Myelodysplastic Syndrome International Working Group Research Articles

Counting Chromosome Abnormalities in Chronic Lymphocytic Leukemia: Comparison of Iscn 2020 and MDS International Working Group Guidelines for Establishing Karyotype Complexity

Karyotype complexity is established by enumerating the number of chromosome abnormalities present in a karyotype. In chronic lymphocytic leukemia (CLL), karyotype complexity, defined as ≥3 chromosome abnormalities, is an important prognostic indicator associated with poor outcomes. Additionally, stratifying patients (pts) by highly complex karyotypes (≥5 chromosome abnormalities) has shown significantly poorer outcomes compared to pts with 3-4 abnormalities (Baliakas, Blood, 2019). In principle, counting chromosome abnormalities is straightforward; however, in practice it can be nuanced, and the number of abnormalities counted for the same karyotype can differ across laboratories. A lack of standardized rules has resulted in variability in establishing complexity across CLL studies. We and others have proposed adapting the international working group on myelodysplastic syndrome (MDS) framework for use in CLL (Chun, Leuk Res, 2010; Jondreville, Am J Hematol, 2020). Additionally, a separate set of guidelines were published in the 2020 International System for Human Cytogenomic Nomenclature (ISCN). To investigate how different guidelines may impact patient categorization in correlative studies, we evaluated karyotype complexity using both guidelines in a previously reported, well-characterized, dataset with long term follow-up of patients with CLL treated with ibrutinib (Kittai, Blood, 2021). 456 patient karyotypes underwent expert review by two cytogeneticists. Discordant scores were discussed to reach consensus. Pts were categorized as not complex (0-2 abnormalities), complex (3-4), or highly complex (≥5) for each set of guidelines. The weighted kappa was used to evaluate agreement between the two guidelines. Progression free survival (PFS) from ibrutinib start and overall survival (OS) were evaluated by the Kaplan-Meier method. Univariable Cox regression model discrimination power for PFS and OS were evaluated by Uno's concordance statistic. MDS guidelines categorized 50.2% as not complex, 19.7% complex and 30.1% as highly complex; similarly, ISCN categorized 50.2% as not complex, 20.2% complex and 29.6% as highly complex. Complexity categories assigned by the two guidelines had a weighted kappa agreement of 0.88 (95% CI 0.84-0.91), with 11% of pts placed in discordant complexity categories. Albeit numbers of pts were small, evaluation of these discordant cases compared to the consensus concordant cases showed outcomes varied. Discordant cases categorized by the MDS guidelines as complex and by ISCN as highly complex showed longer OS compared to the concordant complex and highly complex cases, suggesting ISCN overrated complexity (Fig 1). Conversely, discordant cases categorized by MDS guidelines as highly complex while ISCN categorized as complex showed decreased OS compared to the concordant complex and highly complex cases, suggesting ISCN underrated complexity in these cases (Fig 2). PFS trended similarly for these groups. Both the MDS and the ISCN guidelines showed increased karyotype complexity was significantly associated with shorter PFS (both with p<0.0001) and OS (both with p<0.0001). Comparing the classifiers not complex, complex and highly complex for the entire cohort found no significant difference between the prediction power of the MDS and ISCN guidelines for PFS. For OS, the MDS guidelines had a statistically stronger prediction power compared to ISCN (p=0.0235). Further, when the poorest prognostic group (highly complex) was compared to all others, the MDS guidelines showed significantly stronger prediction power for both PFS (p=0.0359) and OS (p=0.0039) compared to ISCN. Although both sets of guidelines were prognostically significant, in this predominately relapsed/refractory CLL patient population receiving ibrutinib, the MDS guidelines performed more robustly when used as a categorical variable. Clinical trials incorporating karyotype complexity for prognostication, or for treatment stratification, should specify a set of guidelines to apply consistently across the trial. Given the importance of karyotype complexity, particularly with targeted therapies, further studies are needed to evaluate these two sets of guidelines across varying CLL populations to establish recommendations for assigning karyotype complexity uniformly in CLL.

Metformin for treatment of cytopenias in children and young adults with Fanconi anemia

AbstractFanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.

Ivo-Nivo: A Phase II Study of the IDH1 Inhibitor Ivosidenib (AG-120) in Combination with the Checkpoint Blockade Inhibitor Nivolumab for Patients with IDH1 Mutated Relapsed/Refractory AML and High Risk MDS

Background: The normal function of isocitrate dehydrogenase 1 (IDH1) is to catalyze the conversion of cytoplasmic isocitrate to α-ketoglutarate (aKG) in the Krebs cycle. In hematologic malignancies a hotspot mutation at arginine 132 within the conserved active site of IDH1 leads to loss of the expected Krebs Cycle reaction as well as production of the oncometabolite 2- hydroxyglutarate (2-HG). In acute myeloid leukemia (AML) increased cellular 2-HG levels has been shown to impact the tumor microenvironment and promotes tumorigenesis via paracrine stimulation as well repression of the tumor associated immune system. Ivosidenib (AG-120) is a small molecule inhibitor of mIDH1 and is FDA approved for the treatment of patients (pts) with relapsed refractory IDH1 mutant AML. Ivosidenib is known to lower 2-HG levels, independent of response. By reducing 2-HG levels that promote immune escape of IDH-mutant tumors with ivosidenib, we hope to harness the known programmed death receptor pathway dysregulation in AML and high risk myelodysplastic syndrome (MDS). Study Design and Methods: IVO-NIVO is a single arm, multi-institutional phase II investigator initiated clinical trial with a safety cohort to confirm safety and tolerability of combination AG-120 and nivolumab. To be included pts must have MDS or AML with a documented IDH1 mutation in blood or bone marrow within 30 days of inclusion based on mutational testing by PCR or sequencing in a CLIA certified laboratory and be willing to undergo a bone marrow biopsy. Pts will initially start therapy with AG-120, 500mg by mouth daily for 1 cycle. A cycle is defined as 28 days of therapy. On cycle 2 day 1 enrolled pts will receive nivolumab 480 mg that will subsequently be infused every four weeks. Disease response to treatment will be serially assessed through the evaluation of blood (at least monthly) and bone marrow biopsies and aspirates. A complete response assessment will be performed after 6 cycles of therapy. Transplant eligible pts may proceed to allogeneic stem cell transplant (ASCT) if complete response (CR) or morphologic complete remission with incomplete count recovery (CRi) is achieved. Pts that are not eligible for ASCT will continue to receive AG-120- nivolumab combination therapy until documented progression or unacceptable toxicity (figure 1). Safety Cohort: We will have an interim safety analysis after the first 6 pts finishing the first cycle of combination therapy to ensure dosing is safe and tolerable. Pts will undergo clinical assessment with each cycle of therapy, with particular attention to known toxicities like differentiation syndrome that may be life threatening. If 0 to 1 of the first 6 subjects experienced unacceptable toxicities the study will continue as planned. If 2 pts experienced unacceptable toxicities, accrual will be temporarily suspended in order to conduct a review of safety data. If after review, a safety issue is identified and can be corrected, the protocol will be amended accordingly, and enrollment will restart. If an additional 2 pts (4 of 12) or more experience an unacceptable toxicity the patient will be taken off trial and the trial will be terminated. Statistical plan: It is estimated that 45 pts will be enrolled on trial. Using optimal Simon Stage 2 minimax design, if less than 7 of the first 16 pts respond the treatment will be study will be stopped for futility (type 1 error 0.05, type 2 error 0.2). Primary endpoint: We aim to improve the cumulative response rate after 6 cycles of therapy from 40% to 60% (Two-sided alpha risk of 0.05, 1-Beta of 0.8 = 38 pts + 7 additional pts for potential drop-off observed in prior studies) in pts with mIDH1 relapsed/ refractory AML and MDS. Based on published data, it is known that overall response rate is approximately 40% to single agent AG-120 in the relapsed/ refractory IDH1 mutant AML population. Therefore, we expect a 20% ORR improvement compared to historical control after 6 cycles of treatment, based on MDS International Working Group 2006 criteria and AML MDS International Working group MDS/AML criteria. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up), overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) and percentage of pts that can be bridged to ASCT. Disclosures Prebet: novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Consultancy; novartis: Honoraria; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Tetraphase: Consultancy; Agios: Consultancy, Research Funding; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding. OffLabel Disclosure: We will use Ivosidenib and nivolumab in combination as a part of a clinical trial to improve care of patients with relapsed/ refractory AML and MDS

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Recurring mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which translate to therapeutic targets. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations occur in ~20% of AML, and up to 12% of patients with MDS. Three conserved mutational hotspots in the IDH enzymes alter their function and lead to the production of (R)-2-hydroxyglutarate (2HG), an oncometabolite with numerous downstream effects, including impaired DNA damage repair. Specifically, homologous recombination (HR) is impaired by inhibiting the function of histone demethylases that are critical for HR and recruitment of the HR machinery to sites of DNA damage. In HR deficient tumors poly-ADP ribose polymerase (PARP) enzymes mediate a key salvage pathway. PARP inhibition in HR deficient tumors leads to synthetic lethality via simultaneous inhibition of HR and SSB mediated DNA repair. Our group previously demonstrated synthetic lethality with PARP inhibition in IDH mutant cells lines, and other IDH mutant models including primary patient-derived cell lines and genetically-matched tumor xenografts. Study Design and Methods: The PRIME trial (NCI10264) is a proof of concept, biomarker-driven, multi-institution, phase II open label clinical trial to assess the overall response of IDH1/2 mutant relapsed/refractory AML and MDS to PARP inhibitor monotherapy with olaparib. The clinical trial is executed by the Experimental Therapeutics Clinical Trials Network of the NCI. The Cancer Therapy Evaluation Program will provide olaparib. Eligibility criteria include documented IDH1 or IDH2 mutation in blood or bone marrow within 30 days of enrollment based on mutational testing by PCR or sequencing in a CLIA certified laboratory and willingness to undergo a bone marrow biopsy. Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle, using a tablet formulation, until disease progression, unacceptable toxicity, withdrawal of consent or death. Blood and bone marrow samples for 2-HG analysis will be collected prior to starting therapy and after 1 cycle (28 days), cycle 2, 3, 6, 9, 12 or when there is concern for disease progression (Figure 1). A Simon two-stage optimal design will be used to test the null (ORR=10%) versus the alternative hypothesis (ORR=40%) in each arm. In the first stage, 9 patients will be accrued in each arm. If one or fewer responses are observed in these 9 patients, that arm will be stopped early for futility. Otherwise, 11 additional patients will be accrued for a total of 18 in each arm. We reject the null hypothesis if at least 5 responses are observed in these 20 patients. In each arm, we have approximately 90% power to detect a 30% increase in ORR at a one-sided type I error rate of 0.05. Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS International Working Group 2006 criteria and AML MDS International Working Group 2003 criteria after 6 cycles of treatment. Cumulative ORR will include complete remission, complete remission with incomplete blood count recovery, partial response, and bone marrow complete remission. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up) and overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) for the trial. Exploratory studies: The PRIME trial will also test the utility of 2-HG and DNA damage markers such as γ-H2AX as potential biomarkers of response to olaparib. Using multiple viability assays on leukemia cell lines and bone marrow cultures we will assess synergistic therapeutic combinations to further improve outcomes in this patient population. To confirm efficacy in vivo without undue toxicity, promising combination therapies will be confirmed in cytokine-humanized immunodeficient "MISTRG" mice. We will also examine the impact of PARP inhibitors on the genomic, proteomic, metabolomic and immunologic landscape of IDH 1/2-mutant hematologic malignancies using DNA whole exome sequencing (WES), RNA-Seq, and liquid chromatography-mass spectrometry assessment of oncometabolites. Disclosures Bindra: Cybrexa: Consultancy, Equity Ownership. Prebet:pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Genentech: Consultancy; Boehringer Ingelheim: Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; Agios: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria. OffLabel Disclosure: We will be using PARP inhibitors as a novel therapy for patients with relapsed or refractory AML and high risk MDS based on preclinical data.

Choice of Hypomethylating Agent (HMA) for Initial Treatment Does Not Influence Outcome or Survival for Therapy-Related Myeloid Neoplasms (t-MN)

Introduction: T-MN is a serious complication of prior chemotherapy and/or radiation therapy. In 2008, the World Health Organization created a new category for t-MN due to the distinct variance in etiology when compared to de novo myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Compared to de novo MDS/AML, t-MN characteristically has poor risk cytogenetics and a higher incidence of TP53 mutations which are both associated with inferior survival. Small, retrospective analyses have evaluated the efficacy of front-line HMA therapy for t-AML and t-MDS, with response rates of approximately 38% (Klimek et al. Leukemia Res, 2012 and Bally et al, Leukemia Res, 2013). However, the response duration (RD), progression-free survival (PFS), and overall survival (OS) outcomes are poorly characterized in t-MN treated with HMA. This retrospective study evaluates the efficacy and survival of t-MN patients (pts) treated with azacitidine (AZA) or decitabine (DAC) in the largest cohort analyzed to-date. Methods: Our cohort included pts with t-MN at Memorial Sloan Kettering Cancer Center treated with either AZA or DAC from January 1, 2002 to September 30, 2016. The primary objective was to compare the best overall response rate (ORR) between AZA and DAC, including complete remission (CR), marrow CR (mCR), hematologic improvement (HI), and partial response (PR). The best ORR was then compared to stable disease (SD), treatment failure (TF), and progressive disease (PD). Secondary objectives included OS, PFS, and RD. Responses were assessed using the 2006 MDS International Working Group (IWG) guidelines and 2003 AML IWG guidelines. We also assessed the impact of TP53 mutations on response to HMA and survival outcomes. Results: Of the 118 pts (56% male), 76 pts received DAC and 42 pts received AZA. Median age was 70 years (yrs) (range, 25-90). DAC recipients were younger (median 67 yrs, range, 25-85) compared to AZA (median 73 yrs, range, 42-90). More pts with AML were treated with DAC (n=27, 35.5%) and more pts with MDS were treated with AZA (n=36, 85.7%). Most MDS pts had Poor (19.3%) or Very Poor (42%) risk cytogenetics, resulting in a High (23.9%) or Very High (54.5%) overall IPSS-R risk category. Time to response was faster with DAC (9.4 weeks) versus (vs.) AZA (13.3 weeks) with more pts proceeding to hematopoietic cell transplant (HCT) in the DAC group (n=19, 25%) vs. AZA (n=3, 7.1%). Overall, there were no statistical differences in response between AZA and DAC when we analyzed combined TF/PD (45.2% and 32.9%, respectively), SD (14.3% and 25%, respectively), and combined CR/HI/PR (40.5% and 42.1%, respectively) with a p-value of 0.28 (Table 1). However, more patients receiving DAC achieved CR and mCR (18.4% and 14.5%, respectively) vs. AZA (4.8% and 7.1%, respectively) and AZA had a higher HI rate (28.6%) vs. DAC (5.3%). DAC pts also appeared to have higher TF rates (25%) vs. AZA (19%) with more PD in the AZA group (26.2%) vs. DAC (7.9%). Median OS was 10.9 months (mo) and PFS was 5.3 mo (Figure 1). There was no difference in median OS between AZA (11.2 mo) and DAC (10.9 mo, p=0.61) and no difference in the median PFS between AZA (5.1 mo) and DAC (5.3 mo, p=0.83). Lastly, there was no difference in median RD between AZA (4.5 mo) and DAC (3.4 mo, p=0.39). Of the 58 pts with known TP53 mutation status, 29 (50%) had ≥1 TP53 mutation(s). There was no difference in OS and PFS between mutant and wildtype TP53 pts, and no difference in survival between AZA and DAC recipients in the mutant TP53 cohort (Figure 2). Conclusions: This large, retrospective study showed no difference in the ORR between AZA and DAC. The faster response and higher rates of CR and mCR may favor the use of DAC as a bridge to HCT in eligible pts. Conversely, the higher rates of HI seen with AZA can improve the quality of life in MDS pts who are ineligible for HCT. Our results confirm prior reports of poor OS seen in t-MN. In our cohort, we showed no difference in survival outcomes between AZA and DAC. There was also no statistical difference in OS/PFS between DAC and AZA in mutant TP53 pts, however point estimates may indicate a pattern favoring DAC over AZA that needs to be explored in a larger sample size. Although we confirmed the efficacy of HMA in this difficult to treat population, response duration and survival outcomes remain poor. Development of more effective therapies that specifically target the biology of t-MN are needed to improve survival outcomes.

The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort

AbstractMost studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes

AbstractLenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis. The objective of this multicenter, phase 2 expansion trial was to determine the efficacy and safety of combination therapy with azacitidine (75 mg/m2/d for 5 days) and lenalidomide (10 mg/d for 21 days; 28-day cycle) in patients with higher-risk MDS. Among 36 patients enrolled (18 phase 1, 18 phase 2), median age was 68 years (range, 47-78 years) and follow-up was 12 months (range, 3-55 years). IPSS categories included intermediate-1 (n = 5 patients with excess blasts), intermediate-2 (20), and high (11). Common grade 3/4 nonhematologic adverse events included febrile neutropenia (22% of patients), other infection (11%), pulmonary (11%), cardiac (11%), constitutional (11%), and dermatologic (11%). The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response (CR), and 10 (28%) had hematologic improvement. Median CR duration was 17+ months (range, 3-39+); median overall survival was 37+ months (range, 7-55+) for CR patients, and 13.6 months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS. This study is registered at http://www.clinicaltrials.gov as NCT00352001.

Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS)

BackgroundEzatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.ResultsEzatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies.ConclusionsThe tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active.Trial registrationClinicaltrials.gov: NCT01062152

Phase 1 Dose-Ranging Study of Oral Ezatiostat Hydrochloride (Telintra®, TLK199) in Combination with Lenalidomide (Revlimid®) in Patients with Non-Deletion(5q) Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Abstract 2778 Introduction:Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide’s efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures:Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.

Phase 2 Randomized Multicenter Study of Extended Dosing Schedules of Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, In Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

AbstractAbstract 2910 Introduction:MDS is characterized by defects in hematopoietic cell growth, differentiation and apoptosis. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts. The purpose of this Phase 2 study was to determine the efficacy and safety of ezatiostat on extended dose schedules in MDS. Methods:Patients (pts) with International Prognostic Scoring System Low or Int-1 risk MDS were enrolled. After initial dose-ranging in 14 pts, subsequent pts were randomized to 2 selected dose schedules: 37 pts at 3 gm daily for 2 weeks followed by a 1-week rest period and 36 pts at 2 gm daily for 3 weeks followed by a 1-week rest period. Treatment was given until lack of MDS response or unacceptable toxicity. A logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by the MDS International Working Group (2006) criteria. Results:Seventy-three pts were median age 73 years (range 48–89) 70% male, and with World Health Organization classification as follows: 11 refractory anemia (RA), 15 RA with ring sideroblasts, 5 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 9 MDS-unclassified, 3 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 2 Unknown. Fifty pts (68%) were INT-1 risk, 23 (32%) were Low risk; 27 pts (37%) had abnormal karyotypes with 23 (85%) complex/poor prognostic types. RBC transfusion-dependent pts required a median of 6 (range 4–19) U/8 weeks prior to study entry. Prior treatments included: 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors. The HI-E response rate was similar for evaluable pts on the 2 schedules, therefore the data were pooled. The overall HI-E rate was 22% (13/60) [95% CI, 12.1%–34.2%]. The median duration of response was 34 weeks. Eleven of 38 (29%) RBC transfusion-dependent pts had transfusion reductions (reduction of 4U/8weeks) with 4 pts (11%) achieving transfusion independence. A 40% HI-E rate (6/15 pts) [95% CI, 16.3%–67.7%], was observed in pts who had prior lenalidomide, but no prior DMTI, with 5/11 pts (45%) achieving significant RBC transfusion reduction and 3/11 pts (27%) achieving transfusion independence. A 28% HI-E rate (5/18 pts) [95% CI, 9.7%–53.5%] was observed in pts who were lenalidomide and DMTI naive, with 4/8 pts (50%) achieving clinically significant RBC transfusion reduction. Sixteen pts had received prior DMTI but no prior lenalidomide treatment, a 0% HI-E rate (95%CI: 0%-20.6%) was reported. Prior DMTI treatment predicts a 6-fold decrease in the odds for HI-E response to ezatiostat (p=0.027). A 19% HI-Neutrophil (HI-N) rate was observed in 4/21 pts with neutropenia (95% CI, 5.4%–41.9%) and a bilineage (HI-E and HI-N) rate of 20% (95% CI, 5.7%–43.7%) in 4/20 pts with anemia and neutropenia. A 3.7% (95% CI, 0.1%–19%) HI-P rate was observed in 1/27 thrombocytopenic pts and a trilineage (HI-E, HI-N, HI-P) rate of 9.1% (95% CI, 0.2%–41.3%) in 1/11 pts with trilineage cytopenia. There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16] and 1 with del5q. A total of 431 ezatiostat cycles were given, median 4.0 (range 1–14). Only 15 cycles (3.5%) required dose reduction and 37 cycles (8.6%) dose delays. Most common ezatiostat-related adverse events (AEs) were non-hematologic Grade 1 and 2 gastrointestinal (GI) including: nausea (45%, 17%), diarrhea (25%, 8%), and vomiting (30%, 12%). Grade 3 events were: nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Pts with prior DMTI use had GI AEs (Grades 1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), diarrhea (22%, 10%, 5%). DMTI-naive pts had fewer GI AEs (Grades 1, 2, 3): nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), diarrhea (28%, 7%, 2%). Conclusions:Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant reduction in RBC transfusions, including transfusion independence, as well as HI-N and HI-P. Ezatiostat has shown clinically significant efficacy in lenalidomide naive and lenaliomide treated pts. The tolerability and activity profile of ezatiostat may offer an important treatment option for pts with low to INT-1 risk MDS. Disclosures:Raza:Telik, Inc.: Research Funding. Galili:Telik, Inc.: Research Funding. Godwin:Scripps Health: Honoraria. Boccia:Telik, Inc.: Research Funding. Rarick:Telik, Inc.: Research Funding. Meng:Telik, Inc.: Employment, Equity Ownership. Jones:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership, Patents & Royalties. Young:Telik, Inc.: Employment, Equity Ownership. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

A Retrospective Review of Outcomes of Patients with Chronic Myelomoncytic Leukemia Treated with 5-Azacitidine.

The chemotherapeutic agent 5-azacytidine (5-AZA) is an active agent in the treatment of myelodysplastic syndrome (MDS). Phase III data with 5-AZA for MDS of all types suggest a response rate (CR+PR) of 23% and hematologic improvement rate of 37% (Silverman, et al, 2002, JCO , 20:2429). We reviewed the outcomes of patients with the MDS subtype chronic myelomonocytic leukemia (CMML) in order to better characterize outcomes for patients with this specific subtype.Methods: Retrospective analysis of outcomes in 13 patients (median age 67; range 50–82) with CMML, who were drawn from a group of 165 consecutive patients treated with 5-AZA between 1991 and 2004 at UCSF on an NCI Special Exception Program, was performed. All patients signed informed consent to participate in the Expanded Access Protocol and IRB approval at UCSF was obtained to retrospectively review this data. IPSS of patients were 2 LOW, 7 INT-1, 3 INT-2, and 1 HIGH. 11 patients had CMML-1 and 2 patients had CMML-2. Responses were determined using the MDS International Working Group (Cheson et al., 2000 Blood 96:3671) criteria.Results: Three patients (23%) had CR and 6 patients (46%) had HI at 4 months. 9/13 patients had a response at 4 months for an overall response rate of 69% (95% CI 38.6% to 90.0%). Cytogenetic responses were seen in 1 out of 4 evaluable patients. The median AML free survival was 11 months. The median overall survival was 14 months. [Display omitted] Conclusions: For patients with CMML, 5-AZA provides an effective treatment option with significant improvements in peripheral blood counts, marrow blasts, and transfusion requirements. The overall response rate of 69% correlates well with larger studies in MDS.