Emerging Treatment Options for Myelodysplastic Syndromes James K. Mangan, MD, PhD Assistant Professor of Clinical Medicine Abramson Cancer Center, University of Pennsylvania Please note that some of the studies reported in this presentation were presented as an abstract and/or presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
MDS Epidemiology and Diagnosis Diverse group of clonal hematopoietic stem or progenitor cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology, and potential for clonal evolution MDS is a malignancy. BMBx and aspirate necessary for diagnosis Must exclude non-mds causes of cytopenias in presence of some combination of dysplasia, increased marrow blasts, or karyotypic abnormality. 30,000 to 40,000 new cases per year in US
Table: Cytopenic and clonal states and their relationship to MDS. **CHIP: 10% of patients >70 have clonal mutations detectable at an allele frequency of > or = 2% David P. Steensma Blood 2015;126:2349-2351 2015 by American Society of Hematology
Mutation Interpretation in Cytopenic Patients WITHOUT extensive dysplasia, Excess blasts, or an MDS-defining karyotype FAVORS CHIP: FAVORS MDS: Single mutation Multiple mutations Low variant allele frequency (<10%) High variant allele frequency Minimal or no cytopenias Cytopenias, especially progressive Mutation in common CHIP-associated Mutation in genes more commonly genes such as TET2 or DNMT3A associated with MDS (ie U2AF1, p53)
61-year-old woman with no past medical history who suffered a fall at work. She had bruising out of proportion to her injuries and a CBC was drawn which showed pancytopenia. Her blood counts in the ER showed a white count of 2.8, hemoglobin 8.9, and platelets 32,000. Her ANC was around 1000. She underwent a bone marrow biopsy which revealed: normocellular marrow with trilineage hematopoiesis and relative megakaryocytic hypoplasia and relative erythroid predominance. A low grade myelodysplastic syndrome could be ruled out. Cytogenetics were normal. After several months, repeated a BMBx which does not show convincing evidence of MDS. No excess blasts, no molecular abnormalities, cytogenetics are normal. Blood counts have slowly improved over the last year.
IPSS-R (Blood 120:2454, 2012) www.ipss-r.com Improvements over IPSS: -DATA from 7000 MDS pts -5 cytogenetic risk groups (compared to 3) -Severity and type cytopenia taking into account -5 Risk groups; age accounted for -Validated to be effective in treated pts (AJH. 2013;88;566-570)(Blood. 2012; 120(25) 5084-5) -Correlates better with outcome (IPSS, WPSS) in one study Voso et al, J Clin Oncol 2013, MDS Gruppo, n=380
Prognosis: IPSS-R
Somatic mutation in any of the 5 genes (TP53, EZH2, RUNX1, ASLX1, or ETV6) shown in Bejar et al, NEJM 364, 2011 to have prognostic significance independent of the International Prognostic Scoring System (IPSS) identifies patients from that same cohort with shorter overall survival than predicted by the IPSS-R for the 3 lowest IPSS-R risk groups. Bejar R, and Steensma D P Blood 2014;124:2793-2803 2014 by American Society of Hematology
2015 by American Society of Hematology Rafael Bejar et al. Blood 2015;126:907
2014 by American Society of Hematology Bejar R et al. Blood 2014;124:532
MD Anderson scoring systems. Rafael Bejar Hematology 2013;2013:504-510 2013 by American Society of Hematology
Therapies for Lower Risk MDS ESAs: Work well in patients with low transfusion Requirements (<2 units PRBCs/month) and EPO level (<500): 74% response rate. Work poorly in patients with high transfusion Requirements and EPO >500: 7% response rate (Hellstrom- Lindberg et al, BJH 120, 2003). Also clearly inferior responses in higher risk disease.
Key Trials in Lower Risk MDS ECOG 2905: Lenalidomide versus Lenalidomide plus EPO for non-del 5q patients who had failed EPO alone Reduced dose Decitabine vs reduced dose Azacitadine in low or int-1 risk MDS
E2905: Erythroid Responses Outcome Intent to treat, n (%) (N = 163) MER Minor ER Overall ER Lenalidomide (n = 81) 9 (11.1) 15 (18.5) 24 (29.6) Lenalidomide + EA (n = 82) 21 (25.6) 13 (15.9) 34 (41.5) MER after crossover n = 34 7 (21) Wk 16 evaluable, n (%) (n = 117) MER Minor ER Overall ER 8 (14.3) 13 (23.1) 21 (37.5) 20 (32.8) 13 (21.3) 33 (54.1) Multivariate analysis did not identify significant effects of any other factors, including prior azanucleoside, baseline EPO < 500 mu/ml, or IPSS risk level P Value Median duration of MER, mos 13.0 25.4.37.025.68.14.029.83.09 List, AF, et al. ASH 2016. Abstract 223. Slide credit: clinicaloptions.com
E2905: Conclusions Investigators concluded that lenalidomide can restore EA sensitivity in lower-risk MDS pts refractory or unresponsive to ESAs Combination treatment well tolerated with no increased risk of thromboembolism Erythroid CD45 isoform profile is predictive of response to lenalidomide + EA May serve as biomarker to select treatment candidates List, AF, et al. ASH 2016. Abstract 223. Slide credit: clinicaloptions.com
Low-Dose HMAs in LR MDS: Study Design Adult pts with de novo or secondary IPSS low- or intermediate-1 risk MDS, including CMML, ECOG PS 3, adequate organ function, no prior HMA treatment (N = 113) Jabbour EJ, et al. ASH 2016. Abstract 226. ClinicalTrials.gov. NCT01720225. Decitabine 20 mg/m 2 IV Days 1-3 Q4W (n = 73) Azacitidine 75 mg/m 2 IV/SC Days 1-3 Q4W (n = 40) Open-label phase II study Randomized by Bayesian adaptive design; pts more likely to be assigned to better-performing treatment arm Median follow-up: 20 mos Primary endpoint: OIR defined as CR, PR, marrow CR, or hematologic improvement Response assessed by modified IWG 2006 criteria Secondary endpoints: safety, cytogenetic response, transfusion independence, EFS, OS Slide credit: clinicaloptions.com
Low-Dose HMAs in LR MDS: Conclusions Both low-dose HMAs showed activity, were well tolerated in adult pts with LR MDS and no prior HMA use [1] ORR: 60% 1-yr EFS: 65% 1-yr OS: 85% Significantly higher ORR (70% vs 49%; P =.03) reported with decitabine vs azacitidine; particularly among pts with 5% blasts (100% vs 36%; P <.001) Open-label, randomized phase II trial now ongoing to compare low-dose decitabine, low-dose azacitidine, azacitidine x 5 days, and best supportive care in a LR MDS pt population [2] 1. Jabbour EJ, et al. ASH 2016. Abstract 226. 2. ClinicalTrials.gov. NCT02269280. Slide credit: clinicaloptions.com
Luspatercept increases hemoglobin and reduces transfusion Burden in patients with low-intermediate risk MDS: Long- Term results from the Phase 2 PACE-MDS study ASH 2016, Abstract 3168, Platzbecker U et al. 32 patients, all with prior ESAs or high EPO levels. About 80% achieved transfusion independence for at least 8 weeks Drug is administered as a subcutaneous injection once per month Safe: myalgias, fatigue, bone pain common side effects Coming soon: MEDALIST STUDY: 2:1 randomization of luspatercept VS placebo. Open for patients with ringed sideroblasts, SF3B1 mutations
What about High Risk MDS?
Enasidenib in midh2 MDS: Background IDH2 gene mutated in approximately 5% of MDS pts [1] Critical for the citric acid cycle; mutant form can alter gene expression, block differentiation of hematopoietic progenitor cells midh2 produces 2-HG, an oncometabolite that blocks cellular differentiation by altering DNA methylation May represent a therapeutic target Enasidenib (AG-221): first-in-class, potent oral inhibitor of midh2 enzyme [2] Current analysis assessed efficacy, safety of enasidenib in MDS pts with midh2 [3] 1. Medeiros BC, et al. Leukemia. 2016;[Epub ahead of print]. 2. Chen J, et al. Mini Rev Med Chem. 2016;16:1344-1358. 3. Stein EM, et al. ASH 2016. Abstract 343. Slide credit: clinicaloptions.com
Enasidenib in midh2 MDS: Study Design Subset analysis of open-label phase I/II dose escalation/expansion study of enasidenib in hematologic malignancies with IDH2 mutation (N = 239) MDS pts with midh2 R/R RAEB-1/RAEB-2, IPSS-R high-risk disease, or ineligible for other treatment (n = 17) Oral daily enasidenib (50-650 mg in dose escalation; 100 mg in expansion) in continuous 28-day cycles Key endpoints: safety, tolerability, ORR per local investigator (IWG 2006 MDS criteria) Co-molecular profiling with next-generation sequencing Stein EM, et al. ASH 2016. Abstract 343. Slide credit: clinicaloptions.com
Enasidenib in midh2 MDS: Response Response, n/n (%) MDS Pts (N = 17) ORR* 10/17 (59) CR 1/11 (9) PR 1/11 (9) mcr 3/11 (27) Any HI Erythrocytes Platelets Neutrophils Trilineage improvement Bilineage improvement 5/17 (29) 3/15 (20) 4/12 (33) 4/10 (40) 2/5 (40) 2/5 (40) *CR + PR + mcr + HI. Investigator-assessed; pts had 5% BM blasts at BL. 7 of 13 pts (54%) with prior HMA responded to enasidenib Median time to response: 21 days (range: 10-87) Median OS not yet reached with median follow-up of 7.5 mos Stein EM, et al. ASH 2016. Abstract 343. Slide credit: clinicaloptions.com
Enasidenib in midh2 MDS: Conclusions Daily oral enasidenib monotherapy well tolerated in small cohort of pts with midh2 MDS, including many with higher-risk disease 10 of 17 pts showed clinical response, including 7 who failed prior HMA treatment Only 2 pts experienced progressive disease on therapy Investigators suggest that preliminary mutational testing of IDH2 may identify MDS pt subset likely to benefit from enasidenib therapy Stein EM, et al. ASH 2016. Abstract 343. Slide credit: clinicaloptions.com
NIVO or IPI ± AZA in MDS: Study Design Open-label, nonrandomized phase II study with 6 treatment cohorts Pts aged 18 yrs or older with WHO MDS; ECOG PS 2; adequate organ function; no prior tx, or HMA failure*; no history of inflammatory or autoimmune disease or HIV; no active HCV infection (N = 54) HMA Failure Cohorts Tx-Naive Cohorts Cohort #1 Nivolumab 3 mg/kg IV Q2W (n = 15) Cohort #2 Ipilimumab 3 mg/kg IV Q3W (n = 18) *Last HMA cycle within 4 mos; no other tx after HMA. AZA added if no response or progression after 6 cycles Endpoints: ORR, safety Garcia-Manero G, et al. ASH 2016. Abstract 344. Cohort #3 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 3 mg/kg IV Q4W Cohort #4 Azacitidine 75 mg/m 2 IV x 5d Q4W + Nivolumab 3 mg/kg IV D6, D20 (n = 21) Available for current analysis Not included in current analysis Cohort #5 Azacitidine 75 mg/m 2 IV x 5d Q4W + Ipilimumab 3 mg/kg IV D6 Cohort #6 Azacitidine 75 mg/m 2 IV x 5d Q4W + Nivolumab 3 mg/kg IV D6, D20 + Ipilimumab 3 mg/kg IV D6 Slide credit: clinicaloptions.com
NIVO or IPI ± AZA in MDS: Conclusions Early results with short follow-up (median 3 cycles) suggest nivolumab and ipilimumab well tolerated as single-agent or with azacitidine 30% ORR with ipilimumab in pts who failed HMA therapy shows promising single-agent activity as salvage therapy Nivolumab did not show single-agent activity as salvage therapy Encouraging early 65% ORR when combined with azacitidine in previously untreated pts Additional treatment cohorts ongoing Investigators suggest that future randomized trials are warranted Garcia-Manero G, et al. ASH 2016. Abstract 344. Slide credit: clinicaloptions.com
Rigosertib in MDS after HMA failure Large Randomized Phase II of Rigosertib versus Placebo: OS 8.2 months with rigosertib and 5.8 months for placebo, p =.27 (Raza et al, abstract 7031, ASCO 2013). Phase II oral rigosertib trial presented at ASH 2016: Navada et al, abstract 3167). There was 62% ORR after failure of HMA. Phase III trial of IV rigosertib currently open to accrual at Penn
AGENTS AFTER HMA FAILURE Guadecitabine (modification of decitabine designed to increase exposure): phase II trial of IPSS int-2 or high risk MDS (Montalban-Bravo G, ASH 2016, Abstract 346). 40 patients: 28% achieved CR, 23% achieved CR with incomplete count recovery, and 10% achieved hematologic improvement for an ORR of 61%. French phase II after HMA failure was not particularly promising but phase III is planned for HMA failure. Phase III is ongoing.
Clinical Trials for MDS Open at Penn Phase 2 study of tipifarnib in CMML (coming soon) (farnesyltransferase inhibitor, inhibits Ras pathway) Pilot study of Exjade as monotherapy in high risk MDS or AML SGN-33A (vadatuximab talirine) in combination with Vidaza in untreated int-2 or high risk MDS Rigosertib versus physician s choice after failure of a HMA Oral azacitadine alone and in combination with durvalumab (PD-L1 inhibitor) in MDS after HMA failure.
Clinical Trials for MDS Open at Penn BMT-CTN 1102: Hypomethylating agent/best supportive care versus reduced intensity conditioning allo SCT for MDS ages 50-75 IPSS 1.5 or greater. *Observational only *Biological randomization based on presence or absence of matched sibling or 10/10 unrelated donor.