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The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Introduction: In PACE (NCT01207440), patients with refractory chronic-phase chronic myeloid leukemia (CP-CML) with substantial prior second-generation tyrosine kinase inhibitor (TKI) treatment demonstrated deep, lasting responses to ponatinib. However, long-term follow-up identified rates of arterial occlusive events (AOEs) as a risk. OPTIC (NCT02467270) is a randomized Phase 2 trial evaluating ponatinib at 3 starting doses: 45 mg, 30 mg, and 15 mg daily in patients with CP-CML resistant/intolerant to ≥2 TKIs or with a T315I mutation. The interim analysis showed that the 45-mg (vs 30 mg or 15 mg) starting dose (with reduction to 15 mg upon response) provided the best clinical outcomes and responses were maintained in >75% of patients who dose reduced. Here, we present efficacy and safety outcomes by baseline mutation status and line of treatment for the 3 dose cohorts. Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with T315I mutation were randomized to ponatinib starting doses of 45 mg (Cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily (qd). Doses were reduced to 15 mg on achievement of ≤1% BCR-ABL1ISin Cohorts A and B. Doses also could be reduced for safety. The primary endpoint is ≤1% BCR-ABL1IS at 12 months. In this analysis, the outcome was analyzed by baseline mutation status (none, any, T315I, and non-T315I) and number of prior TKIs (≤2 or ≥3) in the intent-to-treat (ITT) population. Treatment-emergent adverse events (TEAEs), serious TEAEs, and AOEs by adjudication were summarized by number of prior TKIs (≤2 or ≥3). Interim analysis results are descriptive. Results: Patients (N=283) were randomized: A/B/C n=94/95/94; median age was 48 y (18‒81 y). Seven patients were excluded from the intent-to-treat population (N=276) because they had atypical transcripts. Mutation status was well balanced between cohorts; 59% had no mutation, 41% had ≥1 baseline mutation, 24% had T315I, and 17% had a non-T315I mutation. In all categories of mutation status, the rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, with the most notable differences seen in patients with T315I (A: 60%, B: 25%, C: 6%) (Table 1). Patients with no mutations or other mutations had smaller differences but the outcomes all still favored 45 mg. Patients in all cohorts were treated with multiple TKIs, with 54% (A), 60% (B), and 53% (C) having 3 or more prior TKIs. The rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, both in patients treated with ≤2 or ≥3 prior TKIs (43% and 49%, respectively) (Table 1). Table 2 shows rates of TEAEs and TE-AOEs by cohort and number or prior TKIs. There was a trend toward higher event rates in Cohort A and for patients treated with ≥3 TKIs. Rates of adjudicated AOEs were low (≤6%) in all 3 cohorts irrespective of the number of prior TKIs. Conclusions: At this interim analysis with a median follow-up of ~21 months, the maximum benefit:risk, regardless of mutation status or number of prior TKIs, was observed in patients treated with a 45-mg starting dose, with a reduction to 15 mg upon achievement of response. Patients with the T315I mutation who initiated ponatinib at 45 mg experienced better response rates than those who initiated ponatinib at 30-mg or 15-mg starting doses. Primary analysis will provide a refined understanding of the benefit:risk profile of 3 different starting doses of ponatinib. Disclosures Cortes: BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; Telios: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hochhaus:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Mauro:Sun Pharma/SPARC: Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Talpaz:Novartis: Research Funding; IMAGO: Consultancy; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Chuah:Korea Otsuka Pharmaceutical: Honoraria; Pfizer: Other: Travel, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Lipton:Bristol-Myers Squibb: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Deininger:SPARC: Research Funding; Novartis: Consultancy, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Other, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Fusion Pharma: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; DisperSol: Consultancy; Leukemia & Lymphoma Society: Research Funding; Gilead Sciences: Research Funding; Ariad: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Pfizer: Honoraria, Other, Research Funding. Schiffer:BMS: Consultancy; Novartis: Consultancy; Takeda: Research Funding. García Gutiérrez:Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. de Lavallade:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Etienne:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Srivastava:Takeda: Current Employment. Rosti:Novartis: Speakers Bureau; Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m2 per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to 1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

Background: Treatment of chronic myeloid leukemia (CML) with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet has been associated with reduced health-related quality of life and very high cost. Discontinuing TKIs with regular monitoring is safe, but little is known about the impact of discontinuation on patient-reported outcomes (PROs). In the largest U.S. study to date, we evaluated molecular recurrence of CML and PROs after TKI discontinuation. Methods: The Life After Stopping TKIs (LAST) study was a prospective single-group longitudinal study. Key inclusion criteria were age > 18 years, patient on TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib) for > 3 years with documented BCR-ABL < 0.01% by PCR for > 2 years, and no previous TKI resistance. We monitored disease outcome (PCRs by central lab) and PROs (PROMIS computerized adaptive tests via REDCap) monthly for the first 6 months, every 2 months until 24 months, then every 3 months until 36 months. Molecular recurrence was defined as > 0.1% BCR-ABL IS by central lab (loss of major molecular response [MMR]). We considered 3 points to be clinically meaningful and hypothesized that by 6 months after TKI discontinuation, fatigue, depression, sleep disturbance, and diarrhea would improve by at least 3 points each, corresponding to a standardized effect size of 0.3. Given reports of a withdrawal syndrome of musculoskeletal pain in some patients after discontinuation, pain was an additional outcome of particular interest. For each PRO domain, we estimated a polynomial piecewise linear mixed effects model that specified one nonlinear trajectory after TKI discontinuation and, for those with molecular recurrence, another trajectory after TKI restart. The models included patient-level random effects for the intercepts and linear slopes. Results: From 12/2014 to 12/2016, 172 patients enrolled from 14 U.S. sites. Median age was 60 years (range 21-86) and 89 (52%) were female. The median time on TKI prior to enrollment was 81 months (IQR 54-123). With a minimum follow-up of 24 months, 107 (62%) patients remained in a treatment free remission (TFR). Reasons for restarting therapy were: loss of MMR by central (n=56) or local (n=2) lab, patient decision (n=4), and withdrawal syndrome (n=3). Missing PRO data was minimal (< 5%) with > 2000 assessments completed. For patients in TFR at 6 months, the average estimated improvement in fatigue was 2.6 points (95% CI 2.5-2.7), depression was 1.9 points (95% CI 1.8-1.9), sleep disturbance was 0.9 points (95% CI 0.8-1.0), and diarrhea was 2.7 points (95% CI 2.6-2.7). The average estimated worsening in pain interference (i.e., the extent to which pain affects daily life) was 0.4 points (95% CI 0.3-0.5). The figure shows the distribution of estimated change for each domain at 6 months. All patients showed improvements in depression, diarrhea, and fatigue. About 1 in 6 patients (17%) experienced a clinically meaningful (i.e., at least 3 points) improvement in fatigue and/or diarrhea at 6 months. Conclusion: The LAST study is the largest US TKI discontinuation study to date, and the first to include comprehensive PRO measurement. For patients in TFR at 6 months, TKI discontinuation conferred modest benefits in fatigue and diarrhea on average, with a negligible increase in pain interference. Some patients experienced more notable improvements in fatigue and diarrhea. Planned secondary analyses will include change over time up to 3 years and evaluation of additional PRO domains, including anxiety, physical function, social function, and sexual function. Our results provide important new evidence to support shared patient-provider clinical decision making regarding TKI discontinuation for patients with CML. Figure. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy. Larson:Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy. Oehler:Blueprint Medicines: Consultancy; NCCN: Consultancy; Pfizer Inc.: Research Funding. Deininger:Humana: Honoraria; Incyte: Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Sangamo: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Ritchie:Tolero: Other: Advisory board; Celgene: Other: Advisory board; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene, Incyte, Novartis, Pfizer: Consultancy; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Genentech: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Atallah:Jazz: Consultancy; Helsinn: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy.

Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo >500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a >2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients ( Results: Among 205 patients randomized, 14 were excluded from the primary analysis due to a 4 month interruption in drug supply. Among the 195 evaluable patients, 96 were assigned to Arm A and 99 to Arm B. Baseline characteristics were well balanced between arms with 85% of patients heavily TD, receiving a median of 4 units/8 weeks. Overall, 93% of patients received prior treatment with Epo and 18% azanucleosides. In an intent to treat analysis, 28/99 patients (28.3%) in Arm B achieved MER compared to 11/96 (11.5%) in Arm A (P=0.004). Among 136 patients who completed 16 weeks of study treatment, 28/72 (38.9%) and 10/64 (15.6%) achieved MER, respectively (P=0.004). Forty-four Arm A non-responders crossed over to combination-therapy with 11 patients (25%) experiencing a MER. Multivariable logistic regression analysis identified only treatment with LEN + EA as an independent covariate for erythroid response (P=0.01). Responses were durable with MER median duration of 23.8 months in Arm B compared to 13 months in Arm A. There was no significant difference in the frequency or distribution of >Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Introduction: Oral novel therapeutics place a high financial burden on patients. A specialty pharmacy at Karmanos Cancer Institute (KCI) was established which streamlines prior authorization, determines patient cost-sharing, then automatically applies for additional financial assistance (through co-pay cards or foundation grant funding as needed) prior to setting final patient cost-sharing and drug delivery. We evaluated patterns of cost and need for additional funding since this program was established. Methods: We used the KCI Specialty Pharmacy dataset for a retrospective review of patients who received prescriptions for hematologic malignancies between March 2018 - May 2019. Oral therapeutics >$10,000/month average wholesale price were considered high cost. We evaluated patients by drug prescribed and insurance type (Medicare, Medicaid, Private) and gathered information on insurer cost, final patient cost-sharing, cost covered by foundation grant assistance (if needed), and cost covered by manufacturer co-pay cards (if needed). We also calculated time in days from prescription written date to date of prior authorization, as well as prescription written date to date of delivery to the patient for all new first-time prescriptions. Results: 214 prescriptions among 100 patients were available for analysis. 2 of these patients switched insurance types. Drugs that were evaluated included imatinib, dasatinib, bosutinib, nilotinib, ponatinib, ruloxitinib, venetoclax, acalabrutinib, ibrutinib, ixazomib, midostaurin, gilteritinib, everolimus (for relapsed Hodgkin lymphoma), vorinostat, and enasidenib. The majority of patients had Medicare +/- supplemental insurance (52%), followed by private insurance (33%), and Medicaid (17%). Among all patients, 35% required additional financial assistance (for 75 claims). Most of these were through foundation grant funding (26% of all patients, 59 claims) and the remaining through manufacturer co-pay cards (9% of all patients, 16 claims). Medicaid patients did not require additional financial aid and have low cost-sharing given cost-sharing subsidies provided by Medicaid. Most of the patients requiring financial assistance were Medicare patients receiving foundation grant funding (Table). There were 10% of patients who did not receive additional assistance, but had high cost-sharing exceeding $100/prescription (range $295-$3514). Claims costs for all prescriptions totaled just over $2,000,000. The majority of the cost was paid by insurers with more than half covered by Medicare, ~$52,950 paid by foundation grant assistance, ~$8,486 paid by manufacturer co-pay cards, and $23,818 by patient cost-sharing. There were 105 first-time prescriptions to evaluate. When comparing the times required for prior authorization and delivery of drugs to patients, median times were similar by insurance type (Table), and most prescriptions received prior authorization approval within 1 day and were delivered within 7 days. Conclusions: Financial assistance was needed for 35% of all patients on novel therapeutics, mostly through foundation grant assistance. Medicare covered half of total 2 million dollar cost. Medicare patients bear the most burden, with 40% requiring foundation grant assistance, and 19% acquiring high co-pays. The KCI Specialty Pharmacy attained a total of ~$61,433 in financial assistance, and provided an efficient process for fast authorization and drug delivery which did not vary by insurance type or need for grants. Disclosures Smith: Genentech Advisory Council: Other: Pharmacy Consultant.

Introduction: RUNX1 (aka AML1; 21q22.12) is indispensable in the establishment of definitive hematopoiesis in humans. Activating RUNX1 mutations are associated with both Acute Myeloid and Lymphoblastic Leukemias (AML, ALL). On the other hand, hypofunctioning RUNX1 mutations cause dominantly inherited Familial Platelet Disorder (FPD). RUNX1 FPD has a high risk for progression to pancytopenia, myeloproliferative disorders (MPD) or AML, hence the new WHO category FPD with myeloid malignancy (FPD-MM). Those with MM carry mutations in other genes seen in AML, MDS. It is a relatively rare disorder with ~75 affected kindreds reported worldwide (Sood, et al. Blood 2017). Detailed reviews of pediatric cases are few. Case Histories: We encountered two children with RUNX1 associated thrombocytopenia; the mutations are novel. The first family is that of 14 yr old AAF, presenting with fainting- blood counts are shown in Table 1; fetal hemoglobin (HbF) was elevated; bone marrow was hypercellular with 6% type 1 blasts, extreme paucity of megakaryocytes, erythroid hyperplasia and large numbers of sea blue histiocytes. The high HbF suggested JMML while the monocyte CD16;14 profile (95.6% CD14+ cells) was similar to that seen in the adult type Chronic Myelomonocytic Leukemia (CMML). Her mother has pancytopenia without excess blasts in the marrow. The second case presented with neonatal thrombocytopenia; father has history of excessive bruising. Results: Blood counts and values for HbF are listed in Table 1. Molecular testing: Case1: A Myeloid gene panel showed RUNX1 - NM_001754.4:c.501delT, p.Ser167Argfs*9; PHF6 - NM_032458.2:c.902dupA, p.Tyr301*; CUX1- NM_001202543.1:c.2378delC, p.Pro793Argfs*26. No mutations were noted in PTPN11, CBL or RAS genes, the latter confirmed by JMML panel done at University of California, San Francisco. UCSF panel identified a mutation in SH2B3, a gene linked to erythrocytosis not caused by JAK2 mutations. Her mother has the same RUNX1 mutation, thus identifying a germline mutation of RUNX1 in her and her child but not the PHF6, CUX1 or the SH2B3 mutations seen in her daughter. A half sibling is unaffected and is a potential transplant donor for the mother. Case2: No coding sequence mutations were detected in genes associated with familial thrombocytopenia including ETV6, GATA1 and RUNX1. Array Comparative Genomic Hybridization studies (Prevention Genetics) identified a heterozygous deletion of the entire exon 5 of RUNX1. To understand the complex findings in family 1 additional studies were done- DRAQ5, CD71, Fetal Hb staining showed that NRBC in Case 1 contained predominantly high HBF cells. LIN28B was markedly elevated in the proband but not the mother (HbF- normal); LIN28B expression was normal in Case 2. Treatment/Outcome: In Case 1, low dose decitabine therapy resulted in the control of MPD features with good Hb recovery and normalization of the monocyte CD16;14 profiles. There was no platelet response to decitabine nor to a course of valproic acid. The child died of fulminant acute graft vs host disease affecting the liver following a 4/6 cord mismatch transplantation. Mother continues to show moderately severe pancytopenia requiring frequent transfusion support. The second child is symptom free with mild thrombocytopenia. Discussion: The hybrid JMML/CMML features in the index child are likely caused by the concurrent CUX1/PHF6/SH2B3 mutations. We are unable to establish if these are true de novo mutations as the father was not available for study; she had no full siblings. Neither high HbF nor high LIN28B are known feature of FPD by itself nor CMML or Polycythemia Vera (p Vera). Recently, the high HbF in JMML has been linked to high expression of LIN28B. SH2B3 mutation may have contributed to the high erythroid proliferation observed in our case. Induced CUX1 haploinsufficiency in mice causes MPD akin to CMML and megakaryocytic (Meg) proliferation (An N, et al. Blood 2018). The virtual absence of Megs in our case indicates that the CUX1 mutation was unable to overcome the Meg ploidization defect caused by the RUNX1 mutation. PHF6 mutations occur in T-ALL and AML but have not been linked to high HbF. Conclusions: Normal HbF and normal LIN28B expression in the mother of Case1 and in Case2 indicate that increased LIN28B is linked to the high HbF in Case 1 and that high LIN28B itself is a consequence of the malignant transformation caused by the concurrent CUX1/PHF6/SH2B3 mutations. Disclosures Chitlur: Baxter, Bayer, Biogen Idec, and Pfizer: Honoraria; Novo Nordisk Inc: Consultancy. Ravindranath:AGIOS: Other: Site Investigator for Pyruvate Kinase Deficiency.

Background: Prior studies have demonstrated disparities in the utilization of stem cell transplant (SCT) based on age, race, and insurance type. Whether delays to SCT occur as a result of these disparities is not well established. We evaluated whether we observed similar trends in a large metropolitan SCT center with a large population of minority patients (pts). Methods: We identified pts at Karmanos Cancer Institute who had their initial SCT consultation from 2009 - 2016, and evaluated pts who received or did not receive SCT for the diagnoses of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), multiple myeloma (MM), or non-Hodgkin lymphoma (NHL). The associations of SCT receipt status with 4 chosen predictors (age at the initial SCT consult (continuous variable), race [Caucasian vs. Non-Caucasian], sex, diagnosis [AML/ALL vs MDS vs. NHL vs MM]) were assessed by logistic regression models. Of those who received SCT, time to SCT was calculated from the date of coordinator intake (date of 1st SCT consult + screening initiated) to the date of SCT. Kaplan-Meier estimates were used to summarize the distributions of time to SCT. Cox proportional hazards regression models were fit to assess associations between 7 prespecified predictors (age, race, sex, diagnosis, type of SCT [Auto vs. Allo], county [Metro (three counties within Metro Detroit) vs. Non-Metro], and insurance [Private vs. Public (Medicaid, Medicare, others)] and time to SCT. Results: 2811 pts were included in our study, and of these 1644 received SCT. In multivariable analyses, non-Caucasian (n= 585 with 495 African-Americans) compared to Caucasian (n=2226) (OR 0.68, p We then evaluated all pts who received SCT (n=1631). 1307 (80%) were Caucasian and 324 (20%) were non-Caucasian (273 were African-Americans). The median time to SCT was 3.24 months for all pts and 75% underwent transplantation by ~4.5 months. In the multivariable analysis, non-Caucasian (median 3.8 months) compared to Caucasian (median 3.28 months) (HR 0.75, p Conclusion: In this large retrospective analysis, we observed that race, age, and diagnosis are independent significant factors impacting receipt of SCT. Race and insurance status were independent factors associated with more prolonged time to SCT. Importantly, the effect of racial disparities in receipt of SCT and time to SCT are declining over time. Further analysis of the impact of social, medical, and financial factors are in progress. Disclosures No relevant conflicts of interest to declare.

Introduction: The development of tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of patients (pts) with chronic myeloid leukemia (CML), with the perception by healthcare professionals that this is now a chronic disease to be managed. However, the need for continuous TKI therapy may result in ongoing toxicities, limits on fertility, and financial hardship. The H. Jean Khoury Cure CML consortium (HJKC3) is a collaborative effort of physicians and researchers at 17 academic centers. The HJKC3-001 2017 Patient Survey sought to define pts' expectations for treatment in CML to serve as a guidepost for future research in this area. Methods: Pts with CML were recruited by HJKC3 physicians, CML advocacy groups, and social media. An online survey platform (Qualtrics®) was used to obtain informed consent and administer the questionnaire. The anonymous survey was designed to gauge priorities for research in CML, understand patient definitions of cure, and elicit patient interest in future directions for CML therapy. Patient demographic and health characteristics were also collected. The data were analyzed using descriptive statistics. Results: Of the 458 pts who completed the survey, the median age of respondents was 54 years (range 18-81); 88% of pts identified as non-Hispanic white, 2% as non-Hispanic black, 2% as non-Hispanic Asian, 4% as Hispanic, and 4% other. Patients rated their overall health as poor (4%), fair (18%), good (40%), very good (28%) and excellent (9%). All but one respondent said that more research was needed for CML, with pts indicating their preferences for where they considered the need was greatest (Table 1). Overwhelmingly, 94% of respondents considered cure in CML as not taking any more pills. All but three respondents had received treatment with a TKI, with 26% (n=119) of pts having previously stopped their TKI medication for at least one month. When presented with the possibility of stopping all future treatment for CML with additional treatment, 97% of pts were willing to add another oral medication to their TKI while 89% of pts would accept intravenous treatment in addition to a TKIs. Half of the pts had discussed treatment discontinuation with their physician, with 45% considering this option in an attempt at treatment-free-remission. Of the pts that stopped taking their TKIs for at least one month, 65% did so because of side effects and another 10% because of cost. Conclusion: This survey demonstrates that pts do not consider disease control with life-long oral medication as cure; rather, cure requires the absence of treatment. Overwhelmingly, pts indicated the importance of continuing CML research with an ultimate goal of treatment-free cure. The advent of oral TKIs has been a tremendous success for pts with this disease. Nevertheless, it remains a source of disruption in pts' lives, particularly through side effects and costs. The HJKC3 was initiated with the goal of curing CML. Disclosures Atallah: Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Abbvie: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding. Goldberg:COTA Inc.: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Druker:ARIAD: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; McGraw Hill: Patents & Royalties; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Oregon Health & Science University: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Celgene: Consultancy. Larson:Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ritchie:Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria.

The management of hematologic malignancies, including chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and acute lymphocytic leukemia (ALL), has led the way in establishing the use of regular laboratory testing to assess for residual disease on an ongoing basis. The goals of

The management of patients with myelodysplasia (MDS) can be quite complex and varies according to both the clinical manifestations in individual patients as well as complicating medical conditions. Allogeneic stem cell transplantation is the only curative treatment, but because of the older age of the patient population must be applied selectively, particularly in those with lower risk MDS as well as in patients whose clinical course is more frankly “preleukemic.” Issues pertinent to the use of 5-azacytidine, decitabine and lenalidomide in patients with both higher and lower International Prognostic Staging System (IPSS) stage disease are discussed.

A variety of patientand product-related factors influenced the outcome of 6379 transfusions given to 533 patients in the Trial to Reduce Alloimmunization to Platelets (TRAP). Responses measured were platelet increments, interval between platelet transfusions, and platelet refractoriness. Patient factors that improved platelet responses were splenectomy and increasing patient age. In contrast, at least 2 prior pregnancies, male gender, splenomegaly, bleeding, fever, infection, disseminated intravascular coagulation, increasing height and weight, lymphocytotoxic antibody positivity, an increasing number of platelet transfusions, or receiving heparin or amphotericin were associated with decreased posttransfusion platelet responses. Platelet factors that were associated with improved platelet responses were giving ABO-compatible platelets, platelets stored for 48 hours or less, and giving large doses of platelets while ultraviolet B (UV-B) or gamma irradiation decreased platelet responses. However, in alloimmunized lymphocytoxic antibody-positive patients, the immediate increment to UV-B-irradiated platelets was well maintained, whereas all other products showed substantial reductions. Refractoriness to platelet transfusions developed in 27% of the patients. Platelet refractoriness was associated with lymphocytotoxic antibody positivity, heparin administration, fever, bleeding, increasing number of platelet transfusions, increasing weight, at least 2 pregnancies, and male gender. The only factors that reduced platelet refractoriness rates were increasing the dose of platelets transfused or transfusing filtered apheresis platelets.

The Cancer and Leukemia Group B (CALGB) study 9222 tested the hypothesis that treatment intensification of acute myeloid leukemia (AML) in first remission with multiple chemotherapy agents is superior to high-dose cytarabine (HiDAC) alone. We enrolled 474 patients younger than 60 years old with untreated de novo AML. Daunorubicin and cytarabine resulted in complete remission (CR) in 342 patients (72%), and 309 of these patients were randomized to receive one of 2 different intensification regimens. The first regimen consisted of 3 courses of HiDAC. The second regimen consisted of one course of HiDAC, a second course with etoposide and cyclophosphamide, and a third course with diaziquone and mitoxantrone. After a median follow-up time of 8.3 years, the median survival for all randomized patients was 2.8 years (95% CI, 1.9-6.8 years). There was no difference in disease-free survival (DFS) between the 2 regimens (P = .66). The median DFS was 1.1 years (95% CI, 0.9-1.7 years) for patients receiving HiDAC and 1.0 year (95% CI, 0.9-1.3 years) for those receiving multiagent chemotherapy. Cytogenetics was the only pretreatment characteristic prognostic for DFS, but there was no evidence of a differential treatment effect within cytogenetic risk groups. Toxicity was greater with multiagent chemotherapy. These 2 postremission regimens produced similar outcomes.

Fludarabine and rituximab combination therapies in chronic lymphocytic leukemia (CLL) have yielded promising early results, but no comparative efficacy data relative to standard fludarabine treatment regimens have been reported. To assess the effect of the addition of rituximab to fludarabine therapy, we retrospectively compared the treatment outcome of patients with similar clinical characteristics enrolled on 2 multicenter clinical trials performed by the Cancer and Leukemia Group B and the US Intergroup that used fludarabine and rituximab (CALGB 9712, n = 104) or fludarabine (CALGB 9011, n = 178). In multivariate analyses controlling for pretreatment characteristics, the patients receiving fludarabine and rituximab had a significantly better progression-free survival (PFS; P < .0001) and overall survival (OS; P = .0006) than patients receiving fludarabine therapy. Two-year PFS probabilities were 0.67 versus 0.45, and 2-year OS probabilities were 0.93 versus 0.81. Infectious toxicity was similar between the 2 treatment approaches. These comparative data are retrospective and could be confounded by differences in supportive care or dissimilar enrollment of genetic subsets on each trial. Confirmation of these findings will require a prospective randomized trial comparing fludarabine and rituximab to fludarabine.

Whites have a more favorable prognosis than African Americans for a number of cancers. The relationship between race and outcome is less clear in acute myeloid leukemia (AML). Using data from 7 Cancer and Leukemia Group B studies initiated from 1985 to 1997, we conducted a retrospective cross-sectional analysis of 2570 patients (270 African American and 2300 white) with de novo AML who received induction chemotherapy. African Americans were younger than whites (48 versus 54 years, P

New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte–mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.

The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m2/d by 7-day infusion, with daunorubicin 60 mg/m2 and etoposide 100 mg/m2 daily for 3 days (ADE), or daunorubicin 40 mg/m2 and etoposide 60 mg/m2 for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P = .008). Nevertheless, disease-free survival (median 7 vs 8 months; P = .38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833–modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P = .03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833–modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P = .07). Further modulation trials in older patients must await the design of less-toxic regimens.

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.

The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients.

Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either 2.5 or 5 μg/kg/day of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) or a placebo administered subcutaneously after completion of chemotherapy. The study evaluated the toxicity of PEG-rHuMGDF and any effect on the duration of thrombocytopenia. Each of 35 patients under 60 years of age received the following therapy: 45 mg/m2 daunorubicin on days 1-3, 100 mg/m2cytarabine (ARA-C) for 7 days, and 2 gm/m2 high-dose ARA-C (HIDAC) for 6 doses on days 8-10. The 22 patients 60 years or older received standard daunorubicin and ARA-C without HIDAC. PEG-rHuMGDF was well tolerated, and no specific toxicities could be attributed to its use. There was no difference in the time to achieve a platelet count of at least 20 × 109/L among the 3 groups (median 28-30 days for patients less than 60 years old and 21-23 days for patients 60 years or older). Patients receiving PEG-rHuMGDF achieved higher platelet counts after remission. However there was no significant difference in the number of days on which platelet transfusions were administered among the 3 groups. The complete remission rate was 71% for patients less than 60 years and 64% for those 60 years or older, with no significant difference among the 3 groups. Postremission consolidation chemotherapy with either placebo or PEG-rHuMGDF was given to 28 patients beginning the day after completion of chemotherapy. There was no apparent difference in the time that was necessary to reach a platelet count of at least 20 or 50 × 109/L or more platelets or in the number of platelet transfusions received. In summary, PEG-rHuMGDF was well tolerated by patients receiving induction and consolidation therapy for AML; however, there was no effect on the duration of severe thrombocytopenia or the platelet transfusion requirement.

Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

Although acute myeloid leukemia (AML) with t(8; 21) (q22; q22) is associated with a high complete remission (CR) rate and prolonged disease-free survival, treatment outcome is not universally favorable. Identifying factors that predict for treatment outcome might allow therapy to be optimized based on risk. AML with t(8; 21) has a distinctive immunophenotype, characterized by expression of the myeloid and stem cell antigens CD13, CD15, CD34, and HLADr, and frequent expression of the B-cell antigen CD19 and the neural cell adhesion molecule CD56, a natural killer cell/stem cell antigen. Because CD56 expression has been associated with both extramedullary leukemia and multidrug resistance, we sought to correlate CD56 expression with treatment outcome in AML with t(8; 21). Pretreatment leukemia cells from 29 adult de novo AML patients with t(8; 21) treated on Cancer and Leukemia Group B (CALGB) protocols were immunophenotyped by multiparameter flow cytometry as part of a prospective immunophenotyping study of adult AML (CALGB 8361). CD56 was expressed in 16 cases (55%). There was no correlation between CD56 expression and age, sex, white blood cell count, granulocyte count, the presence of additional cytogenetic abnormalities, or the presence of extramedullary disease at diagnosis. The CR rate to standard-dose cytarabine and daunorubicin was similar for cases with and without CD56 expression (88% v 92%; P = 1.0). Post-CR therapy included at least one course of high-dose cytarabine in 24 of 26 patients who achieved CR; numbers of courses administered were similar in cases with and without CD56 expression. Although post-CR therapy did not differ, CR duration was significantly shorter in cases with CD56 expression compared with those without (median, 8.7 months v not reached; P = .01), as was survival (median, 16.5 months v not reached; P = .008). We conclude that CD56 expression in AML with t(8; 21) is associated with significantly shorter CR duration and survival. Our results suggest that CD56 expression may be useful in stratifying therapy for this subtype of AML.

Trans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA. In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21waf1/cip1 as well as GADD45 mRNA. Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RARβ and RARγ and express a truncated RARα. Thus, CD437 induction of p21waf1/cip1 and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia.

The Shc gene encodes three proteins that have been implicated as mediators of signal transduction from growth factor receptors and nonreceptor tyrosine kinases to Ras. Overexpression of Shc in established murine fibroblasts results in oncogenic transformation, indicating that Shc has oncogenic potential. Shc proteins contain a carboxy terminal SH2 domain and a novel non-SH2 phosphotyrosine-binding (PTB) domain that specifically recognizes a phosphorylated NPXpY motif in target proteins such as the epidermal growth factor receptor. We show here that Shc is constitutively tyrosine-phosphorylated in all primary acute myeloid leukemias analyzed and that, in some of these leukemias, Shc is associated through its PTB domain with a tyrosinephosphorylated protein of 140 kD (p140) in vivo. In factor-dependent cells, this 140-kD protein can be tyrosine-phosphorylated in vitro in response to cytokines involved in myeloid proliferation and differentiation, ie, granulocyte-macrophage colony-stimulating factor and colony-stimulating factor-1. A similar or identical protein of 140 kD is constitutively bound to the C-terminal SH3 domain of Grb2 in the same acute myeloid leukemias. In addition to p140, other tyrosine-phosphorylated proteins of 61 and 200 kD are constitutively associated with Shc in some of the leukemias analyzed. Our results implicate Shc, Grb2, p140, and additional tyrosine-phosphorylated proteins of 61 and 200 kD in signalling of acute myeloid leukemia cells.

This study evaluated the effect of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the duration of granulocytopenia and thrombocytopenia after intensive consolidation therapy with diaziquone (AZQ) and mitroxantrone for patients less than 60 years of age with acute myeloid leukemia (AML) in complete remission. Patients less than 60 years of age with AML who achieved complete remission (CR) with daunorubicin and cytarabine induction therapy, were scheduled to receive three sequential courses of high-dose cytarabine, cyclophosphamide/etoposide, AZQ, and mitroxantrone in a pilot study to determine their tolerance of these three sequential consolidation regimens. The initial patients treated with AZQ and mitoxantrone experienced prolonged bone marrow suppression and, therefore, subsequent cohorts were treated with G-CSF, 5 μg/kg, beginning the day after completion of the third cycle of chemotherapy. There was a marked decrease in the duration of granulocytopenia less than 500/μL in two groups of patients receiving two different dose levels of AZQ and the same dose of mitoxantrone compared with patients not receiving the G-CSF. There was also a decrease in the need for hospitalization, as well as the duration of hospitalization. There was a trend towards shortening of the duration of thrombocytopenia, as well. The duration of complete remission and overall survival was similar in patients who received or did not receive G-CSF. G-CSF markedly shortened the duration of granulocytopenia in patients with AML receiving intensive postremission consolidation with AZQ and mitoxantrone. There was no adverse effect on CR duration or survival.

A number of randomized trials have recently been completed evaluating the effect of hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor) as adjuncts to the treatment of patients with acute myeloid leukemia. Most studies used the growth factors to decrease the duration of neutropenia with the hope of reducing infectious morbidity and mortality. The results of these trials are generally quite consistent. Virtually all trials showed a modest reduction in the duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and the duration of hospitalization. There was no consistent benefit in terms of improvements in complete response rate, complete response duration, or overall survival. However, it is important that there does not appear to be an increase in the incidence of drug-resistant leukemia in trials in which the growth factor was begun after completion of the chemotherapy. Other trials administered growth factors either before or simultaneous with the chemotherapy in an attempt to enhance chemosensitivity and decrease drug resistance. None of these trials, whether conducted as part of initial induction therapy or in relapse, showed improvements in response rate or survival. Lastly, some anecdotal reports have suggested that occasional patients who receive growth factors as the only therapy for overt leukemia can achieve remission, possibly through a differentiating effect of the growth factor. However, there are very few such reports, and growth factor use in this situation is potentially dangerous and should be performed only in the context of a clinical trial. In summary, there appears to be no role at this time for priming of leukemia cells by growth factors to enhance the effect of chemotherapy, and more in vitro studies should be performed before further clinical trials of this approach. It is clear that growth factors administered after induction and possibly consolidation chemotherapy can shorten the duration of neutropenia, without a significant effect on treatment outcome. It is as yet unclear whether the use of growth factors in this fashion is cost effective.

Despite selection strategies that attempt to maximize the platelet donor pool, significant numbers of alloimmunized patients have few if any available donors. Although the number of potential donors increases when one antigen mismatched platelet transfusions (OAMPT) are considered, transfusions from such donors are often cited to fail to produce satisfactory platelet count increments. The presence of lymphocytotoxic antibody (LCTAB) correlates well with responsiveness to random donor platelet transfusions and serves as a good serologic screen for the diagnosis of alloimmunization. We therefore reviewed the results of OAMPT to alloimmunized patients and assessed the relationship between LCTAB levels in the recipient and posttransfusion platelet count increments. We noted an unexpectedly high percentage of good responses in our patient population: 73% of all OAMPT to recipients with LCTAB < 60% reactive, resulted in successful increments. In recipients with LCTAB > or = 60%, 58% of all transfusions were still successful. Despite a statistically significant inverse relationship between the level of LCTAB and the response of OAMPT to alloimmunized patients, 58% to 73% of recipients will have a satisfactory platelet recovery posttransfusion. These data support extending donor searches for alloimmunized patients to include any single mismatch particularly if a recipient's LCTAB has lower reactivity.

Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin 2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Cremophor (Crem) EL, the vehicle for intravenous delivery of cyclosporin A (CsA), has been reported to counteract multidrug resistance (MDR) in P-glycoprotein (Pgp)-over-expressing cell lines. Because of this, we sought to determine whether Crem functions independently as a modulator of MDR in blast cells obtained from acute myelogenous leukemia (AML) patients, and the nature of its interaction in combination with CsA in reversing an MDR phenotype. In the phenotypically classical MDR AML cell lines HL-60/Vinc (overexpresses Pgp) or HL-60/AR (does not overexpress Pgp), the dose causing half- maximum enhancement (D50) of daunorubicin (DNR, 1 micrograms/mL, 3 hours) accumulation was achieved by the combination of CsA and Crem (CsA/Crem) at 1.2 mumol/L CsA. In contrast, the D50 for Crem alone was approached at an amount that would be needed to suspend 6.2 mumol/L CsA for HL-60/Vinc, and 81 mumol/L CsA for HL-60/AR. The D50 concentrations for CsA alone (dissolved in ethanol, which does not alter DNR accumulation) were also higher than those for CsA/Crem, being 6.5 mumol/L for HL-60/Vinc, and 3.1 mumol/L for HL-60/AR. The maximum absolute level of enhancement of DNR accumulation (Emax) in each cell line was approximately equivalent for CsA/Crem or CsA alone, and was equal to the 3 hr intracellular DNR accumulation observed in parental, drug sensitive HL-60/W cells. For Crem alone, HL-60/AR and HL-60/Vinc cells showed markedly different responses: HL-60/Vinc cells attained intracellular DNR content comparable to HL-60/W, whereas HL-60/AR cells achieved only approximately 35% of this level. Multiple-drug effects were analyzed by calculation of the Combination Index (Chou and Talalay, Adv Enzyme Regul 22:27, 1984), which indicated that CsA and Crem are synergistic in causing enhancement of DNR accumulation in these MDR HL-60 cell lines. In blasts from AML patients, 5 mumol/L CsA/Crem or an equivalent amount of Crem alone each caused significant (P < .001) enhancement of DNR accumulation (60 AML-patient marrow samples) or DNR retention (51 AML-patient marrows). Similarly, CsA/Crem or Crem alone caused significant (P < .01) enhancement of the cytotoxicity of DNR in 36 AML blast cell specimens. The degree of enhancement of accumulation/retention or cytotoxicity by CsA/Crem was approximately equivalent to that obtained with Crem alone. These studies indicate that Crem can reverse an MDR phenotype in patient AML blast cells.

We investigated whether recombinant alpha 2b interferon (r alpha 2bIFN) would reduce the proportion of bone marrow Philadelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients daily with r alpha 2bIFN at 5 x 10(6)IU/m2 subcutaneously. Patients with complete remission, partial remission, or partial hematologic remission received treatment until progression; those with progressive disease were taken off study and observed for survival. Sixty-three (59%) of the patients achieved at least a partial hematologic remission (24 complete remissions and 39 partial remissions). The median time to response for the 63 responders was 3.4 months, with a median duration of remission of 52 months and with 81% of responders continuing in remission beyond 12 months. The median survival for the 107 patients was 66 months. Of 78 patients with cytogenetic follow-up data, 31 (40%) achieved a partial cytogenetic response (n = 17) or a complete cytogenetic response (n = 14). The percentage of cytogenetic responders among all patients was 29% (31 of 107 patients). The median time to first cytogenetic response was 9 months. A major dose reduction of r alpha 2bIFN (> or = 50%) was required at some time during treatment in 38% of patients, 26% required 10% to 49% dose reductions, and 36% had minor dose reductions of < or = 10%. No association was observed between dose received and the attainment of a cytogenetic response. None of the usual prognostic factors (sex, race, performance status, weight loss, time from diagnosis to treatment, hepatosplenomegaly, age, symptoms, hemoglobin, or platelet, blast, basophil, or white blood cell count) were significantly related to survival. These data provide confirmation that major cytogenetic responses to prolonged administration of subcutaneous r alpha 2bIFN occur in 20% to 38% (95% confidence interval) of chronic- phase Ph-positive patients. Although it is hypothesized that patients achieving major cytogenetic responses to r alpha 2bIFN should have prolonged remission duration and survival compared with nonresponders, analyses of the effect of cytogenetic responders by both “landmark” and time-dependent covariate techniques fail to provide statistically significant evidence for an effect of cytogenetic response on remission duration or survival. This may be due in part to an effect size insufficiently large to be detected with the number of patients treated in this study. Thus, confirmation of remission duration or survival benefit, if any, of r alpha 2bIFN therapy in Ph-positive chronic-phase CML must await the outcome of randomized trials comparing IFN with conventional agents.

This work was designed to discern the frequency of expression of classical multidrug resistance (MDR) in acute myeloid leukemia (AML) at the time of diagnosis, using Western blotting for P-glycoprotein (Pgp) and functional assays for an MDR phenotype (enhancement of daunorubicin [DNR] accumulation/retention and cytotoxicity by the known MDR modulators verapamil, cyclosporin A, and progesterone). Blast cells were studied from 49 newly diagnosed AML patients who were subsequently treated with the “3 and 7” combination of cytosine arabinoside (ara-C) and DNR. DNR accumulation (1 microgram/mL, 3 hours) and retention (16 hours) were determined by flow cytometry. Cyclosporin A (CsA, 5 mumol/L) or verapamil (6.6 mumol/L) each caused significant enhancement of DNR accumulation and retention in these blast cell samples (P < .001, Wilcoxon's test). Verapamil or CsA caused greater than 20% enhancement of DNR accumulation or retention in over 25% or 50% of these patients, respectively; however, there was no correlation with the presence or degree of enhancement and response to treatment. Progesterone (10 mumol/L) caused no significant enhancement of DNR accumulation or retention. The effects of the MDR modulators on the cytotoxicity of DNR was also determined in blast cells from 40 of the patients, using a flow cytometric assay. CsA alone was cytotoxic (caused an approximate 20% decrease in cell survival compared with control, P < .001); CsA or verapamil caused enhancement of 1 mumol/L DNR cytotoxicity (P < .001). Greater than 40% enhancement of cell kill by CsA or verapamil was observed in over 75% of patients studied. There was no difference in the degree of enhancement of cytotoxicity between patients clinically sensitive or resistant to treatment. Progesterone caused no enhancement in DNR cytotoxicity. In contrast to the functional assays, highly sensitive immunoblots using the C219 antibody to Pgp showed evidence of low level expression of Pgp in blast cells from only 3 of these patients: 1 was chemotherapy resistant, 2 were sensitive. Thus, although the functional assays suggest a high frequency of expression of a classic MDR phenotype in AML patients at the time of diagnosis, with enhancement by CsA obtained at a clinically relevant concentration (5 mumol/L), the frequency of Pgp expression detectable by C219 Western blots was low in these patients. This could be interpreted either that the method used was not sufficiently sensitive to detect Pgp in all of the blast cell specimens that actually overexpressed mdr1, or that the accumulation/efflux-based MDR phenotype observed is not always mediated by Pgp in these previously untreated patients.

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and - negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR- ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA- positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.

It can be impossible to identify compatible platelet donors for alloimmunized patients whose HLA type cannot be determined or who have uncommon HLA types. We have previously shown that histocompatible donors can be rapidly identified by “mass screening” of platelet concentrates (PC), which are readily available in all blood banks, using a solid-phase adherence platelet cross-matching technique. Compatible PC were given to five alloimmunized patients with multispecific HLA antibodies refractory to random donor (RD) PC and selected single-donor platelet transfusions. After transfusions which produced satisfactory responses, we identified the original whole blood donors to serve as apheresis donors. Thus, the donors selected were compatible in vitro by cross-matching, and in vivo by transfusion. Only 3% to 13% of PC cross-matched for these alloimmunized patients were potentially compatible and it was necessary to screen large numbers (65 to 205 U) of PC per patient. Eighteen of 22 PC-selected transfusions produced satisfactory increments, allowing selection of 12 donors, all of whom were willing to undergo apheresis. Ten of 12 of these single- donor transfusions were successful; the two unsuccessful transfusions were infused 2 weeks after the initial PC cross-match and were still compatible with the original serum, but incompatible with more recent serum, demonstrating a change in antibody reactivity. The HLA types of the successful single donors selected by PC cross-matching differed widely from the patients' HLA types and, therefore, these donors would not have been selected by standard approaches using HLA typing. Cross- matching large numbers of RD PC for the identification of apheresis donors is helpful in the management of the alloimmunized patient and may be of particular utility for blood centers that do not have access to HLA-typed donor pools.

Monitoring BCR-ABL transcript levels in patients on TKI therapy using real-time quantitative PCR is standard of care in the management of CML, and achieving sensitivity to 4.5 logs below baseline is important in patients being considered for TKI discontinuation. In order to accurately assess treatment response, it is essential to ensure that variability in testing methodologies is tightly controlled. This has resulted in substantial efforts to standardize BCR-ABL molecular measurement across laboratories by introducing an International Scale (IS). Here we describe the development and analytical evaluation of Xpert® BCR-ABL Ultra, an automated cartridge-based BCR-ABL monitoring assay incorporating lot-specific standardization to the International Scale as defined by WHO. The BCR-ABL Ultra cartridge simplifies the generation of highly accurate and reproducible assay results by integrating nucleic acid extraction, target amplification, and quantification of the BCR-ABL b3a2 or b2a2 transcripts relative to ABL in peripheral blood specimens. The assay turn-around-time is approximately 2.5 hours and has a %BCR-ABL/ABL(IS) dynamic range of ~6 logs, including two key milestones for the assessment of clinical response at ~10% (IS) (SD=~0.08Log) and ~0.0033% (IS) (SD=~0.25Log) (CMR4.5). Lot-to-lot standardization is achieved using a secondary standard panel of controls derived from and aligned to the first WHO international genetic reference panel. The secondary standards are produced at Cepheid as part of the assay kit manufacturing process and applied to every production lot of cartridges in order to improve assay reliability and reporting comparability. Analytical sensitivity studies using spiked-in CML cell lines demonstrated a limit of detection (LoD) and limit of quantification (LoQ) of 0.003% BCR-ABL/ABL (IS) with a limit of blank (LoB) of 0.00017%. In an analytical specificity study, assay results were negative in 100% of 70 known CML-negative samples, including 20 AML or ALL patients and 50 healthy donors. A study was further conducted to estimate the lower limit of clinical sensitivity using blood from 12 CML patients on TKI therapy who had achieved and maintained MMR with reporting below 0.05% (IS). Eleven out of twelve low CML subjects were detected in at least 19 out of 20 replicates tested per subject over a range of 0.038% (SD=~0.17Log) to 0.0011% (IS) (SD=~0.4Log). In conclusion, the Xpert BCR-ABL Ultra assay demonstrates sensitivity in the range necessary to make clinical decisions regarding the continuation of TKI therapy in patients achieving CMR4.5, and every production lot of cartridges is assigned a unique conversion factor guaranteeing alignment to the WHO International Scale. Disclosures Uy: Novartis: Research Funding.

Introduction Prophylactic platelet transfusions are often performed prior to bronchoscopy or broncho-alveolar lavage (BAL) to prevent bleeding in thrombocytopenic patients. There is a paucity of data to validate this approach, with a platelet transfusion threshold of Methods We identified 150 consecutive patients with platelet counts 30 and/or Cr>2.0) and coagulation studies (PT, PTT, INR) were identified. The British Thoracic Society guidelines1 were used to categorize bleeding as a result of bronchoscopy. Data were analyzed using descriptive statistics. Results The median age was 59 years (range 27-90), with two-thirds of patients (63%) being male. One hundred and seventeen (78%) patients had underlying malignancy and 55 (37%) had thrombocytopenia related to malignancy. Fellows and residents under the supervision of a bronchoscopy certified attending performed all but 4 of the bronchoscopies. Infection (40%) was the primary indication for bronchoscopy with BAL performed in 127 (85%) patients. Fifty-eight of 89 (65%) patients with baseline platelet counts 50,000/mm3. The platelet count did not rise to >50,000//mm3 in many transfused patients. Seventy patients (47%) had counts 50,000/mm3 at the time of bronchoscopy. 49% were receiving immunosuppressive medications, 45% had renal dysfunction and 8% had INR >1.5. Bloody lavage that resolved spontaneously without continuous suctioning (Grade 0) was observed in 9 (6%) patients. Bleeding that required continuous suctioning but then resolved spontaneously (Grade 1) was noted in 1 patient with a platelet count of 61,000/mm3. Of 10 total bleeding events, 7 occurred in patients who were intubated. Two additional patients with platelet counts of 30,000/mm3 and 53,000/mm3 had diffuse alveolar hemorrhage, which was present before bronchoscopy. “Old” blood and blood clots were observed in 6 patients. Discussion The low incidence of bleeding complications from bronchoscopy +/- BAL even in patients with platelet counts Table 1 Platelet count, transfusion history and bleeding complications during bronchoscopy Platelet count at the time of bronchoscopy Number (n) and percentage (%) of patients who underwent bronchoscopy Number of patients who received prior platelet transfusion Bleeding during bronchoscopy n % 0-15,000/mm3 9 6% (9/150) 5 Grade 0=1 pt 16-29 22 15% 16 Grade 0=2 pts 30-39 17 11% 9 Grade 0=1 pt 40-49 22 15% 9 Grade 0=3 pts 50-75 44 29% 14 Grade 1=1 pt 76-100 36 24% 10 Grade 0=2 pts Total 150 63 Grade 0=9 pts, Grade 1=1 pt. 1.Du Rand IA, Blaikley J, Booton R, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013:68 Suppl 1:i1-i44 Disclosures No relevant conflicts of interest to declare.

We analyzed and compared the cost-effectiveness of 2 strategies for treating CML patients -- using imatinib first in all (altering therapy as needed in a stepwise approach) or by physician’s choice, starting either imatinib or one of the approved second-generation tyrosine kinase inhibitors (TKIs) dasatinib or nilotinib. Currently, each TKI is patent-protected and commands about one-third of front-line CML treatment. Life-long treatment is recommended. Imatinib is losing patent exclusivity and facing generic competition presently in the US (in early 2016) and in EU member countries; its price is expected to drop 70-90% within two years following generic entry. We constructed a Markov model simulating outcomes over 5 years when imatinib 400 mg is used first for all incident chronic phase CML patients, or alternatively by physician choice using any of the 3 TKIs first. The model assumes the commercial payer or health system perspective. In the stepwise approach, if imatinib fails, patients are switched to dasatinib or nilotinib in equal proportions. Patients are assumed to switch drugs if they were intolerant or failed standard efficacy endpoints: complete cytogenetic response (CCyR) or major molecular response (MMR) as defined in the ELN recommendations (Baccarani et al. Blood 2013). The model adjusts the price of imatinib over time as generic competition begins within each market: 100% of the branded price for first 6-months; 60-80% for the second 6-months; 10-30% thereafter. For each drug, tolerance, efficacy and probabilities of treatment choice, failure, and switching were drawn from published clinical trials (principally IRIS, ENESTnd, DASISON, and second-line phase II and transplant studies) and used Sokal or Euro risk group data where available. Quality-adjusted life years (QALYs) were based on CML-specific health utilities (Szabo et al, 2010). For the US model, direct medical costs per patient were drawn from Marketscan (2001-2007) and included US annual drug prices: imatinib ($76,800), dasatinib and nilotinib ($102,000). Additional costs included patient monitoring, hospitalization, and allogeneic transplantation, if required. Costs and QALYs were discounted at 3% ($US; 2013 values). Univariate and multivariate sensitivity analyses tested parameters with the greatest impact on results. We also considered cost savings in years 4 and 5 from TKI discontinuation in a fraction of patients achieving MR4.5 in years 2 and 3. Results were interpreted from a willingness-to-pay (WTP) of $100,000/QALY. Compared to physician choice starting any TKI regimen ($172,076; 3.36 QALYs) over the first 5 years, stepwise therapy costs less and offers clinically-equivalent utility ($147,091; 3.25 QALYs) when generic imatinib is available. Thus, stepwise therapy is estimated to have an incremental cost-effectiveness ratio (ICER) of $227,136/QALY. The ICER was favorable for stepwise therapy for each Sokal risk group. The results are robust to changes based on univariate analyses of the most sensitive parameters (imatinib-associated probability of CCyR/MMR, price drops, and the health utility of suboptimal response or treatment failure). A Bayesian multivariate probabilistic sensitivity analysis using 10,000 Monte Carlo simulations suggested that stepwise therapy is cost-effective in 73.3% of simulations (point estimates above the diagonal WTP line in Figure 1). Limitations include efficacy data drawn from prospective trials; thus, results may not apply to patients with co-morbidities, older age, or lack of access to appropriate specialty care. We conclude that when imatinib loses patent protection in 2016 in the US and its price declines, it will be the cost-effective initial treatment strategy for chronic phase CML compared to dasatinib and nilotinib. Our model and results demonstrate that system-level cost-effectiveness can be estimated based on country-specific (1) CML incidence and prevalence, (2) CML treatment patterns and associated costs across all medical inputs, including drugs, (3) expected date for loss of patent exclusivity, and (4) pricing policies for generic drugs and formulary placement decisions. Comparative cost-effectiveness data for the US, UK, and other selected EU countries will be presented. Figure 1 Scatterplot of incremental cost-effectiveness ratios for physician’s choice vs stepwise therapy in Monte Carlo probabilistic sensitivity analysis Figure 1. Scatterplot of incremental cost-effectiveness ratios for physician’s choice vs stepwise therapy in Monte Carlo probabilistic sensitivity analysis Disclosures Larson: Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Apperley:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Baccarani:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Eigendorff:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Martinelli:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mueller:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Niederwieser:Novartis: Research Funding. Saussele:Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Silver:Novartis: Research Funding. Hehlmann:Novartis: Research Funding; Bristol Myers Squibb: Research Funding.

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Table 1 Efficacy results Patients 100 mg QD (n=167) 50 mg BID (n=168) 140 mg QD (n=167) 70 mg BID (n=168) MMR in assessed treated patients, n (%) 73 (46) 70 (44) 68 (44) 69 (46) PFS at 7 yrs, % (95% CI) 42 (33–51) 44 (35–53) 38 (30–47) 44 (35–52) OS at 7 yrs, % (95% CI) 65 (56–72) 70 (62–77) 73 (65–80) 68 (60–75) Table 2 Landmark analysis: Efficacy rates at 7 yrs Patients 100 mg QD (n=165) BCR-ABL ≤ 10% at 3 mos BCR-ABL > 10% at 3 mos PFS, % (95% CI) 56 (43–67) 21 (10–34) OS, % (95% CI) 72 (60–81) 56 (42–68) Transformation-free,a% (95% CI) 93 (84–97) 88 (67–96) a Limited to events during the study therapy as reason for progression not collected in follow-up. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

The use of imatinib mesylate as a specific inhibitory treatment of the BCR-ABL tyrosine kinase has revolutionized the treatment of CML. Although results of treatment in patients in accelerated phase or blast crisis remain suboptimal, the rate of progression to advanced phase from chronic phase has

The management of patients with chronic-phase CML refractory to standard doses of imatinib mesylate includes dose escalation, allogeneic transplantation, or a switch to a new BCR/ABL inhibitor. In this issue of Blood , Kantarjian and colleagues present the results of a multicenter trial demonstrating that, for highly refractory patients, treatment with dasatinib is superior to dose escalation of imatinib mesylate.

Background InO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on a majority of B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Cancer. 2013 Aug 1;119(15):2728-36). Aims To optimize the InO dose and weekly schedule, and evaluate safety and efficacy in CD22+ relapsed/refractory ALL. Methods This phase 1, dose-escalation and expansion study enrolled pts aged ≥18 y with CD22+ refractory/relapsed ALL and no central nervous system disease. InO was administered in 28-d cycles (Table), up to 6 cycles. The final dose was to be determined based on dose-limiting toxicities (DLT) and efficacy, using the MDACC EffTox V2.10 software. Adverse event (AE) severity was assessed per CTCAE V3. DLTs included the following InO -related events in Cycle 1: gr ≥4 nonhematologic AE; prolonged myelosuppression; gr 3 nonhematologic AE >7 d; any AE resulting in permanent InO discontinuation. Complete response (CR) was defined as 100,000/µL and no extramedullary disease; CRi defined as CR without ANC or platelet recovery. Results We report data for 37 pts: median age was 56 y (23-75 y); 65% were male; 17 (46%) pts were in salvage 1, 9 (24%) in salvage 2, and 10 (27%) in salvage ≥3; 7 (19%) pts had prior allogeneic stem cell transplant (SCT); 6 (16%) pts were Ph+; CD22 found on a median of 98% blasts (31.1-100%); median WBC was 5.18×103/mm3 (0.5-67.2×103/mm3). The expansion cohort (n=13) was comprised of pts with higher peripheral blast counts (PBC) and higher risk cytogenetics as compared to the dose escalation group (n=24): median PBC of 4158/µL (0-38,976/µL) and 18/µL (0-10,189/µL), respectively; aberrant baseline cytogenetics were reported in 10/13 (77%) expansion pts including 2 pts Ph+ and 2 pts t(4;11) and 11/24 (46%) escalation pts. Median follow-up in surviving pts was 4.1 mo (1-12.6 mo). Thirty-two pts discontinued InO: 14 due to PD, relapse or resistant disease, 11 proceeded to SCT, 6 due to AEs (1 pt each: gr 3 acute renal failure, gr 2 ascites, gr 2 increased gamma-glutamyl transpeptidase (GGT), gr 5 graft failure, gr 2 constitutional symptoms and gr 2 veno-occlusive disease (VOD)) and 1 to receive maintenance therapy. InO-related ≥gr 3 AEs (≥10% of pts) were thrombocytopenia (30%) and neutropenia (19%). Other ≥gr 3 hepatic AEs included increased ALT (5.4%) and increased GGT (3%). Gr 2 AEs include ascites (2 pts) and VOD (2 pts). Sixteen deaths were reported: ALL (n=11), sepsis following SCT (n=3), graft failure (n=1) and gut GVHD and liver dysfunction (n=1). The RP2D was determined as 1.8 mg/m2/cycle based on efficacy and safety in the dose escalation patients (1 DLT; 89% CR+CRi rate; all remissions were minimal residual disease (MRD) negative ( The remission rate (CR+CRi) for the dose escalation pts (n=24) was 79% (95% CI: 58, 93) and 46% (95% CI: 19, 75) for the dose expansion pts (n=13); 18/19 (95%) escalation pts with CR/CRi and 4/6 (67%) expansion pts with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 29 d (20-85d) and 34 d (22-141d), respectively. Minimum InO concentrations in responders were higher than in pts failing treatment. Summary/Conclusion The RP2D was confirmed as 1.8 mg/m2/cycle, InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this relapsed/refractory population; preliminary efficacy results appear dynamically related to exposure and circulating blasts. Further exploration in CD22+ ALL is ongoing. Disclosures: DeAngelo: Pfizer Inc: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ acute lymphoblastic leukemia; this drug is investigational and is not approved for use in any indication in any country. Stock:Pfizer Inc: Research Funding. Liedtke:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Schiffer:Amgen Inc: Research Funding; Pfizer Inc: Research Funding. Ananthakrishnan:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Liau:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Advani:Pfizer Inc: Research Funding.

Abstract 83 The European APL91 and the North American Intergroup study I0129 reported in the 1990s that ATRA combined with chemotherapy markedly improves the outcome of APL. Large randomized and single arm studies from around the world with both short and relatively long-term follow-up, confirm this impact of ATRA, while optimizing their mode of administration. However, the incidence and outcome of late relapses have not been well established. Furthermore, as strategies to minimize or eliminate chemotherapy by combining ATRA and arsenic trioxide are being adopted, the long-term durability of ATRA and chemotherapy regimens is even more relevant. We now report on late relapses among the APL patients enrolled in the North American Intergroup study I0129 conducted between 4/92 -2/95. Methods: 380 patients (excluding 14 who had never received ATRA, and 3 ineligible) from 6 cooperative oncology groups, were randomized to induction with either ATRA or chemotherapy with daunorubicin and ara-C (DA). Patients then received two cycles of anthracycline-containing consolidation chemotherapy and then irrespective of their induction arm, patients were randomized to receive 1 year of maintenance with ATRA or observation (Obs) (Tallman et al NEJM 1997). Late relapse was defined as relapse 3 years or later from CR. Data analysis as of March 25, 2011 with a median follow-up of 11.8 (ranges 0.4–14.5) years. Results: Of 191 pts on DA and 189 pts on ATRA induction arms, 85 vs. 116 (total 201) were last known to be alive, median OS 3.6 years (95% CI: 2.0, 8.7) vs. not yet reached (p=0.0007), respectively. CR was achieved in 272 (72%) pts, and 113 are known to have relapsed. In addition, 70 relapsed pts. had received ATRA at any time, of them 60 pts relapsed early and 10 pts. relapsed late; 43 pts relapsed patients did not receive any ATRA and all relapsed early (P=0.01). Follow up information is known so far on 5 late relapses. Relapse sites: BM -4 Pts, CNS – 1pt. Late relapse salvage: chemotherapy-5 pts., alloBMT-2 pts., Auto BMT -1pt., arsenic trioxide –none. Of the 10 late relapses, 3 died, all from disease progression. Median duration in CR1 prior to late relapse: survivors vs. died 3.9 and 4.1yrs, respectively. Only 35 (34%) of the early relapses are alive. Two second malignancies in the breast were identified, all in no known relapse pts. Conclusions: This is among the largest studies with very long follow-up to report that, in newly diagnosed APL patients receiving consolidation chemotherapy, the significantly higher OS rate after induction with ATRA compared to chemotherapy, is sustained. Most relapses in APL occur early, including in patients who had received ATRA at any time. Late relapses after 3 years: 1) are uncommon (4%) and are very rare after 4 years (1); at that time CR1 patients are most likely cured; 2) survive longer than early relapses, independent of CR1 duration, implicating the effectiveness of salvage therapy; 3) do not differ from early relapses in WBC and age at diagnosis; 4) were slightly more likely to be on ATRA maintenance. As the number of long-term APL survivors increases, future studies should address survivorship, late treatment-related complications, and determine whether some late relapses represent new therapy-related AML. Finally, if the high rate of early death (Park et al Blood, 2011) can be reduced, more patients will benefit from the high cure rate reported by this and other studies. Disclosures: No relevant conflicts of interest to declare.

4417 Chronic myeloid leukemia (CML) is characterized by the presence of t(9;22) leading to the BCR/ABL fusion gene while other myeloproliferative disorders such as polycytemia vera (PV) and primary myelofibrosis (PMF) may have a point mutation at V617 F codon of janus kinase 2 gene. Myelodysplastic syndrome (MDS) is thought to arise from an abnormality in the hematopoietic stem cell leading to impaired production of blood cells. In these diseases an abnormal clone proliferates and then suppresses normal hematopoiesis. We present 3 very unusual patients in whom CML was diagnosed a few years after the diagnosis of another clonal hematological disorder and in whom there was re-emergence of the original disorder after successful treatment of the CML. The first patient is an 88 yr old female who was diagnosed with PV in 1998 and treated with multiple phlebotomies, hydroxyurea and anagrelide. A bone marrow biopsy in 2002 showed the presence of the t(9;22) in 6 of 6 metaphases. She was treated with imatinib but failed to achieve a complete cytogenetic response and was switched to dasatinib which had to be stopped secondary to congestive heart failure. Nilotinib was then started but she developed QTc prolongation and failed to achieve a cytogenetic response. She was then managed with hydrea for many years and interestingly, manifested prominent cyclic leukocytosis. In 2010, analysis of blood showed a JAK2 mutation. She recently was begun on protocol treatment with ponatinib. Although moderate splenomegaly and leukocytosis persisted after 5 months of therapy, 0/26 metaphases demonstrated t (9;22) while gain/trisomy of 1q, an abnormality commonly seen in other myeloproliferative disorders and in particular, PV, was detected in 11/26 metaphases, The second patient is a 64 year old man who was initially diagnosed with PV during workup for elevated hematocrit in 2002. A JAK2 mutation was detected subsequently. Phlebotomy was discontinued in 2007 and he was maintained on hydroxyurea. In 2010, he was noted to have a WBC of 100,000/ul and underwent a bone marrow biopsy which showed the t(9;22). He was found to be in accelerated phase of CML and was initiated on dasatinib. At last follow up visit, the patient is in a cytogenetic remission for CML but was noted to have elevated hemoglobin; a repeat JAK2 is pending. The third patient is an 82 year old man who was diagnosed in 2005 with MDS with normal cytogenetics, when he was evaluated for macrocytic anemia. He was initially observed and subsequently treated with erythropoietin for decreasing hemoglobin. A bone marrow biopsy was repeated when his hemoglobin continued to decrease in 2009 and showed t(9;22) in 1/20 cells. He was started on imatinib and achieved a complete molecular response. About 3 months later he fractured his humerus and was found to have extramedullary acute myeloid leukemia which was positive by fluorescence in situ hybridization for BCR/ABL. His bone marrow at this time was negative for BCR/AB by RT-PCR but showed dysplatic changes. He was treated with radiotherapy to his arm and was switched to nilotinib. CML continues to be in a molecular remission, with low but stable blood counts. These 3 patients had an antecedent diagnosis of a clonal hematological disorder prior to developing CML. In 2 of the patients the CML became the dominant “bully” clone suppressing the manifestations of the PV clone. With targeted therapy directed at BCR/ABL, the CML clone was suppressed and the underlying disease again became apparent. In one patient, the presumed PV clone had evolved further with typical cytogenetic changes. It is unclear whether the CML developed from the original MPD/MDS clone or whether it represents an entirely independent disorder. In either event, the ability to successfully suppress the CML with specific therapy provides insights into the competitive interactions amongst abnormal clones and indeed, with normal hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

We read with interest Dr Raza's letter[1][1] in response to the International Working Group's (IWG's) proposal to provide standardized response criteria in myelodysplastic syndromes (MDSs).[2][2] Developing consistent guidelines for MDSs presents a challenge since the clinical course of the disease

Abstract 358 Background: Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving dasatinib. These small studies have suggested a relationship between the development of T/NK lymphocytosis with both toxicity and improved response. A recent analysis of CML patients who were resistant to or intolerant of imatinib indicated that lymphocytosis occurs in ∼30% of patients in all stages of CML after treatment with dasatinib (Schiffer 2010 ASCO abstract #6553). In addition, lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions. The DASISION study (CA180-056) compared dasatinib with imatinib in patients with newly diagnosed, previously untreated chronic phase CML. This subanalysis of the DASISION data was undertaken to determine the safety profile, responses, and outcomes in those patients with sustained lymphocytosis. Method: Patients enrolled in the DASISION study were retrospectively evaluated for lymphocytosis (N=516). Lymphocytosis was defined as lymphocytes >3.6 × 109/L on ≥2 occasions after 28 days of treatment. Immunophenotyping was not done as part of these studies. Rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without lymphocytosis. The median follow-up was 14.0 and 14.3 months for dasatinib and imatinib, respectively. Result: Lymphocytosis occurred more frequently and sooner in patients treated with dasatinib compared with imatinib (23.6% vs 5.4% and 3.0 months vs 4.7 months, respectively). Dasatinib-treated patients who developed lymphocytosis had lower baseline Hasford risk scores, whereas imatinib-treated patients who developed lymphocytosis had high Hasford risk scores. In the presence or absence of lymphocytosis, MCyR and CCyR occurred more frequently with dasatinib as compared with imatinib. In dasatinib treated patients, lymphocytosis was associated with a higher MCyR rate (91.8% with vs 83.3% without) and CCyR rate (83.6% with vs 75.1% without). In imatinib-treated patients, lymphocytosis was associated with a lower MCyR rate (50.0% with vs 82.8% without) and CCyR rate (50.0% with vs 69.7% without). Patients with lymphocytosis, compared with those without it, had higher rates of pleural effusion (any grade) on dasatinib (18.0% vs 7.6%, respectively). Only 1 patient treated with imatinib, who did not have lymphocytosis, experienced pleural effusion. Dasatinib-treated patients with lymphocytosis, compared with those without it, had higher rates of fatigue (16.4% vs 9.1%,); this trend was reversed for imatinib-treated patients (7.1% vs 11.9%). Patients with lymphocytosis, compared with those without it had lower rates of myalgias and arthralgias (all grades) on both the dasatinib arm (11.5% vs 18.8%) and the imatinib arm (7.1% vs 24.2%). Conclusion: Lymphocytosis occurred much more frequently and sooner in patients treated with dasatinib than with imatinib. Lymphocytosis was associated with improved responses (MCyR and CCyR) in dasatinib-treated patients. An apparent inverse relationship was observed in imatinib-treated patients, although the number of patients with lymphocytosis was small. It remains to be determined how lymphocytosis, baseline Hasford risk score, and response are correlated. It is possible that some of the antileukemic effects of dasatinib are produced by an immunomodulatory mechanism. Lymphocytosis in dasatinib-treated patients was associated with an increased rate of pleural effusion and a possible decrease in myalgias and arthralgias. Longer follow-up is needed to assess whether lymphocytosis has an effect on PFS. Disclosures: Schiffer: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Cellgenix: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Cortes:Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. le Coutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci:Bristol-Myers Squibb: Employment. Dejardin:Bristol-Myers Squibb: Employment. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy.

Abstract 3439 Introduction: The European LeukemiaNet (ELN) recommendations for the management of chronic phase chronic myeloid leukemia (CP-CML) have provisionally defined criteria for suboptimal and failure to second-generation tyrosine kinase inhibitors (TKIs) (Baccarani et al., J Clin Oncol. 27 (35):6041-51, 2009). We tested the significance of these definitions in 3 studies of dasatinib after imatinib failure. Methods: Data from 1150 treated patients (pts) included in the 3 studies [CA180-013 (n=387); dasatinib only arm of CA180-017 (n=101); CA180-034 (n=662)] were analyzed. For the purpose of this analysis, we modified the 2009 ELN recommendations to add an optimal response category as shown in Table 1. Background: The median age of the pts included in this analysis was 56 yrs (range, 18–85) and the median duration of CML in these pts was 58 months (range, 0.9–250.8). Thirty-eight percent of the pts had received imatinib at a dose > 600mg/day and 45% had been on imatinib therapy >3 yrs. Twenty-four percent of pts included in this analysis had demonstrated imatinib-intolerance. Thirty-five percent of pts had mutations before the start of dasatinib therapy (5% had T315l). Results: Rates of optimal response at 3, 6 and 12 months were 51%, 44% and 36%. Rates of suboptimal response at 3, 6 and 12 months were 7%, 16% and 27%. Rates of failure response at 3, 6 and 12 months were 29%, 34% and 37%. Rates of warning response at 3 and 6 months were 12% and 6%. The starting dose of dasatinib did not influence these response rates. The group defined as suboptimal at 12 months (of whom 52% had already achieved CCyR) had a higher probability of achieving CCyR within 2 yr (83%) compared to the groups defined as suboptimal at 6 months (69%) or 3 months (51%). This suboptimal group at 12 months also had a higher 2 yr progression-free survival (PFS) (92%) compared to the suboptimal groups at 6 months (82%) and 3 months (80%). The probability of achieving an MMR within 2 yr was slightly higher in pts defined as optimal at 6 months (80%) vs. those at 3 months (71%). However, the probability of achieving an MMR within 2 yr showed minimal change for the suboptimal (31-35%) or the failure (5%) response groups defined at 3, 6 and 12 months. The pts with a warnings response had a profile that was intermediate between suboptimal and failure response. Table 2 summarizes 2 yr outcomes based on response. Conclusions: These results suggest that the 2009 ELN provisional response definitions may be helpful in predicting long term outcomes in pts receiving second-line dasatinib therapy. In this cohort of pts, optimal responders identified themselves rapidly as did pts with failure. However, the outcome of pts defined as suboptimal at 12 months appeared more favorable than that of pts defined as suboptimal at 3 and 6 months. This, in addition to the higher proportion of pts classified as suboptimal at 12 months, compared to those classified as suboptimal at 3 and 6 months, may suggest that the ELN defined cut-off between optimal vs. suboptimal at 12 months (i.e. MMR) may need to be modified in order to make the prognosis for suboptimal response more consistent across different time points. Pts classified in the warnings category at 3 and 6 months had an outcome intermediate between those with suboptimal and failure response. Disclosures: Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. LeCoutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

Abstract 2297 Background: BCR-ABL kinase domain mutations occur in 30%-90% of patients (pts) who develop resistance to imatinib. A recent analysis reported that 48% of pts with imatinib resistance or suboptimal response had a baseline mutation at the start of dasatinib therapy (Müller 2009). After 2 years of follow-up, dasatinib treatment of imatinib-resistant pts resulted in notable response rates (complete cytogenetic response [CCyR]: 43% vs 47%) and promising progression-free survival (PFS, 70% vs 80%) in pts with or without baseline mutations, respectively. However, some pts present with two or more co-existing mutations in one or more clones. The outcome of these pts after dasatinib therapy has not been described in detail. Methods: This is a retrospective analysis of pts with CML in chronic phase (CML-CP) receiving dasatinib who were imatinib resistant or intolerant and who had >1 BCR-ABL mutation at baseline. Pts with CML-CP from the phase 3 dose optimization trial (-034) and phase 2 START-C (-013) and START-R (-017; dasatinib only population) studies were evaluated. Since the frequency of >1 mutation was expected to be lower than the rates reported for the presence of any mutation, the inclusion of all 3 studies provided a larger population to determine pt responses and outcomes. A 2-year database was used for all 3 studies. Mutations were detected by conventional Sanger sequencing (sensitivity 10%-20%) after nested RT-PCR amplification of the BCR-ABL transcript. BCR-ABL polymorphisms were excluded from analysis. 1150 pts were included in the analysis: -034 (n=662), -013 (n=387), and -017 (n=101). Similar baseline characteristics among those analyzed included: median age (51-55 years), male (47%-53%), median duration of CML (54-64 months [mos]), prior imatinib therapy lasting >3 years (41%-53%) and prior response rates to imatinib (complete hematologic response [82%-92%], major cytogenetic response [MCyR, 28%-42%], and CCyR [15%-21%]). Only the rate of imatinib intolerance differed among the 3 trials: 26% for -034 and -013, whereas imatinib-intolerant pts were not eligible for the -017 study. Results: Of 1150 pts analyzed, baseline mutation data were available for 1043 dasatinib-treated pts (Table); 641 (61%) had no baseline mutation (202 intolerant) and 402 (39%) had a baseline mutation (18 intolerant). Of those with mutations, 70 (17%) had >1 mutation (4 intolerant) and 16 (4%) had >2 mutations. The TKI-resistant T315I mutation occurred in 21/402 (5%) and 5/70 (7%) of those with 1 or >1 mutation, respectively–with G250E also occurring in 2 of those 5 pts. The 24-mo response rates for pts with >1 mutation at baseline were lower than the rates in those who had only 1 mutation, or no mutations at baseline for MCyR (52.2% vs 56.4% vs 65%) and CCyR (36% vs 45% vs 56%). The 24-mo PFS rates on dasatinib for those with >1, 1, and no mutation were 57%, 73%, and 83%, respectively. While pts who achieved CCyR at 12 mos had excellent 2-year PFS, regardless of whether they had no, 1, or >1 mutation, pts who achieved partial cytogenetic response (PCyR) or less than PCyR at 12 mos had lower 2-year PFS if they carried >1 mutation compared to those with no or 1 mutation. The 2-year overall survival (OS) rates were 93.5% for those without a mutation and similar for those with 1 or >1 mutation (89%). Conclusion: Dasatinib shows considerable efficacy in pts with or without baseline BCR-ABL mutations. However, pts with baseline mutations tended to have lower rates of response and PFS compared with those without mutations at baseline. In addition, the presence of >1 mutation compared with the presence of only 1 mutation yielded the lowest rates of response and PFS. Disclosures: Quintás-Cardama: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Kantarjian: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; Novartis: Consultancy, Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Schiffer: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Cellgenix: Consultancy. le Coutre: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Saglio: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guilhot: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bahceci: Bristol-Myers Squibb: Employment. Lambert: Bristol-Myers Squibb: Employment. Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.