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Recent advances in mds
 

Recent advances in mds

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  • MDS, myelodysplastic syndromes; WHO, World Health Organization.
  • ANC, absolute neutrophil count; Hb, hemoglobin; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes.
  • CCR,c omplete cytogenetic response; Hb, hemoglobin; TI, transfusion independence.
  • AZA, azacitidine; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FAB, French-American-British classification; IWG 2000 HI, International Working Group 2000 hematologic improvement.
  • FDA, US Food and Drug Administration; Int, intermediate; MDS, myelodysplastic syndromes.
  • AML, acute myeloid leukemia; BSC, best supportive care; CCR, conventional care regimens; FAB, French-American-British classification; Int, intermediate; IPSS, International Prognostic Scoring System; LDAC, low-dose Ara-C; RAEB, refractory anemia with excess blasts; RAEB-T; refractory anemia with excess blasts in transformation; SC, subcutaneous.
  • CCR, conventional care regimens.
  • EORTC, European Organisation for Research and Treatment of Cancer; HI, hematologic improvement; Int, intermediate; IPSS, international Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndromes; q8h, every 8 hours; q6w, every 6 weeks
  • AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; HMA, hypomethylating agent; MDS, myelodysplastic syndromes.
  • CMML-2, chronic myelomonocytic leukemia-2; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; RAEB, refractory anemia with excess blasts. 
  • AE, adverse event; AML, acute myeloid leukemia; FN, febrile neutropenia; MDS, myelodysplastic syndromes. 
  • AZA, azacitidine; CALGB, Cancer and Leukemia Group B; CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; IWG Working Group; NCIC, National Cancer Institute of Canada; SWOG Southwest Oncology Group.

Recent advances in mds Recent advances in mds Presentation Transcript

  • RECENT ADVANCES IN MDS DR. R. RAJKUMAR M.D. , D.M CONSULTANT MEDICAL ONCOLOGIST GURU HOSPITAL
  • AGENDA  New biological developments  Risk assessment and prognostic factors  New therapeutic options
  • MYELODYSPLASTIC SYNDROMES  A group of malignant hematopoietic disorders characterized by[1] – Bone marrow failure with resultant cytopenia and related complications – Macrocytic anemia is most common presentation – Dysplastic cytologic morphology is the hallmark of the disease – Tendency to progress to AML  Overall incidence 3.7-4.8/100,000[2] – ≈ 10,000/yr in United States (true estimates ≈ 37,000-48,000) – Median age: 70 yrs; incidence: 34-47/100,000 > 75 yrs[3] 1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York NY: Churchill Livingstone; 2004. pp. 2849-2881. 2. SEER data 2000-2009. 3. SEER 18 Data. 2000-2009.
  • MDS EPIDEMIOLOGY  Overall incidence: 4.4 per 100,000 49.8 50 Overall 40 Males Females 27.1 30 20 9.2 10 0.2 0 0.8 < 40 40-49 2.5 50-59 60-69 Age at Diagnosis (Yrs) 70-79 ≥ 80 SEER Cancer Statistics Review 1975-2008. Section 30, myelodysplastic syndromes (MDS), chronic myeloproliferative disorders (CMD), and chronic myelomonocytic leukemia (CMML).
  • DIAGNOSIS OF MDS  The most common presentation is cytopenia  Diagnosis requires – Peripheral blood examination – Bone marrow aspirate and biopsy – Cytogenetic studies  The diagnosis requires demonstration of dysplastic features in 1 or more cell line Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York, NY: Churchill Livingstone; 2004. pp. 2849-2881.
  • WHO Revisions 2008: MDS Cytogenetic Minimal Criteria  Presence of refractory cytopenia without morphologic features and the following cytogenetic abnormalities considered ―presumptive evidence‖ of MDS Unbalanced Balanced Other -7 or del(7q) t(11;16)(q23;p13.3) -5 or del(5q) t(3;21)(q26.2;q22.1) i(17q) or t(17p) t(1;3)(p36.3;q21.1) Complex karyotype (≥ 3 abnormalities either balanced or unbalanced) -13 or del(13q) del(11q) del(12p) or t(12p) del(9q) t(2;11)(p21;q23) inv(3)(q21q26.2) t(6;9)(p23;q34) idic(X)(q13) Vardiman JW, et al. Blood. 2009;114:937-951.
  • IPSS Is Most Common Tool for Risk Stratification of MDS Score Value Prognostic variable 0 0.5 1.0 1.5 2.0 Bone marrow blasts < 5% 5% to 10% -- 11% to 20% 21% to 30% Karyotype* Good Intermediate Poor -- -- Cytopenias† 0/1 2/3 -- -- -- Total Score 0 0.5 1.0 1.5 2.0 2.5 Risk Low Intermediate I Intermediate II High Median survival, yrs 5.7 3.5 1.2 0.4 *Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities; poor = complex ( 3 abnormalities) or chromosome 7 abnormalities. †Hb < 10 g/dL; ANC < 1800/ L; platelets < 100,000/ L. Greenberg P, et al. Blood. 1997;89:2079-2088.
  • Revised IPSS MDS Cytogenetic Scoring System Cytogenetic Abnormalities Median Survival,* Yrs Median AML Evolution, 25%,* Yrs HR OS/AML* HR OS/AML† -Y, del(11q) 5.4 NR 0.7/0.4 0.5/0.5 Good (72%*/66%†) Normal, del(5q), del(12p), del(20q), double including del(5q) 4.8 9.4 1/1 1/1 Intermediate (13%*/19%†) del(7q), +8, +19, i(17q), any other single or double independent clones 2.7 2.5 1.5/1.8 1.6/2.2 Poor (4%*/5%†) -7, inv(3)/t(3q)/del(3q), double including 7/del(7q), complex: 3 abnormalities 1.5 1.7 2.3/2.3 2.6/3.4 Very poor (7%*/7%†) Complex: >3 abnormalities 0.7 0.7 3.8/3.6 4.2/4.9 Prognostic Subgroups, % Very good (4%*/3%†) *Data from patients in this IWG-PM database, multivariate analysis (n = 7012). †Data from Schanz, et al (n = 2754). Greenberg PL, et al. Blood. 2012;120:2454-2465.
  • Revised IPSS: Prognostic Score Values and Risk Categories/Scores Score Value Prognostic Variable 0 0.5 Cytogenetics Very good -- BM blast, % ≤2 -- Hemoglobin, g/dL ≥ 10 -- ≥ 100 50 to < 100 ≥ 0.8 < 0.8 Platelets, x 109/L 1.0 Good > 2 to < 5 8 to < 10 < 50 1.5 2.0 3.0 4.0 Intermediate Poor Very poor 5-10 > 10 Risk <8 ___ ___ Score ___ Very low ___ ___ ≤ ___ 1.5 ___ --- -- Greenberg PL, et al. Blood. 2012;120:2454-2465. ___ ___ Intermediate > ___ to 4.5 3.0 ___ > 4.5 to 6.0 Very high -- > 1.5 to 3 High ANC, x 109/L Low >6
  • Revised IPSS: Survival by Risk Category Very low Low Intermediate High Very high Proportion of Patients Alive 1.0 0.8 0.6 Median Survival, years (95% CI) 0.4 8.8 (7.8-9.9) 0.2 5.3 (5.1-5.7) 0 3.0 (2.7-3.3) 1.6 (1.5-1.7) 0.8 (0.7-0.8) 0 2 4 Greenberg PL, et al. Blood. 2012;120:2454-2465. 6 8 10 12
  • Topic 2: Treatment Options for Lower-Risk MDS
  • MDS-003: Lenalidomide in MDS With 5q Deletion Study Design Eligibility  IPSS diagnosed low/int 1 MDS  del(5q31)  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Wk R E G I S T E R 0 R E S P O N S E Lenalidomide 10 mg/day PO Lenalidomide 10 mg PO x 21 days 4 8 12 16 20 Yes No Continue Off study 24  Primary endpoint: transfusion independence  Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety List AF, et al. N Engl J Med. 2006;355:1456-1465.
  • MDS-003: Response to Lenalidomide Therapy Response (%) 80 Erythroid Response 99/148 (67%) 112/148 (76%) 100 Cytogenetic Response  Median Hb increase: 5.4 g/dL 62/85 80  Time to response: 4.6 wks (73%)  Duration of response: > 2 yrs Response (%) 100 70 40 70 38/85 (45%) 40 20 20 0 0 TI TI + Minor List AF, et al. N Engl J Med. 2006;355:1456-1465. CCR CCR + PR
  • MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS Eligibility  IPSS diagnosed low/int-1 MDS w/o del(5q) abnormality  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Wk R E G I S T E R 0 R E S P O N S E Lenalidomide 10 mg/day PO Lenalidomide 10 mg PO x 21 days 4 8 12 16 20  Primary endpoint: TI, Hb response  Secondary endpoints: cytogenetic response, safety Raza A, et al. Blood. 2008;111:86-93. 24 Yes No Continue Off study Dose reduction 5 mg QD 5 mg QOD
  • MDS-002: Response to Lenalidomide Therapy Erythroid Response Response (%) Cytogenetic Response  Median Hb increase: 3.2 g/dL  Time to response: 4.8 wks 80  Median duration of response: 41 wks 80 70 40 100 93/214 (43%) 56/214 (26%) Response (%) 100 70 40 20 20 0 0 TI TI + Minor Raza A, et al. Blood. 2008;111:86-93. 4/47 (9%) CCR 9/47 (19%) CCR + PR
  • Azacitidine Treatment for Low- or Intermediate 1–Risk MDS  Pyrimidine nucleoside analogue of cytidine  Approved for use in MDS of the following subtypes – Refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions) – Refractory anemia with excess blasts – Refractory anemia with excess blasts in transformation – Chromic myelomonocytic leukemia  Causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow
  • Randomized Phase II Study of Alternative Azacitidine Dose Schedules Study Design (N = 151) 5-2-2: 75 mg/m2 Eligibility  All FAB  Cytopenia  ECOG PS: 0-3 (n = 50) x6 5-2-5: 50 mg/m2 (n = 51) 5: 75 mg/m2 (n = 50) Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. IWG 2000 HI 12 Cycles AZA x 5 days q4-6 wks
  • Topic 3: Treatment Options for High-Risk MDS
  • Treatment Algorithm 2013: Intermediate 2–/High-Risk MDS Favorable SCT Allogeneic donor Unfavorable SCT candidate No donor Azanucleosides Investigational Field T, et al. Mediterr J Hematol Infect Dis. 2010;2:e2010019. Adapted from NCCN. Clinical practice guidelines in oncology. MDS. v.2.2013.
  • Approximate Life Expectancy After Ablative Allogeneic Transplantation Risk Group, Yrs Low Int 1 Int 2 High Transplantation at Diagnosis 6.51 4.61 4.93 3.20 Transplantation at Yr 2 6.86 4.74 3.21 2.75 Transplantation at Progression 7.21 5.16 2.84 2.75  Median age: 42 yrs  Data precede all FDA-approved drugs for MDS Cutler C, et al. Blood. 2004;104:579-585.
  • Pre-Transplantation Chemotherapy as a Bridge to Transplantation  Retrospective data[1,2] – No benefit from induction chemotherapy prior to transplantation – No survival benefit from azacitidine over chemotherapy prior to transplantation – Caveats: 1) data from 1990s, 2) retrospective, 3) poor description of chemotherapies used – Improved survival in those achieving CR before transplantation  Feasibility data[3-5] – Feasible to give azacitidine or decitabine before transplantation – Rapid donor cell engraftment  Prospective clinical trials needed 1. Nakai K, et al. Leukemia. 2005;19:396-401. 2. Damaj G, et al. J Clin Oncol. 2012;30:4533-4540. 3. De Padua Silva L, et al. Bone Marrow Transplant. 2009;43:839-843. 4. Cogle CR, et al. Clin Adv Hematol Oncol. 2010;8:40-46. 5. Field T, et al. Bone Marrow Transplant. 2010;45:255-260.
  • AZA-001: Trial Design Physician choice of 1 of 3 CCRs 1. BSC only 2. LDAC (20 mg/m2/day SC x 14 day q28-42 days) 3. 7 + 3 chemotherapy (induction + 1-2 consolidation cycles) Stratified by  FAB: RAEB, RAEB-T  IPSS: int 2, high Azacitidine + BSC R A N D O M I Z E (75 mg/m2/day x 7 days SC q28 days) CCR Treatment continued until unacceptable toxicity or AML transformation or disease progression Fenaux P, et al. Lancet Oncol. 2009;10:223-232. (n = 179) (n = 179)
  • Proportion Surviving AZA-001 Trial: Azacitidine Significantly Improves OS HR: 0.58 (95% CI: 0.43-0.77; log-rank P = .0001) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 24.5 mos 15.0 mos Azacitidine CCR 0 5 10 15 20 25 30 Mos From Randomization Fenaux P, et al. Lancet Oncol. 2009;10:223-232. 35 40
  • EORTC-06011 Decitabine Phase III Trial: Study Design  Open-label, multicenter, 1:1 randomized study  IPSS: int-1, -2, and high-risk MDS; ≥ 60 yrs (n = 223)  Primary endpoint: survival Stratification  Cytogenics risk group  IPSS  Primary vs secondary  Study center R A N D O M I Z E 20 mg/m2/day IV recommended in PI Decitabine 15 mg/m2 IV x 4 hrs q8h x 3 days q6w (max 8 cycles) (n = 119) Best Supportive Care (n = 114) Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cycles Exception: CR—2 additional cycles. Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.
  • EORTC-06011: OS With Decitabine Treatment 1.0 BSC Decitabine Log-rank test P = .38 OS (%) 80 60 40 20 0 0 Pts at Risk, n BSC Decitabine 6 12 18 Mos 24 30 71 83 38 53 22 24 10 15 6 4 Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996. 36
  • Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies Type of Salvage Investigational OS (%) 25 0 0 165 NA 3.6 122 NA 4.1 Low-dose chemotherapy 32 0/18 7.3 Intensive chemotherapy 35 3/22 8.9* 44 4/36 13.2*† Allogeneic transplantation 50 Median OS, Mos Investigational therapy Allo-SCT ORR Best supportive care 75 N Unknown 100 37 13/19 19.5*† 365 730 1095 1460 Days Since AZA Failure *Log-rank comparison of BSC vs intensive CT (P = .04), investigational therapy (P < .001), or alloSCT (P < .001). †Comparison of intensive CT vs investigational therapy (P = .05), intensive CT vs ASCT (P = .008), or IT vs ASCT (P = .09). Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.
  • Selected Novel Agents Under Investigation Agent Patient Population Response Higher-risk MDS (n = 58) ORR: IV-15 41%; IV-30 29% Median OS with response: 13.4 mos Median OS: 7.4 mos MDS, CMML, AML (n = 41) ORR (previous treated): 35% (6/17) ORR (tx naive): 73% (11/15) MDS (n = 60) HMA failure (n = 39) 31% (16/51) ≥ 50% blast decrease Median OS with response: 11 mos Sapcitabine[4] Phase I refractory AML/MDS (n = 47) Objective Response: 28% Erlotinib[5] HMA failure higher-risk MDS (n = 35) ORR (evaluable): 19% (5/26) Median OS with response: 16.8 mos Median OS: 6.8 mos Clofarabine[1] Oral azacitidine[2] Rigosertib[3] Dasatinib[6] HMA failure higher-risk MDS, ORR: 16.7% CMML, AML (n = 18) 1. Faderl S, et. al. Cancer. 2012;118:722-728. 2. Garcia-Manero G, et al. J Clin Oncol. 2011;29:2521-2527. 3. Raza, et al. ASH 2011. Abstract 3822. 4. Kantarjian H, et al. J Clin Oncol. 2010;28:285-291. 5. Komrokji R, et al. ASH 2011. Abstract 1714. 6. Vu D, et al. Leuk Res. 2013;37:300-304.
  • Combination Therapy: Lenalidomide + Azacitidine in Higher-Risk MDS  Multicenter, single-arm open-label phase II continuation study (N = 36)  Patient eligibility – Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high (score ≥ 1.5), or revised IPSS score 4 or 5 – No previous treatment with lenalidomide or azacitidine  Maximum of seven 28-day treatment cycles administered – Lenalidomide 10 mg on Days 1-21 – Azacitidine 75 mg/m2 on Days 1-5 – After 7 cycles, patients could continue azacitidine monotherapy off study  Median patient follow-up: 12 mos (range: 3-55) Sekeres MA, et al. Blood. 2012;120:4945-4951.
  • Lenalidomide + Azacitidine in Patients With Higher-Risk MDS: Results  Median CR duration: 17+ mos (range: 3-39+) 100 CR Hematologic improvement Response Rate (%) 90 80  Median OS among CR: 37+ mos (range: 7-55+) 70 60 28 50 40 30 20 44 10 0 Lenalidomide/ Azacitidine (N = 36) Sekeres MA, et al. Blood. 2012;120:4945-4951.  8 patients evolved to AML at median of 18 mos after CR  Treatment well tolerated; FN was most common grade 3/4 AE (22%)  Randomized trial planned to compare azacitidine vs lenalidomide/azacitidine vs azacitidine/vorinostat in higherrisk MDS
  • SWOG-S1117: North American Intergroup Randomized Phase II MDS/CMML Trial AZA (n = 80) Higher-risk MDS (IPSS > 1.5 or blasts > 5%) AZA + Lenalidomide (n = 80) AZA + Vorinostat (n = 80) Clinicaltrials.gov. NCT01522976 Groups: SWOG, ECOG,CALGB, NCIC Total sample size: 240 Primary objective: 20% improvement of RR based on 2006 IWG Criteria Secondary objectives: OS, RFS, LFS Power 81%, alpha 0.05 for each combo arm vs AZA Anticipated time: 2.5 yrs