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Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.
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Hypomethylating Agent therapy in myelodysplastic syndromes with chromosome 3 abnormalities
Clinical Lymphoma Myeloma & Leukemia, 2020Co-Authors: David A Sallman, Mikkael A Sekeres, Elias Jabbour, John Barnard, Najla Al H Ali, Guillermo Garciamanero, Amy E Dezern, David P Steensma, Gail J Roboz, Jaroslaw P MaciejewskiAbstract:Abstract Background Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS; ie, 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 MDS patients with chromosome 3 abnormalities and address the impact of Hypomethylating Agent (HMA) therapy on this patient subset. Patients and Methods Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts). Results Specific 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, while 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 nonchromosome 3–MDS patients (52%, with a 25% complete remission rate) although with higher respons rates in decitabine treated patients (69% versus 45%, P = 0.008). HMA therapy improved the OS of higher-risk MDS patients compared to intensive chemotherapy (median OS of 15.5 vs 8.2 months; Pthinsp=thinsp.017). This improvement remained significant in multivariate analyses (HR 0.60; Pthinsp=thinsp.018). However, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs. Conclusion MDS patients with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.
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results of a phase 1 dose escalation study of ff 10501 01 in patients with relapsed refractory acute myeloid leukemia aml or Hypomethylating Agent hma resistant myelodysplastic syndrome mds
Blood, 2018Co-Authors: Guillermo Garciamanero, Farhad Ravandi, Yesid Alvarado, Naveen Pemmaraju, Kiran Naqvi, Michael R Kurman, Courtney D Dinardo, Elias J Jabbour, Ricardo Delumpa, Timothy MaddenAbstract:Introduction FF-10501-01 is an orally bioavailable potent inhibitor of inosine-5-monophosphate dehydrogenase (IMPDH). In vitro, FF-10501-01 reduced the proliferation of multiple human-derived myeloid leukemia parent and Hypomethylating Agent (HMA)-resistant cell lines in a concentration dependent manner. Incubation of cells with FF-01501-01 also reduced intracellular pools of GMP, GDP and GTP, and this effect was reversed by addition of guanosine, demonstrating that the effect was due to inhibition of IMPDH. FF-10501-01 was evaluated in a Phase 1 clinical trial in patients with relapsed/refractory AML and HMA-resistant MDS and results are presented below. Methods This was an open-label, single-institution, Phase 1, dose escalation study in patients with refractory AML and MDS, or in patients with AML > 60 years of age not eligible for other treatment. The study was conducted as a "3+3" design. The objectives of the study were to describe the adverse event profile, pharmacokinetics, pharmacodynamics, recommended Phase 2 dose (RP2D) and preliminary efficacy of FF-10501-01. Oral FF-10501-01 was administered in escalating doses ranging from 50 - 500 mg/m2 twice daily (BID) for periods of 14, 21 or 28 days in a 28-day treatment cycle and dose escalation to the next dose cohort was governed by the decision of a safety review committee. The pharmacokinetics of FF-10501-01 and its primary active metabolite were determined by measuring blood levels at various times after administration; pharmacodynamics were based on measurements of xanthine monophosphate (XMP) at various time points. The institutional review board of the participating institution approved the protocol and all protocol amendments, and all patients provided written informed consent. Results Thirty-seven patients were treated with FF-10501-01. Most (78%) of patients had AML; the median age of all patients was 78 (range: 58 - 88). All patients had received prior therapy (median number 3, range: 1 - 6) and 3 patients had undergone stem-cell transplantation. FF-10501-01 was well tolerated; the most frequently observed treatment-emergent related adverse events were fatigue (22%), diarrhea (11%), nausea (11%) and oral mucositis (8%). Of all adverse events reported, only 3 were Grade 3 in severity (one episode each of neutropenia, thrombocytopenia and oral mucositis); all others were Grade 1 or 2. The RP2D was determine to be 400 mg/m2 given for 21 days every 28 days. In the MDS cohort, 1 of 8 evaluable patients demonstrated a complete bone marrow response that persisted for 19 months and 3 of 24 evaluable patients with AML demonstrated partial responses; in 1 of these patients, the response persisted for 31 months. One additional patient with AML continued treatment with FF-10501-01 for 14 months without evidence of progression. FF-10501-01 displayed dose proportional pharmacokinetics with no evidence of drug accumulation; mean steady-state observed half-lives ranged from 3 - 9 hours. Blood concentrations of XMP were variable between subjects as a function of dose and time. Following a single administration of FF-10501-01, on average, there appeared to be a reduction in XMP from baseline and maximum inhibition of pre-dose blood concentrations of XMP were consistently near or above 50% following the first administration of FF-10501-01. Conclusion FF-10501-01, was well tolerated and demonstrated evidence of efficacy in a heavily pre-treated population of patients with AML and MDS. FF-10501-01 had predictable pharmacokinetics and pharmacodynamic testing verified its mechanism of action as an IMPDH inhibitor. FF-10501-01 in combination with other Agents, is currently undergoing additional clinical testing. Disclosures Kurman:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. DiNardo:Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria. Madden:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Maier:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Iwamura:Fujifilm Corporation: Employment.
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therapeutic choices after Hypomethylating Agent resistance for myelodysplastic syndromes
Current Opinion in Hematology, 2017Co-Authors: Guillermo Montalbanbravo, Guillermo Garciamanero, Elias JabbourAbstract:Purpose of reviewHypomethylating Agents (HMAs) are the standard of care for patients with myelodysplastic syndromes (MDS). Although these Agents induce responses in up to 40% of patients, most patients ultimately experience loss of response. The purpose of this review is to provide an overview of th
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pembrolizumab a pd 1 inhibitor in patients with myelodysplastic syndrome mds after failure of Hypomethylating Agent treatment
Blood, 2016Co-Authors: Guillermo Garciamanero, Martin S Tallman, Giovanni Martinelli, Vincent Ribrag, Hui Yang, Arun Balakumaran, S Chlosta, Yayan Zhang, Douglas B SmithAbstract:Background: Upregulation of the immune checkpoint receptor PD-1 and its ligands, PD-L1 and PD-L2, has been demonstrated in peripheral blood mononuclear cells from patients with MDS (Yang H et al. Leukemia2014;28:1280-1288). This upregulation is enhanced by epigenetic modifiers, such as 5-azacitidine, and has been associated with poor survival. The PD-1 pathway thus represents an attractive target in patients with MDS that has failed first-line treatment with a Hypomethylating Agent. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands and can restore antitumor immune activity in solid tumors and hematologic malignancies. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b study of pembrolizumab in patients with hematologic malignancies. Results from the MDS cohort of KEYNOTE-013 are presented. Methods: Key eligibility criteria for this cohort included age ≥18 years, primary or secondary MDS with IPSS score of intermediate 1, intermediate 2, or high; and failure (defined as worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to more advanced MDS FAB subtype than at pretreatment) to respond to at least 4 cycles of prior treatment with a Hypomethylating Agent (azacitidine or decitabine). Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by investigator every 6 weeks using IWG 2006 criteria (Cheson BD et al. Blood2006;108:419-425). The primary end points were safety and objective response rate; secondary objectives included overall survival, bone marrow response, and hematologic improvement. Bone marrow samples were collected at predefined time points during the study for analysis of gene expression profiles with the NanoString platform. Results: Among the 28 patients enrolled in the MDS cohort, median age was 73 years (range, 38-84 years), 64% were male, and IPSS scores were intermediate 1 in 10 patients (36%), intermediate 2 in 9 patients (32%), and high in 7 patients (25%). 54% of patients had a FAB classification of refractory anemia with excess blasts. At the time of data cutoff on May 27, 2016, the median follow-up duration was 5.6 months (range, 1-29 months). 10 patients (36%) experienced treatment-related adverse events (AEs); the most frequent were hypothyroidism in 4 patients (14%) and fatigue in 3 patients (11%). Grade 3/4 treatment-related AEs occurred in 2 patients (7%), including grade 3 gastroenteritis and grade 4 tumor lysis syndrome in 1 patient each. 2 patients discontinued because of treatment-related AEs, including grade 4 tumor lysis syndrome in 1 patient, and grade 2 arthralgia, grade 1 musculoskeletal stiffness, and grade 1 peripheral edema in 1 patient. There were no treatment-related deaths. Of the 27 patients evaluated for efficacy, there were no complete remissions (CRs), and 1 patient achieved a partial remission, for an overall response rate of 4% (90% CI, 0.2%-16%). Among the remaining patients, best overall response was marrow CR in 3 patients (11%), stable disease in 14 patients (52%), and progressive disease in 9 patients (33%). Hematologic improvement was seen in 3 patients (11%). The overall survival rate at 24 weeks was 49% across the cohort, including 89% in patients with intermediate 1 IPSS score, 22% in patients with intermediate 2 IPSS score, and 29% in patients with high IPSS score. For patients with intermediate 1 score, the 1-year overall survival rate was 89%; the 2-year overall survival rate was 57%. Biomarker data will be presented. Conclusion: PD-1 blockade with pembrolizumab was associated with a manageable safety profile and potential clinical activity in patients with MDS after failure of first-line treatment with a Hypomethylating Agent. Future studies in combination with azacitidine are planned. Disclosures Martinelli:MSD: Consultancy; Amgen: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Genentech: Consultancy. Ribrag:Pharmamar: Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees; Infinity: Membership on an entity9s Board of Directors or advisory committees; Esai: Membership on an entity9s Board of Directors or advisory committees; Nanostring: Membership on an entity9s Board of Directors or advisory committees; Incyte: Membership on an entity9s Board of Directors or advisory committees. Balakumaran:Merck & Co.: Employment, Other: stock, stock options. Chlosta:Merck & Co., Inc.: Employment, Other: stock, stock options. Zhang:Merck & Co., Inc.: Employment, Other: stock, stock options. Smith:Celgene: Consultancy, Other: member of DSMB.
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impact of Hypomethylating Agent therapy in myelodysplastic syndromes with chromosome 3 abnormalities
Blood, 2015Co-Authors: David A Sallman, Mikkael A Sekeres, Elias Jabbour, John Barnard, Najla Al H Ali, Guillermo Garciamanero, Amy E Dezern, David P Steensma, Gail J Roboz, Cassie ZimmermanAbstract:Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al ., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of Hypomethylating Agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups ( P P P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months ( P /= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients ( P Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity9s Board of Directors or advisory committees; TetraLogic: Membership on an entity9s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity9s Board of Directors or advisory committees. Steensma: Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet: Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List: Celgene Corporation: Honoraria, Research Funding. Komrokji: Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.
Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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Achievement of a negative minimal residual disease state after Hypomethylating Agent therapy in older patients with AML reduces the risk of relapse
Leukemia, 2017Co-Authors: Prajwal Boddu, Hagop M Kantarjian, Gautam Borthakur, Tapan M. Kadia, Jeffrey L. Jorgensen, Naval Daver, Yesid Alvarado, Naveen Pemmaraju, Prithviraj Bose, Kiran NaqviAbstract:Achievement of a negative minimal residual disease state after Hypomethylating Agent therapy in older patients with AML reduces the risk of relapse
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therapeutic benefit of decitabine a Hypomethylating Agent in patients with myeloproliferative neoplasm in blastic phase acute myeloid leukemia mpn aml accelerated phase mpn ap and dipss plus high risk primary myelofibrosis pmf
Blood, 2014Co-Authors: Talha Badar, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Gautam Borthakur, Elias Jabbour, Naval Daver, Naveen Pemmaraju, Sherry R Pierce, Srdan VerstovsekAbstract:Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of Hypomethylating Agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a Hypomethylating Agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active Agents are needed to improve overall outcome. Disclosures No relevant conflicts of interest to declare.
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determinants of demethylation and clinical response in aml patients treated with sgi 110 a novel subcutaneous sq Hypomethylating Agent hma in a phase 1 study
Blood, 2013Co-Authors: Woonbok Chung, Hagop M Kantarjian, John Lyons, Pietro Taverna, Yong Hao, Mohammad Azab, Patricia Kropf, Jean Pierre J IssaAbstract:Introduction SGI-110 is a dinucleotide of decitabine and deoxyguanosine and is a potent inhibitor of DNA methylation in-vitro and in-vivo. A Phase 1 study established the biologically effective dose of SGI-110 in MDS/AML patients as 60 mg/m2 SQ daily x 5 and demonstrated clinical responses that correlated with hypomethylation induction. Here, we analyze AML patients treated at pharmacologically effective doses of SGI-110 to explore determinants of hypomethylation and response. Methods We studied patients with relapsed/refractory AML treated at therapeutic dose ranges of SGI-110 (36 mg/m2-125 mg/m2). DNA methylation pre/post treatment (for pharmacodynamics [PD]) was measured by bisulfite-pyrosequencing for the LINE-1 repetitive element and the INS6 CpG island gene promoter which is highly methylated in all somatic tissues. Gene expression at baseline and after treatment was measured by qPCR. Results We analyzed samples from 27 patients with AML. Median age was 64, (range, 29–86), 18 were Males (67%), 13 (48%) had poor risk cytogenetics at study entry and 59% had prior exposure to a Hypomethylating Agent. Overall, peak LINE-1 demethylation generally occurred on Day 8 and correlated strongly with INSL6 demethylation (R=0.95, p 0.05). Unsupervised classification grouped the patients into four clusters: A (N=2), B (N=6), C (N=10), and D (N=9). Cluster D is characterized by high DNMT3b expression, low P15 expression, low CDA expression and reduced demethylation (demethylation average -10.9% in cluster D compared to -22.7% in clusters B and C, p=0.06). Next, we examined SGI-110 mediated induction of gene expression for the P15, P21, DNMT3B and CTCF genes. P15 was significantly induced in patients who were treated on the daily x 5 regimen (p=0.03) but not in patients receiving the weekly x 3 regimen. In this group of 14 patients with induced P15, P15 induction peaked on Day 8 and averaged a 2.4-fold increase. P15 induction was associated with a trend for increased demethylation on Day 8 (R=0.28) and on Day 29 (R=0.37), p>0.05 for both. Of the 27 patients, 5 showed major clinical responses (2 CR, 3 CRi/CRp). LINE-1 and INSL6 demethylation averaged -21.1% and -16.4% in responders compared to -13.1% and -11.3% in non-responders. A three gene classifier score (low CDA, low P15 and high DNMT3B) was associated with low LINE-1 demethylation (R=0.43, p=0.025) as well as resistance to SGI-110 (mean score 6.2 in non-responders compared to 0.5 in responders, p=0.047). Finally, peak induction of P15 was similar in responders and non-responders, but sustained induction (at Day 29) was higher in responders (3.1 fold) than in non-responders (1.0 fold). While a genetic signature of response could not be identified among those 8 genes that were examined by exome sequencing, mutations in IDH1 or IDH2 were identified in 5 patients. One of these patients was positive for substitution R132H of IDH1 (described to induce epigenetic alterations and may predict poor clinical outcome in AML) and achieved a CR in response to SGI-110 treatment. The TP53 polymorphism NM_000546:c.C215G:p.P72R, (associated with differential response to chemotherapy in AML), was identified in 9 subjects, 3 of whom responded to SGI-110. Conclusions At therapeutic doses of SGI-110, we identified a gene expression signature (high DNMT3B, low P15, and low CDA) that differentiates responders from non-responders to SGI-110 and we find trends for associations between demethylation and response, as well as sustained P15 induction and response. These associations will be further investigated in the ongoing Phase 2 study of SGI-110 in AML. Disclosures: Chung:Astex Pharmaceuticals Inc.: Research Funding. Off Label Use: SGI-110. Taverna:Astex Pharmaceuticals Inc.: Employment. Lyons:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals Inc.: Research Funding. Kropf:Astex Pharmaceuticals Inc.: Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding.
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outcome of elderly patients with acute myeloid leukemia aml post Hypomethylating Agent hma failure
Blood, 2012Co-Authors: Koichi Takahashi, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Tapan M. Kadia, Sherry Pierce, Hady Ghanem, Susan Obrien, Nitin Jain, Guillermo GarciamaneroAbstract:Abstract 2627 Background and Aims: HMA such as 5-azacitadine or decitabine have been increasingly used as induction therapy in elderly patients with AML. The prognosis of such patients who failed initial HMA and the impact of subsequent chemotherapy on outcome are unknown. Therefore the aims of the current analysis are 1) to evaluate the prognosis of elderly patients with AML post HMA failure and 2) to evaluate the efficacy of using intensive cytarabine-based salvage therapy vs. low intensity investigational therapy. Methods: We analyzed 54 patients older than 60 years old with AML who received induction treatment with HMA using either 5-azacitadine (n=17; 31%) or decitabine (n=37; 69%) under various clinical trials. Result: Median age of the group was 68 years (range; 60–84); 39% patients were female. Forty three patients (77%) had performance status (PS) ≤1 and 11 patients had PS of 2 (23%). Mean initial white blood cell count was 10.9 ± 3.2 (x10 3 /μl), hemoglobin 9.9 ± 0.2 (g/dl), platelet count 77 ± 9 (x10 3 /μl), and bone marrow blast count 44 ± 2.9 (%). Cytogenetic category was classified as intermediate in 30 (55%) patients and poor in 24 (45%) based on the MRC criteria. Six patients (11%) carried FLT3-ITD mutation and 1 carried FLT3 D835 mutation. Complete remission (CR) was achieved in 24 patients (44%) with median numbers of cycles required to achieve CR being 3 (range; 1–6). All patients received further salvage therapies, at the time of failure, with a median of 2.5 (range, 2–5) salvage regimens. As part of the salvage regimen, high-dose cytarabine-based regimen (HDAC) was given to 32 patients (59%). Objective response rate to HDAC was 53%, with 18 pts achieving CR. Median number of courses given was 2 (range, 1–7) with a median duration of response of 3 months. No induction death was reported. Stem cell transplant was performed in total of 9 patients (17%) as a consolidation post HDAC (n=4) or as salvage therapy (n=5). With a median follow-up of 5 months post HMA failure, 5 (9%) patients remained alive receiving therapy. The median overall survival (OS) was 5.4 months (range, 2.3–8.5). The 1-year overall survival rate was 26%. There was no difference in OS between patients who received HDAC versus those who received investigational Agents (p=0.25). Conclusion: The outcome of untreated elderly patients with AML who failed HMA is poor with a median survival of 5 months. HDAC based regimen, although active with low treatment related morbidity, yielded no survival improvement compared to investigational Agents. Such patients should benefit from more innovative approaches. Disclosures: Ravandi: Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding.
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failure of Hypomethylating Agent based therapy in myelodysplastic syndromes
Seminars in Oncology, 2011Co-Authors: Tapan M. Kadia, Elias Jabbour, Hagop M KantarjianAbstract:Hypomethylating Agents such as 5-azacytidine or decitabine have been a major breakthrough in the treatment of patients with myelodysplastic syndromes (MDS). They have been shown to improve transfusion requirements and to change the natural history of the disease. However, with increasing cumulative clinical experience, it has become apparent that these Agents are not curative and have their own shortcomings. There is a subgroup of patients who do not respond to frontline therapy and a large, growing cohort of patients that lose response or progress while on Hypomethylating Agent–based therapy. There are no standard treatment options in this arena and it is therefore a focus of significant research interest. Since the mechanisms of resistance to Hypomethylating Agents are not known, selection of therapy is largely empiric but must take into account the age, comorbidities, and performance status of the patient, as well as the characteristics of the disease at the time of treatment failure. Higher intensity approaches and allogeneic stem cell transplant can yield improved response rates and long-term disease control but should be limited to a selected cohort of patients who can tolerate the treatment-related morbidities. For the majority of patients who likely will be better candidates for lower intensity therapy, several novel, investigational approaches are becoming available. Among these are newer nucleoside analogues, inhibitors of protein tyrosine kinases, molecules that interact with redox signaling within the cell, immunotherapy approaches, and others. Patients with MDS whose disease has failed to respond to Hypomethylating Agent therapy should be referred for clinical trials when available. As we learn more about the patterns and mechanisms of failure, the next challenge will be to determine which therapies are suitable for each individual patient.
Elias Jabbour - One of the best experts on this subject based on the ideXlab platform.
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Hypomethylating Agent therapy in myelodysplastic syndromes with chromosome 3 abnormalities
Clinical Lymphoma Myeloma & Leukemia, 2020Co-Authors: David A Sallman, Mikkael A Sekeres, Elias Jabbour, John Barnard, Najla Al H Ali, Guillermo Garciamanero, Amy E Dezern, David P Steensma, Gail J Roboz, Jaroslaw P MaciejewskiAbstract:Abstract Background Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS; ie, 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 MDS patients with chromosome 3 abnormalities and address the impact of Hypomethylating Agent (HMA) therapy on this patient subset. Patients and Methods Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts). Results Specific 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, while 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 nonchromosome 3–MDS patients (52%, with a 25% complete remission rate) although with higher respons rates in decitabine treated patients (69% versus 45%, P = 0.008). HMA therapy improved the OS of higher-risk MDS patients compared to intensive chemotherapy (median OS of 15.5 vs 8.2 months; Pthinsp=thinsp.017). This improvement remained significant in multivariate analyses (HR 0.60; Pthinsp=thinsp.018). However, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs. Conclusion MDS patients with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.
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therapeutic choices after Hypomethylating Agent resistance for myelodysplastic syndromes
Current Opinion in Hematology, 2017Co-Authors: Guillermo Montalbanbravo, Guillermo Garciamanero, Elias JabbourAbstract:Purpose of reviewHypomethylating Agents (HMAs) are the standard of care for patients with myelodysplastic syndromes (MDS). Although these Agents induce responses in up to 40% of patients, most patients ultimately experience loss of response. The purpose of this review is to provide an overview of th
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impact of Hypomethylating Agent therapy in myelodysplastic syndromes with chromosome 3 abnormalities
Blood, 2015Co-Authors: David A Sallman, Mikkael A Sekeres, Elias Jabbour, John Barnard, Najla Al H Ali, Guillermo Garciamanero, Amy E Dezern, David P Steensma, Gail J Roboz, Cassie ZimmermanAbstract:Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al ., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of Hypomethylating Agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups ( P P P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months ( P /= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients ( P Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity9s Board of Directors or advisory committees; TetraLogic: Membership on an entity9s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity9s Board of Directors or advisory committees. Steensma: Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet: Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List: Celgene Corporation: Honoraria, Research Funding. Komrokji: Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.
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therapeutic benefit of decitabine a Hypomethylating Agent in patients with myeloproliferative neoplasm in blastic phase acute myeloid leukemia mpn aml accelerated phase mpn ap and dipss plus high risk primary myelofibrosis pmf
Blood, 2014Co-Authors: Talha Badar, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Gautam Borthakur, Elias Jabbour, Naval Daver, Naveen Pemmaraju, Sherry R Pierce, Srdan VerstovsekAbstract:Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of Hypomethylating Agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a Hypomethylating Agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active Agents are needed to improve overall outcome. Disclosures No relevant conflicts of interest to declare.
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Acute Myeloid Leukemia After Myelodysplastic Syndrome and Failure of Therapy With Hypomethylating Agents: An Emerging Entity With a Poor Prognosis
Clinical Lymphoma Myeloma and Leukemia, 2014Co-Authors: Elias Jabbour, Guillermo Garcia-manero, Farhad Ravandi, Sherry Pierce, Hady Ghanem, Xuelin Huang, Susan O'brien, Stefan Faderl, Sangbum Choi, Srdan VerstovsekAbstract:We assessed the outcomes of 63 patients with acute myeloid leukemia (AML) arising from myelodysplastic syndrome (MDS) after Hypomethylating Agent failure. Their median age was 63 years. All 63 patients had received ≥ 1 salvage regimens for AML, and 35 patients (55%) had received ≥ 2. Of the 31 patients (49%) who had received high-dose cytarabine (HDAC) at first relapse, 2 (6%) achieved complete remission (CR) and 4 (13%) CR with incomplete platelet recovery (overall response rate, 19%). Of the 32 patients (51%) who had received other treatments, including investigational Agents, 4 (12%) achieved CR and 4 (12%) CR with incomplete platelet recovery (overall response rate, 24%). The median response duration was 20 weeks. With a median follow-up of 42 months from the AML diagnosis, the median survival (21 weeks) was similar between the 2 groups. The 1- and 2-year survival rate was 19% and 8%, respectively. Multivariate analysis identified low albumin, HDAC treatment, and platelet count 65 years as independent adverse factors for survival. Thus, the outcome of AML evolving from MDS after Hypomethylating Agent failure is poor and not improved with HDAC. Novel therapies directed toward this emerging entity are urgently needed.
Gautam Borthakur - One of the best experts on this subject based on the ideXlab platform.
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A phase 2 clinical trial of eltrombopag for treatment of patients with myelodysplastic syndromes after Hypomethylating-Agent failure.
Leukemia & Lymphoma, 2019Co-Authors: Mahesh Swaminathan, Gautam Borthakur, Tapan M. Kadia, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Kristy Bodden, Brittany Yearby, Marina Konopleva, Joseph D. KhouryAbstract:Hypomethylating Agents (HMA) are the standard of care for treatment of myelodysplastic syndromes (MDS). HMA-failure MDS has extremely poor prognosis. This study was designed to explore the utility ...
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Achievement of a negative minimal residual disease state after Hypomethylating Agent therapy in older patients with AML reduces the risk of relapse
Leukemia, 2017Co-Authors: Prajwal Boddu, Hagop M Kantarjian, Gautam Borthakur, Tapan M. Kadia, Jeffrey L. Jorgensen, Naval Daver, Yesid Alvarado, Naveen Pemmaraju, Prithviraj Bose, Kiran NaqviAbstract:Achievement of a negative minimal residual disease state after Hypomethylating Agent therapy in older patients with AML reduces the risk of relapse
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initial results of a phase 2 study of guadecitabine sgi 110 a novel subcutaneous sc Hypomethylating Agent for patients with previously untreated intermediate 2 or high risk myelodysplastic syndromes mds or chronic myelomonocytic leukemia cmml
Blood, 2016Co-Authors: Guillermo Montalbanbravo, Jorge E. Cortes, Farhad Ravandi, Gautam Borthakur, Naval Daver, Yesid Alvarado, Prithviraj Bose, Koichi Takahashi, Michael Andreeff, Courtney D DinardoAbstract:INTRODUCTION: Guadecitabine (SGI-110) is a next generation Hypomethylating Agent (HMA) formulated as a dinucleotide of decitabine and deoxyguanosine, with an increased length of exposure compared to decitabine due to reduced metabolism by cytidine deaminase. Previous phase 1 and phase 2 clinical trials of guadecitabine demonstrated clinical activity both in untreated and previously treated patients with MDS, with good tolerance. Improving the current response and survival outcomes of patients with higher risk MDS and CMML, particularly in the presence of very high risk biological features, is fundamental. In the current clinical trial we assessed the activity of guadecitabine in patients with higher-risk MDS and CMML as front-line therapy. METHODS: We are conducting a single arm, non-randomized phase 2 clinical trial of guadecitabine for patients with newly diagnosed MDS or CMML classified as Intermediate-2 or High risk by IPSS. Treatment consisted of guadecitabine at a dose of 60mg/m2 sc daily for 5 days (days 1-5) every 28 days. The primary endpoint was complete response (CR). Secondary objectives included overall response rate (ORR), survival and transfusion independence. Responses were evaluated following the revised 2006 International Working Group (IWG) criteria. Sequencing data was obtained at the time of pre-treatment evaluation by the use of a 28-gene next generation sequencing platform. Study included stopping rules for response and toxicity whereby the study would stop if the CR rate was unlikely (chance 30% was >95%, respectively. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 40 patients were enrolled between November 2014 and June 2016. Thirty-seven (93%) were evaluable for toxicity and 36 (90%) for response at the time of analysis. Patient characteristics are shown in Table 1. Median age was 67 years (range 48-86). A total of 34 (85%) patients had MDS and 6 (15%) had CMML. Thirty-six (90%) were classified as int-2 risk and 4 (10%) as high risk by IPSS. A total of 9 (23%) had normal karyotype and 18 (45%) had complex karyotype. Sequencing data was available in 38 (95%) patients. Identified mutations are shown in Figure 1A, with TP53 mutations being the most frequently detected in 15 (38%) patients. Following a median of 6 treatment cycles (range 1-17), 10 (28%) subjects met the primary endpoint by achieving CR. ORR was observed in 22 (61%) subjects, with 4 (10%) hematologic improvement (HI) and 9 (23%) CRi defined as mCR+HI. Median best response occurred by 3 cycles (range 1-6). Of subjects evaluable for cytogenetic response, (n-26; 72%), 6 (21%) achieved a complete cytogenetic response (CCyR). Seven (19%) subjects responded sufficiently to be removed from the study and proceed to allogeneic stem cell transplantation. Only one (3%) patient had transformation to acute myeloid leukemia. Median follow up was 4 months (range 0-19 months). Median OS was 15.2 months (95% CI 12.13-18.25 months) (Figure 1B) and median EFS was 10.8 months (95% CI 6.9-14.76 months) (Figure 1C). At the present time of follow up, no significant differences in survival were observed based on achievement of response (NR vs 15 months, p=0.142) or CR (13.6 vs 15.1 months, p=0.474). A total of 31 (84%) patients experienced at least one AE during therapy with 4 (11%) patients having related grade ≥3 non-hematologic AEs including fatigue, febrile neutropenia and oral mucositis. Therefore, stopping rule for toxicity was not met. Most common grade 1-2 AEs included fatigue (35%), nausea (24%) and dyspnea (24%). Dose reductions due to cytopenias were required in 12 (33%) patients. Early 8-week mortality occurred in 2 (5%) patients, one due to non-related cardiac arrest and one due to sepsis. CONCLUSION: Guadecitabine is a well-tolerated and active new HMA for patients with higher-risk MDS and CMML even in the presence of adverse biological features such as high frequency of complex karyotype, therapy related disease and TP53 mutations. Further follow up is required to assess survival benefit in terms of OS and leukemia-free survival. Disclosures Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Novartis: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy.
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treatment with Hypomethylating Agents before allogeneic stem cell transplant improves progression free survival for patients with chronic myelomonocytic leukemia
Biology of Blood and Marrow Transplantation, 2016Co-Authors: Sameh Gaballa, Riad El Fakih, Julianne Chen, Uday R. Popat, Carlos E Buesoramos, Piyanuch Kongtim, Antonio M Jimenez, Gabriela Rondon, Gautam BorthakurAbstract:The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with Hypomethylating Agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving Hypomethylating Agents and 41 receiving cytotoxic chemotherapy. Patients treated with a Hypomethylating Agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other Agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a Hypomethylating Agent (43%) than in those treated with other Agents (27%; P = .04). Our data support the use of Hypomethylating Agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings.
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therapeutic benefit of decitabine a Hypomethylating Agent in patients with myeloproliferative neoplasm in blastic phase acute myeloid leukemia mpn aml accelerated phase mpn ap and dipss plus high risk primary myelofibrosis pmf
Blood, 2014Co-Authors: Talha Badar, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Gautam Borthakur, Elias Jabbour, Naval Daver, Naveen Pemmaraju, Sherry R Pierce, Srdan VerstovsekAbstract:Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of Hypomethylating Agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a Hypomethylating Agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active Agents are needed to improve overall outcome. Disclosures No relevant conflicts of interest to declare.
Farhad Ravandi - One of the best experts on this subject based on the ideXlab platform.
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results of a phase 1 dose escalation study of ff 10501 01 in patients with relapsed refractory acute myeloid leukemia aml or Hypomethylating Agent hma resistant myelodysplastic syndrome mds
Blood, 2018Co-Authors: Guillermo Garciamanero, Farhad Ravandi, Yesid Alvarado, Naveen Pemmaraju, Kiran Naqvi, Michael R Kurman, Courtney D Dinardo, Elias J Jabbour, Ricardo Delumpa, Timothy MaddenAbstract:Introduction FF-10501-01 is an orally bioavailable potent inhibitor of inosine-5-monophosphate dehydrogenase (IMPDH). In vitro, FF-10501-01 reduced the proliferation of multiple human-derived myeloid leukemia parent and Hypomethylating Agent (HMA)-resistant cell lines in a concentration dependent manner. Incubation of cells with FF-01501-01 also reduced intracellular pools of GMP, GDP and GTP, and this effect was reversed by addition of guanosine, demonstrating that the effect was due to inhibition of IMPDH. FF-10501-01 was evaluated in a Phase 1 clinical trial in patients with relapsed/refractory AML and HMA-resistant MDS and results are presented below. Methods This was an open-label, single-institution, Phase 1, dose escalation study in patients with refractory AML and MDS, or in patients with AML > 60 years of age not eligible for other treatment. The study was conducted as a "3+3" design. The objectives of the study were to describe the adverse event profile, pharmacokinetics, pharmacodynamics, recommended Phase 2 dose (RP2D) and preliminary efficacy of FF-10501-01. Oral FF-10501-01 was administered in escalating doses ranging from 50 - 500 mg/m2 twice daily (BID) for periods of 14, 21 or 28 days in a 28-day treatment cycle and dose escalation to the next dose cohort was governed by the decision of a safety review committee. The pharmacokinetics of FF-10501-01 and its primary active metabolite were determined by measuring blood levels at various times after administration; pharmacodynamics were based on measurements of xanthine monophosphate (XMP) at various time points. The institutional review board of the participating institution approved the protocol and all protocol amendments, and all patients provided written informed consent. Results Thirty-seven patients were treated with FF-10501-01. Most (78%) of patients had AML; the median age of all patients was 78 (range: 58 - 88). All patients had received prior therapy (median number 3, range: 1 - 6) and 3 patients had undergone stem-cell transplantation. FF-10501-01 was well tolerated; the most frequently observed treatment-emergent related adverse events were fatigue (22%), diarrhea (11%), nausea (11%) and oral mucositis (8%). Of all adverse events reported, only 3 were Grade 3 in severity (one episode each of neutropenia, thrombocytopenia and oral mucositis); all others were Grade 1 or 2. The RP2D was determine to be 400 mg/m2 given for 21 days every 28 days. In the MDS cohort, 1 of 8 evaluable patients demonstrated a complete bone marrow response that persisted for 19 months and 3 of 24 evaluable patients with AML demonstrated partial responses; in 1 of these patients, the response persisted for 31 months. One additional patient with AML continued treatment with FF-10501-01 for 14 months without evidence of progression. FF-10501-01 displayed dose proportional pharmacokinetics with no evidence of drug accumulation; mean steady-state observed half-lives ranged from 3 - 9 hours. Blood concentrations of XMP were variable between subjects as a function of dose and time. Following a single administration of FF-10501-01, on average, there appeared to be a reduction in XMP from baseline and maximum inhibition of pre-dose blood concentrations of XMP were consistently near or above 50% following the first administration of FF-10501-01. Conclusion FF-10501-01, was well tolerated and demonstrated evidence of efficacy in a heavily pre-treated population of patients with AML and MDS. FF-10501-01 had predictable pharmacokinetics and pharmacodynamic testing verified its mechanism of action as an IMPDH inhibitor. FF-10501-01 in combination with other Agents, is currently undergoing additional clinical testing. Disclosures Kurman:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. DiNardo:Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria. Madden:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Maier:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Iwamura:Fujifilm Corporation: Employment.
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initial results of a phase 2 study of guadecitabine sgi 110 a novel subcutaneous sc Hypomethylating Agent for patients with previously untreated intermediate 2 or high risk myelodysplastic syndromes mds or chronic myelomonocytic leukemia cmml
Blood, 2016Co-Authors: Guillermo Montalbanbravo, Jorge E. Cortes, Farhad Ravandi, Gautam Borthakur, Naval Daver, Yesid Alvarado, Prithviraj Bose, Koichi Takahashi, Michael Andreeff, Courtney D DinardoAbstract:INTRODUCTION: Guadecitabine (SGI-110) is a next generation Hypomethylating Agent (HMA) formulated as a dinucleotide of decitabine and deoxyguanosine, with an increased length of exposure compared to decitabine due to reduced metabolism by cytidine deaminase. Previous phase 1 and phase 2 clinical trials of guadecitabine demonstrated clinical activity both in untreated and previously treated patients with MDS, with good tolerance. Improving the current response and survival outcomes of patients with higher risk MDS and CMML, particularly in the presence of very high risk biological features, is fundamental. In the current clinical trial we assessed the activity of guadecitabine in patients with higher-risk MDS and CMML as front-line therapy. METHODS: We are conducting a single arm, non-randomized phase 2 clinical trial of guadecitabine for patients with newly diagnosed MDS or CMML classified as Intermediate-2 or High risk by IPSS. Treatment consisted of guadecitabine at a dose of 60mg/m2 sc daily for 5 days (days 1-5) every 28 days. The primary endpoint was complete response (CR). Secondary objectives included overall response rate (ORR), survival and transfusion independence. Responses were evaluated following the revised 2006 International Working Group (IWG) criteria. Sequencing data was obtained at the time of pre-treatment evaluation by the use of a 28-gene next generation sequencing platform. Study included stopping rules for response and toxicity whereby the study would stop if the CR rate was unlikely (chance 30% was >95%, respectively. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 40 patients were enrolled between November 2014 and June 2016. Thirty-seven (93%) were evaluable for toxicity and 36 (90%) for response at the time of analysis. Patient characteristics are shown in Table 1. Median age was 67 years (range 48-86). A total of 34 (85%) patients had MDS and 6 (15%) had CMML. Thirty-six (90%) were classified as int-2 risk and 4 (10%) as high risk by IPSS. A total of 9 (23%) had normal karyotype and 18 (45%) had complex karyotype. Sequencing data was available in 38 (95%) patients. Identified mutations are shown in Figure 1A, with TP53 mutations being the most frequently detected in 15 (38%) patients. Following a median of 6 treatment cycles (range 1-17), 10 (28%) subjects met the primary endpoint by achieving CR. ORR was observed in 22 (61%) subjects, with 4 (10%) hematologic improvement (HI) and 9 (23%) CRi defined as mCR+HI. Median best response occurred by 3 cycles (range 1-6). Of subjects evaluable for cytogenetic response, (n-26; 72%), 6 (21%) achieved a complete cytogenetic response (CCyR). Seven (19%) subjects responded sufficiently to be removed from the study and proceed to allogeneic stem cell transplantation. Only one (3%) patient had transformation to acute myeloid leukemia. Median follow up was 4 months (range 0-19 months). Median OS was 15.2 months (95% CI 12.13-18.25 months) (Figure 1B) and median EFS was 10.8 months (95% CI 6.9-14.76 months) (Figure 1C). At the present time of follow up, no significant differences in survival were observed based on achievement of response (NR vs 15 months, p=0.142) or CR (13.6 vs 15.1 months, p=0.474). A total of 31 (84%) patients experienced at least one AE during therapy with 4 (11%) patients having related grade ≥3 non-hematologic AEs including fatigue, febrile neutropenia and oral mucositis. Therefore, stopping rule for toxicity was not met. Most common grade 1-2 AEs included fatigue (35%), nausea (24%) and dyspnea (24%). Dose reductions due to cytopenias were required in 12 (33%) patients. Early 8-week mortality occurred in 2 (5%) patients, one due to non-related cardiac arrest and one due to sepsis. CONCLUSION: Guadecitabine is a well-tolerated and active new HMA for patients with higher-risk MDS and CMML even in the presence of adverse biological features such as high frequency of complex karyotype, therapy related disease and TP53 mutations. Further follow up is required to assess survival benefit in terms of OS and leukemia-free survival. Disclosures Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Novartis: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy.
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therapeutic benefit of decitabine a Hypomethylating Agent in patients with myeloproliferative neoplasm in blastic phase acute myeloid leukemia mpn aml accelerated phase mpn ap and dipss plus high risk primary myelofibrosis pmf
Blood, 2014Co-Authors: Talha Badar, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Gautam Borthakur, Elias Jabbour, Naval Daver, Naveen Pemmaraju, Sherry R Pierce, Srdan VerstovsekAbstract:Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of Hypomethylating Agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a Hypomethylating Agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active Agents are needed to improve overall outcome. Disclosures No relevant conflicts of interest to declare.
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Acute Myeloid Leukemia After Myelodysplastic Syndrome and Failure of Therapy With Hypomethylating Agents: An Emerging Entity With a Poor Prognosis
Clinical Lymphoma Myeloma and Leukemia, 2014Co-Authors: Elias Jabbour, Guillermo Garcia-manero, Farhad Ravandi, Sherry Pierce, Hady Ghanem, Xuelin Huang, Susan O'brien, Stefan Faderl, Sangbum Choi, Srdan VerstovsekAbstract:We assessed the outcomes of 63 patients with acute myeloid leukemia (AML) arising from myelodysplastic syndrome (MDS) after Hypomethylating Agent failure. Their median age was 63 years. All 63 patients had received ≥ 1 salvage regimens for AML, and 35 patients (55%) had received ≥ 2. Of the 31 patients (49%) who had received high-dose cytarabine (HDAC) at first relapse, 2 (6%) achieved complete remission (CR) and 4 (13%) CR with incomplete platelet recovery (overall response rate, 19%). Of the 32 patients (51%) who had received other treatments, including investigational Agents, 4 (12%) achieved CR and 4 (12%) CR with incomplete platelet recovery (overall response rate, 24%). The median response duration was 20 weeks. With a median follow-up of 42 months from the AML diagnosis, the median survival (21 weeks) was similar between the 2 groups. The 1- and 2-year survival rate was 19% and 8%, respectively. Multivariate analysis identified low albumin, HDAC treatment, and platelet count 65 years as independent adverse factors for survival. Thus, the outcome of AML evolving from MDS after Hypomethylating Agent failure is poor and not improved with HDAC. Novel therapies directed toward this emerging entity are urgently needed.
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outcome of elderly patients with acute myeloid leukemia aml post Hypomethylating Agent hma failure
Blood, 2012Co-Authors: Koichi Takahashi, Jorge E. Cortes, Hagop M Kantarjian, Farhad Ravandi, Tapan M. Kadia, Sherry Pierce, Hady Ghanem, Susan Obrien, Nitin Jain, Guillermo GarciamaneroAbstract:Abstract 2627 Background and Aims: HMA such as 5-azacitadine or decitabine have been increasingly used as induction therapy in elderly patients with AML. The prognosis of such patients who failed initial HMA and the impact of subsequent chemotherapy on outcome are unknown. Therefore the aims of the current analysis are 1) to evaluate the prognosis of elderly patients with AML post HMA failure and 2) to evaluate the efficacy of using intensive cytarabine-based salvage therapy vs. low intensity investigational therapy. Methods: We analyzed 54 patients older than 60 years old with AML who received induction treatment with HMA using either 5-azacitadine (n=17; 31%) or decitabine (n=37; 69%) under various clinical trials. Result: Median age of the group was 68 years (range; 60–84); 39% patients were female. Forty three patients (77%) had performance status (PS) ≤1 and 11 patients had PS of 2 (23%). Mean initial white blood cell count was 10.9 ± 3.2 (x10 3 /μl), hemoglobin 9.9 ± 0.2 (g/dl), platelet count 77 ± 9 (x10 3 /μl), and bone marrow blast count 44 ± 2.9 (%). Cytogenetic category was classified as intermediate in 30 (55%) patients and poor in 24 (45%) based on the MRC criteria. Six patients (11%) carried FLT3-ITD mutation and 1 carried FLT3 D835 mutation. Complete remission (CR) was achieved in 24 patients (44%) with median numbers of cycles required to achieve CR being 3 (range; 1–6). All patients received further salvage therapies, at the time of failure, with a median of 2.5 (range, 2–5) salvage regimens. As part of the salvage regimen, high-dose cytarabine-based regimen (HDAC) was given to 32 patients (59%). Objective response rate to HDAC was 53%, with 18 pts achieving CR. Median number of courses given was 2 (range, 1–7) with a median duration of response of 3 months. No induction death was reported. Stem cell transplant was performed in total of 9 patients (17%) as a consolidation post HDAC (n=4) or as salvage therapy (n=5). With a median follow-up of 5 months post HMA failure, 5 (9%) patients remained alive receiving therapy. The median overall survival (OS) was 5.4 months (range, 2.3–8.5). The 1-year overall survival rate was 26%. There was no difference in OS between patients who received HDAC versus those who received investigational Agents (p=0.25). Conclusion: The outcome of untreated elderly patients with AML who failed HMA is poor with a median survival of 5 months. HDAC based regimen, although active with low treatment related morbidity, yielded no survival improvement compared to investigational Agents. Such patients should benefit from more innovative approaches. Disclosures: Ravandi: Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding.