Therapy For MDS Research Articles

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

Iron Chelation Therapy in MDS – The Final Answer

Iron Chelation Therapy in MDS – The Final Answer

The Role of DNA Methyltransferase Inhibitors in the Modern Therapy of MDS

The Role of DNA Methyltransferase Inhibitors in the Modern Therapy of MDS

CPX-351 Therapy for MDS After Hypomethylating Agent Failure

CPX-351 Therapy for MDS After Hypomethylating Agent Failure

Pre-transplant hypomethylating agents do not influence post-transplant survival in myelodysplastic syndrome

Information on the use of hypomethylating agents (HMAs) as a pre-transplant cytoreductive therapy in MDS is limited. We retrospectively evaluated outcomes of 172 adult MDS patients, who underwent allogeneic hematopoietic stem cell transplantation between January 2000 and December 2016. Patients were divided into three groups: group 1 – pre-transplant blasts <5% with HMA (n = 42), group 2 – pre-transplant blasts ≥5% with HMA (n = 38), group 3 – no HMA (n = 92). With a median follow up of 4.08 years, 1-year survival and relapse rates for groups 1, 2, and 3 were 75%, 40.2%, and 60.71%, respectively; and 17.6%, 26.6%, and 9.8%, respectively. Multivariate analysis revealed adverse relapse (HR 3.54; p = .03) in group 2 compared to groups 1 and 3, while no difference in overall survival was noticed. Our study shows no survival association with pre-transplant HMA; although, higher relapse rate was observed in the non-responding patients indicating possible chemotherapy resistant disease.

A Meta-Analysis of Higher-risk Myelodysplastic Syndrome Trials to Evaluate the Relationship between Short-term Endpoints and Overall Survival.

Background: The objective of this work was to evaluate the relationship between the response rates and median overall survival (OS) in higher-risk myelodysplastic syndrome (HR-MDS) to determine whether response rates could be used as predictors of median OS.Methods: Relevant MDS clinical trials were identified through a review of published literature. Weighted linear regression was performed with various linearizing transformations of response rates and median OS using the in-house built HR-MDS clinical trials database. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively.Results: Twenty-five trials involving 38 cohorts were included in the meta-analysis. The analysis demonstrated that partial response (PR) or better rate (sum of complete response (CR), marrow complete response (mCR) and PR rates) was a strong predictor of median OS (adjusted R2=0.64). The median OS was 3.3 months longer (P < 0.005) with azacitidine treatment compared to treatment with other drugs for a given response rate and prior therapy status. We also have shown that the median OS of treatment naïve HR-MDS patients was 4.5 months longer (P < 0.0001) compared to that of previously treated patients for a given response rate and treatment group.Conclusion: Significant correlation between PR or better rate and median OS in HR-MDS highlights the potential to use PR or better rate as a surrogate endpoint to accelerate development of novel therapies for MDS.

Pre-Transplant Hypomethylating Agents Do Not Influence Post-Transplant Outcomes in Myelodysplastic Syndrome

Introduction: Use of cytoreductive therapy pre-transplant has remained a debatable issue in the management of MDS. Induction chemotherapy has been attempted with no clear advantage. However, the information on pre-transplant hypomethylating agents (HMA) as a debulking/bridging therapy in MDS is unclear. This study evaluates the impact of pre-transplant HMA on post-transplant outcomes in MDS.Methods: We retrospectively evaluated clinical outcomes of adult MDS patients, who underwent allogeneic stem cell transplant (ASCT) at out institute. We divided patients who received pre-transplant HMA into <5% blasts (group 1) and ≥ 5% blasts (group 2) at transplant and compared transplant outcomes of both these groups with untreated patients (group 3). The objectives were to determine rate of GVHD, non-relapse mortality (NRM), relapse rate, progression free survival (PFS) and OS.Results: Between January 2000 and December 2016, 174 patients with MDS underwent ASCT. Of these, 80 patients received pre-transplant HMA, and 42 had <5% blast (group 1) and 38 had ≥ 5% blasts (group 2) at transplant. Ninety-four patients did not receive HMA (group 3). Monosomy 5, 7 or del 5q was noted in 10%, 8% and 15% of patients, in group 1, 2 and 3, respectively, whereas complex cytogenetics were noted in 26%, 26% and 28% of patients, in group 1, 2 and 3, respectively. Median number of blasts at transplant was 0%, 10% (range, 5-19), 3% (range, 0-40), in group 1, 2 and 3, respectively. Thirty-nine percent patients received matched related, and 61% received matched unrelated donor transplants. Bu-Flu-TBI (53%) was the most commonly used conditioning regimen followed by Bu-Flu (41%).With a median follow up of 4.08 years, the cumulative incidence of grade III-IV aGVHD at 6 months was 9.5% (95% CI, 3-20.7%), 28.9% (95% CI, 15.5-43.9%), and 27.7% (95% CI, 19-37%) for group 1, 2 and 3, respectively (p=0.05). The 1-year cumulative incidence of cGVHD was 54.9% (95% CI, 37.4-69.4%), 28.4% (95% CI, 14.4-44.3%), and 51.1% (95% CI, 40.4-60.7%) (p=0.04), for group 1, 2 and 3, respectively. The 1-year OS for group 1, 2 and 3 was 75% (95% CI, 62.6-89.7%), 40.2% (95% CI, 26.5-61%), and 59.3% (95% CI, 50.1-70.1%), respectively; whereas PFS was 67.5% (95% CI, 54.4-83.8%), 34.8% (95% CI, 22.2-54.7%), 55.1% (95% CI, 45.9-66.2%), respectively. The 1-year outcomes in group 1, 2 and 3 were 17.6% (95% CI, 7.6-31%), 26.6% (95% CI, 13.6-41.6%), and 9.6% (95% CI, 4.7-16.6%) (p=0.07), respectively, for relapse; 14.8% (95% CI, 5.9-27.6%), 38.2% (95% CI, 22.4-53.9%), and 35.2% (95% CI, 25.7-44.9%) (p=0.11), respectively, for NRM. Multivariable analysis demonstrated that ≥5% blast at transplant, complex karyotype and high R-IPSS were associated with poor PFS and OS, whereas Complex karyotype was associated with higher relapse rate, poor PFS and OS.Conclusion: Our study shows pre-transplant disease burden and complex karyotype as independent risk factors for poor outcomes. No survival benefit was noted with pre-transplant HMA in MDS. [Display omitted] DisclosuresDeol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy.

Negative Prognostic Relevance of a Specific 3-Gene Cluster in Myelodysplastic Syndromes during Azacitidine and Lenalidomide Therapy

Background and Rationale. Azacitidine (AZA) is a standard first-line therapy in high-risk MDS. Also its combination with Lenalidomide (LEN) has been tested, but its molecular effect is still under investigation. Here we analyzed the effect of AZA+LEN therapy on gene mutations and microRNA expression in MDS patients.Patients and Methods. This study included 44 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR) or any hematologic improvement were considered as responders, while patients showing stable disease or disease progression were considered as non responders. Molecular analyses were performed at baseline and during the therapy. Gene mutations were studied by an Illumina Cancer Myeloid Panel and an Ion Torrent specific panel, whereas microRNAs expression was assessed using an Affymetrix miRNA 4.0 array.Results. 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases). 13 patients showed a positive response within the 4th cycle (T4) and maintained it at T8; 9 patients showed a positive response within T4 and lost response at T8; 4 patients responded after T4 and maintained the response at T8; 8 patients never responded. Molecular analyses were performed on serial samples (baseline, T4 and T8) available for 30 patients. Results from the Illumina analysis on cancer myeloid genes showed that 3/30 cases had no mutations at all, all other cases showed mutations both at baseline and during the therapy. The most frequently mutated genes were ASXL1 (14 cases = 47%), TET2 (11 cases = 37%), RUNX1 (8 cases = 27%) and SRSF2 (5 cases = 17%). All samples with a decreasing variant allele frequency (VAF) had a favourable response at T8 (CR, marrow CR or PR), while none of the non responders showed a decreasing VAF.Ion Torrent analysis of 24 inositide-specific genes showed that all patients had mutations both at baseline and during the therapy. Interestingly, all patients responding at T4 and losing response at T8, as well as cases that did not respond, acquired the same 3 point mutations at T8, affecting respectively PIK3CD (D133E), AKT3 (D280G) and PLCG2 (Q548R) genes. Patients responding at T4 and losing response at T8 showed these mutations even at T4. Kaplan-Meier analyses revealed that the presence of these mutations was significantly associated with a decreased duration of therapy (39.5 vs 8.5 months; p<0.05) and duration of response (36 vs 6 months; p<0.05).As for microRNA profiling, paired analysis between responders and non responders showed specific clusters of up- or down-regulated microRNAs. Interestingly, unpaired analysis on patients responding at T4 and losing response at T8 showed 18 up- and 11 down-regulated microRNAs, like miR-3613-3p and miR-6757-5p, whose predicted targets are our 3 genes among the others. Also in patients never responding to the therapy there was a specific cluster of 3 up- and 12 down-regulated microRNAs and, interestingly, 7 of these microRNAs, like miR-4786-5p or miR-6853-3p, targeting our 3-gene cluster among the others, were altered also in patients losing response.Conclusions. Our results show that the presence of a common cluster of point mutations affecting 3 inositide-specific genes (PI3KCD, AKT3, PLCG2, all regulating cell proliferation), is significantly associated with loss of response to AZA+LEN therapy. Moreover, also a cluster of 7 microRNAs, targeting our 3 genes among the others, is associated with unfavourable outcome. Further studies are warranted to confirm these data, to further analyze the role of this 3-gene cluster and to identify the specific targets for the dysregulated microRNAs identified. DisclosuresGobbi:Janssen: Consultancy; Amgen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfister: Membership on an entity's Board of Directors or advisory committees. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Finelli:Janssen: Consultancy, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Phase II Study of CPX-351 (Cytarabine: Daunorubicin) Liposome Injection in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) at High Risk for Induction Mortality

Phase II Study of CPX-351 (Cytarabine: Daunorubicin) Liposome Injection in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) at High Risk for Induction Mortality

Combined venetoclax and alvocidib in acute myeloid leukemia.

More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25–50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T.

Spliceosomal mutations, especially mutations in SF3B1, are frequently (>80%) identified in patients with refractory anemia with ringed sideroblasts (RARS) and myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T; previously known as RARS-T), and SF3B1 mutations have a high positive predictive value for disease phenotype with ringed sideroblasts. These observations suggest that SF3B1 mutations play important roles in the pathogenesis of these disorders and formation of ringed sideroblasts. Here we will review recent insights into the molecular mechanisms of mis-splicing caused by mutant SF3B1 and the pathogenesis of RSs in the context of congenital sideroblastic anemia as well as RARS with SF3B1 mutations. We will also discuss therapy of SF3B1 mutant MDS, including novel approaches.

216 - Using Genetic Engineering to Improve the Bispecific Antibody Platform for MDS Therapy

A probabilistic model V̇M∝1−exp[−z⋅(σT/σC)m], originally developed for comminution processes, is applied to cement-based materials, eroded by water-driven abrasive particles with velocities as high as 552 m/s. In the equation, V̇M is the volumetric erosion rate, and the ratio σT/σC is the dimensionless impact stress (tensile stress/compressive strength). Based on experimental investigations, values for the scale parameter (z) and the shape parameter (m) are estimated for five cement-based materials. Results of Spearman׳s rank coefficient calculations show that the scale parameter is particularly sensitive to the compressive strength, and this effect is explained through higher flaw densities in low-strength materials.

A Phase I Dose Finding Trial of Eltrombopag during Consolidation Therapy in Adults with Acute Myeloid Leukemia Employing a Unique Dosing Design: PrE0901, a Precog Study

Introduction: High-dose cytarabine consolidation chemotherapy for acute myeloid leukemia (AML) induces profound transient myelosuppression. Thrombocytopenia is a limiting factor in chemotherapy administration for maintaining dose intensity and schedule as thrombocytopenic-related hemorrhage may contribute to significant morbidity and mortality. Therapeutic and prophylactic platelet (plt) transfusions remain the treatment of choice but the benefits typically last only 3-7 days, are expensive, time consuming, and may induce alloimmunization and transmit infection. PrE0901 was a phase I multi-center study to evaluate the safety and toxicity of eltrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, for plt recovery in AML patients (pts) receiving consolidation therapy.Methods: The primary objectives were to determine the safety, tolerability, and optimal dosing of eltrombopag while describing the kinetics of plt recovery in AML pts receiving intensive consolidation. Plt recovery was defined as a sustained plt count of ≥ 20 x 109/L following the nadir with no plt transfusions in prior 7 days or a continued upward trend in plt count for at least 2 successive measurements despite no plt transfusions in 48 hours. We used a standard 3+3 design utilizing a novel dose escalation/de-escalation strategy for pts in either first or second complete remission, ≥18 and ≤70 years of age, who had an ECOG performance status of 0-2. Cytarabine was administered at 3 g/m2 (1.5 g/m2 for pts >60 years) IV over 3 hours twice daily on days 1,3,5. Eltrombopag at assigned dose was administered with a first cycle of cytarabine only. Planned eltrombopag dose levels -2, -1, 1, 2, 3, 4, and 5 were 50, 100, 150, 150, 150, 200, and 300 mg, respectively (Table 1). Eltrombopag was to start on days X, X, 3, -1, -5, -5, and -5 relative to day of cytarabine start and levels -2, -1, 1, 2, 3, 4, and 5, respectively, with day X being variable depending on timing of observed dose limiting toxicities (DLTs). The eltrombopag was continued until plt recovery or for up to 35 consecutive days, whichever occurred first. An exploratory objective was to determine if eltrombopag had an effect on TPO and EPO blood concentrations in this setting.Results: Accrual began on July 31, 2012 and the trial closed on January 8, 2016 upon recommendation after an independent Data and Monitoring Committee reviewed a separate trial of eltrombopag therapy in MDS which demonstrated futility. 104 pts were screened. 54 declined participation and 35 were deemed medically ineligible. A total of 15 eligible pts were enrolled; 14 were treated on study with one pt being withdrawn prior to starting treatment due to infection. Three pts were treated at each of dose levels 1-4 and two were treated on dose level 5. No DLTs were observed. Median time to plt recovery of all pts treated on study was 22.5 (range 16-43) days. Pts in cohort 1 dosed with eltrombopag 150 mg daily starting on day 3 of consolidation demonstrated the fastest plt recovery (median =19 days; range 19, 19, 19) compared to cohort 2 who received 150 mg daily starting on day -1 of consolidation and recovered the slowest (median 23 days; range 16, 23, 43). Dose escalation in terms of starting eltrombopag further in advance of chemotherapy exposure as within cohort 3 (150 mg starting day -5) was associated with a median plt recovery of 27 (range 22, 27, 27) days. Eltrombopag dose intensification with cohort 4 at 200 mg daily and cohort 5 at 300 mg daily was associated with median plt recoveries of 24 (range 18, 24, 26) and 23 (range 19, 27) days, respectively. Kinetics of plt recovery for all cohorts are represented in Figure 1 and duration of eltrombopag exposure for each individual patient is represented in Table 2.Conclusions: Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed. The results for cohort 1 [eltrombopag 150 mg daily starting on day 3 of consolidation] demonstrated the fastest plt recovery. Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression. [Display omitted] [Display omitted] [Display omitted] DisclosuresStrickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding.

Bromodomain and Extra-Terminal Motif Proteins (BETs) Mediate 5-Azacitidine Resistance in Myeloid Leukemia through Recruitment of an Active RNA Polymerase II Complex

Background: BETs are evolutionarily conserved proteins that specifically bind to acetyl-lysines on histones and other proteins to recruit transcriptional machinery and influence gene expression (Shi and Vakoc. 2014 Mol Cell 54, 728-736). Small molecules that target BETs, such as JQ1 and I-BET, can effectively inhibit the growth of midline carcinoma cells that have a BRD4-NUT gene fusionas well as leukemia cells, such as AML, which have a diverse genetic background and do not have BRD4 rearrangements. DNA methyltransferase (DNMT) inhibitors, such as azacitidine (5-AZA) and decitabine, have been proven effective in some patients with hematologic malignancies including AML and MDS. However, the detailed mechanisms underlying the selectivity and resistance of these epigenetic-modifying drugs remain elusive. Our previous genome-wide epigenetic profiling data have demonstrated epigenetic inactivation of the SPI1/PU.1 pathway in cytogenetically normal MDS with erythroid predominance (Cheng et al. 2013 Leukemia 27, 1291-1300). This study aims to elucidate the role of chromatin structure in the regulation of response to epigenetic drugs in MDS and AML.Methods: Co-immunoprecipitation (co-IP) coupled with RNase/DNase digestion, super-resolution two-photon stimulated-emission depletion (STED) confocal microscopy, high-throughput sequencing and chromatin conformation capture (3C) were used.Results: Our data demonstrate that GATA1 and SPI1/PU.1, erythroid- vs. myeloid-determining transcription factors (TFs), selectively interact with specific sets of DNA/histone modifiers, such as TET2, DNMTs and EZH2, to form distinct lineage-specific, drug-responsive chromatin structures at specific gene loci. The interactions between the TFs, DNA/histone modifiers and chromatin structures are highly sensitive to RNase and DNase digestions, i.e., dependent on native chromatin environment. Our experiments show that hnRNPK, a conserved factor in the heterogeneous nuclear RNA-binding protein (hnRNP) complexes, directly interact with the lineage-determining TFs and DNA/histone modifiers as well as RNAs/DNAs to form distinct chromatin-structures in MDS/AML cells. Epigenetic drugs, such as 5-AZA, efficiently disrupt the hnRNPK-mediated chromatin structures in 5-AZA-sensitive MDS/AML cells, but not in 5-AZA-resistant MDS/AML cells. Our data demonstrate a marked (~4-6 fold) increase in BRD4, BRD2 and DNMT1 in the 5-AZA-resistant MDS/AML cell lines compared to the 5-AZA-sensitive MDS/AML cell lines. Strikingly, a massive amount of BRD4-associated RNA polymerase II (pol-II) is observed in the 5-AZA-resistant MDS/AML cells, but not in the 5-AZA-senstive MDS/AML, and there is approximately 70-80 fold increase in BRD4-associated pol-II, but not in BRD4-associated GATA1, in the 5-AZA-resistant cells compared to the 5-AZA-sensitive cells. Such BRD4-associated pol-II is almost exclusively in a processive pol-II complex that is associated with the phosphorylated C-terminal domain (S2p/S5p-CTD) of pol-II, and sensitive to JQ1. Furthermore, JQ1 significantly decreases the interactions between BRD4 and lineage-determining TFs GATA1 and SPI1/PU.1, in the 5-AZA-sensitive MDS/AML cells, but not in the 5-AZA-resistant MDS/AML cells. A very low concentration (0.01 uM) of JQ1 can re-sensitize the 5-AZA-resistant MDS/AML cell lines and completely reverse the drug resistance to 5-AZA, suggesting a BET-mediated 5-AZA-resistance in those cells. Genome-wide chromatin immunoprecipitation coupled with high-throughput sequencing has been carried out to map the BRD4-associated RNA pol-II at the genome-wide level in the 5-AZA resistant and sensitive MDS/AML cells. Our experiments using clinical specimens demonstrate a positive correlation between MDS/AML progression and increase in expression of hnRNPK, BRD2 and BRD4, confirming their importance and clinical relevance.Conclusion: Our study has revealed a novel drug resistance mechanism that operates through BET-mediated recruitment of an active pol-II complex and induction of drug-responsive chromatin structural changes in MDS/AML cells (Fig 1). Such BET-mediated changes in pol-II complexes and chromatin structure could become useful biomarkers to predict drug responses, leading to rational designs and actionable targets to reprogram therapeutic drug susceptibility for more effective therapy in MDS and AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ruxolitinib (RUX) in Combination with Azacytidine (AZA) in Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Background:Clinical trials exclusively focusing on pts with MDS/MPN are lacking.AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs.Aim:To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487).Methods:A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts.Results: 34 pts were enrolled between March 1, 2013 and June 30, 2016. Baseline characteristics are summarized in table 1. 21 pts remain alive after a median (med) follow-up of 14.2 months (range, 0.5-32.7+).Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). 32 pts were enrolled before April 1 2016 wereevaluable for response. Responses were noted in 16 (50%) pts. Details of responses are shown in table 2. Med time to IWG response was 1.8 mos (range, 0.7-11.0+) and the med duration of response is 7 mos (range, 2.3-31.8+). Seven (44%) of the IWG responses occurred after the addition of the AZA. There was a trend to higher IWG-responses in JAK2 mutated versus non-mutatedpts (7/8 versus 9/24 responses, P=0.18). Additionally, 9 pts had >5% pretreatment BM blasts and 7 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (range, 2.6-11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 5 of 20 (25%) evaluable pts after a med of 5.5 mos (range, 2.0-5.6+) on therapy. The reduction in fibrosis was by one grade in all 5 cases.Oneptexperienced grade 3/4 non-hematological toxicity of limb edema. New onset grade 3/4anemiawas seen in 24 pts [71%; of which 7 (21%) had a >/=2+ grade change] and new onset grade 3/4 thrombocytopenia in 18 (53%) pts, respectively.The AZA was started in cycle 4 in 14 pts (41%). The AZA was started earlier due to leukocytosis or increased blasts in 16 pts (47%): in cycle 1 (n=8), cycle 2 (n=5), and cycle 3 (n=3); 2 never started AZA due to low counts and 2 pts are too early to start AZA.23 (68%) pts have discontinued protocol therapy due to leukocytosis (n=7), progression to AML (n=5), stem cell transplant (n=3), lack of response (n=2), progressive thrombocytopenia (n=1), pneumothorax (n=1), concurrent T-cell neoplasm (n=1), and loss of insurance (n=1).Thirteen (38%) pts have died: pneumonia (n=4), sepsis (n=4), progression to AML (n=4), and uncontrolled leukocytosis in oneptwith Ph- CML. The med overall survival (OS) for all 34 pts is 25.4mos+ (range, 1.0-32.7+). The MDS/MPN-U patients had a significantly better med OS (26.4+ months) as compared to the CMML (15.0+ months) andaCML(1.5+ months)pts, respectively (P=0.01).Conclusion: Concomitant administration of RUX with AZA demonstrated an IWG-response rate of 50% in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. The benefit seems to be more profound in pts with MDS/MPN-U and MDS/MPNpts with JAK2 mutations. This combination warrants further evaluation. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Verstovsek:Pfizer: Research Funding; Geron: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Galena BioPharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lilly Oncology: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; CTI BioPharma Corp: Research Funding.

Is Less More in Therapy for High-Risk MDS in the Elderly?

Is Less More in Therapy for High-Risk MDS in the Elderly?

Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase

Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1α (CK1α), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 Å crystal structure of DDB1-CRBN bound to lenalidomide and CK1α. CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin-loop located in the kinase N-lobe. We show that CK1α binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1α, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.