Median Transformation-free Survival Research Articles

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

NFE2 Mutations Impact AML Transformation and Overall Survival in Patients with Myeloproliferative Neoplasms (MPN)

Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF <5% may refer to a minor clone without clinical relevance. NFE2 mutations were present in 7.3%, 5.3% and 3.6% of PV, PMF and ET patients respectively. No significant association between the presence of NFE2 mutation and clinical/molecular MPN characteristics (driver mutation, constitutional symptoms, splenomegaly, blood counts, cytogenetic and other molecular features) was observed using a logistic regression association model. Median follow-up was 103.8 months, IQR [47.2; 175.6]. In terms of response to therapy, 52.8% of patients achieved complete response, complete hematological response or clinical improvement in NFE2 mutated vs 61.7% in non-mutated patients (p= 0.026). Interestingly, presence of a NFE2 mutation (HR 9.92, 95%CI[3.21; 30.64], p< 0.001), age at diagnosis (HR 1.09, 95%CI[1.05; 1.12], p< 0.001), PMF subtype (HR 6.92, 95%CI[2.81; 17.06], p < 0.001) and high-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1) (HR 2.45, 95%CI[1.14; 5.28], p=0.021) were independently associated with AML/MDS transformation free survival (TFS) in a COX regression multivariate analysis (Figure A). Presence of a NFE2 mutation was also independently associated with overall survival (OS) (HR 9.37, 95%CI [4.18; 21.03], p<0.001) (Figure B). Median TFS were 216.1 months and not reached, while median OS were 144.2 months and not reached for NFE2 mutated and non-mutated patients, respectively. No difference was observed in terms of thrombo-hemorrhagic events (HR 0.73; 95%CI [0.10; 5.21], p=0.752) and secondary myelofibrosis free survivals (HR 0.67; 95%CI [0.09; 4.87], p=0.693). Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

Genomic Context and TP53 Allele Frequency Define Prognostic Subgroups and Response Outcomes in TP53 Mutated Myelodysplastic Syndromes

Genomic Context and TP53 Allele Frequency Define Prognostic Subgroups and Response Outcomes in TP53 Mutated Myelodysplastic Syndromes

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium.

The hypomethylating agents (HMAs) azacitidine and decitabine are most commonly used to treat patients with higher-risk myelodysplastic syndromes (MDS). To the authors' knowledge, the prognosis of patients with low-risk and intermediate-1-risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure has not been explored comprehensively. The clinical characteristics and treatment outcome of 438 patients with low-risk and intermediate-1-risk MDS who were treated with HMAs were retrospectively analyzed. Using the International Working Group response criteria, the overall objective response to HMA was 35% with a median of 6 cycles of HMA administered, and the median response duration was 7 months. Only 7% of patients had disease that transformed into acute myeloid leukemia while receiving therapy. Of the 290 patients who were evaluable at the time of HMA failure, 77% remained in the lower-risk disease categories. On multivariate analysis, baseline neutropenia, intermediate-risk and poor-risk baseline karyotype, and lack of response to HMA were found to be independently associated with a higher risk of disease progression. With a median follow-up of 16 months, the median transformation-free survival and overall survival (OS) after HMA failure were 15 months and 17 months, respectively. On multivariate analysis, only The University of Texas MD Anderson Global Scoring System was found to be independently predictive of outcome, with patients with higher-risk categories having poor transformation-free survival (hazards ratio [HR], 1.5; P = .003) and OS (HR, 1.8; P = .002). The administration of salvage therapy was independently associated with better OS only (HR, 0.8; P = .01). Outcomes of patients with lower-risk MDS after HMA failure are poor and the treatment of these patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population.

Impact Of The Achievement Of a Complete Cytogenetic Response (CCyR) On Outcome In Patients (pts) With Myelodysplastic Syndromes (MDS) Treated With Hypomethylating Agents (HMA)

BackgroundEpigenetic therapy with HMA is now the standard of care for pts with MDS with complete response (CR) rates of 7% to 35% and median survival of 20 to 24 months (mos). Large studies have demonstrated the relevance of karyotype abnormalities as an independent prognostic factor in predicting outcome in MDS pts. In pts with chronic myeloproliferative neoplasms (e.g. chronic myeloid leukemia), the achievement of CCyR has proven to correlate with improved outcomes: less transformation into acute myeloid leukemia and better overall survival. However this phenomenon has not been examined thus far in pts with MDS, where the response criteria are still predominantly based on morphologic basis. AimsTo assess the impact of CCyR on outcome in pts with MDS treated with HMA Methods216 consecutive pts with MDS and abnormal karyotype treated with HMA between 4/04 and 10/12 were reviewed. Response criteria were based on the International Working Group (IWG) 2006 criteria. CCyR was defined as achievement of a diploid karyotype among at least 20 metaphases analyzed. ResultsMedian age was 66 years (21-90). IPSS was high-risk in 22%, intermediate-2 in 55%, intermediate-1 in 21%, and low-risk disease in 3%. 54% were secondary MDS; 43% were therapy-related MDS. Cytogenetic analysis revealed a complex karyotype in 24%, predominantly demonstrating abnormalities in chromosomes 5 or 7 (37%) and other abnormalities (39%). 69% were treated with decitabine based therapy (single agent in 47%) while 31% were treated with 5-azacitidine (single agent in 20%). Best responses were CR in 64 pts (33%), CR without platelet recovery (CRp) in 15 pts (8%), partial response (PR) in 4 pts (2%), hematologic improvement (HI) in 10 pts (5%), and stable disease (SD) in 5 pts (3%). Furthermore, CCyR was achieved in 68 pts (31%): 45/79 pts with CR/CRp (57%), 3/19 pts with PR/HI/SD (16%), and 20/118 pts with no morphologic response (17%) (p<0.01). In addition, higher rates of CCyR were observed among pts with intermediate-2 risk disease (IPSS) compared to those with high-risk disease (68% vs 18%; p=0.02) and among pts with de-novo MDS compared to therapy-related MDS (68% vs 32%; p=0.05). By multivariate analysis, clinical parameters associated with the achievement of CCyR were morphologic CR/CRp (OR=4.24; p<0.001) and therapy related MDS (OR=0.40; p=0.01). Median follow-up was 43 mos (range 34-57). Median overall survival (OS) and transformation-free survival (TFS) were 14 and 10 mos respectively. The 2-year OS and TFS rates were 25% and 18%, respectively. The median OS and TFS for pts with and without CCyR were 20 and 11 mos (p=0.007), and 14 and 9 mos (p=0.039) respectively. Pts who achieved CCyR in addition to their morphologic CR/CRp had a trend for better outcome compared to pts who achieved morphologic CR/CR only, with a median OS of 18 mos versus 15 mos (p=0.42), respectively, and a median TFS of 14 mos versus 9 mos (p=0.32). ConclusionOur results indicate that CCyR can occur at a rate of 31% in pts with MDS treated with HMA. Pts presenting with primary MDS and attaining a morphologic response to HMA are more likely to achieve a CCyR. Furthermore we identified a significant association/correlation between the achievement of CCyR and better OS and TFS, independent of attaining a morphologic response. Therefore, the achievement of CCyR should be considered a new milestone in the management of pts with MDS. Disclosures:No relevant conflicts of interest to declare.

Refined MD Anderson Prognostic Scoring System (MDAPS-R) for Chronic Myelomonocytic Leukemia (CMML)

Abstract 3797 Background: Since the time of initial proposal of the MD Anderson Prognostic Score (MDAPS) in 2000, there has been substantial development in diagnosis and treatment for patients (pts) with CMML. MDAPS did not incorporate cytogenetic abnormalities, which is one of the most important factors of prognostication in other myeloid malignancies. Therefore, we analyzed a large cohort of patients with CMML and developed new prognostic scoring system that also incorporates cytogenetic abnormalities (named MDAPS-R). Methods: From 2003 and 2012, we identified 358 pts with diagnosis of CMML, using standards strictly defined by World Health Organization (WHO) criteria. Potential prognostic factors were identified by log-rank test. Of those, independent prognostic factors were extracted after Cox proportional hazard regression. Based on the relative strength of hazard ratio (HR), MDAPS-R was developed and was verified by log-rank test. Result: Median age of the analyzed group was 68 years (range:23–89);113 (32%) pts were female. Two hundred twenty one (62%) pts were classified as CMML-1 and 104 (29%) were CMML-2 (unknown in 33 pts). Thirty nine (11%) pts had prior exposure to chemotherapy and/or radiation therapy. Mean (± SE) white blood cell count (WBC) was 24.5 ± 1.5 (x103/μL), hemoglobin (Hb) was 10.8 ± 0.1(g/dL), platelet count (Plt) was 132 ± 7.0 (x103/μL) and bone marrow blast count (BMBL) was 6.9 ± 0.3 (%), respectively. Cytogenetics was diploid in 224 (63%) pts. Trisomy 8 was detected in 14 (4%) pts, del 20q in 12 (3.4%), -Y in 13 (3.6%), del 7q/-7 in 25 (7%), and del 5q/-5 in 10 (2.8%) pts, respectively. Complex cytogenetic abnormality was detected in 16 (4.5%) pts. Two hundred eighty (78%) pts had RAS mutation analysis and 49 (18%) had NRAS mutation while 16 (5.7%) had KRAS mutation. FLT3 alteration was tested in 297 pts (83%):3 (1%) had D835 mutation while 10 (3.4%) had ITD. JAK2 mutation was tested in 161 (45%) pts of which 19 (12%) had V617F mutation. Less commonly occurring mutations included: NPM1 (5/88 tested), c-kit (3/156), CEBPA (6/83), IDH1 (1/59), IDH2 (3/58), and DNMT3a (1/4). During the median follow up duration of 15 months (range; 1–145), 53 (15%) pts transformed to acute leukemia and 182 (51%) pts died. Median transformation free survival (TFS) and overall survival (OS) of the analyzed group was 24.9 months (range; 1–145) and 26.8 months (range; 1–145), respectively. Log-rank test identified significant covariates in association with OS that include: BMBL ( 10; P = 0.01), Hb ( 4.0; P 700; P 2.5; P 4.0; P = 0.012). None of the molecular mutations had impact on OS. After being fitted into Cox proportional hazard regression, following covariates remained independently significant: BMBL ≥10 % (vs. 700 IU/L (vs. ≤700; HR = 1.5), ALC > 2.5 × 103/μL (vs. 4.0 mg/L (vs. ≤ 4.0; HR = 1.6), and complex cytogenetics or del 7q/-7 (vs. diploid; HR = 2.3 and others vs. diploid; HR = 1.5). We developed MDAPS-R based on relative strength of HR in each of these above factors (1 point assigned to each of the following: BM BL 910 %, Hb 4.0 mg/L; 0 points for diploid cytogenetics, 2 points for −7/del 7q or complex cytogenetics, and 1 point for all other abnormal karyotype). Among 358 pts, 282 (79%) were evaluable for analysis via MDAPS-R. MDAPS-R stratified pts into 4 distinct prognostic groups: score 0–1 = low risk (N = 70, median OS 56 months), 2–3 = intermediate-1 risk (N = 133, median OS 28 months), 4–5 = intermediate-2 risk (N = 68, median OS 18 months), and 6–7 = high risk (N = 11, median OS 7.5 months) (P Conclusion: We propose a refined version of MDAPS (MDAPS-R) specifically for pts with CMML that incorporates cytogenetic abnormalities. This model may help risk-stratified decision making in CMML pts. Disclosures: No relevant conflicts of interest to declare.

Refined MD Anderson Prognostic Scoring System (MDAPS-R) for Chronic Myelomonocytic Leukemia (CMML)

Abstract 3797 Background:Since the time of initial proposal of the MD Anderson Prognostic Score (MDAPS) in 2000, there has been substantial development in diagnosis and treatment for patients (pts) with CMML. MDAPS did not incorporate cytogenetic abnormalities, which is one of the most important factors of prognostication in other myeloid malignancies. Therefore, we analyzed a large cohort of patients with CMML and developed new prognostic scoring system that also incorporates cytogenetic abnormalities (named MDAPS-R). Methods:From 2003 and 2012, we identified 358 pts with diagnosis of CMML, using standards strictly defined by World Health Organization (WHO) criteria. Potential prognostic factors were identified by log-rank test. Of those, independent prognostic factors were extracted after Cox proportional hazard regression. Based on the relative strength of hazard ratio (HR), MDAPS-R was developed and was verified by log-rank test. Result:Median age of the analyzed group was 68 years (range:23–89);113 (32%) pts were female. Two hundred twenty one (62%) pts were classified as CMML-1 and 104 (29%) were CMML-2 (unknown in 33 pts). Thirty nine (11%) pts had prior exposure to chemotherapy and/or radiation therapy. Mean (± SE) white blood cell count (WBC) was 24.5 ± 1.5 (x103/μL), hemoglobin (Hb) was 10.8 ± 0.1(g/dL), platelet count (Plt) was 132 ± 7.0 (x103/μL) and bone marrow blast count (BMBL) was 6.9 ± 0.3 (%), respectively. Cytogenetics was diploid in 224 (63%) pts. Trisomy 8 was detected in 14 (4%) pts, del 20q in 12 (3.4%), -Y in 13 (3.6%), del 7q/-7 in 25 (7%), and del 5q/-5 in 10 (2.8%) pts, respectively. Complex cytogenetic abnormality was detected in 16 (4.5%) pts. Two hundred eighty (78%) pts had RAS mutation analysis and 49 (18%) had NRAS mutation while 16 (5.7%) had KRAS mutation. FLT3 alteration was tested in 297 pts (83%):3 (1%) had D835 mutation while 10 (3.4%) had ITD. JAK2 mutation was tested in 161 (45%) pts of which 19 (12%) had V617F mutation. Less commonly occurring mutations included: NPM1 (5/88 tested), c-kit (3/156), CEBPA (6/83), IDH1 (1/59), IDH2 (3/58), and DNMT3a (1/4).During the median follow up duration of 15 months (range; 1–145), 53 (15%) pts transformed to acute leukemia and 182 (51%) pts died. Median transformation free survival (TFS) and overall survival (OS) of the analyzed group was 24.9 months (range; 1–145) and 26.8 months (range; 1–145), respectively.Log-rank test identified significant covariates in association with OS that include: BMBL (<10 vs. ≥10; P = 0.024), WBC (≤10 vs. >10; P = 0.01), Hb (<12 vs. ≥12; P < 0.001), CMML subtype (CMML-1 vs. 2; P = 0.007), prior exposure to chemo and/or radiation (Yes vs. No; P < 0.001), cytogenetics (diploid vs. complex or del7q/-7 vs. others; P < 0.001), serum β2 microglobulin (β2MG) (≤4.0 vs >4.0; P < 0.001), serum LDH (≤700 vs. >700; P < 0.001), peripheral absolute lymphocyte count (ALC) (≤2.5 vs. >2.5; P < 0.001), and peripheral absolute monocyte count (≤4.0 vs. >4.0; P = 0.012). None of the molecular mutations had impact on OS. After being fitted into Cox proportional hazard regression, following covariates remained independently significant: BMBL ≥10 % (vs. <10; HR = 1.6), Hb < 12 g/dL (vs. ≥12; HR = 1.9), LDH > 700 IU/L (vs. ≤700; HR = 1.5), ALC > 2.5 × 103/μL (vs. <2.5; HR = 1.7), β2MG > 4.0 mg/L (vs. ≤ 4.0; HR = 1.6), and complex cytogenetics or del 7q/-7 (vs. diploid; HR = 2.3 and others vs. diploid; HR = 1.5). We developed MDAPS-R based on relative strength of HR in each of these above factors (1 point assigned to each of the following: BM BL ’10 %, Hb<12 g/dL, LDH 700 IU/L, ALC .2.5 × 103/μL, and β2MG > 4.0 mg/L; 0 points for diploid cytogenetics, 2 points for −7/del 7q or complex cytogenetics, and 1 point for all other abnormal karyotype). Among 358 pts, 282 (79%) were evaluable for analysis via MDAPS-R. MDAPS-R stratified pts into 4 distinct prognostic groups: score 0–1 = low risk (N = 70, median OS 56 months), 2–3 = intermediate-1 risk (N = 133, median OS 28 months), 4–5 = intermediate-2 risk (N = 68, median OS 18 months), and 6–7 = high risk (N = 11, median OS 7.5 months) (P < 0.001, Figure 1A). MDAPS-R also predicted TFS in the same cohort (median TFS: low = 54, int-1 = 26, int-2 = 15, and high = 7 months, P < 0.001, Figure 1B). Conclusion:We propose a refined version of MDAPS (MDAPS-R) specifically for pts with CMML that incorporates cytogenetic abnormalities. This model may help risk-stratified decision making in CMML pts. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Very High Rate of Leukemic Transformation and Poor Survival in Patients with Lower Risk Myelodysplastic Syndrome (MDS) Who Dynamically Acquire FLT3 Molecular Alteration (FLT3m): Study of 290 MDS Patients with Sequential Mutation Analysis

AbstractAbstract 3802 Background and Aims:Molecular alterations of FLT3, in particular internal tandem duplication (ITD) in the juxtamembrane domain or point mutation in the tyrosine kinase domain (TKD), are found in approximately 30% of acute myeloid leukemia (AML). In contrast, FLT3 molecular alteration (FLT3m) is not commonly detected in MDS patients with reported incidence of 0.6–6%. Limited data is available for its prognostic significance in MDS, especially when it is dynamically acquired during the follow up. The aims of this study were to evaluate: 1) the incidence of dynamic acquisition of FLT3m in lower risk MDS patients; 2) the association between FLT3m acquisition and other molecular/cytogenetic aberrations and 3) the prognostic impact of dynamic FLT3m acquisition on AML transformation and survival. Methods:We analyzed 290 patients with low and intermediate-1 (Int-1) risk MDS by IPSS (lower risk MDS), who were tested for FLT3m by semi-quantitative DNA-based PCR capillary electrophoresis assay on at least two occasions (at time of diagnosis and at least once thereafter) between 1/2000 and 1/2010. Result:Median age of the analyzed cohort was 64 years (range, 23–91), and 62% were female. Seventy five (26%) patients were IPSS low risk and 215 (74%) were int-1 risk. RAEB was the most frequent WHO diagnosis (N = 107, 37%), followed by RCMD (N = 78, 27%) and RA (N = 74, 26%). Sixty three percent (N = 183) of the patients had diploid cytogenetics at diagnosis. FLT3m was detected in total of 15 (5%) patients, of which 4 (1%, ITD = 3 and TKD = 1) were detected at initial diagnosis and 11 (4%, ITD = 9 and TKD = 2) were acquired during the follow up. Median time to FLT3m acquisition was 10 months (range, 1–53). Positive statistical association was observed between acquisition of FLT3m and NPM1 mutation (P = 0.004), while negative association was observed against RAS mutation (P = 0.013). Statistical association was not observed between FLT3m acquisition and other covariates that include: age, WHO classification, initial bone marrow blast, cytogenetics, cytogenetic evolution, and molecular mutations other than NPM1 and RAS. Eight (73%) patients with FLT3m acquisition had diploid cytogenetics at diagnosis while 3 had abnormal karyotype at the beginning: inv(3)(q21q26.2), del(11)(q13q23) and dup(2)(p15p23), respectively. Of those 8 patients whose initial cytogenetics were diploid, 4 acquired cytogenetic evolution (of which 3 acquired trisomy 8) concomitantly with FLT3m acquisition. Other 2 patients acquired NPM1 mutation and another patient acquired NRAS mutation in addition to FLT3m. There was only 1 patient whom we could not identify any other genetic alterations accompanied by FLT3m acquisition. After median follow-up duration of 31 months (range, 2–147), 75 [26%] patients transformed to AML in the entire cohort. Median transformation free survival (TFS) and OS of the entire cohort were 34 months (range; 1–147) and 36 months (range; 2–147), respectively. Strikingly, all 11 patients who acquired FLT3m experienced AML transformation (100%), with a median time to transformation of 11 months (range; 4–53). Acquisition of FLT3m was detected prior to transformation in 3 patients and at the time of transformation in 7 patients. One patient acquired FLT3m after the transformation. Log-rank test showed that median TFS and OS were both significantly shorter in the FLT3m acquired group than in the non-acquired group (Figure: TFS = 11 vs. 35 months; OS = 13 vs. 38 months, both P < 0.001). By fitting FLT3m acquisition and cytogenetic evolution as time-dependent covariates, Cox proportional hazard regression showed that age > 60 years (vs. ≤ 60, HR = 1.5, P = 0.008), having cytogenetic evolution (vs. no, HR = 5.3, P < 0.001), and FLT3m acquisition (vs. no, HR = 3.4, P < 0.001) independently predicted worse TFS. Conclusion:Approximately 4% of patients with lower risk MDS acquired FLT3 molecular alteration during their follow-up, and acquisition of such alteration was strongly associated with AML transformation (100%), with significant impact on TFS. Additionally, in 88% of the patients who acquired FLT3m and transformed to AML, other molecular and cytogenetic aberrations were accompanied, that may account for the classical “2-hit” model of AML transformation. This result supports the importance of monitoring for FLT3 mutation in lower risk MDS patients upon or even before disease progression, especially in the new era of FLT3 inhibitors. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Acquisition of Cytogenetic Abnormalities (CA) Is a Very Poor Prognostic Feature in Patients (pts) with Low and Intermediate-1 (int-1) Risk Myelodysplastic Syndromes (MDS),

Abstract 3802 Background and Aim:The impact of the CA on prognosis and transformation into acute myeloid leukemia among pts with low and int-1 risk MDS is not known. The aims of the study were to assess the impact of CA on the natural history of pts with lower risk MDS and to identify factors associated with its development. Methods:We reviewed 721 pts clinical records of low and intermediate risk MDS pts from 2000–2010 and conducted a retrospective analysis of all pts with at least two consecutive cytogenetic analysis (365 patients, 51%). The acquisition of CA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases, or otherwise confirmed by FISH. Cox proportional hazards regression models were fit to assess the association between transformation-free survival (TFS) or overall survival (OS) and pt characteristics. The acquisition of CA was fitted in the Cox model as a time-dependent covariate. The association between the acquisition of CA and pt characteristics was assessed through univariate and multiple logistic regression models. Results:CA was detected in 107 pts (29%) after a median follow-up of 34 months (mos). CA was observed in a median number of 4 metaphases (range, 2–30). At diagnosis, 21% and 79% of pts who acquired CA were low-and int-1risk MDS; 50% were diploid, 22% harbored chromosome 5 /7 abnormalities. At the time of acquisition of CA, the median percentage of bone marrow blasts was 4% (range, 0% to 89%), the median WBC, hemoglobin and platelets were 3.1 × 109/L, 9.5 g/dL, and 65 × 109/L, respectively; pts were low, int-1, int-2, and high-risk MDS in 3%, 42%, 26%, 29%, respectively. The median TFS and OS were 31 (95% CI: 27– 37) and 34 (95% CI: 30 – 44) mos respectively. Assessing CA as time-dependent covariate, patients with CA had a worse TFS and OS, with a median TFS and OS of 16 and 18 mos compared to 56 and 60 mos, respectively in pts without CA. Based on the multivariable Cox model and after adjusting for effects of all other covariates, pts who had acquired CA had an increased risk of transformation (HR=1.46; p-value = 0.01) or death (HR=1.50; p-value = 0.01). By multivariate analysis, female pts with prior chemotherapy had an increased risk of developing CA (OR= 5.26; p-value <0.0001). 96 pts had history of previous malignancy treated with chemotherapy +/− radiation therapy. Of those, 34 (35%) patients acquired CA. Median time from previous chemotherapy to the acquisition of CA was 61 mos (range, 11 to 180). Pts previously treated who did not acquire CA had similar outcomes to those who had never been treated and did not develop CA, while those who did develop CA whether they were previously treated or not had worse TFS and OS. Conclusion:CA occurs at a rate of 29% of pts with lower risk MDS, more common among pts with previously treated malignancy, and has a significant impact on TFS and OS, possibly reflecting genomic instability in the natural history of MDS. Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Decitabine (DAC) Can Be Safely Reduced After Achievement of Best Response In Patients (pts) with Myelodysplastic Syndrome (MDS)

AbstractAbstract 1858DAC is standard therapy in pts with MDS. Current recommendations suggest a dose of 20 mg/m2 IV daily for 5 days every 4 weeks for as many cycles as possible to secure the best outcome. However, this therapy is associated with frequent grade 3–4 hematologic toxicity, requiring dose reduction (DR) and frequent dose delay (DD). We investigated the outcome of pts who had DD/DR and whether the timing of this dose modification relative to the time of response is relevant. Pts enrolled in phase II trials using DAC for frontline therapy for MDS were analyzed: 124 pts were treated at the dose of 10 mg/m2 IV daily × 10 days (n=17), 20 mg/m2 subcutaneously daily × 5 days (n=14), and 20 mg/m2 IV daily × 5 days (n=93). Median age was 65 years (range 37–90). Median follow up was 48 months. Seventy six pts responded, with 54 (44%) achieving a complete response (CR), 5 (4%) marrow CR, and 17 (14%) clinical benefit. The median transformation free survival (TFS) and overall survival (OS) was 13 and 20 months, respectively. Responders had better performance status (p=0.015), better baseline hemoglobin (p=0.006) and lower baseline blast percentage (p=0.05) than non responders. Sixty five pts (53%) had DR by at least 25% or DD (defined by a delay beyond 5 weeks between cycles) for a median of 7 days (range, 1 to 97), 25 had both. The main reasons for DR/DD were myelosuppression in 48 pts (74%) and infection in 10 pts (15%). Pts with DD/DR were more likely to have diploid cytogenetics (p=0.001) and received more DAC cycles (4 versus 11; p=0.001). There were no other statistically significant differences in characteristics between pts who had DD/DR versus those who did not. DD occurred after a median of 2 courses, with a median of 4 delays per pt (range, 1 to 22). DR occurred after a median of 7 courses (range, 2 to 24) with a median reduction of 25%. The median number of courses with DR was 6 (range, 1 to 18). Thirty five pts (54%) underwent DD/DR after achieving an objective response including 27 (42%) after CR. There was a trend for more durable responses in favor of pts requiring DD/DR after the achievement of an objective response (median not reached) compared to those who required DD/DR before (median of 18 months) (p=0.5). The 2-year OS rate trended higher for pts who had DD/DR after obtaining best response compared to those who had DD/DR prior to best response. The median OS was 30 and 22 months, respectively (p=0.15). There was no worsening in outcome when comparing pts who had no DD/DR to those who had DD/DR after the achievement of an objective best response. Transformation free survival (TFS) rates also trended higher for those with DD/DR after response compared to those who required DD/DR before. The median TFS was 27 and 18 months, respectively (p=0.12).In conclusion, DAC is effective in treating pts with MDS; DD/DR can be safely accomplished once the pt has achieved the best objective response (preferably CR) without impacting outcome. Prospective evaluation of an approach conceiving a loading dose for induction of a best objective response followed by a maintenance schedule is to be considered. Disclosures:Ravandi:Eisai: Honoraria, Research Funding. Cortes:Eisai: Research Funding.

Myelodysplastic Syndrome with Fibrosis: Experience of a Single-Institution with 139 Patients.

Abstract 2775Poster Board II-751 Background:A fraction of patients with MDS present with bone marrow fibrosis in addition to dysplastic hematopoiesis. It is believed that MDS patients who present with fibrotic features in the bone marrow constitute a group with worse survival. Aims:To describe clinical features and survival outcomes of patients with a diagnosis of MDS with myelofibrosis treated at the M.D. Anderson Cancer Center. Methods:We carried out a retrospective review of patients who had a diagnosis of MDS in the presence of grade 2+ or greater fibrosis. Relevant clinical data at presentation was reviewed. Survival was estimated by Kaplan-Meier method. Results:From 1997 until 2008, 129 patients with a diagnosis of MDS with myelofibrosis and 10 patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis were seen at our institution. Median age was 64 years (range 27–85). Subclassification by the World Health Organization criteria included refractory anemia (N=16, 12%), refractory anemia with ringed sideroblasts (N=4, 3%), refractory cytopenias with multilineage dysplasia (N=16, 12%), refractory anemia with excess blasts (RAEB; N=62, 45%), 5q- syndrome (N=2, 1%) and therapy-related MDS (t-MDS; N=29, 21%). Marrow reticulin fibrosis was graded in 115 patients, being grade 2 in 34 patients (30%), grade 3 in 40 patients (35%) and grade 4 in 41 patients (35%). Splenomegaly was present in 16 patients (12%), being more common in patients with a morphological diagnosis of CMML (9% vs 50%, p=0.001), and the median spleen size below the left costal margin was 8 cm (range 2–10). The median white blood cell count at diagnosis was 3.6×109/L (0.6–60.7), hemoglobin 9.6 g/dL (5.1–14.4) and platelet count 53×109/L (6–1195). Median lactate dehydrogenase level was 621 IU/L (range 263–4037). The median bone marrow blasts percentage was 4% (0–19%). Cytogenetic analysis was available in 127 (91%) cases, and was abnormal in 63 (50%) patients. The most common abnormalities were: complex karyotype in 35 patients (28%), −7/del(7q) in 7 patients (6%), del(20q) in 6 patients (5%), −5/del(5q) and trisomy 8 in 4 patients (3%) each. Analysis of the JAK2V617F mutation was done in 30 patients, being positive in 6 (20%; RAEB=3, t-MDS, CMML and 5q− syndrome in one each). One additional patient with RAEB was positive for the MPLW515K mutation. After excluding patients with CMML and t-MDS, the International Prognostic Scoring System (IPSS) score was available in 92 patients. IPSS scores were distributed as follows: low (N=15; 16%); intermediate-1 (N=47; 51%); intermediate-2 (N=25; 27%) and high (N=5; 6%). Median transformation-free survival (TFS) was 16 months (range 0–127) and median overall survival (OS) was 20 months (range 0–130) for the whole cohort. There was no difference in OS (p=0.18) or TFS (p=0.24) by degree of fibrosis. OS was influenced by the IPSS score, median OS being 38, 21, 11 and 5 months for patients with Low, Int-1, Int-2 and High risk scores, respectively (p=0.01). Similarly, median TFS was 29, 18, 10 and 5 months for patients with Low, Int-1, Int-2 and High risk scores (p=0.007). For patients with t-MDS, median TFS and OS were 15 months both, not different from patients without previous history of chemotherapy and/or radiation therapy (p=0.84 and p=0.73, respectively). Conclusion:In our cohort of patients with a diagnosis of MDS with myelofibrosis, we found a higher prevalence of JAK2 mutations and splenomegaly than previously reported. More detailed mutation analysis is in progress. The degree of fibrosis did not influence survival in our patients. The median OS and TFS for patients with Low/Int-1 risk is inferior to that reported in the literature for patients with MDS without fibrosis with similar risk. Thus, early treatment strategies should be considered for patients with MDS who present with fibrotic features in the bone marrow. Disclosures:No relevant conflicts of interest to declare.