002), white blood cell count (X109/L) (21.4 (1.1-182.5) vs 5.8 (2.4-23.2) P<0.0001), and platelet count (X109/L) (71 (8-437) vs 250 (17-561) respectively. Aggressive chemotherapy therapy was given to 58 (83%) and 20 (77%) of patients with and without bone marrow involvement (P=0.6). The median survival was 17 and 20 months with and without bone marrow involvement (P=0.4). Of those with bone marrow involvement, 49 (70%) achieved complete remission, and 26 (53%) of those individuals subsequently relapsed.Conclusion: The treatment outcome of patients with myeloid sarcoma with or without bone marrow involvement seems the same. The conventional risk factors, antecedent hematological neoplasms and cytogenetic findings, have significant impact on survival. DisclosuresAl-Kali:Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract 5302: Genome-wide methylation analysis reveals multiple epigenetic subtypes of acute myeloid leukemia

Abstract Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy for which known molecular features, while useful, are inadequate for determining the likelihood of durable remission following chemotherapy. Our study examines multiple DNA methylation patterns associated with AML curability and clinical features, and expands on preliminary work relating epigenomic phenotype to survival. Methods: To measure genome-wide CpG methylation we used Digital Restriction Enzyme Analysis of Methylation (DREAM) on a cohort of 101 AML samples and 25 normal blood controls. We used methylation data from 194 patient samples from The Cancer Genome Atlas (TCGA) on the Illumina Infinium HumanMethylation450 platform as validation. Statistical analysis was done using R. Results: DREAM analysis of 3,003 CpG sites (with standard deviation &amp;gt; 20% across AML cases) revealed three distinct DNA methylation patterns by hierarchical clustering. A group of 22 AML cases demonstrated significant hypermethylation at many loci compared to normal blood, consistent with a CpG Island Methylator Phenotype (CIMP). Kaplan-Meier analysis demonstrated that CIMP-AML cases had significantly longer OS than either non-CIMP cluster (median OS, years: CIMP = 14, hypomethylator = 1.47, non-CIMP-2 = 1.04, log-rank p = 0.0021). In this dataset CIMP was prognostic independent of cytogenetic risk, and antecedent hematologic malignancy (AHD). We also found that CIMP-AML was significantly enriched in IDH1/2 mutations (32% of CIMP-AML vs. 9% of non-CIMP-AML, p = 0.02). Differential methylation analysis to characterize the specific CpG sites within the genome that define CIMP-AML demonstrated widespread hypermethylation predominantly at CGIs. Using a robust Cox regression approach, we identified candidate markers of CIMP in our DREAM dataset (sensitivity = 73%, specificity = 100%). We validated the presence of CIMP-AML in independent data from TCGA which demonstrated a consistent pattern regarding survival (median OS, years: CIMP = 2, non-CIMP = 1, log-rank p = 0.0109), and the enrichment of IDH1/2 mutations (30% of CIMP-AML vs. 14% of non-CIMP-AML, p = 0.02). Our DREAM analysis also revealed a distinct cluster of AML cases with a hypomethylator phenotype (HMP). This novel HMP-AML subtype was more common than CIMP, and was associated with intermediate OS. Differential methylation analysis revealed that HMP-AML is defined by loss of methylation predominantly at non-CGIs. HMP-AML demonstrated a relative enrichment for DNMT3A mutations (24% of HMP-AML vs. 7% of non-HMP-AML, p = 0.10). Conclusions: We propose that CIMP-AML is associated with CGI hypermethylation, IDH1/2 mutations, and favorable prognosis. Our Cox regression strategy identified a small group candidate biomarkers of CIMP-AML. In addition, we identified a novel HMP-AML phenotype associated with non-CGI hypomethylation, DNMT3A mutations, and an intermediate prognosis. Citation Format: Andrew D. Kelly, Heike Kroeger, Jumpei Yamazaki, Rodolphe Taby, Frank Neumann, Justin T. Lee, Rong He, Shoudan Liang, Yue Lu, Matteo Cesaroni, Sherry A. Pierce, Steven M. Kornblau, Carlos E. Bueso-Ramos, Farhad Ravandi, Hagop M. Kantarjian, Jaroslav Jelinek, Jean-Pierre J. Issa. Genome-wide methylation analysis reveals multiple epigenetic subtypes of acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5302. doi:10.1158/1538-7445.AM2015-5302

Comparison of Acute Panmyelosis with Myelofibrosis and Acute Megakaryoblastic Leukemia: A Mayo Clinic Study

IntroductionAcute panmyelosis with myelofibrosis (APMF) is classified under acute myeloid leukemia not otherwise specified by World Health organization (WHO). The clinical course of this entity is rapidly progressive and fatal, therefore, it is essential to make the accurate diagnosis and distinguish it from its mimickers, particularly acute megakaryoblastic leukemia; AML-M7 (AMKL). The main objective of this study is to identify clinical and pathologic features which could help distinguish APMF from AMKL.MethodsWe evaluated all patients treated at our institution between 1994 and 2013, with APMF and AMKL. We retrospectively reviewed their clinical data, laboratory results, and initial bone marrow morphologic evaluation. The lineage of blasts was evaluated using immunohistochemical staining with antibodies to CD34, anti-megakaryocyte antibodies CD41, CD61, and polyclonal factor VIII. Flow cytometry and cytogenetic studies were reviewed.Resultsi) Clinical characteristics28 patients were studied which included 8 with APMF (median age 63 years) and 20 with AMKL (median age 65 years). Splenomegaly was commonly seen in AMKL (40%) as opposed to APMF (12.5%) (P=0.21). None of the APMF patients had an antecedent hematologic malignancy, compared to 50% of AMKL patients (p=0.02). Accordingly, APMF patients had a lower incidence of the JAK2V617F mutation compared to AMKL (14% vs. 78%, p=0.04).ii) Pathological featuresPatients with APMF had a hypercellular marrow with increased erythropoiesis (87% vs. 10%, p<0.01) and granulopoiesis (100% vs. 25%, p<0.01), with lower bone marrow blast percentage (14% vs. 33%, p<0.01), with all blasts staining positive for CD34 (p=0.23) compared with AMKL. In AMKL, the majority of blasts stain positive for anti-megakaryocytic antibodies CD61 (100% vs. 30%, p=0.02), CD41 (75% vs. 20%, p=0.10), and factor VIII (50% vs. 20%, p=0.02). On flow cytometry, all cases of APMF demonstrated multilineage proliferation with subsets of blasts positive for CD61, CD117, and MPO. In comparison, all cases of AMKL expressed megakaryocytic marker CD61.iii) TreatmentHalf of our patients received intensive induction chemotherapy in each group. Median survival was similar in APMF and AMKL of 8.6 and 7.6 months respectively (P=0.82). Of the 8 APMF patients, two are alive, with follow-up duration of 14 and 20 months, respectively. In the AMKL group, only one patient is alive, with follow-up duration of 55 months. All three patients have undergone allogeneic bone marrow transplant.ConclusionIn summary, our study illustrated important clinical and pathologic differences between APMF and AMKL, two similar but distinct conditions. Allogenic stem cell transplant has shown promise in limited number of cases. Future trials evaluating the efficacy of novel therapies are warranted.Table 1Clinical and Laboratory features including treatment details of patients with APMF and AMKLAPMFN=8AMKLN=20P-valueAge in years (median)63650.11Gender, M:F5:310:100.69Splenomegaly at diagnosis, n (%)1 (12.5)8 (40)0.21Antecedent hematological malignancy08- myeloproliferative neoplasm 2- myelodysplastic syndromes0.02Hgb [median] g/dl9.68.70.73WBC [median] x 109/L1.14.40.15Platelets [median ] X 109/L28360.29Blast % [median]2130.47LDH [median]4227090.12JAK2V617F mutation, n (%)1/7 (14)7/9 (78)0.04Bone marrow Cellularity, n (%): - Hypercellular - Normocellular - Hypocellular8 (100) 13 (65) 4 (20) 3 (15)0.07 0.29 0.54↑erythropoiesis, n (%)7 (87)2 (10)<0.01Left shift, n (%)5 (62)6 (30)0.20↑granulopoiesis, n (%)8 (100)5 (25)<0.01Left shift, n (%)8 (100)9 (55)0.01↑megakaryopoiesis, n (%)7 (87)16 (80)1.00Micromegakaryocytes, n (%)7 (87)18 (90)1.00↓megakaryocyte nuclear lobulation, n(%)7 (87)12 (60)0.21Clustering of megakaryocytes, n (%)5 (62)13 (65)1.00BM blast % [median]3314<0.01% of blasts CD34 + [median]100300.23% of blasts + for megakaryocyte markers [median] - CD61+ - CD41+ - Factor VIII+30 20 20100 75 500.020.10 0.01Reticulin fibrosis ≥ 3+, n (%)5 (62)9 (45)0.67Complex karyotype, n (%)4(50)10(50)1.00Treatment, n (%) - Induction chemotherapy - Hypomethylating agent - Clinical trial - Supportive care4 (50) 0 0 4(50)10(50) 2(10) 2 (10) 6(30)Allogeneic bone marrow transplant, n (%)3 (38)3 (15)Overall survival in months (median)8.677.610.82 DisclosuresNo relevant conflicts of interest to declare.

Big Data Analysis of Treatment Patterns and Outcomes Among Elderly Medicare Acute Myeloid Leukemia Patients

Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of 66 years. Over half of the patients are diagnosed at age 65 or older and have shown no improvement in outcomes compared to younger patients in last few decades. The goal of the study was to examine the patient characteristics associated with receiving treatment and the survival outcomes in an older population in routine clinical practice.Methods: This retrospective cohort analysis utilized data from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The database is a nationally representative collection of Medicare patients in 18 population-based SEER cancer registries from diverse geographic areas representative of about 26% of the United States population. The analysis included 8336 first primary AML patients diagnosed between January 1, 2000 to December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis. Chi-square test for categorical variables and ANOVA or t-test for continuous variables was used to assess differences in patient and disease related characteristics by treatment status. Kaplan-Meier curves and Cox proportional hazards regression assessed survival by treatment status adjusting for age, sex, race, prior myelodysplastic syndrome (MDS), poor performance indicators (PPI), comorbidity, income, education, marital status, year of diagnosis and geographic region. Logistic regression modelling assessed patient characteristics predictive of not receiving treatment.Results: There were 3327 (40%) patients who received treatment with chemotherapy within 3 months of diagnosis and 5009 (60%) patients who did not receive treatment. Treatment rates increased over the study time-period from 35% in the year 2000 to 50% in 2009 (p<.0001). Treated patients were younger (75 vs. 81 years), more likely male (55% vs. 50%), married (61% vs. 47%), lower incidence of antecedent hematologic malignancy (15% vs. 19% prior MDS), less likely to have poor performance indicators (7% vs. 17%) and had lower comorbidity score (p<.0001) than untreated patients. In the treated cohort, 57%, 25%, 10% and 8% had NCI comorbidity score of 0, 1, 2, and ≥3 respectively. In the untreated cohort, 47%, 25%, 14% and 14% had NCI comorbidity score of 0, 1, 2, and ≥3 respectively. The most common comorbidities were hypertension (51%), hyperlipidemia (33%), coronary artery disease (25%), diabetes (21%), and atrial fibrillation (19%). In the logistic regression analysis, increasing age, increasing comorbidity score, black race, prior MDS and PPI were shown to significantly decrease the likelihood of receiving treatment. The median unadjusted overall survival was 2.5 months for the overall population and was longer for treated patients (6.1 months) compared to untreated patients (1.5 months; log rank p <.0001; Figure 1). In multivariate survival analysis, treated patients exhibited a 43% lower risk of death compared to untreated patients (HR=0.57; 95% CI=0.54-0.60). Increasing age, increasing comorbidity score and PPI were significantly associated with higher mortality risks.Conclusions: Although therapy use has increased over time, this large observational study showed that about 60% of elderly AML patients remain untreated following diagnosis. In the multivariate survival analysis, use of anti-leukemic therapy was associated with significant survival benefit in this cohort of patients. These results suggest an opportunity to improve treatment strategies and delivery to optimize patient outcomes in elderly AML patients. [Display omitted] DisclosuresSatram-Hoang:Genentech, Inc.: Consultancy. Reyes:Genentech, Inc.: Employment. Hurst:Genentech, Inc.: Employment.

Influence of type of antecedent disorder on outcome of therapy-related AML.

6628 Background: Therapy-related AML (tAML) is an increasingly recognized consequence of chemoradiotherapy among cancer survivors but the latency period from antecedent diagnosis to its development is variable and not well-defined. Metaphase cytogenetics (MC) at tAML diagnosis effect prognosis, but the influence of the type of antecedent disorder for which treatment was previously given is less clear. Methods: We assessed retrospectively whether the type of antecedent diagnosis requiring therapy that led to tAML was predictive of response and overall survival (OS) following development of tAML. Results: Of 64 tAML patients (pts) treated with 7+3 chemotherapy over a seven year period, 67% had prior chemo/radiotherapy for a solid tumor (ST), 27% for a hematologic malignancy (HM), and 6% for an autoimmune disorder (AI). At tAML diagnosis, 18 pts (28%) had unfavorable MC, 33 (52%) intermediate, and 12 (19%) favorable, by CALGB risk criteria. The median latency from chemo/radiotherapy exposure to tAML was 4.7 years (range .5 – 41.5) and was inversely correlated to pt age (younger pts had longer latency, even if <65 years, Spearman r=-.42, p=.002). In multivariable analysis age at primary diagnosis (p<.001) and prior mitotic inhibitor exposure (p=.03) were predictors of shorter latency. Median age was 60 years, and 41 pts (64%) achieved CR. Age >60 was the only significant factor predictive of poor response. 2-year OS was 28%, with an estimated median OS of 11.7 months. Unfavorable MC (p=.01, hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.14-2.73) and an antecedent HM or AI (p=.04, HR 1.92, 95% CI 1.02-3.58) were independent predictors of inferior OS. There was a trend for worse OS among pts developing tAML 3-10 years following exposure, compared to tAML <3 or >10 years. Pts with unfavorable MC or with intermediate MC and tAML arising from HM or AI had significantly worse median OS than pts with favorable MC or with intermediate MC and tAML arising from ST (8.1 vs 20.8 months, p=.01, HR 2.24, 95%CI 1.21-4.15). Conclusions: The type of antecedent disorder for which pts receive therapy prior to development of tAML is relevant prognostically. Compared to pts treated for prior ST, pts treated for prior HM or AI exhibit worse OS to induction chemotherapy for tAML.