Excess Of Blasts In Transformation Research Articles

Use of Oral Hypomethylating Agents for the Treatment of Myelodysplastic Syndromes

Introduction Myelodysplastic syndromes (MDS) are genomically complex clonal hematopoietic stem cell neoplasms leading to myelodysplasia and ineffective hematopoiesis.1,2 MDS is a disease of older age, clinically manifesting as symptomatic cytopenias with an added propensity for transformation to acute myeloid leukemia (AML).3 The treatment of MDS is based on a risk-adapted approach per the International Prognostic Scoring System (IPSS)4 or the modified IPSS-R.5 Allogeneic stem cell transplantation (ASCT) is the only curative strategy, but most patients are not eligible due to their age or other comorbidities.6 In these patients, hypomethylating agents (HMA, either decitabine or azacitidine) are the mainstay of therapy to either alleviate cytopenias or impede disease progression. 7 Decitabine (DEC) and azacitidine (AZA) are approved to treat patients with MDS, including previously treated and untreated, de novo, and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups.7

Refractory Anemia With Excess Blasts In Transformation (Acute Myeloid Leukemia with 20-29% Blasts) in Older Adults is Less Aggressive Than Acute Myeloid Leukemia With ≥30% Blasts

BackgroundThe current WHO Classification defines acute myeloid leukemia (AML) in most cases as a myeloid neoplasm with ≥20% bone marrow (BM) or peripheral blood (PB) blasts. However, it is controversial whether AML cases with 20-29% BM blasts, referred to as oligoblastic AML or refractory anemia with excess blasts in transformation (RAEBT), should be considered as AML or myelodysplastic syndrome (MDS) in terms of treatment approach and prognosis. MethodsWe retrospectively studied 573 patients aged ≥50 years diagnosed after the year 2004 with de novo AML, including 142 with 20-29% BM blasts (RAEBT) and 431 with ≥30% BM blasts (AML30). Patients with t(15;17), t(8;21), inv(16)/t(16;16), or history of any prior myeloid neoplasm were excluded. Clinicopathologic and genetic features, treatments, and outcome of RAEBT were compared to AML30. The clinicopathologic and genetic features of RAEBT were also compared to 152 de novo MDS patients with 10-19% BM blasts (RAEB2) diagnosed over the same time period. Fisher's exact and Wilcoxon tests were used to compare categorical and continuous variables between groups, respectively. Overall survival (OS) was estimated using the method of Kaplan and Meier and the log-rank test was used to compare OS between groups. Univariate and multivariable Cox proportional hazards regression was used to assess the impact of the two groups along with other risk factors in OS. ResultsCompared to AML30 patients, RAEBT patients were older and had lower white blood count and BM cellularity, but had higher hemoglobin, platelet count, and UKMRC karyotype risk score and greater morphologic dysplasia (Table 1).RAEBT and RAEB2 patients were similar with respect to age, peripheral counts, BM cellularity, and karyotype risk scores. In the subsets of patients in whom they were assessed, FLT3 and NPM1 mutations and monocytic features occurred more commonly in AML30 than in RAEBT (Table 1). RAEBT patients were treated more often with hypomethylating agents and less often with intensive therapy (anthracycline/cytarabine) compared to AML30 patients, whereas allogeneic stem cell transplant frequency was similar. With 55.5 months median follow-up, OS of RAEBT patients was superior to that of AML30 patients (p=0.003)(Figure 1). Multivariable analysis showed that RAEBT (p<0.0001), hemoglobin ≥10.3 g/dL (p=0.045), intermediate UKMRC karyotype score (p<0.0001), normal bone marrow karyotype (p=0.0005), intensive therapy (p<0.0001), and stem cell transplant (p<0.0001) were associated with longer OS.Table 1Comparison of RAEBT and AML30 groupsRAEBT (n=142)AML30 (n=431)p valueMedian age in years6763<0.0001Median white blood count (x 109/L)2.389.20<0.0001Median hemoglobin (g/dL)9.809.200.0007Median platelets (x 109/L)76600.01Median BM cellularity (%)6090<0.0001Morphologic dysplasia(% with >10% erythroid / myeloid / megakaryocytic dysplasia)53 / 53 / 4631 / 25 / 27<0.0001 / <0.0001 / <0.0001Monocytic or myelomonocytic differentiation23/115 (20%)137/342 (40%)<0.0001UKMRC karyotype scores(% intermediate / adverse / missing)61 / 35 / 569 / 26 / 50.049FLT3-ITD mutation3/94 (3%)59/247 (23%)<0.0001NPM1 mutation1/55 (2%)46/151 (30%)<0.0001Supportive care only11/142 (8%)38/431 (9%)0.86Hypomethylating agent as initial therapy36/142 (25%)36/431 (8%)<0.0001Intensive therapy as initial therapy73/142 (51%)310/431 (72%)<0.0001Stem cell transplant41/142 (29%)118/431 (27%)0.7412-month OS [95% CI]60% [46-74%]51% [47-55%]0.00348-month OS [95% CI]29% [22-36%]20% [17-24%]▪ ConclusionsRAEBT is more similar to RAEB2 than to AML30 in terms of its clinicopathologic and cytogenetic features. In spite of less frequent treatment with intensive chemotherapy and higher karyotype risk, RAEBT patients had superior OS compared with AML30 patients. In a prior study (Estey E et al. Blood 1997;90:2969), RAEBT and AML30 patients treated with intensive therapy had similar outcomes; the advent of hypomethylating agent therapy may in part account for the differences found in our study. Our findings favor considering RAEBT in a disease category separate from AML with higher blast counts. Disclosures:No relevant conflicts of interest to declare.

A Phase 1 Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes: University of California Hematologic Malignancies Consortium (UCHMC) Study 1503

Introduction: Higher risk myelodysplastic syndromes (HR-MDS) have poor outcomes, particularly after hypomethylating agent (HMA) failure. The HMA azacitidine (AZA) is a standard of care for HR-MDS and works through several mechanisms, including inhibition of NF-kB signaling. Ibrutinib (IBR) inhibits Bruton9s Tyrosine Kinase (BTK) and has an antiproliferative effect on myeloblasts in preclinical models through BTK binding and inhibition of NF-kB signaling. IBR also has immunomodulatory activity mediated through binding interleukin-2-inducible kinase (ITK) and promoting Th1-polarized immunity, which is decreased in HR-MDS. These features suggest that the combination of IBR and AZA may improve outcomes in HR-MDS. Methods: This is an ongoing multicenter prospective Phase 1 dose-escalation trial of IBR in combination with AZA in patients with HR-MDS (NCT02553941). Results of the dose escalation phase are reported. Eligibility included World Health Organization or French-American-British classification-defined MDS and Revised International Prognostic Scoring System (IPPS-R) intermediate or higher risk. Any prior therapy was allowed or patients could be untreated if unfit for, or had refused, high intensity chemotherapy. Transfusion-dependent patients were eligible. Patients received AZA 75 mg/m2 IV/SC daily for 7 days and IBR orally daily for 28 days. Cycles repeated every 28 days. Dose-escalation used a 3+3 design with IBR dose levels of 420 mg (Cohort 1) and 560 mg (Cohort 2). The primary objective was to determine the safety and tolerability of IBR in combination with AZA. Adverse events (AEs) were monitored throughout treatment, and dose-limiting toxicities (DLT) were assessed during cycle 1. The secondary objective was to assess preliminary efficacy using modified International Working Group Response Criteria. Exploratory objectives evaluated pharmacodynamic and biological effects of the combination, including BTK occupancy in CD34+ bone marrow mononuclear cells (BMMC). Results: As of June 1, 2017, 9 patients [89% male, median age 80 years (range 64-81)] were enrolled into Cohort 1 (n=3) and Cohort 2 (n=6). MDS subtypes included single lineage dysplasia (n=1), multilineage dysplasia (n=1), excess blasts (EB)-1 (n=2), EB-2 (n=3), refractory anemia with EB in transformation (n=1) and unclassifiable (n=1). IPSS-R scores were intermediate (n=2), high (n=2) and very high (n=5). Three patients were HMA-naive and six had prior HMA therapy [AZA (n=3), decitabine (n=2), both (n=1)]. All patients completed cycle 1. No DLTs were observed. All patients experienced at least one treatment-emergent adverse event (TEAE). Seven patients experienced a grade 3-4 TEAE with neutropenia (n=6), thrombocytopenia (n=3) and febrile neutropenia (n=3) most common. Four patients (three in Cohort 1 and one in Cohort 2) experienced a serious adverse event including febrile neutropenia (n=3) and gastric hemorrhage (n=1). No patients experienced atrial fibrillation. Median time on study was 160 days (range 42-283) with a median of five cycles (range 1-10) received. Six patients remain on IBR plus AZA, and three patients have discontinued study therapy (two disease progression and one withdrawal of consent and subsequent death on hospice). Four patients have reduced AZA to 5 days per cycle per investigator discretion, and four patients have had interruptions of IBR dosing due to febrile neutropenia (n=3) and concurrent azole use (n=1). Three patients (33%) achieved complete remission (CR), one (11%) had a partial remission (PR), and five (55%) had stable disease (SD). All three CRs occurred in patients without prior HMA exposure and included one complete and two partial cytogenetic responses. CR was achieved after 1, 4 and 6 cycles in these patients. One patient (11%) with SD had a hematologic improvement-erythroid response (HI-E). The overall hematologic normalization rate (CR+PR+HI) was 55%. BTK occupancy in CD34+ BMMC after cycle 1 was 42.0% and 51.7% in two patients at IBR 420 mg and 41.5% in one patient at IBR 560 mg. Conclusions: The combination of IBR and AZA demonstrates a tolerable safety profile in patients with HR-MDS. No DLTs were observed at either IBR dose level. The combination shows promising preliminary efficacy, including responses in patients with prior HMA exposure. CD34+ BMMC BTK occupancy was seen. An expansion cohort at the IBR 560 mg dose level in AZA-naive patients is ongoing. Disclosures Jonas: AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees; Rigel: Consultancy. Logan: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Astellas: Research Funding; Shire: Consultancy; Kite: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Jazz: Consultancy. Abedi: Takeda: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding. Bejar: Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Genoptix: Consultancy, Honoraria, Patents & Royalties; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria. Wieduwilt: Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding. Curtin: Amgen, Celgene, Onconova, Pharmacyclics: Research Funding.

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia

AbstractAllogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 × 109/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell–depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Myelodysplastic syndrome survival and secondary AML trends in the United States.

7552 Background: Myelodysplastic syndrome (MDS) is a rare heterogeneous group of hematologic stem cell disorders. The most recent FDA therapies approved for the treatment of MDS were decitabine (May 2006), lenalidomide (June 2005), and azacitidine (November 2004). This analysis utilized a population-based cancer registry to identify changes in survival rates and secondary AML rates among patients with MDS. Methods: SEER 18 regions database (November 2017 submission) was accessed to obtain data on survival and secondary malignancies using SEER*Stat 8.3.6. ICD-O-3 codes were used to identify patients with refractory anemia (RA), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, refractory cytopenia with multilineage dysplasia, MDS with 5q deletion, therapy-related MDS, and MDS, not otherwise specified. An observed survival analysis was conducted using a cohort diagnosed between 2001 and 2004 and another diagnosed between 2009 and 2012. Secondary AML risk was calculated using multiple primary - standardized incidence ratios (MP-SIR) to obtain observed/expected (O/E) ratio. Results: Three-year observed survival rates for patients diagnosed between 2001 and 2004 was 53.2% (50.4%, 55.9%) and was 61.2% (57.9%, 64.3%) for patients diagnosed between 2009 and 2012. There was no observed survival difference among other MDS subtypes. O/E ratio for development of AML among patients with RA was 2.77 (0.57, 8.11) for patients diagnosed between 2001 and 2004, and 49.49 (33.39, 70.65) for patients diagnosed between 2009 and 2012. Conclusions: Survival among patients diagnosed with RA has improved in recent years, whereas survival among other subtypes of MDS has not changed. Secondary AML rates have increased among RA patients identified in the population-based cancer registry.

Induction, Bridging, or Straight Ahead: The Ongoing Dilemma of Allografting in Advanced Myelodysplastic Syndrome

Induction, Bridging, or Straight Ahead: The Ongoing Dilemma of Allografting in Advanced Myelodysplastic Syndrome

PS1344 PHASE 1/2 STUDY OF DSP‐7888 IN PATIENTS WITH HIGHER‐RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS) AFTER FAILURE OF AZACITIDINE (AZA) THERAPY

Background:Although azacitidine (AZA) is the standard frontline therapy for higher‐risk (HR) myelodysplastic syndromes (MDS), approximately 40% of patients fail to respond and almost all responders eventually relapse. The prognosis for patients after AZA failure is poor with no approved therapeutic options and a median overall survival (OS) of approximately 6 months from treatment failure (Prebet T, et al. J Clin Oncol. 2011;29:3322–7.). Wilms’ tumor 1 (WT1) is constantly expressed in the leukemic cells of acute leukemia and MDS, and it is considered a prominent therapeutic target for MDS. DSP‐7888 is a WT1‐based cancer vaccine containing peptides that induce WT1‐reactive cytotoxic T lymphocytes and helper T cells. A partial peptide of DSP‐7888, WT4869 showed preliminary clinical activity in HR‐MDS (Ueda Y, et al. Cancer Sci. 2017;108:2445–53.). We hypothesized that DSP‐7888 could have significant clinical activity in HR‐MDS.Aims:This uncontrolled, open‐label, multicenter Phase 1/2 clinical trial was designed to determine the recommended dose (RD) of DSP‐7888 and evaluate its safety and clinical activity, including OS, in patients with HR‐MDS after AZA treatment failure (NCT02436252).Methods:The RD of DSP‐7888 was determined in Phase 1 using a 3+3 design that included two dose levels (3.5 and 10.5 mg/body). Eligible patients had HR‐ or lower‐risk MDS but not chronic myelomonocytic leukemia or refractory anemia with excess blasts in transformation. To evaluate clinical activity, the Phase 2 trial included 42 patients with MDS who showed no response to AZA treatment (including eligible patients from Phase 1). Patients were administered DSP‐7888 in solution intradermally with the RD—100 μL at six sites for 10.5 mg. Study drug was given every 2 weeks for 6 months and then every 2 to 4 weeks until no clinical benefit was seen. The primary endpoint was OS. Written informed consent was obtained from all patients.Results:Overall 47 patients received DSP‐7888 in Phase 1 (n = 12) and Phase 2 (n = 35). No dose‐limiting toxicities (DLT) were observed for 3.5 mg or 10.5 mg in the DLT evaluation period (first 2 cycles of DSP‐7888 in Phase 1). RD was determined to be 10.5 mg.The safety population included all patients who received the study drug (N = 47). The most common adverse events (AEs) were injection site reactions (ISR) in 91.5% (n = 43) of all patients; 27.9% were grade 1, 37.2% grade 2, 34.9% grade 3, and no grade 4. Other than ISR, AEs related to study drug seen in &gt;5% included pyrexia (10.6%) and febrile neutropenia (8.5%).The Phase 2 clinical activity analysis was performed on patients with HR‐MDS (N = 42) and included those from Phase 1 who met the criteria (n = 7); 76.2% were male and median age was 74.0 years (range: 63–93). The median OS was 8.5 months (90% CI: 6.8–11.1). The disease control rate was 19.5% with a median duration of response of 2.7 months. (The disease control rate included patients who had achieved a complete response [CR], partial response, marrow CR, or stable disease.) Hematologic improvement was seen in 9.8% of patients. The median time to transformation to acute myeloid leukemia or death was 5.7 months (90% CI: 3.6–7.1).Of the 42 patients, 37 were evaluable for WT1 reactive immune response and the results are shown in the Table.Summary/Conclusion:DSP‐7888 was tolerable and showed signs of clinical activity in patients with HR‐MDS; those who had a positive immune response showed a significantly longer OS than those who were negative. Identifying the optimal population for treatment with DSP‐7888 is important for further investigations.image

Myelodysplastic and myeloproliferative disorders of childhood.

Myelodysplastic syndrome (MDS) and myeloproliferative disorders are rare in children; they are divided into low-grade MDS (refractory cytopenia of childhood [RCC]), advanced MDS (refractory anemia with excess blasts in transformation), and juvenile myelomonocytic leukemia (JMML), each with different characteristics and management strategies. Underlying genetic predisposition is recognized in an increasing number of patients. Germ line GATA2 mutation is found in 70% of adolescents with MDS and monosomy 7. It is challenging to distinguish RCC from aplastic anemia, inherited bone marrow failure, and reactive conditions. RCC is often hypoplastic and may respond to immunosuppressive therapy. In case of immunosuppressive therapy failure, hypercellular RCC, or RCC with monosomy 7, hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning regimens is indicated. Almost all patients with refractory anemia with excess blasts are candidates for HSCT; children age 12 years or older have a higher risk of treatment-related death, and the conditioning regimens should be adjusted accordingly. Unraveling the genetics of JMML has demonstrated that JMML in patients with germ line PTPN11 and CBL mutations often regresses spontaneously, and therapy is seldom indicated. Conversely, patients with JMML and neurofibromatosis type 1, somatic PTPN11, KRAS, and most of those with NRAS mutations have a rapidly progressive disease, and early HSCT is indicated. The risk of relapse after HSCT is high, and prophylaxis for graft-versus-host disease and monitoring should be adapted to this risk.

Survival Trends Among Patients with High Risk Myelodysplastic Syndrome in Pre- and Post-Hypomethylating Era: A SEER Population Based Study.

Background:The myelodysplastic syndrome (MDS) includes a diverse group of clonal hematopoietic stem cell malignancies primarily affecting older individuals. It is characterized by bone marrow failure, peripheral blood cytopenias, and reduced survival. Treatment is based on prognostic scoring system and the pathology. Higher-risk disease carries a significant risk of progression to Acute Myelogenous Leukemia (AML). In these patients, treatment includes either an allogeneic stem cell transplantation (SCT) or a hypo-methylatingagent. Elderly patients with MDS usually are not a suitable candidate for allogeneic stem cell transplant given their age and other associated comorbidities. In this subset of patients, hypomethylatingagents, namely azacitidineor decitabineare the preferred treatment options. The effect of the introduction of therapeutic advances has not been well understood at the population level.We conducted this study to compare relative survival rates of elderly patients (≥65 years) with MDS in pre- and post- hypomethylatingagent era.Methodology:We utilized the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER-18) database to identify patients diagnosed with MDS. MDS subtype, namely Refractory anemia with excess blasts [Code: 9983/3] and Refractory anemia with excess blasts in transformation [Code: 9984/3] have the highest risk rate of transformation to AML. We opted to focus on these high risk MDS subtype. We limited our analysis to patients who are ≥ 65 years of age. On May 19, 2004, the U.S. Food and Drug Administration approvedazacitidinefor MDS. We defined our timeframes as follows: pre-hypomethylatingera (from 1994 to 2003) and post-hypomethylatingera (from 2005 to 2011). We analyzed one- and two-year relative survival rates (RS) of MDS patients. Several cohorts categorized by race (Caucasians and African Americans), gender and age (65-80, ≥ 80) were compared to assess the survival differences across our two defined eras. Z-test was used to compare the survival rates.Results:The database comprised of 2,665 patients (691 in pre and 1,974 in post). Overall there was an improved survival in post-hypomethylatingera (1-year: 43.8±2.0% vs. 50.2±1.2, Z-score= 2.993, p-value=0.0028; 2-year: 22.3±1.7 vs. 26.9±1.1, Z score= 3.202, p value=0.0014). There was a significant improvement in 1-year RS for males and 2-year RS for females. Elderly Caucasians also had survival benefit in post-hypomethylatingera. There was no survival benefit observed for African Americans however this did not reach statistical significance. A survival benefit was observed for elderly (65-79 years) and very elderly (≥ 80 years, only 2-year RS) population.Conclusion:The survival of myelodysplastic syndrome has improved significantly in post-hypomethylatingera. Improvements in supportive care, utilization of allogeneic stem cell transplant, andhypomethylatingagetnsmay all have contributed to this observation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A new complex karyotype in a unique de novo myelodysplastic syndrome case involving ten chromosomes and monoallelic loss of TP53

Myelodysplastic syndrome (MDS) is a group of clonal stem cell disorders characterized by cytopenia, dysplasia in one or more cell lineages, and ineffective hematopoiesis. MDS is associated with high risk of progression to acute myeloid leukemia. At initial diagnosis, clonal cytogenetic aberrations are present in 40–70% of patients with de novo (primary) MDS and in 65–95% of patients with therapy-associated ones (t-MDS). Most commonly observed abnormalities present in MDS are monosomy 5 and 7, trisomy 8, deletions of long arm of chromosome 20 as well as complex karyotypes. Loss or gain of chromosomal material is known to be related to disease development and progression.In a de novo adult MDS case banding cytogenetics, refined by array-proven multicolor banding (aMCB) revealed a unique complex karyotype involving ten chromosomes that include del(5q), del(7q), deletions in parts of both chromosomes 10, and a dic(7;17). Interestingly, the dic(7;17) leads to monosomy of the tumor suppressor gene TP53. The patient had an immunophenotype consistent with refractory anemia with excess blasts in transformation (RAEB-t) according to French–American–British (FAB) classification.To the best of our knowledge, a comparable adult MDS case associated with such a complex karyotype and loss of TP53 was not previously reported. As most of complex aberrations were found simultaneously in all studied malignant cells this may be a hint on an initial one step development of this complex rearrangement by chromothripsis.

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome.

GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).

Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20-29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naïve adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20-29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P = 0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60-69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 10(9) /L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P = 0.0015), and peripheral blasts (HR 1.25, P = 0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20-29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy.

Allogeneic Transplantation in Elderly Patients with AML and MDS Comparing Reduced-Intensity Conditioning with Flamsa-Busulfan Versus Fludarabine/BCNU/Melphalan

▪By reducing treatment intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become feasible for elderly patients. Different reduced-intensity conditioning (RIC) regimens are available, but there is little consensus about the optimal preparative regimen to use, in particular with regard to the outcomes counterbalancing the aim of feasibility and tolerability with higher rates of relapse. Here, we retrospectively evaluate the outcome of sequential therapy employing RIC with fludarabine 30 mg/m2, cytarabine 2g/m2 and amsacrine 100 mg/m2 for 4 days (FLAMSA; Schmid C et al. JCO 2005) followed by busulfan 10 x 0.8 mg/kg (FLAMSA-Bu) compared to RIC utilizing fludarabine 5 x 30 mg/m2, carmustine (BCNU) 2 x 150 mg/m2 and melphalan 110 mg/m2 (FBM; Marks R et al. Blood 2008) in elderly patients treated consecutively at our institution between July 2005 and October 2012.We analyzed the course of 114 patients (pts) with acute myeloid leukemia (AML; n=99) or myelodysplasia (MDS; n=15) aged ≥ 59 years with 59 pts aged ≥ 66 years who were treated with either FLAMSA-Bu (n=66; n=24 ≥ 66 years) or FBM (n=48; n=35 ≥ 66 years). All patients received sero-therapy with anti-thymocyteglobuline (ATG). Median patient age was 66 years for the entire cohort (68 years FBM; 64 years FLAMSA-Bu). 36 patients (75%) of the FBM and 42 patients (63 %) of the FLAMSA-Bu group suffered from high risk disease defined as relapsed or refractory AML or refractory anemia with excess of blasts in transformation (RAEB-T). The hematopoietic cell transplantation comorbidity index (HCT-CI) was higher for the patients of the FBM group than for the FLAMSA-Bu group with 26 (54 %) versus (vs) 24 patients (36 %) scoring ≥ 2 (p 0.085). Graft source after conditioning with FBM/FLAMSA-Bu was bone marrow (1/2), G-CSF mobilized peripheral blood stem cells (40/62) and double-umbilical cord-blood (7/1). In 23 pts (20 %) HLA-matched related and in 91 pts (80 %) HLA-matched unrelated donor transplantation was performed. Engraftment failure was observed in 1 patient after FLAMSA-Bu, while engraftment was achieved in all evaluable patients of the FBM group in a median of 23 days vs 18 days after FLAMSA-Bu (p 0.003), while 7 pts with double-umbilical cord-blood transplantation where included in the FBM group vs 1 pt in the FLAMSA-Bu group. Non-hematological treatment-related acute toxicity ≥ CTC III (gastrointestinal, hepatic, cardiovascular, renal, centralnervous system) occurred in 12/48 pts (25 %) after FBM and in 18/66 pts (27 %) after FLAMSA-Bu. Incidence of severe acute (III-IV) and chronic GvHD was 22.9 %/16.6 % for FBM vs 18.2 %/19.7 % for FLAMSA-Bu, respectively. After conditioning with FBM 2/48 pts vs 9/66 pts after FLAMSA-Bu were diagnosed with a secondary malignancy (p 0.08). Non-relapse mortality (NRM) after 12 months was 26.8 % for FBM versus 25.2 % for the FLAMSA-Bu group. Incidence of relapse after FBM vs FLAMSA-Bu conditioning was 22.9 % vs 15.2 % after 1 year and 31.3 % vs 16.7 % after 2 years. Occurrence of relapse was significantly related to an incomplete or mixed chimerism (donor cells ≤ 95 % in peripheral blood and/or bone marrow) at day +30 (p 0.001).After a median follow up of 31.4 months (range 4.4-97.5) estimated overall survival (OS) and relapse-free survival (RFS) after 2 years was 55.4 % and 51.4 % for the FBM vs 58 % and 56.7 % for the FLAMSA-Bu group, respectively. Analyzing different subgroups, FBM conditioning might be favorable for pts aged ≥ 66 years when suffering from high risk AML (n=26): Within this group 1-year OS after FBM vs FLAMSA-Bu was 71.4 % vs 66.7 % (p 0.58) and 1-year RFS was 71.4 % vs 58.3 % (p 0.59), respectively. Notably, for pts at highest risk (aged ≥ 66 years and suffering from secondary or therapy-related AML; n=24) the benefit of FBM conditioning becomes more pronounced: 1-year OS after FBM vs FLAMSA-Bu was 62.5 % vs 37.5 % (p 0.26) and 1-year RFS 54.2 % vs 37.5 % (p 0.17).Both conditioning regimens are feasible, and provide similar rates of acute toxicity, NRM and GvHD. There might be evidence for a benefit of conditioning with FBM for the subgroup of “the oldest patients at highest risk”. Taking into account that there is an increasing group of ‘medically fit’ elderly patients in the field of allogeneic transplantation, prospective clinical trials are needed to investigate different conditioning regimens considering their special requirements. DisclosuresNo relevant conflicts of interest to declare.

Incidence and Outcomes of Pediatric Myelodysplastic Syndrome in the US

Background There is lack of epidemiological data on pediatric myelodysplastic syndrome (p-MDS) in the literature. MDS became reportable to the Surveillance, Epidemiology and End Results (SEER) Program in 2001, providing an opportunity to estimate the incidence and survival of pediatric patients with MDS in the United States. Methods We utilized data from the National Cancer Institute SEER-18 to determine the incidence and long term overall survival (OS) of pediatric patients (ages 0 to 20 years) diagnosed with de novo MDS or therapy-related MDS. Inclusion criteria was diagnosis of MDS (International Classification of Diseases-Oncology, Third Edition, ICD-O-4 codes 9980/3, 9991/3, 9992/3, 9982/3, 9985/3, 9983/3, 9986/3, 9986/3, 9989/3, 9985/3, 9975/3, and 9987/3) between 2001 and 2011. Follow up was updated through the end of 2011 (November 2013 submission). Overall survival was estimated using the method of Kaplan-Meier. A Cox proportional hazard model was used to compare the effects of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) on survival. Results The incidence of p-MDS was 1.16 cases/1 million population*year. A greater incidence occurred in children younger than 1 year of age possibly reflecting congenital bone marrow failure syndromes (Figure 1). A total of 314 p-MDS cases were included in the analysis with median follow up of 31 months (range 0-131). Median age of patients was 9 years; 167 (53.3%) had MDS unclassifiable (NOS), 40 (12.7%) had therapy-related MDS (t-MDS), 44 (14%) had refractory anemia with excess blasts (RAEB), 32 (10.3%) had refractory anemia (RA), 17 (5.4%) had refractory cytopenia with multilineage dysplasia (RCMD), 6 (1.9%) had refractory anemia with ring sideroblasts (RARS), 5 (1.6%) had refractory anemia with excess blasts in transformation (RAEBT), and 3 (0.9%) had MDS associated with isolated del(5q). Male patients comprised 154 (49%) of cases. Racial groups included white (218, 69.4%), 52 (15.7%) black, 37 (11.8%) of other races, and 7 (2.3%) the race was unknown. The 5 year-OS for the entire cohort was 68% (95% C.I.=62.3-73.7). Patients with t-MDS had significantly worse 5 year-OS (41.2%; 95%C.I.=23.8-58.6) compared to those with de novo MDS (71.3%; 95%C.I.=65.3-77.2; P=0.004, Figure 2). In multivariate analysis of age, race, gender, histological subtype, and etiology (de novovs. therapy-related) utilizing Cox regression model, only t-MDS was associated with higher risk of death (HR=2.07, 95% C.I.=1.25-3.42, P=0.005). Conclusions Pediatric MDS is a rare disorder, with higher incidence among children younger than 1 year of age. Over two thirds of p-MDS patients will become long-term survivors, although significantly inferior outcome is seen in t-MDS. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Azacitidine As Post-Remission Therapy in Elderly Patients with Acute Myeloid Leukemia Significantly Prolongs Disease-Free Survival: Interim Results from a Prospective, Randomized, Open-Label, Phase III Multicenter Trial

Background: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%), which partially explains a median survival of 7 to 12 months. Several studies have suggested that maintenance therapy may improve CR duration and long-term, disease-free survival (DFS). Grovdal et al (2010) treated 60 elderly patients with high-risk myelodysplastic syndrome (MDS) or AML with cytarabine-based induction therapy resulting in CR in 24 patients who continued on to 5-Azacitidine (5-Aza) maintenance therapy. The median duration of CR was 13.5 months. The median OS for the 5-Azacitidine-treated group was 20 months.Aims: The present phase III, prospective, randomized, open-label, multicenter trial is designed to assess the efficacy of post-remission treatment with 5-Aza versus best supportive care (BSC) in 54 patients > 60 years of age with AML in CR after conventional induction (“3+7”) and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between; secondary endpoints are the difference in overall survival (OS) at 2 and 5 years, the number and length of hospitalizations and quality of life in the 2 arms in the 2-year post-remission period.Methods: Patients with newly diagnosed AML with > 30% myeloid marrow blasts, either “de novo” or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with a performance status < 3 are included. Standard induction chemotherapy consists of two courses of “3+7” (Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7). Patients in CR receive consolidation with cytarabine 800 mg/m2 3 hour infusion bid days 1-3. Patients in CR are randomized 1:1 to recieve best supportive care (BSC) or 5-Aza according to the following schema: 50 mg/m2 s.c. or i.v. for 7 days (5 + weekend off + 2) every 28 days and increase dosing after 1st cycle, if well tolerated, to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4 years and six months post-remission.Results: At the time of the present interim analysis 88 patients have been included in the study. Median age at diagnosis was 71, interquartile range (IQR) 66-75 years, male/female 45/43. During induction-consolidation chemotherapy, 31 patients were relapsed/refractory, 14 died, 5 refused to continue, 3 were excluded for protocol violation, 1 was lost to follow-up and 6 have not yet reached consolidation treatment. Twenty-eight patients have been randomized and 9 have more than 1 year follow-up (7 5-Aza patients, 2 BSC patients). The characteristics of randomized patients are shown in the table. The median observation time is 42.3 weeks and 12 patients are still in CR. Twelve patients in the BSC arm have experienced AML recurrence versus 4 patients in the 5-Aza arm at 9,17,42,56 weeks, respectively. Median DFS in the BSC arm is shorter (14 weeks, IQR 9-50 weeks) compared to that observed in the 5-Aza arm (median not reached at 2 years, P=0.008; Figure 1). At 2 years post-randomization 10 patients have died: 4 in 5-Aza arm versus 6 in BSC arm. All deaths occurred after AML recurrence. Median OS in 5-Aza arm is not reached at 2 years, versus 57 weeks, IQR 25-NA weeks in the BSC arm (P= 0.219, Figure 2). Grade 3-4 adverse events in the 5-Aza arm included neutropenia in 3 cases and one hospitalization for pericarditis, concomitant to AML recurrence. No serious adverse events were experienced in the BSC arm.Conclusions: Preliminary results indicate that in elderly AML patients receiving standard induction-consolidation chemotherapy, 5-Aza post-CR is well-tolerated and significantly prolongs DFS. The trial is ongoing and may provide further insight on the impact of post-remission 5-Aza treatment on OS in this elderly population. [Display omitted] [Display omitted] [Display omitted] DisclosuresOliva:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Speakers Bureau. Off Label Use: Azacitidine is indicated for treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.. Musto:Celgene: Advisory Board Other, Honoraria.

Cytogenetics and clinical features of pediatric myelodysplastic syndrome in Japan.

We analyzed the cytogenetics and clinical features of pediatric myelodysplastic syndrome (MDS) in Japan. Data on patients (<16 years) diagnosed with MDS from 1990 to 2000 were retrospectively collected from pediatric hematologists in 234 institutions. Chromosome analysis was successfully performed in 255 of 277 MDS patients. The numbers of patients with refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEBt), chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia were 67 (24%), 51 (18%), 51 (18%), 20 (7%), and 65 (23%), respectively. The other 23 patients (8%) could not be classified specifically. The distribution of childhood MDS in Japan according to the French-American-British subclassification was similar to that in other countries. However, we identified a higher incidence of therapy-related cases. As for relationship between cytogenetics and prognoses, abnormal karyotypes were related to poorer prognoses than normal karyotype (P < 0.01). However, patients with trisomy 8 had prognoses comparable to those with normal karyotypes. Complex karyotypes were associated with poorer prognoses among RAEB and RAEBt patients. In conclusion, prognosis of pediatric MDS is related to cytogenetics. A more precise diagnosis and classification system is needed for childhood MDS.

Outcome Of Patients With Myelodysplastic Syndrome (MDS) With Bone Marrow Blasts Between 10-30% Treated With Hypomethylating Agents Versus Intensive Chemotherapy

BackgroundIn 2001, the World Health Organization modified the French-American-British (FAB) classification for myelodysplastic syndrome (MDS) by folding the refractory anemia with excess blasts in transformation (RAEB-t) category into acute myeloid leukemia (AML). Whether this group of patients (pts) should be treated with AML versus MDS therapy remains controversial. A subset analysis of the AZA-001 trial showed that azacitidine prolongs overall survival (OS) in elderly pts with low blasts AML (bone marrow blasts [BM] 20-30%). AimTo compare the clinical outcome and OS of patients with MDS or AML with BM blasts between 10-30%, treated with hypomethylating agents (HMA) vs intensive chemotherapy (IC). Patients and MethodsWe conducted a retrospective analysis of newly diagnosed pts with MDS (or AML by WHO) and BM blasts between 10-30% treated with either HMA (alone or in combination with investigational therapies) or IC on clinical trials. Eligibility was based on pt characteristics and specific protocol inclusion criteria. A univariate Cox proportional hazards regression model was used to evaluate the overall effects of treatments and outcome (remission duration (RD), and OS). Then a regression model with the interactions between treatments and baseline covariates were used for subgroup analysis. The final model was obtained by a stepwise selection using 0.05 as a cut off of significant values. Results330 patients were included in the final analysis, with 93 (28%) HMA-treated pts and 237 (72%) pts treated with IC. Clinical characteristics at diagnosis are summarized in Table1. The overall response rate (ORR= CR+CR p) was 42% for the pts who treated with HMA and 60% for pts treated with IC (P = 0.01). The median RD was similar between the two groups (14.7 mos (m) vs. 14.7 mos, respectively, P = 0.74). Early induction mortality was also similar among the two groups (4-week mortality was 5% vs. 7%, respectively, and the 8-week mortality was 10% vs. 13 %, respectively). With median follow up of 37 mos (range, 1-94 mos), the median OS was 18.8 mos for pts who treated with HMA vs. 14.6 mos for pts treated with IC (P = 0.32). Moreover, the BM blasts percentage did not impact the overall outcome. In multivariate analysis, treatment with IC was associated with worse OS compared to HMA (HR 2.09, 95% CI 2.07-3.17, P = 0.003) but not for RD (HR 0.43, 95% CI 0.89-2.68, P = 0.13).Table 1Patients' characteristics and responsesCharacteristicsAll patients No.%HMA No.%IC No.%P- valueNumber330932823772Age, yearsMedian646662<0.001Range13-9013-9017-84Age, years0.03< 6518757444714360> 651434349539440SexMale194595963135570.28Female13641343710243History of prior Cx and /or Rx0.26Yes752325275021No25577687318779IPSSHigh181604148140650.02Intermediate-21073638456932Intermediate-11246763Not applicable30NA8NA22NRCytogenetic analysisDiploid/-Y13342343999430.825-/7-1113532377934Other862327245923Complex cytogeneticsYes11234333579330.76No732220225322Bone marrow blasts %10- 2016751646910343<0.000121-3016349293113457Median WBC x109/L Range2.7(0.4 123.4)2.5(0.4-25.6)2.9(0.9-123.4)0.01Median hemoglobin g/dl Range9.4 (4.2-13.5)9.7(6.8-13.5)9.1(4.2-13.5)0.02Median platelets x103/mL Range57 (3-746)62(11-588)55(3-746)0.23Median bone marrow blasts %Range19 (10-30)15(10-30)20(10-30)<0.0001 ConclusionAlthough patients with MDS or AML with BM blasts between 10-30% initially achieve a higher ORR when treated with IC compared to HMA-based therapy, the OS was better for pts treated with HMA after accounting for all other covariates. Interestingly, BM blast percentages within this cohort did not impact overall outcome suggesting that pts with BM blasts 20-30% may achieve better outcome with MDS therapy. Disclosures:No relevant conflicts of interest to declare.

A phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome

Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m(2) via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55-84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate-1, five intermediate-2 and two high-risk. Median chemotherapy courses were one (1-3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction - from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non-haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35-72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS.

Multivariate and Subgroup Analyses of a Multinational Phase III Trial of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia

AbstractAbstract 3618 Introduction:A recent phase III trial compared efficacy and safety of decitabine with those of patient's treatment choice (TC) of supportive care or low-dose cytarabine in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics (Kantarjian et al. J Clin Oncol 2012;30:2760; NCT00260832). At the planned clinical cutoff date in 2009 (396 deaths), a nonsignificant trend toward increased median overall survival (OS) was seen with decitabine (7.7 months; 95% confidence interval [CI] 6.2, 9.2 months) vs TC (5.0 months; 95% CI: 4.3, 6.3 months); estimated hazard ratio (HR) 0.85 (P=.108). A 2010 post hoc analysis of mature data (446 deaths) from this study showed that the median OS had not changed but HR had improved (0.82; 95% CI 0.68, 0.99; nominal P=.037) and favored decitabine versus TC. At the 2009 cutoff, remission rates (complete response [CR] or CR with incomplete platelet recovery [CRp] were significantly improved with decitabine (17.8%) vs TC (7.8%; P=.001). Decitabine was generally well tolerated. A multivariate analysis was conducted using the mature (2010) data to identify potential predictors of OS in this older population with AML. Methods:Eligible patients were aged ≥65 years with newly diagnosed de novo or secondary AML (≥20% blasts), poor- or intermediate-risk cytogenetics, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Patients were randomized 1:1 to receive decitabine (20 mg/m2 intravenously once daily for 5 consecutive days every 4 weeks) or TC (supportive care or cytarabine 20 mg/m2 subcutaneously once daily for 10 days every 4 weeks), stratified by age, cytogenetic risk, and ECOG PS. A multivariate Cox proportional hazards model was used to investigate the effects of the following demographic and baseline characteristics on OS in addition to treatment effect: sex, age (<70, 70–<75, or ≥75 years), baseline cytogenetic risk (intermediate vs poor), AML type (de novo vs secondary), baseline ECOG PS (0/1 vs 2), geographic region (North America/Australia, Western Europe, Eastern Europe, Asia), baseline bone marrow blasts (>50% vs ≤50%), baseline platelet count (analyzed at each unit of 100 × 109/L) and baseline white blood cell (WBC) count (analyzed at each unit of 25 × 109/L). These potential prognostic factors were evaluated simultaneously, and values were not adjusted for multiple testing. Results:Of 485 randomized patients, 242 received decitabine and 243 received TC (cytarabine, n=215; supportive care, n=28). Baseline patient demographics and clinical characteristics were similar between groups and indicated a high-risk population: 71% of patients were aged ≥70 years, 35.3% had secondary AML, 36.0% had poor-risk cytogenetics, and 25.8% had ECOG PS 2 or higher; median baseline proportion of blasts in bone marrow was 46.0%. Patient characteristics that appeared to adversely affect OS at the 0.05 level included more advanced age, poorer baseline ECOG PS, poor cytogenetics, higher bone marrow blast count, low baseline platelet count, high WBC count, and geographic region (Western vs Eastern Europe) (Table). Conclusions:In older patients with AML, OS was associated with prognostic factors of age, ECOG PS, cytogenetic risk, baseline bone marrow blasts, baseline platelet counts, and baseline WBC in addition to responding differently to decitabine vs TC (supportive care or cytarabine). Treatment response is related both to patient and disease status in older patients with AML.TableMultivariate Analysis of Effects of Baseline Patient Demographics and Clinical Characteristics on Overall SurvivalVariableHR95% CIP valueTreatment: decitabine vs TC0.80(0.65, 0.98).030Age group70–74 vs <70 years1.31(1.00, 1.71).047≥75 vs <70 years1.56(1.20, 2.03).001Baseline cytogenetic risk: intermediate vs poor0.70(0.57, 0.87).001Baseline ECOG PS: 0 or 1 vs 20.77(0.61, 0.98).032Geographic region: Eastern vs Western Europe0.65(0.48, 0.88).005Baseline bone marrow blast: >50% vs ≤50%1.36(1.10, 1.67).005Baseline platelets (109/L)0.78a(0.66, 0.91).002Baseline WBC (109/L)1.26b(1.05, 1.51).015aHR <1 = lower risk associated with each additional 100 × 109/L in baseline platelet counts.bHR >1 = higher risk associated with each additional 25 × 109/L in baseline WBC counts. Disclosures:Mayer:Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Decitabine is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Delaunay:Novartis, Genzyme: Consultancy. Jones:Eisai Inc: Employment. Berrak:Eisai Inc: Employment. Kantarjian:Eisai: Research Funding.

Outcome of Patients with Myelodysplastic Syndrome (MDS) with Bone Marrow (BM) Blasts Between 10 to 30% Treated with Hypomethylating Agents Versus Intensive Chemotherapy

AbstractAbstract 4928 BackgroundIn 2001, the World Health Organization modified the French-American-British (FAB) classification for MDS by folding the refractory anemia with excess blasts in transformation (RAEB-t) category into acute myeloid leukemia (AML). Since then, controversy exists regarding whether this subset of pts should be treated with AML (ie cytotoxic therapy) or MDS therapy (hypomethylating agents, HMA). Furthermore, a subset analysis of the AZA-001 trial has shown that azacitidine prolongs overall survival (OS) compared to intensive chemotherapy (IC) in pts with AML and BM blasts of 20–30%. The purpose of this analysis is to evaluate the clinical outcome and OS of pts with MDS and BM blasts between 10–30% who were treated with HMA vs IC. Patients and MethodsWe conducted a retrospective analysis of newly diagnosed pts with refractory anemia with excess blasts-2 (RAEB-2) and RAEB-t according to FAB classification criteria that were treated at one institution with frontline therapy between 1/2000 and 10/2011. For the purpose of this analysis, pts were divided into 4 groups based on their treatment: 1) hypomethylating agents (HMA) only (azacitidine and decitabine), 2) hypomethylating agents in combination with investigational drug (HMA-I), 3) intensive chemotherapy (IC, mainly cytarabine based regimens), and 4) investigational agents (I-A). Responses were defined as achieving a complete remission (CR), complete remission without platelet recovery (CRp), or complete remission with incomplete recovery (CRi) as defined by the International Working Group criteria (Cheason BD, J Clin Oncol. 2003). OS was calculated by using the Kaplan-Meier method, and survival curves were compared by using the log-rank test. The Gehan-Wilcoxon method was used to evaluate OS at early time point. ResultsThree hundred forty-nine pts were included in the final analysis. 53 pts (15%) were treated with HMA, 40 pts (11%) with HMA-I, 237 pts (68%) with IC, and 19 pts (5%) with I-A. Pts’ clinical characteristics are summarized in table 1. 20 pts (38%) achieved a response in HMA group, 19 (48%) in HMA-I, 143 (60%) in IC, and 1 (5%) in I-A group (P <0. 001). Response duration was 19. 3 months (m), 14. 7 m, 14. 5 m, and not reached, respectively, (P = 0. 62). 4 weeks mortality was 1 (2%), 2 (5%), 10 (4%) and 2 (11%) respectively, (P = 0. 36). With a median follow up of 37 m (1–96), the median OS was 21. 8 m, 16. 1 m, 14. 6 m, and 15. 8 respectively, (P = 0. 15). The OS was higher in pts who were treated with HMA vs IC by using Gehan-Wilcoxon test (P = 0. 04). In subgroup analysis, pts with BM blasts between 20–30% had higher response rates when they were treated with IC (63%) compared to HMA (44%), HMA-I (38%), and I-A (13%), (P = 0. 008); however, the remission duration 16 m, not reached, 15 m, and 8 m, respectively, (P = 0. 28), and the OS 16 m, 27 m, 24 m, and 8 m respectively, (P = 0. 2) were not significant. ConclusionAlthough pts with MDS and BM blasts between 10–30% achieved higher response rates when they treated with IC vs HMA, pts with BM blasts between 20–30% had similar OS when they were treated with HMA vs IC. There was a trend toward increased survival early after treatment administration in favor of HMA. This data suggests that IC is not superior to HMA in the treatment of this subgroup of pts.Table 1:Patients' characteristics and responsesParameterTotalHMAHMA-IICI-ANumber349534023719Age, N (%)>65159 (46)30 (57)19 (48)94 (40)16 (84)< 65190 (54)23 (43)21 (52)143 (60)3 (16)RAEB-1, N (%)187 (54)17 (32)15 (38)146 (62)9 (47)RAEB-2, N (%)162 (46)36 (68)25 (62)91 (38)10 (53)History of prior chemotherapy/XRT, N (%)77 (22)13 (25)12 (30)50 (21)2 (11)Median WBC x109/L, (range)2.7 (0.4–124.4)2.2 (0.4–15.5)2.8 (1.2–25.6)2.9 (0.9–124.4)2.4 (1.5–9.1)Median hemoglobin g/dl, (range)9.5 (4.2–13.5)9.8 (6.8–13.2)9.7 (7–13.5)9.1 (4.2–13.5)10.1 (6.7–12.7)Median platelets x103/mL, (range)57 (3–746)65 (11–588)60 (14 – 384)55 (3–746)61 (22–321)Median bone marrow blasts %, (range)18 (10–30)14 (10–30)17 (10–26)20 (10–30)18 (10–27)Cytogenetic analysis, N (%)Normal141 (40)23 (43)11 (28)99 (42)8 (42)-5/-7119 (35)16 (30)16 (40)70 (33)8 (42)Others77 (22)12 (23)9 (22)53 (22)3 (16)Insufficient metaphases12 (3)2 (4)4 (10)6 (3)0IPSS score, N (%)High192 (55)20 (38)21 (53)140 (59)11 (58)Intermediate-2113 (32)25 (47)13 (33)69 (29)6 (32)Intermediate-112 (3)3 (6)3 (8)6 (3)0Not applicable32 (9)5 (9)3 (8)22 (9)2 (11) Disclosures:No relevant conflicts of interest to declare.