ALBERT

Description: Background: Patients with acute myeloid leukemia (AML) presenting with hyperleukocytosis have frequent complications and early mortality. Pulmonary, central nervous system, and cardiovascular complications are common. Attempts to improve outcomes in the 10% of AML patients arriving with hyperleukocytosis have included leukapheresis. No prospective randomized study has supported the use of leukapheresis, and retrospective reports have revealed persistently poor outcomes as well as emerging concerns of acquired coagulopathy and worsening hypoxemia after leukapheresis. While many centers use a leukapheresis protocol processing two blood volumes, Johns Hopkins protocol routinely processes three-five blood volumes. This study aimed to assess coagulopathy, hypoxemia, and mortality with large volume leukapheresis. Methods: 32 patients with newly diagnosed AML treated with large volume leukapheresis for WBC depletion are included in this report. Demographic, clinical, laboratory, and apheresis-related data were collected. Coagulopathy and hypoxemia-related metrics were evaluated within 6 hours before leukapheresis and within 6 hours of completion of leukapheresis. Descriptive and inferential statistics (chi square and Mann-Whitney U test) were used to compare pre and post-leukapheresis findings and assess clinical outcomes. Results: Twenty-nine of 32 (93.8%) patients presented with symptomatic leukostasis (with pulmonary and/or CNS symptoms in 26/29). Median blood volume processed was 14.8 liters (range 4-23.4L). Mean platelet count decreased from 60x109/L to 37x109/L after leukapheresis (p

Description: Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.

Description: Key Points Posttransplantation cyclophosphamide is effective as sole GVHD prophylaxis for myeloablative HLA-matched–related or –unrelated BMT. Despite low chronic GVHD with PTCy, relapse and survival are comparable with outcomes reported using other GVHD prophylactic approaches.

Description: Abstract 866 Acute myeloid leukemia (AML) is a hematologic malignancy characterized by increased myeloproliferation and a block in differentiation of hematopoietic stem/progenitor cells, leading to infiltration of immature blasts in the bone marrow and peripheral blood. FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase expressed in hematopoietic stem/progenitor cells. It can activate cell growth/proliferation pathways via STAT5, AKT/PI3K, and RAS/MAPK signaling. Greater than 35% of AML patients harbor a constitutively activating mutation in the FLT3 gene, and the most common type, an internal tandem duplication (ITD), confers poor prognosis. These ITD mutations typically occur in the juxtamembrane domain and consist of variable length sequence repeats. In addition, activating mutations in the kinase domain are observed in 7–10% of patients. Thus, FLT3 is a validated target for the treatment of AML. Towards this end there have been a number of clinical trials testing the clinical efficacy of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3 mutant AML, either alone or combined with chemotherapy. While some patients have responded, there have been many others who fail to demonstrate significant improvement. Additionally, many patients who initially respond to FLT3 TKI have developed resistance. Inadequate achievement of FLT3 inhibition has been one of the factors limiting efficacy in these trials. This appears most often to be due to a combination of insufficiently potent drugs, decreased efficacy against some FLT3 activating mutations, high plasma protein binding, and the selection for resistance-conferring point mutations within the FLT3/ITD gene. For all of these reasons, there is the need to develop additional FLT3 TKIs able to overcome some of these limitations. We report for the first time on TTT-3002, a kinase inhibitor that has activity against FLT3 and may overcome some of the limitations that current FLT3 TKIs have demonstrated in clinical trials. TTT-3002 is one of the most potent FLT3 inhibitors discovered to date with regard to both inhibition of FLT3 autophosphorylation and cell proliferation. Utilizing human FLT3/ITD mutant leukemia cell lines the half maximal inhibitory concentration (IC50) for inhibiting FLT3 autophosphorylation was less than 250 pM. The IC50 for TTT-3002 in inhibiting proliferation in these same FLT3/ITD expressing cells was 490–920 pM. TTT-3002 also showed potent activity when tested against a broad spectrum of known, non-ITD FLT3 activating mutations, including the most frequently occurring D835Y mutation. It also shows potent activity against a number of FLT3/ITD resistance mutations that have been selected for in patients from clinical trials of other FLT3 TKI or through in vitro drug screening. Studies utilizing human plasma samples from healthy donors and AML patients determined that TTT-3002 is only moderately protein bound, resulting in high levels of free drug able to bind target, and thus maintain activity, in the presence of physiological concentrations of major human plasma proteins including alpha-1-acid glycoprotein and human serum albumin. Therefore, relatively low levels of total drug would need to be achieved in vivo to achieve an effective concentration of free drug in clinical trials. These encouraging findings have been validated both ex vivo and in vivo utilizing mouse models of FLT3-associated AML. Survival and tumor burden of mice in a number of FLT3/ITD transplant models is significantly improved by administration of TTT-3002 via oral dosing. Finally, we demonstrate that TTT-3002 is cytotoxic to leukemic blasts isolated from FLT3/ITD expressing AML patients, while displaying minimal toxicity against normal hematopoietic stem/progenitor cells from healthy bone marrow donors. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI that may overcome some of the limitations of other TKI in the treatment of FLT3-mutant AML. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points No overall clinical benefit was seen after the addition of lestaurtinib to standard chemotherapy for newly diagnosed FLT3-mutated AML. Lower rates of relapse and improved overall survival were seen in patients who achieved sustained levels of FLT3 inhibitory activity.

Description: Abstract 1516 Background: Sorafenib is a potent inhibitor of FLT3 kinase with demonstrable clinical activity in patients with acute myeloid leukemia (AML) and FLT3-ITD mutation, but not those with FLT3-D835 mutation. Objectives: To determine the long term outcome of patients with AML treated with the combination of Sorafenib, cytarabine and idarubicin, and in particular those with FLT3-ITD mutation. Method: Between October 2007 to March 2010, 62 patients with newly diagnosed, previously untreated AML, were treated with Sorafenib 400 mg orally twice daily (BID) for 7 days, cytarabine 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if 〉 60 years of age), and idarubicin at 12 mg/m2 IV daily for 3 days on an IRB-approved clinical trial. After achieving remission, patients received up to 5 cycles of consolidation with sorafenib 400 mg BID continuously and abbreviated doses of cytarabine and idarubicin given at approximately one month intervals. Results: 62 patients were treated on the phase II portion of the study. Median age was 53 years (range, 18 – 66) and 12 (19%) patients were 〉 60 years. 23 (37%) had FLT3 mutations including 17 with FLT3-ITD, 4 with FLT3-D835, and 2 with both mutations. Cytogenetics was diploid in 36 (58%), chromosome 5 and 7 deletion in 4 (6%) and 1 (2%) respectively, complex in 8 (13%), miscellaneous in 13 (21%). Median white blood cell count (WBC) at diagnosis was 7.25 × 109/L (range, 0.6 – 225), and 28 (45%) patients had WBC 〉 10 × 109/L; among these, 12 (43 %) had FLT3-ITD. After induction, 49 (79 %) patients achieved CR and 5 (8%) CR with incomplete platelet recovery (CRp). 1 (2%) patient died before response assessment could be performed and 7 (11%) were non responders. Patients with FLT3-ITD were more likely to achieve a CR/CRp than patients without FLT3-ITD [18/19 (95%) patients vs. 36/43 (83%) patients, respectively (p=0.23)]. To date, 32 (59%) of the responders have relapsed including 10 of 18 (56%) patients with FLT3-ITD and 22 of 36 (61%) patients without FLT3-ITD (P=0.86). 35 patients received salvage therapy; 14 died after receiving salvage therapy, 11 achieved a second CR and 10 were refractory. After a median follow up of 40.6 months (range, 5.7 to 50 months), the median DFS and OS were 13 months and 29 months, respectively. Hematopoietic stem cell transplantation (HSCT) was performed in 34 (55 %) patients, including 23 in CR, and 11 with active disease. Stem cell source was from related donors in 15 (44%), unrelated donors in 9 (26%), cord blood in 7 (21%), and haploidentical donors in 3 (9%) patients. Overall, 35 (56%) patients have died; 16 (26%) had infectious complications, 12 (19%) multi-organ failure, 9 (15%) graft versus host disease, and 10 (16%) other causes with some patients having overlapping causes. Three-year disease free survival (DFS)(in patients achieving CR, n=54) and overall survival (OS) (n=62) were 34% and 47%, respectively (Figures 1 and 2). Conclusion: Combination of sorafenib, idarubicin and cytarabine is an effective regimen with durable responses in patients with newly diagnosed AML, particularly those with FLT3-ITD. Disclosures: Ravandi: Bayer: Research Funding; Onyx: Research Funding.

Description: Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

Description: Background: Despite recent advances in the therapeutic armamentarium for AML, outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20%. Multiple immune aberrations in AML lead to immune suppression, exhaustion, and senescence. Programmed Death-1 (PD-1), a co-inhibitory receptor (IR) on immune cells, suppresses immune activation and is exploited by leukemic cells to evade immune surveillance. PD-1 and other IRs are up-regulated during disease progression. We hypothesized that pembrolizumab, a monoclonal antibody targeting PD-1, after HiDAC would stimulate a T-cell mediated anti-leukemic immune response. Methods: Eligibility for this study included R/R AML 18-70 years, ECOG PS 0-1 and adequate organ function. Treatment consisted of HiDAC (60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14. The primary objective of this study was to estimate the overall complete remission (CR + CRi) rate. Secondary objectives included assessment of safety, durability of CR, overall survival (OS) and biomarker correlates of response. Overall responders were eligible to receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (alloSCT) was permissible before or after maintenance phase. Results: Thirty-seven pts were enrolled and evaluable (Table 1). Sixteen (43%) pts had refractory disease and 16 (43%) pts had relapsed AML with CR1 duration 3: n=1), AST elevation (32%; Grade 〉3: n=1), fatigue (27%), alkaline phosphatase elevation (24%), and maculopapular rash (19%; Grade 〉3: n=2). Grade 〉3 immune-related adverse events (iRAE) were rare (maculopapular rash: n=2, AST/ALT increase: n=2, right upper quadrant pain with lymphocytic infiltrate in liver: n=1) and self-limiting. Five (14%) pts required steroid administration for grade 2 hyperbilirubinemia (n=1), grade 3 ALT elevation (n=1), grade 3 AST elevation with liver biopsy revealing no evidence of iRAE (n=1), grade 3 bilirubin subsequently deemed to be a delayed hemolytic transfusion reaction (n=1), and grade 3 systolic dysfunction without evidence of myocarditis by endomyocardial biopsy or cardiac MRI (n=1). Sixty-day mortality was 3% (1/37) due to progressive AML. Median time to full neutrophil (〉1x109/L) and platelet (〉100x109/L) recovery was 32 and 31 days, respectively. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% [29%,63%] and 38% [22%,55%], respectively, meeting the primary endpoint of the study. Notably, 13/28 (46%) pts receiving HiDAC + pembrolizumab as their first salvage regimen achieved CR/CRi. Two pts refractory to HiDAC (administered within past 6 months) achieved CR including one pt who was refractory to HiDAC salvage 1 month prior to enrollment and ultimately achieved CR without evidence of minimal residual disease. Nine (24%) pts received an alloSCT. There were no instances of Grade 〉3 acute GVHD or veno-occlusive disease post-alloSCT. Nine (24%) pts received maintenance phase pembrolizumab (median # of cycles = 3; range: 1-12) for CR (n=8) or PR (n=1). Seven out of 9 pts relapsed/progressed after maintenance phase. Median follow-up among survivors, and median OS, event-free survival and disease-free survival was 7.8 months, 8.9 months [6.0,13.1], 6.9 months [4.2,11.5], and 5.7 months [1.9,7.3], respectively. Conclusions: Pembrolizumab can be safely administered after HiDAC salvage in R/R AML. Severe iRAE's were uncommon despite administration after cytotoxic chemotherapy. The addition of pembrolizumab to HiDAC led to an encouraging overall CR rate meeting the primary endpoint of the study. Immunogenomic biomarker analyses consisting of B cell receptor amplicon sequencing, RNA-seq of blasts and CD8+ T cells, CD8+ T cell receptor repertoire, whole exome sequencing and flow cytometry analyses are ongoing to determine predictors of response. These results warrant further investigation of IR blockade and other immunomodulatory therapeutic strategies after intensive cytotoxic chemotherapy in AML. Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; AsystBio Laboratories: Consultancy; Pfizer: Honoraria; Tolero: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria; AbbVie: Honoraria. Vincent:Pharmacyclics: Research Funding; Merck: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy. Coombs:Dedham Group: Consultancy; Covance: Consultancy; Cowen & Co.: Consultancy; Octopharma: Honoraria; H3 Biomedicine: Honoraria; Loxo: Honoraria; Pharmacyclics: Honoraria; Medscape: Honoraria. Webster:Pfizer: Consultancy; Amgen: Consultancy; Genentech: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Smith:Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Agios: Consultancy. Levis:Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Serody:Merck: Research Funding; GlaxoSmithKline: Research Funding. Gojo:Amphivena: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Pembrolizumab is investigational for AML.

Description: Cytogenetics is the most important predictor of outcomes in AML. Traditional metaphase cytogenetics (MC), can detect abnormalities in only 40–60% of AML patients. Whole genome scanning by single nucleotide polymorphism arrays (SNP-A) can identify somatic chromosomal changes in hematopoietic malignancies and, due to its superb resolution, may detect previously cryptic unbalanced defects, even in samples deemed “normal” or uninformative using MC. Through simultaneous detection of loss of heterozygosity (LOH) and gene copy number changes, SNP-A also facilitate the identification of somatic segmental uniparental disomy (UPD). Here we tested whether SNP-A analysis could improve the detection rate of chromosomal defects in AML and enhances the prognostic value of MC. Analyses were performed using 250K and/or 6.0 Affymetrix SNP arrays on 140 primary (p) and secondary AML (sAML) patients (newly diagnosed= 107, relapsed=15, remission= 12, persistent=6) and 116 healthy controls. Data on cytogenetic detection rate, complete remission (CR), overall survival [OS], relapse free survival [RFS], remission duration [RD], and event free survival [EFS]) rates were obtained from patients who received induction chemotherapy. We also performed Flt-3 ITD, Flt-3 TKD and NPM-1 mutation analysis and integrated the clinical outcomes with SNP-A results. For patients in whom new defects were detected, germ-line DNA was also analyzed whenever technically possible. The cytogenetic abnormality detection rate in patients with active disease was higher with SNP-A compared to MC (pAML, 75% vs 43% p=

Description: The WHO classification recognizes chronic myelomonocytic leukemia (CMML) as an overlap syndrome sharing clinical and histomorphologic features with both MDS and MPD. Unlike in CML or classical MPD, which are often characterized by recurrent translocations or activating mutations, only 1/3 of CMML patients harbor lesions (e.g. balanced translocations that include PDGFb as a fusion partner). Also frequent are unbalanced aberrations similar to those seen in classical MDS. Of note is that IPSS assigns prognosis only to a portion of patients with CMML (those with 〉10% of blasts and/or high WBC counts). Since chromosomal defects have a major impact on the diagnosis and prognosis of myeloid malignancies, it is likely that cytogenetic methods with higher resolution and an ability to detect uniparental disomy (UPD) could explain clinical heterogeneity and point to potential therapeutic targets in CMML. We applied 250K SNP-arrays (SNP-A) to examine karyotype and identify previously cryptic defects in patients with low grade and advanced forms of CMML. SNP-A allows for detection of clones spanning 25–50% of total cell population, and fidelity of LOH calls is 〉99% as shown by analysis of chromosome (chr.) X in males. Any deletions, duplications, and/or UPD found by SNP-A in 76 controls or those on internet databases were considered copy number variants (CNV) and excluded from analysis. In total, we studied 77 patients with CMML; 42/77 showed abnormal MC, including most often lesions commonly associated with MDS/CMML, such as +8 (N=5) and +19 (N=2). DNA was available for SNP-A karyotyping in 46 patients. Abnormal karyotype was detected in 19/46 patients (40%) by MC compared to 37/46 patients (79%) by SNP-A. Examples of newly detected lesions included microdeletions of chrs. 12 and 7, and various micro-duplications/deletions. Remarkably, we found (perhaps in analogy to UPD9p seen in MPD) a high prevalence of segmental UPD, occurring in 20/47 patients (43%) with significant recurrence on chrs. 4 (N=4), 6 (N=4), and 11 (N=4). 7/20 patients had UPD as a sole or isolated abnormality. In 3 these patients, UPD11q was the sole contributing lesion while in one patient with UPD11, only one additional lesion, a small microdeletion of chr. 3, was found. Of note is that previously we have found also UPD11q in 4/29 patients with MDS/MPD-U. When we analyzed SNP-A results in CMML patients according to blast counts (CMML-1/2) and WBC (myeloproliferative type (MP) vs. myelodysplastic type (MD)), CMML-2 patients showed a higher frequency/more complex lesions, likely acquired in the process of transformation (1.5 vs. 2.2 avg. lesions). In addition to identifying abnormal overlapping/recurrent aberrations, SNP-A karyotyping has a potential clinical utility. When we stratified patients according to SNP-A detected lesions, we found a statistically significant difference between overall survival of patients with normal MC and normal SNP-A vs. those with normal MC but abnormal SNP-A (p=0.03, 40.2 vs. 7.3 months). In summary, SNP-A-based karyotyping complements MC and allows for precise definition of chr. aberrations in patients with CMML, including copy-neutral LOH. UPD is common in CMML and overlapping regions may point to potential causative genes.