Oligoblastic Acute Myeloid Leukemia Research Articles

Favorable Outcomes for High-Risk MDS and Oligoblastic AML with MDS-Related Changes with Reduced Intensity Allogeneic Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide

Introduction: Newer classification systems label myelodysplastic syndrome (MDS) with 10-20% blasts and acute myeloid leukemia (AML) with MDS-related changes (AML-MR) on a continuum as they share common biologic features. The prognostic implication of blast percentage is less clinically relevant particularly in diseases with high-risk molecular features such as MDS/AML with TP53 mutations. The recently introduced Molecular International Prognostic Scoring System (IPSS-M) allows for a more personalized prognosis for MDS patients (pts) than the prior revised IPSS (IPSS-R), but it is less clear if this translates to better therapeutic choices or outcomes for pts. Allogeneic bone marrow transplantation (BMT) remains the only potentially curative approach. Increasingly clinical trials of novel compounds combined with hypomethylating agents (HMAs) have not shown improved efficacy over single agent HMAs, necessitating further study of BMT approaches for durable disease control across the spectrum of disease biology. No uniform approach to the conditioning regimen and GVHD prophylaxis for this pt population has proven superior. In the current study, we describe the outcomes of BMT with post-transplant cyclophosphamide (PTCy) for patients with high-risk MDS and oligoblastic AML-MR, and analyze the prognostic implication of their chromosomal and molecular profiles within the international scoring systems. Patients and methods: This is a retrospective analysis of patients with 5-30% blasts and IPSS-R ≥3 who underwent BMT with PTCy at Johns Hopkins Hospital between 1/2013 and 12/2020. Next generation sequencing (NGS) was performed within 12 months of diagnosis. Kaplan-Meier analysis was performed to evaluate overall survival (OS) and relapse-free survival (RFS). Competing risks analysis was performed to evaluate the incidence of relapse and non-relapse mortality (NRM). Cox-regression models were performed in univariate analyses with false discovery rate adjustment and then subsequently conducted for multivariable analyses to identify statistically significant and independent prognostic factors. Results: Ninety-four consecutive patients (65% male) were identified with a median age of 61 (range 22 - 75) years at diagnosis. Median follow-up was 4.8 years (range 5 days-9.6 years) post BMT. Two-thirds (63%) underwent haploidentical transplantation, and 91% received reduced intensity conditioning with Fludarabine, Cyclophosphamide, and TBI. Median age at BMT was 65 years (range 22 - 76). The median time from diagnosis to BMT was 7.9 months. 52 (57%) received HMA based treatment and 36 (39%) intensive chemotherapy prior to BMT. Graft failure occurred in 6 patients (6.4%) The 5-year OS rate was 53% (95% CI: 43%-65%), the 5-year RFS rate was 47% (95% CI: 38%-59%) ( Figure 1A). The incidence of relapse was 21% (95% CI: 13% - 30%) at 1 year and 31% (95% CI: 21% - 40%) at 2 years after BMT ( Figure 1B). NRM rate in the first-year was 7% (95% CI: 2%-13%) and 11% (95% CI: 4%-17%) in the first two years ( Figure 1B). The incidence of acute GVHD (aGVHD) grades 3 to 4 was 3.2%, whereas chronic GVHD (cGVHD) presented in 12 patients (12.7%) with only 2 patients (2.1%) having moderate to severe disease based on the NIH grading criteria. Univariate analysis showed that higher IPSS-R (HR 1.68, 95% CI 1.39 - 2.04), poor or very poor karyotype risk (HR 7.48, 95% CI 3.49 - 16.02), complex karyotype (HR 3.72, 95% CI 2.01 - 6.88), higher IPSS-M (HR 1.72, 95% CI 1.38 - 2.14), TP53 mutations (HR 6.53, 95% CI 3.36 - 12.7) and RAS mutations (HR 4.96, 95% CI 1.7 - 14.5) were associated with worse OS. IPSS-R was significantly correlated with the patients' response to bridge therapy (OR 1.34, P=0.036). IPSS-R, IPSS-M, poor or very poor karyotype risk, complex karyotype, TP53 and any RAS mutations and response to bridge therapy were independently associated with worse OS and RFS ( Table 1, Figure 1C). Conclusion: This retrospective analysis supports that BMT with PTCy is a durable approach for patients with high-risk MDS and oligoblastic AML-MR leading to high OS and RFS associated with a promising safety profile with low NRM and severe GVHD incidence. IPSS-R, IPSS-M, karyotype and response to bridge therapy are independent predictors of OS and RFS post-BMT. The presence of TP53 and/or RAS mutations defines a sub-group of patients with dismal outcomes representing an unmet need within this patient population.

NPM1-Mutated Myeloid Neoplasms: Updated Outcomes with High-Intensive Chemotherapy Regardless of the Blast Percentage

Background: The most recent World Health Organization (WHO) classification has stablished NPM1-mutated myeloid neoplasms (MNs) to be acute myeloid leukemia (AML) regardless of bone marrow (BM) blast percentage. In contrast, the new International Consensus Classification (ICC) considers NPM1-mutant MNs as AML only in the presence of ≥10% BM blasts. Previous studies from our group and others have reported favorable outcomes of NPM1-mutant MNs with <20% blasts when treated with intensive chemotherapy. Here we seek to further evaluate clinical outcomes of this group of pts. Methods: We retrospectively re-evaluated the patient's characteristics, disease features and outcomes in patients with NPM1-mutated oligoblastic AML (<20% blasts) (oligo-AML). In addition, we also evaluated the clinicopathological characteristics in a cohort of patients with secondary NPM1-mutated AML (sAML), the majority of which had received treatment before progressing to AML. The Kaplan-Meier method was used to estimate the overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS). Results: We identified 54 patients with NPM1-mutated oligo-AML. Median age was 62 years (range, 19-87) and most of them were female (59%). Median bone marrow (BM) blasts was 10%. Most patients could have been classified as CMML-2 (7/54, 13%), MDS-EB1 (7/54, 13%) and MDS-EB2 (24/54, 44%), based on the 2016 WHO classification. Median NPM1 variant allele frequency (VAF) was 0.38 (range, 0.05-0.52) and 38 patients (70%) had normal karyotype. These patients harbored a median of 1 co-mutation (range, 0-5), predominantly DNA methylation pathway, such as DNMT3A (31%) or TET2 (23.5%), or RAS pathway, mainly NRAS (25.5%), but rarely exhibited mutations in other functional pathways (Figure 1). Twenty-three patients (43%) progressed to AML with >20% BM blasts within a median of 10.7 months. Of 54 patients, 46 patients (82%) received chemotherapy-based regimens [61% low-intensity chemotherapy (LI-Chemo) based on hypomethylating agents or low-dose cytarabine and 21% high-intensity chemotherapy (HI-Chemo)] and 21 patients (39%) received a stem cell transplant (SCT). With a median follow up of 67.6 months (LI-Chemo of 48.3 months; HI-Chemo of 71.4 months), the median OS, EFS and RFS was 30.4 months, 30.4 months and 14.7 months for the LI-Chemo group, respectively, but median OS, EFS and RFS were not reached (NR) for HI-Chemo group. However, when compared by age, patients with <60 years had trends to have better OS with LI-Chemo or HI-Chemo than patients aged ≥60 years (Figure 2). In addition, 5 patients received chemotherapy-based regimens with venetoclax, however improved OS was only seen when combined with HI-Chemo and SCT (n=2, with a median OS NR without deaths, likely related to younger people). In parallel, we identified 31 patients with NPM1-mutated sAML progressed from oligo-AML. Median age was 67 years (range, 31-83) and female were 58%. Median BM blasts was 40%. Median NPM1 VAF was 0.38 (range, 0.02-0.56). Most patients did not exhibit clonal cytogenetic evolution and remained with a diploid karyotype (65%). Seventy-four percent of patients (17 out of 23 tested) had known prior NPM1-mutated oligo-AML, and in 6 patients NPM1 mutation was acquired at progression. Median number of co-mutations were 3 (range, 0-7). DNTM3A (65%) or TET2 (33.3%) mainly co-occurred with RAS pathway mutations, and in particular FLT3-ITD (26.7%) or FLT3-TKD (13.3%) (Figure 1). Eleven of 31 patients (36%) received LI-Chemo regimens, whereas 15 of 31 patients (48%) had HI-Chemo regimens. Nine patients (29%) underwent SCT. With a median follow up of 39.6 months (LI-Chemo of 55.5 months; HI-Chemo of 39.4 months), the median OS, EFS and RFS was 11.4 months, 12.4 months and NR for LI-Chemo, respectively; and 13.2 months, 6.5 months and NR for HI-Chemo, respectively. No significant differences were seen depending on the number of therapies received for previous oligo-AML. Previously untreated patients who received a venetoclax-based regimen with SCT had prolonged survival (n=4, median OS NR, with median follow up of 41 months). Conclusions: NPM1-mutated acute myeloid leukemia can be treated as such irrespective of blasts burden. For these cases, especially young patients, should be treated with intensive chemotherapy and subsequent allogeneic stem cell transplant as a clear curative approach.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database.

Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P = .129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00-1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13-1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation.

A Multi-Center Phase Ib Trial of the Histone Deactylase Inhibitor (HDACi) Entinostat in Combination with Anti-PD1 Antibody Pembrolizumab in Patients with Refractory/Relapsed Myelodysplastic Syndromes (RR-MDS) or Oligoblastic Acute Myeloid Leukemia (RR-AML) after Hypomethylating Agent (HMA) Failure

Introduction: Pts with MDS and HMA failure have a poor prognosis and need novel therapies. Success with anti-PD1 therapy in myeloid malignancies has been limited and resistance mechanisms are poorly understood. Preclinical data suggest that myeloid-derived suppressor cells (MDSCs) contribute to MDS progression (Chen et al. JCI 2013). and may mediate resistance to anti-PD1 therapy (Kim et al. PNAS 2014). As HDACi decrease MDSCs, synergistic anti-tumor efficacy with anti-PD-1 has been hypothesized leading to this phase Ib study (NCT02936752) of the HDACi entinostat and anti-PD1 antibody pembrolizumab in pts with MDS or oligoblastic AML and HMA failure. Methods: We conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase Ib trial. Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Pts had to have adequate end organ function and ECOG performance status ≤2. The dose-escalation part used 2 dose levels (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. In cycle 1, pts received only entinostat to determine its impact on MDSCs separately from pembrolizumab. Toxicities were tabulated and graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to trial therapy: Grade (G) 3/4 non-hematologic toxicity, any ≥G3 immune related adverse events (IrAEs) or any IrAE resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if they were unrelated to MDS and lasted for >42 days. The primary endpoint was safety and determination of the maximum tolerated dose. The secondary endpoint was the overall response rate defined as a composite of complete remission, partial remission, and hematologic improvement (HI) per the 2006 IWG response criteria in MDS and change in MDSCs and PD1/PDL-1 in BM. Results: Between 06/26/2017 and 02/03/2021, we enrolled 28 pts (25 MDS and 3 AML). Median age was 74 years (range [R], 57-86), all pts had received prior HMA with 5 pts (18%) having had ≥3 prior lines of therapy. Median IPSS-R at screening for MDS pts was 5.5 (R: 2-10). Baseline demographic and clinical characteristics are shown in Table 1. During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to early disease progression during DLT period), and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH), while 2 pts experienced DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. Thus, DL1 was expanded, and another 15 pts were enrolled at DL1. Across the entire study, pts received a median of 3 cycles of therapy (R: 1-12 cycles). The most frequent cause of treatment discontinuation was disease progression in 9 pts. Four pts died during the study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). A summary of the AEs is presented in Table 2. Hematologic AEs were common. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). Potential IrAEs of any grade were reported in 5 pts including G3 pneumonitis in 2 pts. Serious AEs were reported in 14 pts; 8 of which were potentially attributed to treatment. Among the 19 pts with the first BM efficacy assessment after 3 months, no pt achieved a protocol-defined response. However, 2 pts had mCR (BM blasts decreased from a baseline of 7% and 10% to 2% and 4%, respectively) without HI. Twelve pts had stable disease, while 5 had progressive disease. With a median follow-up of 5.9 months (R: 0.5 - 59.1 months), median OS was 6.9 months (95% CI: 4.8 - 13.6 months). Correlative studies are being conducted. Conclusion: In this multi-center phase 1b investigator-initiated trial in MDS and oligoblastic AML pts after HMA failure, entinostat + pembrolizumab at DL1 was reasonably tolerated but had limited therapeutic efficacy. Ongoing correlative work will explore the disconnect between the preclinical and clinical data regarding potential synergy of entinostat + pembrolizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

“REAL-WORLD” RESULTS OF HYPOMETHYLANT THERAPY IN MYELODYSPLASTIC SYNDROME, CHRONIC MYELOMONOCYTIC LEUKEMIA AND OLIGOBLASTIC ACUTE MYELOID LEUKEMIA

Myelodysplastic Syndrome (MDS) represents a heterogeneous group of myeloid neoplasms, resulting in progressive bone marrow failure and cytopenias. Although the allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential curative treatment, only few patients are candidates. In this regard, hypomethylating agents (HMA)- Azacitidine (AZA) and decitabine (DEC) - appears as a standard treatment for higher-risk MDS, in addition to being considered in oligoblastic acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Although AZA improved the overall survival (OS) in clinical trials, results in real-world are discordant. This study aims to evaluate the clinical characteristics and outcomes of MDS patients treated with HMA in an academic hospital. Retrospective cohort, over 18 years of age, diagnosed with MDS, oligoblastic AML and CMML, de novo or secondary, treated with HMA and followed up at the cytopenias outpatient clinic at HCFMUSP from 2010 to June 2021. Data were collected from medical records and stored in REDcap. IWG 2006 criteria were used for response assessment. Kaplan-Meier curves were used for survival graphs, and Cox model regression for uni and multivariate analysis. 70 patients, 60 (85%) treated with AZA and 10 (15%) with DEC. Median age at diagnosis was 60.9 years (IQR 48.7 – 68.3), 61.4% male. In relation to diagnoses, 28 had de novo MDS (32.9% with excess of blasts; 4.3% with multilineage dysplasia; 2.9% with ring sideroblasts); 7 had AML (10%); 24 secondary myeloid neoplasm (21.4% therapy related; 7.1% with germline/ Fanconi predisposition; 5.7% after acquired aplastic anemia). The median score of IPSS and IPSS-R was respectively 1.5 and 6.0 (high risk). Before treatment 35.4% of patients had poor or very-poor karyotype. Response evaluation was assessed in 51 patients (72.8%) at the end of fourth cycle. The overall response rate (ORR) was 66.6%, including complete, partial and marrow responses, besides hematological improvement. Twelve patients (17%) undergone HSTC. The median OS, since starting HMA, was 11.5 months (IQR 8.1 – 13.8 95% CI), with median follow-up of 15.9. In univariate analysis, variables associated with worse OS were late initiation of HMA (HR 2.39 95% CI 1.18 – 4.84, p =0.015), age (HR 1.03 95% CI 1.01 – 1.05, p =0.007), poor-risk karyotype (HR 4.8 95% CI 2.29 – 10, p <0.001), hemoglobin < 8.5 (HR 3.44 95% CI 1.56 – 7.88, p =0.002) and platelets < 80.000 (HR 3.5 95% CI 1.49 – 8.23, p =0.002). In multivariate analysis, parameters associated with worse OS were transfusion dependency (HR 2.26 95% CI 1.27 – 4.04, p = 0.006) and poor karyotype (HR 2.53 95% CI 1.41 – 4.57, p =0.002). Thirty-five patients (50%) had febrile neutropenia, and 30% delayed one or more cycles. The results reinforce the poor outcomes of higher-risk MDS despite the use of HMA. Some real-world studies previously published had already showed a suboptimal drug benefit, probably by the underutilization and low persistence of the treatment, in a subgroup of critically ill patients. This retrospective analysis confirms the poor prognosis of higher-risk MDS treated with HMA. Poor-risk karyotype and transfusion dependency are the main factors that impact the outcomes.

Outcome of therapy-related myelodysplastic syndrome and oligoblastic acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A propensity score matched analysis.

Therapy-related myelodysplastic syndromes (t-MDS) are generally progressive and associated with poorer outcomes than de novo MDS (d-MDS). To evaluate the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for t-MDS, we conducted a propensity score matched-pair analysis of patients with t-MDS and d-MDS using a nationwide database. A total of 178 patients with t-MDS underwent allo-HSCT between 2001 and 2018, and 178 out of 3123 patients with d-MDS were selected. The probability of 3-year overall survival rate was 40.0% and 50.0% in the t-MDS and d-MDS groups, respectively (p=0.032). The 3-year transplant-related mortality was 30.9% and 19.0% in the t-MDS and d-MDS groups, respectively (p=0.005). The 3-year cumulative incidence of relapse was 32.8% and 33.0% in the t-MDS and d-MDS groups, respectively (p=0.983). A multivariate analysis identified four adverse factors for overall survival in the t-MDS group: age≥55years (hazard ratio [HR], 2.09; 95% CI, 1.11-3.94; p=0.023), the poor cytogenetic risk group (HR, 2.19; 95% CI, 1.40-4.19; p=0.019), performance status at allo-HSCT 2-4 (HR, 2.14; 95% CI, 1.19-3.86; p=0.011), and a shorter interval from diagnosis to transplantation (<8months; HR, 1.61; 95% CI, 1.00-2.57; p=0.048). The most frequent cause of transplant-related death was the infectious complications (21.6%) in t-MDS group and organ failure (12.5%) in d-MDS group. In conclusion, allo-HSCT potentially provides long-term remission in patients with t-MDS; however, further efforts to reduce transplant-related death are needed.

Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

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.

Predictive Factors of Overall Survival and the Completion of Four Cycles of Azacitidine: An MDS-CAN Study

Predictive Factors of Overall Survival and the Completion of Four Cycles of Azacitidine: An MDS-CAN Study

Natural Killer Cell Cytotoxicity Is a Predictor of Outcome for Patients with High Risk Myelodysplastic Syndrome and Oligoblastic Acute Myeloid Leukemia Treated with Azacytidine

Introduction: Hypomethylating agents (HMA) have shown significant therapeutic efficacy in the treatment of patients with MDS and AML. Although it has been suggested, that HMA act through re-activation of tumor-suppressor genes, the exact mechanism of their action has not been completely elucidated yet. The aim of our study was to identify predictors of outcome for patients treated with azacytidine (AZA).Patients and Methods: Eighteen patients with high risk MDS (RAEB-II) and oligoblastic AML (20-30% bone marrow blasts) were included in this study. Patients were not eligible for intensive induction chemotherapy due to age, or presence of comorbidities. All patients were selected for treatment with AZA.NK-cytotoxicity against K562, Rajii, and the percentage of various immune regulatory subpopulations in the peripheral blood (PB) was measured after 3-6 cycles of AZA. A previous short exposure to AZA was required with the aim: 1) to examine the effect of AZA on these populations, and 2) to identify biomarkers with the potential to predict outcome after treatment with AZA.NK-cytotoxicity against K562 and Rajii was tested by using a flow cytometry based assay as previously described (1).Quantitative estimation of immune regulatory subpopulations in PB of patients was performed by using flow cytometry. The number of myeloid derived suppressor cells (MDSCs) (CD33+/CD11b+/CD14-/HLADRlow/-) was expressed as percentage among CD45+ PB monocytes. The number of Tregs (CD3+/CD4+/CD25+/Foxp3+) was expressed as percentage among CD3+/CD4+ PB lymphocytes. The number of double negative TCRαβ (CD3+/TCRαβ+/CD4-/CD8-) was expressed as percentage among PB CD3+ lymphocytes.Comparison between groups was performed by using Mann-Whitney test for continuous variables. Receiver operating curve analysis (ROC) was performed with the aim to determine the ability of various parameters for the prediction of 2-year survival. Kaplan-Meier and log rank test were used for estimating the probability of overall survival (OS).ResultsNK cytotoxicity: The median NK-cytotoxicity against K562 of patients and healthy donors was 21.8% (95% CI, 7.5 - 32.6) and 41.8% (95% CI, 11.4 - 56.1). Patients with MDS/AML after a short exposure to azacytidine had a significantly reduced NK-cytotoxicity against K562 as compared with NK cytotoxic activity of healthy donors (p=0.01). NK cytotoxic activity against Rajii of both patients and healthy donors was very low to absent (data not shown).Immune regulatory cells: The median MDSCs of patients and healthy donors was 0.41% (95% CI, 0.13 - 1.26) and 0.60% (95% CI, 0.30 - 1.94). There was no difference between MDSCs in the PB of patients and healthy donors. There was no difference in the number of Tregs and double negative TCRαβ cells between patients and donors (data not shown).NK cytotoxicity is a predictor of overall survival in patients treated with AZA: The ability of various parameters including the PB percentage of MDSCs, Tregs, and double negative TCRαβ, as well as of NK cytotoxic activity to predict survival at 2 years after treatment with AZA was examined by using ROC analysis. NK cytotoxic activity was the only predictor of OS for patients treated with AZA (AUC=0.875, 95% CI, 0.635 - 0.979, p<0.0001). NK-cytotoxicity above 20.85% was estimated as the best cut off with sensitivity and specificity 80% and 87% in predicting 2-year survival (Figure 1A). In multivariate analysis, NK cytotoxicity above 20.85% (high NK-activity) was the only parameter statistically associated with significantly improved OS [HR=0.10, 95% CI, 0.01 - 0.90, p=0.041] (Figure 1B).Conclusions: Our study showed that NK cytotoxicity is a predictor of the outcome for patients treated with AZA. Patients with high NK-activity after a short course of AZA had significantly improved OS as compared with patients with low NK-activity. The results of our study suggest that the therapeutic activity of AZA is at least partly mediated by an immunomodulatory effect.

A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia

PurposeTo determine the safety of tipifarnib in combination with escalating doses of bortezomib and to determine the maximum tolerated dose in patients with untreated high-risk MDS and oligoblastic acute myeloid leukemia, who were not eligible for intensive therapy. Experimental DesignIn a "3 + 3″ design, patients received fixed doses of tipifarnib 200 mg bid (days 1–21) and escalating doses of bortezomib (days 8, 15, 22) every 4 weeks in 4–6 cycles. ResultsThe combination was tolerated well by the 11 patients in this study without reaching the maximum tolerated dose. Myelosuppression was the most frequent side effect, but usually of short duration. Interestingly a complete response with or without complete count recovery was observed in three patients and three additional patients had stable disease. The median duration of overall survival was 449 days. Two patients were still alive at 4.0 and 4.3 years, including one patient in continuing CR. ConclusionsThe combination of tipifarnib and bortezomib was tolerated well and appeared to have clinical activity in patients with high-risk MDS and AML with low counts of marrow blasts. Our results warrant further evaluation in a phase II study.

Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities

BackgroundAbnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset. Patients and MethodsThrough the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts). ResultsSpecific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3–MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P = .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P = .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs. ConclusionPatients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes.

Background:5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied.Methods:This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA.Results:The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system.Conclusions:ECOG PS and SF levels > 520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores’ predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.

Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Phase 2 Results of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Comprehensive geriatric assessment predicts azacitidine treatment duration and survival in older patients with myelodysplastic syndromes

BackgroundTreatment of older patients with myelodysplastic syndrome (MDS) is based on disease biology and performance status. Performance status, however, does not reflect increasing co-morbidities, functional dependence or psychosocial issues in older patients. Patients and MethodsThis prospective study evaluated the burden of geriatric related health issues, assessed feasibility of “tailored” Comprehensive Geriatric Assessment (CGA), and compared treatment duration and survival in older patients with MDS and oligoblastic acute myeloid leukemia with and without deficits in CGA domains (n = 98). ResultsAlthough only 27 (28%) patients had an Eastern Cooperative Oncology Group score ≥2, 78% (n = 77) patients had deficits in at least one CGA domain. Deficits were spread across all CGA domains, including dependence for instrumental activity of daily living (iADL; n = 33, 34%).Importantly, patients who were dependent for iADL (3.7 ± 2.6 vs 12.1 ± 7.9; p = .009), had cognitive impairment (3.5 ± 2.1 vs. 10.9 ± 7.9; p = .034) or impaired mobility (3.8 ± 2.5 vs. 13.2 ± 7.6; p = .001) completed significantly less azacitidine cycles as compared to those without these deficits.Cox-proportional regression showed that iADL dependency (hazard ratio 3.37; p = .008) and higher comorbidities (hazard ratio 4.7; p < .001) were associated with poor prognosis independent of disease related factors. Poor survival of iADL dependent patients was seen in both azacitidine (6 vs 19 months; p < .001) and supportive care cohorts (26 vs 48 months; p = .01). ConclusionCGA detected geriatric related health issues, predicted poor survival and identified patients less likely to continue and benefit from azacitidine. Hence, CGA should be included in the treatment decision algorithm of older patients with MDS.

Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine

The aim of the present study was to identify biomarkers predictive of the outcome of patients with high-risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (AZA). We prospectively examined the association between NK-cytotoxic activity, myeloid-derived suppressor cells (MDSCs), and T-regulatory cells (Tregs) on the overall survival (OS) of patients. Patients with NK-cytotoxicity above a critical threshold had a longer duration of response and survived longer than patients with severe impairment of NK-cytotoxicity. The numbers of MDSCs, and Tregs in the PB of patients after a short exposure to AZA were not different from normal donors. In conclusion, the results of our study suggest that the therapeutic activity of AZA is at least partly mediated by an immunomodulatory effect. To our knowledge, this is the first study reported so far, that shows a positive correlation between NK cytotoxicity and OS of AZA-treated patients.

Clonal Suppression of TP53 Mutant MDS and Oligoblastic AML with Hypomethylating Agent Therapy Improves Overall Survival

Background Hypomethylating agent (HMA) therapy represents the standard of care for patients with higher risk myelodysplastic syndromes (MDS) although only 50% of patients respond to treatment. Recent evidence from molecular profiling through next-generation sequencing (NGS) in myeloid diseases has been conflicting as to the value of somatic mutations as a biomarker for response to HMA. In particular, there have been conflicting data on response rates and outcomes in TP53 mutant (MT) MDS and acute myeloid leukemia (AML) based on azacitidine versus decitabine (Welch et al., NEJM 2016; Garcia-Manero et al., NEJM 2017). However, the TP53 mutant cohorts in these studies were small (median 23 patients, range 13-39) and heterogeneous based on treatment status (treatment naïve versus relapse/refractory). Therefore, our goal was to characterize outcomes of TP53 mutant MDS patients who received frontline HMA therapy.Patients and MethodsTP53 MT MDS and oligoblastic AML (20-30% blasts) cases were retrospectively identified from the Moffitt Cancer Center MDS database. All patients had NGS of TP53 and up to 53 additional genes performed prior to the initiation of HMA. The lower limit of VAF detection was set at 5% and the minimum depth of coverage at each position was 500X. Clinical variables and outcomes of MDS patients were characterized at the time of sample procurement. Fisher's exact tests were used for comparative analyses. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of HMA initiation. Response rates and outcomes of TP53 MT patients were compared to a cohort of wildtype (WT) patients (n=63).Results From May 2013 to May 2018, a total of 71 patients with TP53 mutant MDS were identified with a median age of 68 years (39-82) and male predominance (66%). Fourteen patients (20%) had multiple mutations in TP53. Of the cohort, 82% of patients (n=58) were treated with azacitidine (88% (n=51) with AZA monotherapy; 12% (n=7) with AZA in combination (2 pts with lenalidomide and 5 pts with investigational agents)) with 18% (n=13) receiving decitabine. The median # of HMA cycles was 4 (range 1-33). Thirteen pts (18%) proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Of the cohort, 18% (n=13) obtained complete remission (CR) with 39% (n=28) overall response rate (ORR). There was no difference in CR or ORR in pts treated with AZA vs DAC (P=0.24 and P=0.2, respectively). At a median follow up 20 months, the median OS of the entire cohort was 9.7 months. There was no difference in median OS between AZA vs AZA combo vs DAC (7.6 vs 15.2 vs 12.5 months; P = 0.44; Figure 1A). TP53 variant allele frequency (VAF > 20% vs ≤ 20%) was not predictive of outcomes to HMA (7.8 vs 10.4 months, P = 0.36).However, TP53 MT patients who had clonal response to HMA (i.e. VAF < 5%; n=19 (27%)) had improved OS (14.5 vs 7.5 months; HR 0.33, 95% CI 0.18 to 0.59; P = 0.001; Figure 1B). In multivariable analysis incorporating age, revised international prognostic scoring system (IPSS-R) category, HSCT status, or type of HMA, TP53 clonal clearance remained an independent covariate for improved OS (HR 0.34, 95% CI 0.16 to 0.72; P = 0.005). Pts who underwent HSCT (n=13) had a trend for improved OS (14.5 months vs 7.9 months; P = 0.09). Notably in transplanted pts who had serial TP53 NGS (n=7), pts who achieved a VAF < 5% had significant improved OS (16.3 months vs 8.9 months; P=0.03). Compared to higher risk MDS/AML TP53 WT patients treated with HMA, there was no difference in CR (18% vs 14% (P = 0.64) or ORR rates (39% vs 40%). In contrast, TP53 MT patients had significantly inferior OS with HMA therapy (9.7 vs 15.4 months; HR 2.14, 95% CI 1.32. to 3.27; P = 0.001; Figure 1C).Conclusion In this large cohort of higher risk MDS and oligoblastic AML pts who received frontline HMA therapy, TP53 MT patients have significantly inferior OS with no significant differences in response rates or outcomes by HMA. TP53 MT patients who achieve maximum clonal suppression with HMA treatment (i.e. VAF < 5%) have improved OS as well as improved outcome with HSCT. Novel therapy targeting TP53 mutation is needed to improve outcomes. [Display omitted] DisclosuresSallman:Celgene: Research Funding, Speakers Bureau. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.

Red Cell Alloimmunisation Is Associated with Increased Red Cell Transfusion Requirements in Myelodysplastic Syndrome

Up to 90% of MDS patients require red blood cell (RBC) transfusions. Literature addressing incidence and impact of alloimmunization in MDS is limited. We previously reported that 11% RBC-transfused MDS patients develop alloantibodies and RBC-transfusion requirement increases following alloimmunization (Singhal et al Haematologica 2017).This study aims to assess mechanism of increased RBC transfusion requirement following alloimmunization in MDS patients by comparing RBC-transfusion requirement following single and multiple alloantibodies, and impact of autoantibody on transfusion requirement.Primary MDS (PMDS), oligoblastic acute myeloid leukemia (AML) and therapy-related myeloid neoplasm (t-MN) patients enrolled in the SA-MDS registry (n=1002) between Nov 1991-Jun 2017, followed up for >3 months, received at least 1 unit of RBC and did not develop alloantibodies before first RBC transfusion were selected for analysis. Cumulative incidence (CI) of RBC-alloimmunization and clinical impact of alloimmunization including autoantibody formation and change in RBC-transfusion requirements was assessed. We also assessed risk factors for alloimmunization using recursive partitioning and Cox-regression.Seven hundred and sixty-two patients (76%) were eligible for analysis; 584 (76.5%) PMDS, 56 (7.3%) oligoblastic AML and 123 (16%) were t-MN. The median age was 72 years (range 18-97) and 489 (64%) were males. According to the Revised International Prognostic Scoring System (IPSS-R), 44.9% and 54.9% patients were classified as IPSS-R Very low/Low risk and Intermediate/High/Very high risk, respectively. The CI of alloimmunization in RBC-transfused patients was 15% (Fig 1A) and alloantibodies were most commonly against K (32%), E (26%), C (18%), Jka (10%) & Duffy (3%) antigens. Interestingly, 53% (53/99) of alloimmunized patients had single alloantibody while 46% (46/99) had multiple alloantibodies detected simultaneously or subsequently.RBC requirement was significantly higher in alloimmunized compared to non-alloimmunized patients (80±95 vs 41±58, p<0.0001; Fig 1B). This difference is unlikely due to difference in overall survival (OS) as median OS of the two groups was not significantly different (27.5 vs 33.7 months; p=0.2). Importantly, RBC requirement of alloimmunized patients significantly increased after alloantibody formation (22±38 vs 57±82, p<0.0001; Fig 1C). This increase is unlikely to be due to difference in follow-up period before and after alloimmunization (12.3 vs 10.7 months; p=0.9).RBC transfusion requirement increased following single (24±44 vs 49±91; p=0.005; Fig 1D) and multiple (21±31 vs 67±70; p<0.0001; Fig 1E) alloantibody formation. RBC requirement prior to alloimmunization was not significantly different between patients with single and multiple alloantibodies (24±44 vs 21±31; p=0.9); however following alloimmunization, it was higher in patients with multiple alloantibodies compared to single alloantibody (49±91 vs 67±70; p=0.06).Increase in RBC requirement following alloimmunization could partly be due to autoantibody formation.The 12-month CI of autoantibody formation was significantly higher in alloimmunized patients compared to non-alloimmunized (31 vs 1.7%; p<0.0001; Fig 1F) and 26% of autoantibodies were detected within 3 months of alloimmunization indicating temporal relation between alloimmunization and autoantibody formation. Within alloimmunized patients, more patients with multiple alloantibodies developed autoantibodies as compared to patients with single alloantibody (67% vs 31%; p<0.001). We then compared impact of autoantibodies on RBC transfusion requirements. Baseline RBC requirement in alloimmunized patients with and without autoantibodies was not significantly different (25.4±34.6 vs 20.4±41.5; p=0.2). However, RBC transfusion requirement following alloimmunization was significantly higher in patients developing autoantibodies compared to patients without autoantibodies (82.51±110 vs 35.61±35.93; p=0.003).In our large cohort of 1002 patients, 15% of RBC transfused patients develop alloantibodies, most commonly against Rh and Kell. The RBC transfusion requirement increases after alloimmunization, most probably due to formation of multiple subsequent alloantibodies and autoantibodies. Hence, we recommend extended phenotype matched RBC transfusion to MDS patients. [Display omitted] DisclosuresRoss:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Hiwase:Celgene: Research Funding; Novartis: Research Funding.

Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)