Hypomethylating Agents Failure Research Articles

Combination of 5-Azacytidine and ABT-199 Has a Synergistic Apoptotic Effect in High-Risk MDS/sAML after HMA Failure

Introduction:Myelodysplastic syndromes (MDS) are one of the most common haematological disorders of the older patient. Allogeneic stem cell stransplantation (ASCT) is the sole curative treatment. The number of eligible patients is limited due to age and comorbidities and only approximately one-third of these patients are cured by ASCT. Further therapeutic strategies such as hypomethylating agents (HMA) have often a short response duration.We recently found that ABT-199 effectively induces apoptosis in the leukemic progenitor compartment of higher-risk MDS and sAML patients, whereas healthy controls and low-risk patients remain unaffected (Jilg et al., 2016). These data suggest that pro-apoptotic ABT-199 might harbor potential as a novel treatment modality in higher-risk MDS patients. However, it remains unclear whether ABT-199 is a powerful option in patients after HMA failure. Synergistic effects of ABT-199 and 5-azacytidine (5-AZA) were also not analyzed in primary material of MDS/sAML patients yet.Here we investigate the effect of ABT-199 as single treatment and in combination with 5-azacytdine in bone marrow samples of 28 high-risk MDS/sAML patients under HMA therapy. We measured induction of apoptosis after ABT-199/5-azacytidine treatment and analyzed the effect on colony forming capacity.Methods:Purified bone marrow mononuclear cells (BMMNC) were treated with 1μM ABT-199 or a soluble control (DMSO) and/or 5-AZA (from 0.25µM to 10µM) for 72h in vitro. Apoptosis was analyzed by flow cytometry after staining for 7-AAD, Annexin V, and CD34 as a progenitor marker. The long-term survival was investigated by colony formation assay. Control samples were obtained from human femoral heads discarded after implantation of total endoprosthesis of the hip joint from hematologically healthy age-matched donors. Combination indices were calculated using ComboSyn.Results:28 primary samples of patients under HMA treatment (complete response n=5; stable disease n=10 and primary failure n=13) were treated with either ABT-199 single and/or combination therapy with ABT-199 and 5-AZA. Combination therapy showed a clear synergistic effect with the most favorable combination index (CI=0.1446) at ABT-199 (1µM) and 5-AZA (1µM). As expected ABT-199 only showed reduced activity in patients with complete remission. However BCL-2 inhibition effectively decreased the number of viable CD34+ cells in patients with stable disease under HMA treatment. Patients with HMA have a very poor prognosis. As expected 5-AZA (1µM) had only slight effects on MDS stem/progenitor cells of these patients in the ex vivo setting. ABT-199 monotherapy was still able to effectively induce apoptosis in a 72h read-out. Combination therapy (ABT-199 and 5-AZA at a concentration of 1µM each) efficiently induced apoptosis in the CD34+stem/progenitor cells as well as in the bulk of BMMNCs. When compared with single treatment, we found that induction of apoptosis was significantly increased in the stem/progenitor population from patients with HMA failure after combination treatment (ABT-199 mono vs combination p= 0.0089 and 5-AZA mono vs. combination p=0.0006).Conclusion:To identify novel treatment options in higher-risk MDS/sAML patients, we analyzed the apoptotic effect of ABT-199 single and ABT-199/5-azacytidine in combination in primary samples of patients under 5-azacytidine treatment.ABT-199 and 5-azacytidine showed strong synergistic effects with the most favorable combination index with 5-azacytidine (1µM) and ABT-199 (1µM).Monotherapy with ABT-199 was able to induce cell death ex vivo in high-risk MDS/sAML evenafter HMA failure. Combination therapy induced apoptosis very effectively and significantly reduced colony forming capacity. Age-matched healthy controls were only marginally effected.We therefore conclude that combination of low-dose 5-azacytidine with ABT-199 is more effective than single treatment in this pre-treated cohort of high-risk MDS/sAML patients. Since patients with HMA failure have a very poor prognosis with limited treatment options combination therapy of ABT-199 and 5-azacytidine seems to be a promising therapy option. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study Evaluating the Combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS)

A Phase II Study Evaluating the Combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS)

Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or Relapsing after Azacitidine (AZA) Treatment

Background: Hypomethylating agents (HMAs) have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and median survival after HMA failure is only about 6 months (Prebet et al, JCO 2011). Guadecitabine (GDAC, SGI-110) is a novel HMA dinucleotide of Decitabine and deoxyguanosine, administered SC, which results in extended DAC exposure. In a phase I-II study in AML (Issa, Lancet Oncol, 2015) a dose of 60mg/m2/day for 5 consecutive days was recommended. We designed a national multicenter phase II study evaluating the efficacy of GDAC in higher-risk MDS patients, refractory or relapsing after AZA (NCT02197676). Methods: Main inclusion criteria were (1) IPSS int-2 or high MDS, or CMML with WBC 10%, or AML with 20-30% marrow blasts (2) Refractory to 6 cycles of AZA or relapsing after response, but without overt progression (i.e., greater than doubling of marrow blasts compared to pre AZA values) (3) Age ≥ 18 years (4) Normal liver and renal functions. Patients received GDAC 60mg/m2/d x5 d every 28 d until progression, death or no response after 6 cycles (extended to 9 cycles after the 20 first pts). Global DNA methylation was assessed at baseline and on d 8, 15, 22 and 28 of cycle 1 in blood, and on d 28 of cycles 1 , 3 and 6 in BM and blood ,using bisulfite-converted DNA followed by pyrosequencing technology measuring 3 representative CpG sites of the LINE-1 promoter region. An intent-to-treat analysis was performed on June 2016, with a median FU of 9.6 months Results: Between Aug 2014 and Jan 2016, 56 pts from 13 centers were enrolled, M/F: 37/19, median age 75 years [IQR, 69-76]. 15 patients had primary resistance after 6 cycles of AZA, and 41 patients had relapsed after a response and a median of 13 AZA cycles [IQR 9.75-23]). 15 pts had IWG 2006 progression between onset of AZA and inclusion. At inclusion, WHO classification was RCMD in 2 pts, CMML in 1 pt, RAEB-1 in 11 pts, RAEB-2 in 31 pts and AML in 11 pts; . IPSS was int-1, int-2 and high in 4 (6%), 27 (50%) and 23 (42%) pts, resp. (2NA), and R-IPSS was low, int., high and very high in 1 (2%), 3 (6%), 13 (26%), and 34 (60.7%) pts resp (5NA). 43 (77%) pts were RBC transfusion-dependent (TD) and ECOG was >1 in 5 (9%) pts. The average baseline LINE-1 methylation level in the 45 pts evaluated was 73% in blood and 72% in BM. One pt died before any treatment, and 55 patients received at least one cycle of GDAC, with a median of 3 cycles [IQR, 2-5.5]. 9 pts responded (8 after 3 cycles) with 1 (3%) CR, 2 (5%) CRp, 5 (14%) marrow CR and 1 HI; ie an ORR of 16% (95%CI, 8-28%). Responses were seen in 4/15 (26.6%) primary refractory, and in 5/41 (12.2%) relapsing patients (p=NS). On average, the maximum LINE-1 demethylation occurred during the first cycle on day 8 in blood (median -11.3%), and on day 28 in BM (median -3.1%). Median duration of response was 9 months including so far 2 responses ≥ 1 year (12 and 18 months). 49 SAE occurred in 44 pts, and were mostly hematological, with myelosupression in 35/56 (63%) of pts 49 patients ended the study, because of progression (n=20), death (n=14), investigator or patient decision (n= 8), toxicities (n= 6) and pt withdrawal (n=1). Median OS from inclusion was 6.7 months (IC95% [5.6-11.8]). 33 pts had died, because of MDS progression in 14 (42%), infection in 13 (39.3%), bleeding in 1 (3%), and other causes in 5 (15%) pts (2 UK, 2 general deterioration, 1 heart attack). No significant prognostic factor of response to GDAC, including age, sex, ECOG, TD, baseline Hb, platelet, ANC, marrow blast %, cytogenetics, IPSS, IPSS-R, type of AZA failure (primary or secondary), LINE1 baseline methylation or demethylation rate was found. OS was significantly shorter in pts with high IPSS (HR=2.1, 95%CI, 1.04-4.20, p=0.04), and with very poor IPSS-R cytogenetics (HR=4.3, 95%CI, 2.0-9.1, p=0.0015), the latter remaining prognostic in multivariate analysis. Using the recent prognostic model for MDS pts having failed HMA (Nazha et al, hematologica 2016), that includes ECOG>1, very poor cytogenetics, age, marrow blasts >20%, TD, platelets Conclusion: Response rates with GDAC, in this population of higher risk MDS, CMML or low blast count AML with failure to AZA (and often with IWG 2006 progression) were modest. Tolerance was similar to that of conventional HMA treatment. Disclosures Beyne-Rauzy:Celgene, Novartis: Honoraria. Park:Novartis: Research Funding. Jueliger:astex: Employment. Bevan:astex: Employment. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

Optimal Treatment Order of Lenalidomide and Hypomethylating Agents for Lower-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium

▪IntroductionWhile lenalidomide (LEN) is the standard of care for treatment of red blood cell (RBC) transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS) with chromosome 5q deletion (del 5q), it is widely used off-label in the non-del5q setting. In the MDS-002 and MDS-005 studies, 26% of TD non-del5q LR-MDS patients became RBC transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment option for TD anemia in lower-risk non-del 5q MDS after hypomethylating agents (HMAs). Thatrecommendationhas led to wide use of HMAs as frontline therapy after erythroid stimulating agents (ESA) failure in LR-MDS. The response rate to LEN after HMA failure, however, is not known, as MDS-002 and MDS-005 excluded patients previously treated with HMAs. To assess the best order of LEN and HMA in optimizing response potential in lower-risk MDS, we examined response rates to each drug when treatment order (LEN followed by HMA or HMA followed by LEN) differed.MethodsWe identified patients with LR- MDS (International Prognostic Scoring System (IPSS) low or intermediate-1 (int-1) risk groups) within the MDS Clinical Research Consortium database who received both LEN and HMA as first or second line therapy after ESA failure or patients who had low chance of response to ESA. We excluded patients with isolated del5q or del q + one additional cytogenetic abnormality. The primary objective was to compare rates of erythroid hematological improvement (HI-E), defined using 2006 International Working Group criteria (IWG 2006), between patients who received LEN as first line therapy followed by HMA as second line (LEN 1st line group) versus those who received LEN as second line therapy after HMA (LEN 2nd line group).ResultsWe identified 144 patients who received both HMA and LEN as first and second line therapies: 80 patients were in group 1 (LEN 1st line) and 64 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table 1. There were no statistically significant differences between the 2 groups.The rate of HI-E was 20% (16/80) for the LEN 1st line group compared to 11% (7/64) in the LEN 2nd line group. (p=.046). There were no differences in response rates to HMA between the two groups: In the LEN 1st line group, response to 2nd line HMA was 30% (24/78) compared to 39% (25/64) for those who received HMA as first line (p=.2).There was no difference in overall survival (OS) between the two groups, The median OS was 79 months (mo) the LEN 1st line group compared to 61 mo in Len 2nd line group (p= .4). The rate of AML transformation was 9% in Len 1st line group compared to 22% in Len 2nd line group rate (p=.03). There was no difference in AML free survival (78mo versus 61mo respectively, p=0.4). In multivariable analyses adjusting for age, sex, and IPSS-R order of treatment still did not impact overall survival.ConclusionLEN yields a higher rate of HI-E in LR- MDS when used as first line therapy, but responses to HMAs were similar when used before or after LEN. The rate of AML transformation was lower when LEN was used as first line. The order of treatment does not impact overall survival. Lenalidomide should be used prior to HMA if it is to be considered for treatment of anemia in non-del5q LR-MDS. [Display omitted] DisclosuresKomrokji:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy; Boehringer-Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.

Phase 2 Trial of Smoothened (SMO) Inhibitor PF-04449913 (PF-04) in Refractory Myelodysplastic Syndromes (MDS)

▪Introduction: MDS encompasses a heterogeneous group of clonal neoplastic hematopoietic stem cell diseases characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia (AML). While the advent of hypomethylating agent (HMA) therapy has modestly improved survival in higher-risk MDS, outcomes following HMA failure are dismal. The hedgehog (HH) signaling pathway is an important regulator of hematopoietic cell survival and differentiation, with upregulation of HH target genes and signaling proteins a frequent occurrence in MDS and AML. PF-04449913 (PF-04) is an orally bioavailable inhibitor of Smoothened (SMO), which demonstrated antileukemic activity in a prior phase 1 study. We performed a phase 2 study of PF-004449913 in patients with MDS following HMA failure.Objectives: 1) primary: to estimate overall IWG-2006 response rate (CR + PR + HI + marrow CR) to PF-04449913 in patients with relapsed/refractory MDS and CMML; 2) secondary: to assess safety , overall survival, time to AML transformation, and effect of PF-04 on HH target gene expression.Methods: This was a single center, open-label phase 2 study. Key eligibility criteria included: 1) patients age ≥ 18 with MDS, CMML, or AML (20-29% blasts) following failure of HMA; 2) ECOG 0-2; 3) Adequate kidney and hepatic function. Treatment consisted of PF-04 at 100 mg/day in 4-week cycles for 4 cycles, with continuation allowed for achievement of stable disease or better. Dose increase to 200 mg/day was permitted after cycle 2 for patients with stable disease. Bone marrow biopsy for response assessment occurred after cycle 2, cycle 4, and every 4th cycle thereafter. For correlative studies, total cellular RNA was isolated from ficolled mononuclear cells in baseline marrow samples, and qPCR performed for expression of GLI1, PTCH1, and SMO).Results: Thirty five patients were enrolled, 24M and 11F. Median age was 75 years (range 55-88). A majority of patients had higher-risk (54%) vs lower-risk (43%) MDS by IPSS at time of enrollment. A total of thirty four patients (97%) had received prior azacitidine for a median of 9 cycles (range 1-88), while 6 patients had received decitabine for a median of 4 cycles (5 of whom had also received azacitidine). The median number of cycles of PF-04 received was 3 (range 1-11). All 35 patients were evaluable for response. Two of 35 patients (6%) achieved response per MDS IWG 2006 criteria, including one patient with HI-N/HI-P and another with marrow CR and HI-N. Nineteen additional patients (54%) had stable disease following cycle 2 (8 weeks). With a median follow-up of 10.1 months, the median survival for all treated patients was 10.2 months (95% CI 6.8-13.6 mo)(Figure 1). Median survival for patients with low/INT-1 risk MDS was longer than for INT-2/high risk patients (22.4 mo vs 7.5 mo, p=0.013). Six patients (17%) died while on-treatment, but none of the deaths were considered related to PF-04. The most common treatment-emergent adverse events included myalgia/muscle cramps (65%), dysgeusia (60%), nausea (31%), anorexia (31%), oral mucositis (25%), and AST elevation (22%). The vast majority of these events were grade 1/2. Except for infection (11%), there were no treatment-emergent grade 3/4 events in > 10% of patients. Only 5 patients (14%) required dose reduction to 50 mg/day due to intolerance. In the pharmacodynamics analysis, responding patients had higher baseline expression of SMO, PTC ,and GLI1 than non-responders, while non-responders had higher post-treatment increases in these transcripts compared with responders.Conclusions: PF-04 was well tolerated in patients with advanced, HMA refractory MDS, but had limited efficacy in this unselected, heavily pre-treated patient population. The pharmacodynamic analysis suggests predictive potential of HH pathway gene expression for response warranting further investigation. [Display omitted] DisclosuresKomrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy. Sweet:Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding.

CC-486 (Oral Azacitidine) in Patients with Hematological Malignancies Who Had Received Prior Treatment with Injectable Hypomethylating Agents (HMAs): Results from Phase 1/2 CC-486 Studies

CC-486 (Oral Azacitidine) in Patients with Hematological Malignancies Who Had Received Prior Treatment with Injectable Hypomethylating Agents (HMAs): Results from Phase 1/2 CC-486 Studies

Treatment options for patients with myelodysplastic syndromes after hypomethylating agent failure.

The treatment of patients with myelodysplastic syndromes (MDSs) has hinged primarily on supportive care (ie, blood transfusions, colony stimulating agents, iron chelation, etc.) and the US Food and Drug Administration-approved agents, including 5-azacytidine, deoxyazacytidine, and lenalidomide. For patients no longer benefitting from these agents, there is a paucity of effective therapies. The challenges at this time include our limited understanding of the mechanisms of resistance to these therapies and the variables employed to select next best therapies for patients based on: (1) their performance status and medical comorbidities; (2) the molecular feature(s) of their MDS; (3) the prior treatments they have received; and (4) the long-term goal(s)/possibilities for their future treatment (ie, transplant vs no transplant).

Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing after, or Are Refractory to, Hypomethylating Agent (HMA) Therapy

▪Background: HMA therapy is standard of care for patients with MDS. Outcome post HMA failure is poor with a median survival of 4-6 months. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. The objective of this phase II trial is to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy.Methods: Eligible patients were adults older than 18 years with MDS intermediate-1 and higher by the IPSS, who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an Eastern Cooperative Oncology Group performance status of </=2 at the time of study entry. Responses were defined according to International Working Group 2006 criteria. Induction therapy consisted of clofarabine 10-15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 10-15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities.Results: From January 2012 to August 2015, 80 eligible patients were enrolled in this prospective study (NCT01444742) and received a median of 2 cycles (range, 1-12) (Table 1). The overall response rate (ORR) was 46% (16 [20%] achieved complete remission (CR), 17 [21%] marrow CR, 1 [1%] partial response (PR), 3 [4%] hematological improvement (HI)) with a median response duration of 7 months. The median time to response was 42 days (range, 9-191). By multivariate analysis, complex karyotype was the only independent factor predicting for response (hazard ratio [HR] 0.13; 95% confidence interval [CI]: 0.03- 0.62; p=0.01). Of the 37 patients with diploid karyotype, the overall response was 68% (7 [19%] achieved CR, 15 [41%] marrow CR, 1 [3%] PR, 3 [4%] HI). Nine of the responding patients received subsequent allogeneic stem cell transplant (ASCT). With a median follow-up of 24 months (range: 1-51 months), the median event-free survival (EFS) and overall survival (OS) times were 5 months (95% CI: 2.7-6.3) and 11 months (95% CI: 6.5-14.9), respectively (Figure 1). The median OS for responding and non-responding patients was 24 months (95% CI: 11.7-35.6) and 5 months (95% CI: 2.8-6.2), respectively (p<0.001). There was no difference in OS whether patients were censored or not at the time of ASCT (p=0.463). At last follow-up, 22 patients (28%) remained alive: 1 is receiving low-dose clofarabine and cytarabine, 5 are alive in response after ASCT, 9 are receiving salvage therapy, 1 went to hospice, and 6 were lost to follow-up. By multivariate analyses, complex karyotype, platelet count less than 30 x 109/L, and poor performance status were independently associated with poor survival. In addition, the response to the combination of low-dose clofarabine and cytarabine was independently associated with better OS (HR 0.17; 95% CI 0.09-0.36; p<0.001). Grade ≥ 3 therapy-related toxicity included infections (34%), increased liver functional tests (8%), acute renal failure (3%), skin rash (3%), syncope (1%), and rectal bleeding (1%). Twenty-two (28%) patients had clofarabine dose reduction after a median of 2 courses. After 47 patients were enrolled and several patients experienced infections during induction, the protocol was amended to reduce the dose of clofarabine to 10 mg/m2 per day for 5 and 3 days during the induction and consolidation phases, respectively. There was no difference in responses before and after the modification to the protocol’s dosing schedule (p=0.314).Conclusion: The combination of low-dose clofarabine and cytarabine in patients with higher-risk MDS after HMA failure resulted in an ORR of 46% and median OS of 11 months and may be particularly effective in patients with diploid karyotype. Our results also indicate that the combination of low-dose clofarabine and cytarabine may be useful as a bridge to ASCT in eligible patients. [Display omitted] [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Abbvie: Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Outcome of Elderly Patients after Failure to Hypomethylating Agents Given As Frontline Therapy for Acute Myeloid Leukemia (AML): Single Institution Experience

Background: AML outcome in elderly patients unfit for intensive chemotherapy continues to be challenging. Hypomethylating agents (HMA) can be effective in these patients but responses are short-lived (Fenaux et al, JCO 2009; Dombret et al Blood 2015). Even though HMAs achieve superior response rates to supportive care alone, complete remissions (CR) are rarely achieved and often quickly lost when they occur. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs.Methods: A total of 56 AML patients' data from Feb 2007 to June 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients were considered for our study if they received HMA as frontline therapy for their AML. Patients who received HMAs after induction chemotherapy failure or for their MDS were excluded. Response was identified based on IWG AML criteria (Cheson et al, JCO 2003). Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10.Results:i)Characteristics at Diagnosis: We identified 56 AML patients treated with HMA as frontline therapy with median age of 76 years (range, 59-91), 68% of which were males. Cases were classified as AML with myelodysplasia related changes in 25%, and therapy related myeloid neoplasm in 2%, and not otherwise specific in 73%. Out of 56 cases, 23% were secondary to MDS, 2% ET (Essential Thrombocytopenia), 5% PV (Polycythemia Vera), 5% MF (Myelofibrosis), 4% from CMML (Chronic Myelomonocytic Leukemia); while 61% were de novo AML. Per cytogenetics data, 2% were considered favorable risk, 62% intermediate, and 36% poor (34% had complex karyotype).ii)Clinical outcome to Frontline HMA: Out of 56 patients, 15(27%) patients received azacitidine (AZA) and 41 (73%) received decitabine (DAC) with a median number of cycles of 4 (range 1-62). Median number of cycles was higher for AZA vs DAC (8 vs 4, p =0.3). CR was found in 10 (18%), CR with incomplete count recovery in 3 (5%), partial remission (PR) in 3 (5%) patients, with overall response of 28% and median response duration of 10 months (range, 1-78 months). Thirteen (81%) out of 16 responders relapsed. Therefore, only 53 patients were included in primary or secondary failure analysis.iii)Clinical outcome to Frontline HMA failure: Out of 53 patients, 12 (23%) received subsequent treatments. Out of the 12 patients, 3 (25%) received another HMA (switch), 2 (17%) subcutaneous low dose cytarabine, 4 (33%) intensive chemotherapy, while 3 (25%) received either therapy on a clinical trial or targeted therapy. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Only one patient had third salvage therapy and did not respond. No patient was able to proceed to allogenic hematopoietic cell transplantation. Median overall survival (mOS) for this group was 2 months. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs 2 months, p = 0.0009).Conclusions: Elderly patients diagnosed with AML who are unfit for intensive chemotherapy have a poor prognosis. HMA can get some patients into remission but most patients will ultimately fail. Outcome for patients who have primary or secondary (relapse) failure is very poor with a median OS of 2 months. Switch of HMA did not result in any response. Response to salvage therapy continues to be low but offering salvage therapies seem to improve OS. Our study provides historical data for future novel therapies, which are sorely needed for these patients. [Display omitted] DisclosuresAl-Kali:Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

A Randomized Phase II Study of Low-Dose Decitabine Versus Azacitidine in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium

▪Background: The outcome of patients (pts) with lower-risk myelodysplastic syndrome (MDS) is heterogeneous, with some pts having a particularly poor prognosis. Low doses of hypomethylating agents (HMAs) have been shown to be active in lower-risk MDS. We evaluated the relative safety and efficacy of low-dose decitabine (DAC) and azacitidine (AZA) in pts with lower-risk MDS.Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts with prior HMA exposure were excluded. Pts were randomized in a Bayesian adaptive design to receive either AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle; pts were more likely to be assigned to the better performing treatment arm. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), marrow CR, and hematologic improvement. Secondary outcomes included safety profile, cytogenetic response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myeloid leukemia (AML) or death from any cause.Results: Between 11/2012 and 2/2016, 113 pts with lower-risk MDS have been treated, 40 (39%) with AZA and 73 (71%) with DAC. The median age of the entire cohort was 70 years (range, 44-88 years), and the majority of pts (81%) were intermediate-1-risk by IPSS. Baseline characteristics of the 2 treatment groups were well-balanced and are summarized in Table 1.The median number of cycles received was 9 (range 1-41 cycles). Of the 39 pts in the AZA arm and 70 pts in the DAC arm who have received at least 2 cycles of therapy and were evaluable for response, the OIR was 53% in both groups. The CR rate with AZA and DAC was 38% and 29%, respectively (P=0.29). Among pts with abnormal karyotype at baseline, complete or partial cytogenetic response was observed in 24% of pts in the AZA arm and in 63% of pts in the DAC arm (P=0.01); the rate of complete cytogenetic response was 6% and 26% in the two groups, respectively (P=0.09). Of the 18 pts in the AZA arm and the 38 pts in the DAC arm who were transfusion dependent at baseline and evaluable for response, 17% and 32% achieved transfusion independence, respectively (P=0.24)The median duration of follow-up for the entire cohort was 20 months (range, 2-42 months). Twenty four pts in the AZA arm (60%) and 23 pts in the DAC arm (32%) have come off study due to lack of response or progressive disease. There was a trend toward prolonged EFS with DAC compared to AZA (median EFS: 19.6 months vs. 13.7 months; 1-year EFS rate: 73% vs. 57, respectively; P=0.15; Figure 1A). Twelve pts in the AZA arm (30%) and 17 pts in DAC arm (23%) have died. The median OS was similar between DAC and AZA (median OS not reached for both; 1-year OS rate: 87% vs. 84%, respectively; P=0.80; Figure 1B). Progression to AML occurred in 5 pts (13%) in the AZA arm and 6 pts (8%) in the DAC arm.Both agents were overall well-tolerated. Cycle delays were required in 23% and 37% of pts and dose reductions were required in 5% and 12% of pts treated with AZA and DAC, respectively. Infection or neutropenic fever occurred 2 pts (5%) treated with AZA and in 5 pts treated with DAC (7%). No grade 4 adverse events were observed in either treatment arm.Conclusions: Low-dose AZA and DAC are effective and well-tolerated in pts with lower-risk MDS. Early results suggest that low-dose DAC may result in superior EFS compared to low-dose AZA. A randomized trial comparing low-dose AZA, low-dose DAC, AZA x 5 days, and best supportive care in lower-risk MDS is ongoing. [Display omitted] [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.

Thioguanine Combined with Decitabine Can Overcome Resistance to Hypomethylating Agents: Final Results of a Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/Decitabine Combination in Patients with Advanced Myeloid Malignancies

Background: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that combination treatment with thioguanine and decitabine can restore therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. To test the safety and synergistic efficacy of this combination in patients with advanced myeloid malignancies, we performed a Phase I dose-escalation trial of thioguanine given with decitabine.Patients and Methods: Patients with untreated AML ≥60 years of age and ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. The primary objective was to determine the maximum tolerated dose (MTD) of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Patient-specific pharmacodynamic measures to assess the biologic activity of thioguanine-decitabine were also performed. These included an in vitro chemosensitivity assay, BH3 profiling to measure the degree to which the leukemic blasts were primed for apoptosis, and genome-wide analysis of DNA methylation changes.Results: Twelve patients (median age 67; range 56-83) with de novo AML (n=1), secondary AML (n=6), relapsed/refractory AML (n=4), and chronic myelomonocytic leukemia (CMML) (n=1) were treated. Three patients experienced dose-limiting toxicity (DLT), which were acute renal failure requiring hemodialysis (80 mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120 mg/m2), and grade 4 sepsis preventing continued treatment (120 mg/m2). Thioguanine at 80 mg/m2 was determined to be the MTD. Eleven of the 12 patients completed the first induction cycle, and 6 patients completed a second, identical induction cycle. The median number of cycles administered was 3 (range 1-8). One patient experienced a DLT prior to the first response assessment and was removed from study. The ORR in this intent-to-treat study was 67% (8/12). Six patients achieved a CR or CRi, one obtained a morphologic leukemia-free state, and one patient had a PR. Responses were observed in all disease types. Five of the 8 responses, including 4 CR/CRi, were achieved with thioguanine at 80 mg/m2, suggesting no loss of efficacy at the MTD compared with the higher dose level. All 11 evaluable patients had ≥50% reduction in bone marrow blast percentages after induction therapy. Six patients had previously received single-agent hypomethylating therapy, and 5 (83%) of these patients responded, demonstrating that thioguanine-decitabine can rescue prior hypomethylating agent failure. Out of the 8 responders, four (50%) proceeded to allogeneic stem cell transplantation (SCT), two relapsed after CR or CRi, one had a CNS-only relapse after achieving a CR, and one patient experienced DLT and was removed from the study. Of the four patients who proceeded to allogeneic SCT, two patients died in CR from transplant-related toxicity, one relapsed, and one patient remains alive and in remission greater than 2 years. Median PFS in responding patients was 42 weeks (range, 10-not reached, weeks). In vitro pharmacodynamic studies currently have been completed on samples from the first 6 patients treated on this trial. The chemosensitivity assay results on pre-treatment mononuclear cells directly correlated with initial response. In addition, significant apoptotic priming of the blasts, as suggested from BH3 profiling, also corresponded to initial clinical response.Conclusions: Thioguanine-decitabine can be administered safely and induce remission, even among patients who had previously been treated with hypomethylating agents. Intriguingly, preliminary results from the chemosensitivity screening assay and BH3 profiling correlated well with clinical responses. Additional correlative studies including DNA methylation analysis are ongoing to better understand the mechanism of synergy between thioguanine and decitabine. A multi-center Phase II trial is planned. DisclosuresJurcic:Astellas: Research Funding. Letai:Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic Syndromes.

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.

Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic Syndromes

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.

Survey of experts on therapeutic policies and proposals for the optimal timing for allogeneic peripheral blood stem cell transplantation in transfusion-dependent patients with myelodysplastic syndrome-refractory anemia.

BackgroundMost hypomethylating agent (HMA) responders with myelodysplastic syndrome (MDS) eventually need allogeneic stem cell transplantation (SCT) because they often acquire resistance to HMAs within two years of treatment. Considering the nature of MDS and the poor outcomes of SCT when performed after confirming the progression of MDS to acute myeloid leukemia (AML), allogeneic SCT should be performed with caution in patients with low-risk MDS.MethodsTo address low-risk MDS, the Korean AML/MDS working party group designed a survey for 34 MDS experts in Korea on therapeutic HMA and allogeneic SCT policies for low-risk MDS. The level of consensus was defined as the percentage of agreement among the experts.ResultsWith regard to the optimal time for allogeneic SCT for HMA responders with MDS-RA, 76% experts agreed that allogeneic SCT should be performed when a patient has a low platelet count. With regard to the relapse pattern that was most commonly found during HMA treatment in responding patients with MDS-RA, 54% experts agreed that the most common pattern that indicated HMA failure was the gradual worsening of cytopenia.ConclusionThe optimal time to perform allogeneic SCT in RA patients who achieved hematologic complete remission during HMA treatment is when the platelet count decreases. However, these suggestions need to be evaluated in larger future studies. Therefore, careful decisions should be taken at each step of allogeneic SCT to maximize the outcomes for patients with MDS-RA and iron overload.

Lenalidomide As a Second-Line Therapy after Failure of Hypomethylating Agents in Patients with Myelodysplastic Syndrome

Background: There is no standard therapy after the failure of hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) without only providing supportive cares including transfusion or cytokine therapies when the patient is not eligible for allogeneic hematopoietic cell transplantation. Lenalidomide is the treatment of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS patients showed that transfusion independency rate was 26% which was relatively acceptable and suggested that lenalidomide could be used for non-5q deletion MDS patients.Method: We conducted the prospective phase II trial to evaluate the efficacy of lenalidomide for patients who failed to HMA (ClinicalTrials.gov Identifier: NCT01673308). Patients took lenalidomide 10mg daily for 3 weeks and rested for a week. New cycle began every 4 weeks. The primary objective was the objective response rate (ORR; CR+PR+marrow CR+HI). Unknown or not evaluable response were regarded as failure. The planed sample size was 29 (P0: 10%, P1: 30%, α-error:0.5, β-error:0.2) patients. The major inclusion criteria were adult MDS by WHO classification and they should be treatment failure after HMAs (azacitidine or decitabine) which were defined as either intolerant to HMAs or progressive disease after HMA.Results: Total 31 patients were included in this analysis. Among them, 1 patient didn't receive study drug at all. Male was 21 (67.7%) patients. Median age was 68 (range 40-82) years. Reasons for stopping HMA were no response in 10, progression in 14, adverse events in 3 and other causes in 4 patients. WHO classification was follows; RA in 4, RARS in 1, RCMD in 8, RAEB-1 in 4, RAEB-2 in 8, MDS with 5q deletion in 2 and not known in 4 patients. IPSS at study enrollment were low (n=4), INT-1 (n=12), INT-2 (n=9), high risk (n=3) and unknown (n=3) risk. Revised IPSS were very low (n=3), low (n=3), intermediate (n=5), poor (n=2), very poor (n=8) and unknown risk (n=3). Median cycles of lenalidomide was 3 (range 0-21). The responses after 4 cycles were CR in 5, PR in 2, SD in 5, failure in 12, unknown in 7 patients. The maximal responses were CR in 5, marrow CR in 1, PR in 4, HI-E in 1, SD in 5, failure in 14 patients. Best ORR was 11/31 (35.5%) patients, with 16/31 receiving clinical benefit (52%, inclusive of SD). The toxicity profile was tolerable except for hematological toxicities including neutropenia and thrombocytopenia. Among 2 patients with 5q deletion, 1 patient achieved CR but 1 patient failed. Median overall survival was 8.936 (95% CI 0.0-19.685) months which compares with a historical estimate in HMA failures of 4.3-5.6 months. Two patients received alloHCT after progression or failure to lenalidomide. Causes of death were infection (n=8) and bleeding (n=1). Patients who failed to benefit from lenalidomide showed significantly poorer survival when comparing with patients who achieved ORR or SD (median overall survival 2.990 vs. 17.774 months; p=0.010). Among 17 patients who had achieved ORR or SD, 6 patients didn't progress while 8 patients progressed and 3 patients were lost to follow up.Conclusion: Lenalidomide showed reasonable response and excellent overall survival after failure of HMA in adult MDS with tolerable toxicities. Therefore, lenalidomide can be a promising option after failure of HMA even in non-5q deletion MDS. DisclosuresKim:Alexion Pharmaceuticals: Research Funding; Celgene: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

Phase I/IB Study of Azacitidine and Hedgehog Pathway Inhibition in Myeloid Malignancies

Background: Hypomethylating agents (HMA) such as 5-Azacitidine (Aza) have overall responses rate of ~35-50% in acute myeloid Leukemia (AML) and higher risk myelodysplastic syndrome (MDS) patients (pts). However, eventually all pts develop resistance on therapy. To improve upfront response rates and to address HMA failure, we performed genome-scale RNAi screens targeting genes on chromosomes 5 and 7, recurrent cytogenetic abnormalities in AML/MDS. These screens identified Hedgehog pathway (Hh) genes as potentially targetable vulnerabilities with Aza. Combination experiments with smoothened (SMO) inhibitors (SMO is a central activating gene within the Hh pathway) showed pre-clinical synergy. These and additional published data support the Hh pathway as a targetable vulnerability in AML, and provide a rational for a trial.Methods: A phase I/Ib protocol of the oral SMO inhibitor LDE225 (Sonidegib) in combination with Aza in untreated and relapsed/refractory (rel/ref) AML, chronic myelomonocytic leukemia (CMML), MDS, or MDS/myeloproliferative neoplasm overlap pts. Objectives of the phase I part are to determine safety, toxicity and MTD and for the phase Ib part to assess the preliminary overall efficacy. Sonidegib was started at dose level (DL) 0 at 400mg oral daily continuously and Aza at the approved doses (75mg/m2 x 7 days or days 5-2-2) with dose adjustment per label. A classical 3+3 design was used and DLT (CTCAE v4.0) defined as > grade 3 CPK elevation or hepatic or non-hematologic adverse events (AEs) lasting > 7 days or any grade 4 event, except for hematologic toxicities. DLT was assessed after 42 days when steady-state concentrations of Sonidegib were reached. Pharmacokinetic assessments were not performed for this study.Results:Patients and Dose Levels: Between 5/22/2014 and the data cut-off date (7/20/2015), 36 pts were enrolled. Median age was 72 y (range 52-85 y) and 64% were male. Most AML pts (23 of 24) had intermediate or unfavorable cytogenetics and most MDS/CMML pts were in the int.- to high-/very high-risk group (IPSS-R). Six pts were treated at DL-0 of Sonidegib 400mg/day and one DLT of CPK elevation was observed. Another patient had grade 4 neutropenia (which at the time was included in the DLT definition, later removed). Due to overall tolerance of the combination at DL 0 and investigator assessment, despite only 1/6 pts having a formal DLT, DL -1 at Sonidegib 200mg was explored at which 0/3 pts (1 pt non-evaluable) had DLT and the phase Ib portion was opened at DL -1. To date a total of 24 AML (13 newly dx, 11 rel/ref), 11 MDS/CMML (5 newly dx, 6 rel/ref ) and 1 myelofibrosis pt have been enrolled.Safety and Tolerability: An initial safety and efficacy assessment for 25 of the 29 pts treated on the phase Ib (n=26) + the MTD cohort of 200 mg (n=3) and for who at least 2 cycles of treatment follow up was available, showed that all pts experienced at least one grade-3 or 4 hematologic AE with a lower rate in the untreated vs. treated cohort. Other, non-hematologic grade-3 and 4 AEs respectively were seen in 24 and 28% of patients-most commonly hyponatremia and fatigue, known AEs for this drug class. Treatment delays occurred in 28% of pts and Aza or Sonidegib dose reductions in 16%. 23 (79%) pts are alive and 6 have died (21%), with one death while pt was actively treated but was deemed unrelated; 11 pts remain on study, with the remainder showing disease progression (n=3) or taken-off study for other reasons (n=3 each for AEs and did not want further treatment; n=4 other).Efficacy: As of 7/20/15 with a median treatment duration of 2 cycles, 2/5 untreated MDS/CMML pts achieved CR/CRi; 1 HMA rel/ref AML had CR; 1 untreated AML pt each had PR and MLFS. 90% of pts have not progressed. Updated results will be presented at the ASH 2015 meeting; by then all 29 pts will have completed a minimum of 4-6 cycles on study and full efficacy and AE result on all pts will be reported. To date the OS at 6 mo is 77% (95% CI: 44-97%) with a median PFS of 4 mo (range: 2-NR). Many pts in the untreated cohorts have just enrolled.Conclusion: Hh pathway inhibition with the clinically well tolerated SMO inhibitor Sonidegib in combination with Aza in MDS and AML pts is well tolerated with mostly hematologic AEs as expected with early signs of clinical activity in untreated and HMA-failure pts. Full efficacy results of 29 pts and updated safety data will be reported for this first combination trial of a SMO inhibitor in combination with a HMA in MDS and AML pts. DisclosuresMesa:Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding. Al-Kali:Novartis: Research Funding.

Eltrombopag Use in Chronic Myelomonocytic Leukemia (CMML) Patients: A Cautionary Tale

▪IntroductionThrombocytopenia is a management challenge for Myelodysplastic syndromes (MDS) patients (pts). The outcome of MDS Pts after hypomethylating agents (HMA) failure is poor. Eltrombopag is an oral, small non-peptide thrombopoietin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We report our experience among CMML pts treated with eltrombopag in the context of a phase I MDS study.MethodsThis is a phase I study. Pts are allocated to dose cohorts of 50, 100, 150, 200 mg/day. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. All pts had HMA failure. The mean platelet count within a month of enrollment must be ≤ 50 X 109/L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis > grade 3. We identified CMML pts and compared the responses and adverse events to MDS patients.ResultsAmong 33 pts enrolled on the phase I study, 7 were CMML pts. Table-1 summarizes baseline characteristics. The median age of CMML pts was 76 years, all were white males. Five pts were CMML-2. Majority were classified as higher risk by IPSS, revised IPSS and MD Anderson model. Four pts were proliferative CMML. Among CMML pts, one received eltrombopag at 50 mg, 2 pts at100 mg, 2 pts at 150 mg, and 2 pts at 200 mg. Three pts completed 8 weeks to be evaluable for response and toxicity.Hematological improvement or better by IWG 2006 criteria (HI+) was observed in 6/26 (23%) MDS pts and 1/7 (14%) CMML pts (p 0.16). The responding CMML pt had bilineage response. Five non CMML pts had a platelet response. Two CMML pts became platelet transfusion independent compared to 4 non CMML pts. The rate of AML transformation was 39% and 29% respectively in MDS and CMML pts (p 0.14). The median OS was 7 months for CMML pts compared to 5 months for non-CMML (p 0.2).Five (71%) CMML pts developed leukocytosis on treatment compared to 3 MDS pts (12%). (p 0.001). (3 out of 5 pts had proliferative type CMML). Leukocytosis developed within first cycle in all pts. In 2 CMML pts, leukocytosis resolved after stopping treatment. Four CMML pts (57%) showed peripheral myeloblasts on treatment compared to 11 (42%) in the MDS group (p 0.2). One CMML pt (14%) developed grade 3 fibrosis from grade 0-1 at baseline compared to 3 MDS pts (12%). Data will be presented on ongoing Next generation sequencing for somatic mutations comparing CMML pts to MDS pts and those who developed leukocytosis/circulating myeloblasts to pts who did not.ConclusionsEltrombopag yielded lower responses in CMML pts after HMA failure compared to MDS pts but namely due to stopping treatment in majority of pts due to leukocytosis or circulating myeloblasts. At the time being, eltrombopag should only be offered to CMML pts in the context of clinical trials.Table 1Baseline CharacteristicsCMML (n=7)MDS (n= 26)P valueAgeMean77.5750.20GenderMale7 [100%]18 [69%]0.09RaceWhite7 [100%]24 [92%]0.40ECOG PS0 11 [14%] 6 [86%]6 [23%] 20 [77%]0.70MyeloblastsPlateletsHgbWBCMean % Mean Mean Mean9 30 10.5 1413 22 9.5 30.08 0.20 0.20 0.03Cytogenetic RiskGood Intermediate Poor4 [57%] 2 [29%] 1 [14%]15 [56%] 3 [11%] 8 [33%]0.40WHO classificationRCMD RAEB-1 RAEB-2 RAEB-t (AML) CMML-1 CMMl-2 MDS/MPN-U Del 5q0 0 0 0 2 [29%] 5 [71%] 0 06 [23%] 7 [27%] 11 [42%] 1 [4%] 0 0 0 1 [4%]IPSSLow Int-1 Int-2 High1 [14%] 0 4 [57%] 2 [29%]0 11 [42%] 9 [35%] 6 [23%]0.05R-IPSSVery low Low Intermediate High Very High0 1 [14%] 0 5 [72%] 1 [14%]0 2 [8%] 5 [19%] 9 [35%] 10 [38%]0.20 DisclosuresPadron:Novartis: Speakers Bureau; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Amgen: Consultancy; Kalo-Bios: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Pharmacyclics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Off Label Use: use of eltrombopag in MDS and CMML.

Fusion Transcript Reduction in Core Binding Factor Acute Myeloid Leukemia: Maintenance Strategy with Hypomethylating Agents

Introduction: Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacytidine (AZA), can be used for MRD elimination to ultimately prolong relapse free survival.Methods: We performed a retrospective analysis of 23 patients with CBF-AML who received HMA after fludarabine, cytarabine and G-CSF (FLAG) with low dose gemtuzumab or idarubicin induction/consolidation. RTPCR from peripheral blood or bone marrow was obtained approximately every 3 months. Mutations in KIT, FLT3ITD, FLT3D835 and RAS genes were tested at baseline.Results: A total of 23 patients [t(8;21)=15 and inv(16)=8] received maintenance HMA. The reason for transition to HMA was persistent PCR positivity in 13 patients (57%), prolonged myelosuppression precluding chemotherapy based consolidation in 9 patients (39%), and molecular relapse after allogeneic stem cell transplant (SCT) in 1 patient (4%). Three of these patients received salvage clofarabine, cytarabine and idarubicin (CIA) for relapsed CBF-AML after FLAG based therapy and then went on HMA for molecular MRD. Of 23 patients, 21 received DAC and 2 received AZA. Median age at diagnosis was 53 (range, 23-70). Patients received a median of 6 cycles of FLAG based induction/consolidation (range, 1-7) prior to transitioning to HMA. The median number of HMA cycles received was 6 (range, 1-17). Seventeen patients had detectable MRD (RTPCR ≥ 0.01) at initiation of HMA maintenance with a median RTPCR of 0.06 (range, 0.03-0.91). All 17 patients were in morphologic and cytogenetic complete remission (CR) when HMA was initiated. Of these 17 patients, 5 patients (29%) had progressive disease post HMA initiation, including 1/7 with t(8:21) and 4/10 with inv(16). The RTPCR values preceding HMA in these 5 patients were 0.34, 0.06, 0.08, 0.01, and 0.01, respectively (median=0.06). All 5 patients had an increase in the RTPCR value soon after the initiation of HMA. RTPCR for these 5 patients following the first or second cycle of HMA was 3.84, >100, 77.48, 1.33, and 0.17, respectively. Four [inv(16)=3 and t(8;21)=1] of these 5 patients had a RAS mutation, while the patient with t(8;21) had a concomitant KIT mutation, and another patient with inv(16) had a FLT3D835 mutation. All five patients failing HMA proceeded to SCT, and 3 are alive and disease free post SCT. For the 12 patients without HMA failure, the median RTPCR at HMA initiation was 0.06 (range, 0.01-0.91). Unlike the HMA failure subset described above, 11 of these patients had a reduction in RTPCR by first or second subsequent measurement following initiation of HMA. One patient is in early follow up. All 6 patients who started HMA with undetectable MRD remain MRD negative (RTPCR < 0.01) and in remission. Eight patients continue on maintenance therapy. Median follow up is 11.3 months (range, 2.9-67.7).Conclusions: Despite a favorable prognosis in CBF-AML, relapse remains the primary cause of treatment failure. Identifying patients who are more likely to relapse will be beneficial in extending relapse free survival. Hypomethylating agents can potentially be used in patients with detectable RTPCR to prolong remission. Determining which patients would benefit most from this therapy is an important task. This data suggests that patients with low levels of RTPCR (between 0.01 and 0.05) following induction/consolidation chemotherapy might benefit most from maintenance HMA, particularly those that have a reduction in RTPCR on first or second subsequent measurement following initiation of hypomethylating agent therapy. DisclosuresDaver:ImmunoGen: Other: clinical trial, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria.

Stabilization of Myelodysplastic Syndromes (MDS) Following Hypomethylating Agent (HMAs) Failure Using the Immune Checkpoint Inhibitor Ipilimumab: A Phase I Trial

Background: Patients (pts) with higher-risk (HR)-MDS in whom HMAs fail have a dismal prognosis with a median overall survival (OS) of <6 months. Immune tolerance and evasion by malignant cells have been recognized as important mechanisms of progression in cancers including MDS. Immune checkpoint inhibition with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab improved outcomes in pts with solid tumors by overcoming this resistance mechanism. We hypothesized that CTLA-4 blockade in pts with HR-MDS post HMAs failure would be tolerable and lead to meaningful clinical responses.Methods: In an investigator-initiated, CTEP-sponsored phase 1b study, eligible pts with HR-MDS (defined by Intermediate-2 or high IPSS score, or intermediate-1 with ≥5% blasts in bone marrow [BM] or transfusion needs) who had primary or secondary failure of HMAs (≥4 cycles) received ipilimumab monotherapy at 2 dose levels (DL); DL1 used 3mg/kg and DL2 used 10mg/kg. In the induction phase [Figure 1], 4 doses were administered at 3-week intervals. Responding Pts and those with stable disease (SD) at end of induction received a maintenance phase with 4 more doses of ipilimumab administered at 3-month intervals (study total is 8 doses). BM biopsies were obtained at baseline, post cycles 2, 4, and before each maintenance dose. The primary objectives were to determine the tolerability of ipilimumab and identify the optimal dose for dose expansion. Toxicities were graded according to CTCAE 4.0 criteria. Responses were evaluated using International Working Group 2006 criteria at end of induction and before each maintenance dose. Overall survival (OS) was calculated from first dose of ipilimumab until death using Kaplan-Meier methods with censoring at time of allogeneic stem cell transplantation (alloSCT) or cutoff date for data collection on 6/30/2015.Results: Eleven pts were enrolled on the dose-escalation part of the study; 6 on DL1 and 5 on DL2. Median age was 63 years (range, 50-79). Five pts had received 2 prior lines of therapy (including HMAs) while 6 pts had received only HMAs; median number of HMAs cycles 5; range, 4-18. Five pts had a normal karyotype while each of the following categories were present in one pt: del5q, del7q, complex, trisomy 8 (2 pts unsuccessful karyotyping). At baseline, 4 pts were platelet transfusion-dependent and 5 were red blood cell transfusion-dependent. Median platelet count was 25×10⁹/L (range, 12-61×10⁹/L), median white blood cell count was 1.5×10⁹/L (range, 1.05-7.6×10⁹/L), median absolute neutrophil count was 0.28×10⁹/L (range, 0.06-4.7×10⁹/L), median hemoglobin was 9.4 gm/dL (range 7.6-10.8 gm/dL), and median BM blast percentage was 9% (range, 2-30%). All pts in DL1 received ≥2 ipilimumab doses; 2 received 6 or 8 doses. Three of 6 pts in DL1 developed grade 3 immune-related adverse events (IRAEs) while 4 of 5 pts at DL2 developed grade 3 IRAEs. Four pts (36%) experienced no IRAEs (3 at DL1 and 1 at DL2). All IRAEs were reversible with stopping ipilimumab +/- initiation of systemic steroids. No pt died due to an IRAE and all patients were successfully weaned from steroids. The spectrum of IRAEs was similar to that of ipilimumab use in pts with solid malignancies (rash, hepatitis, and diarrhea/colitis). Overall no pts had objective responses. Three pts (27.3%) had SD for >6 months; one had a prolonged SD after an IRAE, and one experienced an ongoing SD for >16 months. Three pts underwent alloSCT post ipilimumab without any additional toxicities and remain in complete remission at 2, 12 and 18 months post alloSCT, respectively. Median and mean OS for entire cohort (censoring at time of alloSCT) was 368 and 352 days, respectively (95%CI for mean OS, 264-440 days) [Figure 2]. Correlative studies evaluating dynamic changes in T-cell subsets, myeloid derived suppressor cells, cytokine levels, and T-cell receptor repertoire are in progress.Conclusions: Monotherapy withanti-CTLA-4 antibody ipilimumabat 3mg/kg is tolerable and can lead to prolonged disease stabilization. This dose is currently being evaluated further in a dose-expansion multi-center study. AlloSCT appears feasible post ipilimumab use but further data are needed. These results provide rationale for further exploration of immune checkpoint inhibition therapy in pts with MDS. [Display omitted] [Display omitted] DisclosuresOff Label Use: Ipilimumab for MDS. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Improved Outcomes of Low-Dose Cytarabine Regimen By Increased Dose and Duration of Cytarabine in Combination with Oral Etoposide for Elderly Acute Myeloid Leukemia

Background: For elderly patients unfit for intensive chemotherapy in acute myeloid leukemia (AML), low-dose cytarabine (LDAC; 20 mg SQ BID for 10 days) still remains to be the standard treatment, despite its unsatisfactory complete response (CR) rate of 18% and median overall survival (OS) of < 6 months (Burnett, 2007). Recently, there have been huge efforts to develop more effective and less-toxic therapies, such as decitabine, azacitidine, clofarabine, or gemtuzumab ozogamicin, but their benefits were not concrete, even though they were compared to the classical LDAC. To improve outcomes of the classical LDAC, we modified it by giving a higher dose of cytarabine for an extended duration in combination with oral etoposide. Herein, we present the results.Methods: Between 2002 and 2014, 93 consecutive older (≥ 60 years) patients with AML, who were unfit for intensive chemotherapy, received 1st cycle of modified LDAC (mLDAC) regimen consisting of cytarabine (20 mg/m2 SQ BID) and oral etoposide (50 mg PO BID) for 14 days. Thereafter, they received additional subsequent cycles (for a maximum of 7 cycles) for 10 days every 6 to 8 weeks. We retrospectively analyzed their overall response (OR), disease-free survival (DFS), and overall survival (OS) rates. In this analysis, OR was defined as CR plus CR with incomplete platelet recovery (CRp) or blood count recovery (CRi).Results: The median age of patients in our cohort, including 69 (74.2%) with poor performance status (ECOG ≥ 2), 15 (16.1%) with AML with myelodysplastic-related changes or secondary AML, and 13 (14.0%) with poor cytogenetic risk, was 68 years (range, 60-83). The median number of mLDAC regimen cycles which they received was 2 (range, 1-8). Clinically relevant toxicities of grade III-IV including nausea/vomiting, diarrhea, hyperbilirubinemia and neutropenic fever were observed in 4 (4.3%) patients, 6 (6.5%), 3 (3.2%), and 42 (45.2%), respectively, which were comparable with those of classical LDAC (Burnett, 2007). The early mortality rates at 30 and 60 days were 11.8% and 15.0%, respectively. The OR was observed in 45 (48.4%) patients, including 34 (36.6%) CR, 7 (7.5%) CRp, and 4 (4.3%) CRi, within two cycles of mLDAC. With median follow-up duration of 26.1 months, the median DFS and OS were 6.2 and 15.8 months, respectively. For patients who achieved OR, they were 14.5 and 36.9 months, respectively. The OR of patients who had poor cytogenetic risk was not significantly different compared to others (57.1%, 46.2%, and 38.5% for favorable, intermediate, and poor cytogenetics, respectively; P=0.50). However, they showed significantly shorter median DFS (9.8, 6.6, and 5.1 months, respectively; P=0.01) and OS (NR, 1.4, and 5.1 months, respectively; P=0.01) with significantly shorter OR duration (30.6, 19.1, and 8.6 months, respectively; P=0.01). Between 2009 and 2014, among 17 patients treated with hypomethylating agents (HMA; 14 decitabine and 3 azacitidine), 1 CR and 3 partial response were achieved with a median survival of 5.5 months, and 5 patients after HMA treatment failure received subsequent mLDAC, and 3 achieved additional CR (n=2) and CRp (n=1).Conclusions: These results suggest that the outcomes of classical LDAC in elderly patients with AML can be improved by modifying it, with improved response and survival rates without increasing toxicities, even in patients with poor cytogenetics. Additionally, mLDAC could induce clinical responses in patients with HMA failure. Our mLDAC regimen may become another therapeutic option with emerging novel agents for elderly patients with AML, and these should be confirmed by large randomized trials. DisclosuresNo relevant conflicts of interest to declare.