MDS overview 전남대학교김여경

MDS overview 전남대학교김여경

2008 WHO Classification of MDS Name Abbreviation Key Feature Pts, % Refractory cytopenia, with unlineage, dysplasia Refractory anemia with ring sideroblasts RA Anemia and erythroid dysplasia 10 RN Neutropenia and granulocytic dysplasia < 1 RT Thrombocytopenia and megak. dysplasia < 1 RARS 15% ring sideroblasts 5 5q- syndrome del(5q) Isolated 5q31 deletion, anemia, hypolobated megakaryocytes Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts, type 1 Refractory anemia with excess blasts, type 2 RCMD Multilineage dysplasia with > 1 cytopenia With or without ring sideroblasts RAEB-1 5% to 9% blasts 20 RAEB-2 10% to 19% blasts ± Auer rods 20 Unclassifiable MDS-U Does not fit other categories 10 Childhood MDS RCC Often hypocellular; pancytopenia Rare 5 20

Case 2000 Isolated thrombocytopenia BM: Dx: Tx: Normocellular marrow, 46, XY ITP corticosteroid, splenectomy 2009 Isolated thrombocytopenia 지속 6,000 /ul (4,200/uL), 13.4 g/dl, 2,000/uL, LDH 600 IU/L Spleen scan: asplenia (+) PBS: H-J body (+) 다음단계의검사혹은치료는? 1. Danazol 2. Cyclosporin 3. Rituximab 4. Eltrombopag / Romiplostim 5. BM reexamination

Diagnosis 10~20% : hypocellular marrow (+) 60 세미만환자 : <30%, 60 세이상환자 : <20% 형태학적이상만으로골수형성이상증후군을확진하기어려울때 : 핵형이상을확인. 처음부터진단이어려운경우 : 수개월간의간격을두고반복적으로세포유전학검사를포함하여골수생검을시행. 이형성혹은세포유전학적이상이없는경우이나지속적으로말초혈액혈구감소증이있는경우 : 주기적으로말초혈구검사및세포유전학검사를포함한골수생검을추적검사.

Differential Diagnosis 골수내이형성증이반드시클론성질환이라는증거는되지않기때 문에진단전골수이형성증을유발할수있는다른원인들에대한확 인이반드시필요 Vit. B12, folate def. Toxic agents : As, alcohol, chemotherpeutic agents, 조혈촉진인자치료병력 감염 : HIV, parvovirus B19 선천성적혈구이형성빈혈 Paroxysmal nocturnal hemoglobinuria (PNH)

Case 2009 Isolated thrombocytopenia BM: Blast 2%, Megakaryocytes dysplasia, Cellularity 70%, 46, XY Dx: ITP, R/O MDS, RT 치료는? (1) Danazol (2) Cyclosporin (3) Rituximab (4) Eltrombopag / Romiplostim (5) Azacitidine

Romiplostim in LR-MDS Some pts: increase in the blast proportion!! 1. Kantarjian HM, et al. Blood. 2010;116:3163-3170. 2. Lyons et al. ASH 2009. Abstract 1770. 3. Kantarjian HM, et al. J Clin Oncol. 2010;28:437-444.

Case 2011. 4,000 /ul (1,600/uL), 8.0 g/dl, 1,000/uL BM: blast 7.2%, cellularity 92-95%, 47,XY,+8 Dx: MDS, RAEB-1 치료는? (1) Darbepoietin (2) ATG / Cycloporin (3) Lenalidomide (4) Azacitidine / Decitabine (5) Allo SCT

Case 2011. 4,000 /ul (1,600/uL), 8.0 g/dl, 1,000/uL BM: blast 7.2%, cellularity 92-95%, 47,XY,+8 Dx: MDS, RAEB-1 Tx: decitabine 4 cycles and allo SCT 2012. Relapse Pending state of AML Tx: RI induction chemotx and allo SCT

International Prognostic Scoring system (IPSS) 1997 Score value Variable 0 0.5 1 1.5 2 Marrow blasts (%) < 5 5~10 11~20 21~30 Karyotype* Good Intermediate Poor Cytotpenia** 0, 1 2, 3 *Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex ( 3 abnormalities) or chromosome 7 anomalies; Intermediate = other **Neutrophil < 1,800/uL, platelets < 100,000/uL, Hb < 10 g/dl Risk category Overall score Median survival (y) 25% AML progression (y) Low 0 5.7 9.4 Intermediate-1 0.5~1.0 3.5 3.3 Intermediate-2 1.5~2.0 1.1 1.1 HIgh 2.5 0.4 0.2 Greenberg P, et al. Blood. 1997;89:2079-2089; correction: 1998;91:1100.

Limitations of IPSS Not validated in numerous patient subsets Secondary MDS CMML with WBC > 12 x 10 9 /L Previously treated patients Children Limited number of karyotypes Only 3 categories Many common karyotypes omitted Does not account for molecular heterogeneity Omits validated prognostically relevant information LDH Mutations (eg, TP53, TET2) Performance score Marrow fibrosis, ALIP Absolute lymphocyte count

WHO-based Prognostic Scoring System (WPSS) Variable Scores 0 1 2 3 WHO category RCUD, RARS, RCMD RAEB-1 RAEB-2 MDS with isolated del(5q) Karyotype* Good Intermediate Poor Severe anemia Absent Present (Hb < 9 g/dl, male; < 8g/dL, female) *Good = normal, -Y alone, del(5q) alone, del(20q) alone; poor = complex ( 3 abnorm alities) or chromosome 7 anomalies; Intermediate = other WPSS risk Sum of individual variable scores Very low 0 Low 1 Intermediate 2 High 3~4 Very high 5~6

Revised International Prognostic Scoring system (IPSS-R) 2012 Score value Variable 0 0.5 1 1.5 2 3 4 Cytogenetics* Very good Good Intermediate Poor Very poor Marrow blasts (%) 2 > 2~< 5 5~10 > 10 Hemoglobin (g/dl) 10 8~<10 < 8 Platelets (x 10 9 /L) 100 50~< 100 < 50 ANC (x 10 9 /L) 0.8 < 0.8 1. New marrow blast categories 2. Refined cytogenetic abnormalities & risk groups : 16 (vs. 6) specific abnormalities, 5 (vs 3) subgroups 3. Evaluation of depth of cytopenias : clinically & statistically relevant cut-points used 4. Inclusion of differentiating features (for survival) : Age, PS, s-ferritin, LDH, B2-mg (provisional) 5. Prognostic model with 5 (vs 4) risk categories : improved predictive power Schanz J, et al. J Clin Oncol. 2012;30:820-829.

IPSS-R: Cytogenetic scoring & risk group Subgroup Cytogenetics OS AML evolution yrs 25%, yrs Very good -Y, del(11q) 5.4 NR Good normal, del(5q), del(12p), del(20q), 4.8 9.4 double including del(5q) Intermediate del(7q), +8, +19, i(17q), 2.7 2.5 any other single or double independent clones Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q) 1.5 1.7 complex (3 abnormalities) Very poor complex (> 3 abnormalities) 0.7 0.7 IPSS-R Overall score Median 25% AML risk category survival (y) progression (y) Very low 1.5 8.8 not reached Low > 1.5 ~ 3 5.3 10.8 Intermediate > 3 ~ 4.5 3 3.2 High > 4.5 ~ 6 1.6 1.4 Very high > 6 0.8 0.7 Greenberg P, et al. Blood. 2012 in press

IPSS-R Survival related to Age Formula to generate the age-adjusted risk score in the figure: (yrs - 70) x [0.05 (IPSS-R risk score x 0.005)] Greenberg P, et al. Blood. 2012 in press

http://www.ipss-r.com/ IPSS-R calculator

Fraction Survival Fraction AML-Free Survival IPSS-R and MDS outcome OS Transformation to AML 1.0 Very good (n = 81; events: 34) Good (n = 1809; events: 890) Intermediate (n = 529; events: 312) Poor (n = 148; events: 109) Very poor (n = 187; events: 158) 1.0 Very good (n = 72; events: 6) Good (n = 1611; events: 284) Intermediate (n = 457; events: 145) Poor (n = 129; events: 56) Very poor (n = 167; events: 47) 0.8 Log-rank P <.001 0.8 Log-rank P <.001 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 50 100 150 200 250 300 350 0 50 100 150 200 250 300 350 Mos Mos Schanz J, et al. J Clin Oncol. 2012;30:820-829.

Goals of MDS Therapy Select best treatment -Response according to predictive variables -Consider type and severity of cytopenia(s), age, and possible comorbidities LR-risk -Improve blood counts, quality of life; decrease infections -Decrease transfusion requirement, potentially improve survival HR-risk -Prolong survival, delay progression to AML Cheson BD, et al. Blood. 2000;96:3671-3674

Treatment: LR-MDS NCCN Clinical Practice Guidelines ver 2. 2014

Treatment: LR-MDS NCCN Clinical Practice Guidelines ver 2. 2014

Treatment: HR-MDS NCCN Clinical Practice Guidelines ver 2. 2014

GESMD Therapeutic algorithm for LR-MDS Grupo Espanol de Sindromes Mielodisplasicos (GESMD) Sanz GF, 2013 EHA

GESMD Therapeutic algorithm for HR-MDS Sanz GF, 2013 EHA

Predictive variables for ESA response in MDS Biological Clinical Endogeneous EPO levels < 500 U/L Marrow blast < 10% IPSS low, Int-1 Diagnosis of RA Normal karyotype Transfusion independence Short duration of Disease Santini, et al. The Oncologist 2011;16:35-42

IST of LR-MDS predictors of response Age < 60 yrs Normal karyotype Hypoplastic marrow HLA-DRB1-15 Ag Molldren 2002, Sauntaragiah 2002, 2003, Lim 2007, Sloand 2008

Phase III EPIC Trial: Mean Deferasirox Dose & Median Change in s-ferritin Cappellini MD, et Cappellini al. Haematologica. MD, et al. Haematologica. 2010;95:557-566

Deferasirox in Transfusion-Dependent MDS (Prospective Study): Results Improvement in serum ferritin levels from baseline (-264 ng/ml) Deferasirox associated with 15% probability of achieving transfusion independence Caveat: only 45% of patients completed planned 1 yr of treatment Toxicity profile consistent with previous studies : 70% experienced toxicity (27% grade 3) Angelucci E, et al. ASH 2012. Abstract 425.

AZA-001: Trial Design Physician choice of 1 of 3 CCRs 1. BSC only 2. LDAC (20 mg/m 2 /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 R A N D O M I Z E Azacitidine + BSC (75 mg/m 2 /day x 7 days SC q28 days) CCR (Conventional care) (n = 179) (n = 179) Treatment continued until unacceptable toxicity or AML transformation or disease progression Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

Proportion Surviving AZA-001 Trial: Azacitidine Significantly Improves OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 15.0 mos HR: 0.58 (95% CI: 0.43-0.77; log-rank P =.0001) 24.5 mos CCR 5 10 15 20 25 30 35 40 Mos From Randomization Azacitidine Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

Decitabine Phase III MDS Trial: Study Design Open-label, multicenter, 1:1 randomized study IPSS: int-1, int-2, and high-risk MDS patients eligible Primary endpoints: response, time to AML/death IWG response criteria utilized for assessment Eligible patients (N = 170) R A N D O M I Z E D Stratification IPSS Type of MDS (primary or secondary) Decitabine + Supportive Care 15 mg/m 2 / over 3 hrs q8h x 3 days q6w (n = 89) Supportive Care ABX, GFs, and/or transfusions (n = 81) Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Decitabine Phase III Trial: Response to Decitabine (ITT) *For patients with a confirmed date of progression. Best response observed after 2 cycles (median number of cycles = 3) Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Phase III EORTC 06011: LD Decitabine vs BSC in Elderly, Int- or High-Risk MDS 3-day inpatient schedule Stratified by IPSS score, primary vs secondary disease, cytogenetic risk, study center Stop at 2 cycles beyond CR or max of 8 cycles Patients with intermediate- or hi gh-risk MDS or CMML, 60 yrs of age or older, 11% to 20 % blasts or < 11% with poor cyto genetics or 21% to 30% with stab le disease for 1 mo (N = 233) Decitabine 15 mg/m 2 IV over 4 hrs q8h x 9 q6w (n = 119) Best Supportive Care (n = 114) Primary endpoint: OS Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Phase III Study of LD Decitabine vs BSC in Elderly, Int- or High-Risk MDS: Results Median cycles of decitabine: 4 2 cycles: 38% Compare with a median of 9 cycles in AZA-001 study Responses in treatment arm (IWG 2000 criteria): 34% 13% CR, 6% PR, 15% HI Median time to best response: 3.8 mos Median time to CR: 5.8 mos; PR: 2.9 mos; HI: 3.8 mos Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Overall Survival: EORTC-06011 100 90 80 70 60 50 40 30 20 10 No difference in median OS: 10.1 mos for decitabine vs 8.5 mos for supportive care (P =.38) Supportive care Decitabine Median (mos): 10.1 vs 8.5 HR: 0.88 (95% CI: 0.66-1.17; log rank P =.3 8) 0 0 6 12 18 24 30 36 42 Mos O N Patients at Risk, n 96 114 71 38 22 10 6 3 99 119 83 53 24 15 4 4 Wijermans P, et al. ASH 2008. Abstract 226.

Progression-Free Survival: EORTC-06011 100 90 80 70 60 50 40 30 20 10 Supportive care No difference in progression to AML: 8.8 mos for decitabine vs 6.1 mos for supportive care (P =.24) Decitabine Modestly but significantly improved median PFS (including higher-risk MDS) : 6.6 mos for decitabine vs 3.0 mos for supportive care (P =.004) 0 0 6 12 18 24 30 36 Mos O N Patients at Risk, n 105 114 33 15 7 3 1 113 119 62 32 11 2 0 Wijermans P, et al. ASH 2008. Abstract 226.

LD-Decitabine & OS in elderly MDS Not optimal decitabine schedule (3-day inpatient vs 5-day outpatient treatment) Small numbers of cycles 40% received 2 cycles or less Median of 4 cycles vs 9 cycles in AZA-001 Higher-risk patient group Control arm lived median of 15 mos in AZA-001 vs 8.5 mos in EORTC study Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Hypomethylating Agents Relative merits of azacitidine vs decitabine Role for 1 hypomethylating agent when the other has failed Is there a survival advantage when decitabine is administered using current c ommon practice (ie, 5-day regimen, more cycles)? Optimal dose/schedule What to do once patient achieves CR (ie, maintenance dosing question; need for maintenance seems to be established) What to do in patients without a response Molecular predictors of response Use in combination therapies Actual mechanism of action

Predictive factors for response to hypomethylaing agents Clinical Positive Negative Doubling platelets BM blasts > 15% Previous therapy Transfusion dependency Marrow fibrosis gr 3 Molecular Positive Negative Mutated TET2 Mutated p53 Mutated DNMT3a Abnormal/complex karyotype Mutated IDH1/2 Mutated ASXL1 Mutated EZH2 Santini V. 2012 ASH

TET2 mutations & response to azacitidine Itzykson et al. Leukemia 2011

Mutational status in LR-MDS Bejar et al. JCO 2012

IPSS-R in Azacitidine-Treated MDS Retrospective study of 265 patients with intermediate-2- or high-risk MDS treated in French tertiary care centers AZA prognostic scoring system (reported previously by GFM): low risk = 0, intermediate risk = 1-3, high risk = 4-5 R-IPSS used to examine response to azacitidine and OS GFM: Groupe Francais des Myelodysplasies Ades L, et al. ASH 2012. Abstract 422.

IPSS-R in Azacitidine-Treated MDS R-IPSS strongly prognostic for OS in azacitidine-treated patients with Overall Sruvival high-risk MDS 1.00 Not predictive of response to azacitidine Prognostic value refined with use of azacitidine scoring systems 0.75 0.50 0.25 0 P =.0001 0 20 40 60 80 Months Ades L, et al. ASH 2012. Abstract 422

Continued Azacitidine treatment after first response? Time to 1 st response in HR-MDS Silverman LR et al. Cancer 2011;117:2697-702

Continued Azacitidine treatment after first response? Continued azacitidine Tx after 1 st response improves quality of response in HR-MDS 52%: 1 st response = best response 48%: improvement in their 1 st response with continued therapy (1 st R: HI -> PR or CR) Silverman LR et al. Cancer 2011;117:2697-702

Combination therapy with hypomethylating agents in MDS N ORR Azacitidine Phenylbutyrate 32 34% Azacitidine Valproic acid, ATRA 62 46% Azacitidine Entinostate 136 43% Azacitidine Lenalidomide 18 71% Azacitidine Thalidomide 36 58% Decitabine G. O. 33 42% Azacitidine Entanercept 32 72% Azacitidine Erythropoietin 32 44% Azacitidine Romiplostim 40 23% Decitabine Romiplostim 40 16% Santini V. 2012 ASH

Outcome After Azcitidine Failure in MDS *Includes AZA001, GFM, and JHU studies. Decitabine only. 1. Lin K, et al. ASH 2010. Abstract 2913. 2. Prebet T, et al. ASH 2010. Abstract 443. 3. Jabbour E, et al. Cancer. 2010;116:3830-3834.

Survival after Azacitidine failure with Salvage treatments in HR-MDS/AML Palliative care vs. Intensive CTx p=0.04 vs. Investigational Tx. p<0.001 vs. AlloHSCT p< 0.001 Intensive CTx vs. IT p=0.05 vs. ASCT p=0.008 IT vs. ASCT p=0.09 Prebet et al. J Clin Oncol 2011; 29: 3322

AlloSCT in MDS Transplantation is the only curative method in MDS Best results with young age, marrow blasts < 5%, absence marrow fibrosis, interval to SCT < 5 years, matched sibling donor Very limited donor availability, advanced age 75% of pts with MDS >60 Treatment-related mortality 34-55% Relapse 19-34% High treatment-related morbidity : Patients may have RFS, but not truly DFS 25% 33% 42% TRM DFS Relapse

HSCT outcomes in MDS Ghulam J. M. et al. ASH 2012

Timing of Transplantation Approximate Life Expectancy (Yrs) for Ablative Allogeneic Transplantation Transplantation at Diagnosis Transplantation in 2 Yrs Transplantation at Progression Low 6.51 6.86 7.21 Int-1 4.61 4.74 5.16 Int-2 4.93 3.21 2.84 High 3.20 2.75 2.75 Low & Int-1 : benefit for delaying SCT Int-2 & high : delay in time to SCT is associated with a loss in survivorship Cutler et al. Blood 2004

Timing of Transplantation Gain in expected survival since diagnosis according to IPSS & WPSS models under different policies with respect to a non-transplantation policy Alessandrino E. P. et al. GITMO, Am J Hematol 2013 in press

Timing of Transplantation Allo SCT offers optimal survival benefit when it is performed early in INT-1 IPSS or Intermediate WPSS Alessandrino E. P. et al. GITMO, Am J Hematol 2013 in press

Induction prior to allosct Disease stage & cytogenetics: predictors of OS, relapse and NRM Before allosct -decrease pre-transplant disease burden -time to find optimal donor Infection or comorbidity -lose a chance for transplantation

Pre-transplant Azacitidine 3 yr OS Relapse Damaj et al, JCO 2012;30:4533-4540

Pre-transplant Azacitidine agvhd: N-S extensive cgvhd: higher in AZA-ICT group (p=0.049) TRM For the purpose of reducing tumor burden before allosct AZA showed comparative OS, EFS, relapse and NRM compare with ICT Damaj et al, JCO 2012;30:4533-4540

Pre-transplant Hypomethylating Agents 2yr DFS 49 AZA, 4 DEC, 3 AZA-DEC Response to HMT G-COR: continued response G-NoC: no change G-LOR: loss of response G-DP: progression G-stable Yahng SA et al. Eur J Haematol 2013;90:11-20

Pre-transplant Hypomethylating Agents Independent risk factor for DFS, relapse : Response to HMA & Karyotype at HSCT Yahng SA et al. Eur J Haematol 2013;90:11-20

Post-transplant Salvage Usually relapse within 1 or 2 years after HSCT Number of patients relapsing after allosct as a function of time elapsed from transplantation 26 24 22 20 18 16 14 12 10 8 6 4 2 0 0 50 150 250 350 450 550 650 750 850 > 900 Days post Transplant

Post-transplant Salvage MRD based preemptive 5-Aza Tx in MDS/AML after allosct (RELAZA trial) (n=20) DC, donor chimerism Platzbecker U. et al. Leukemia 2012;26:381-389

Post-transplant Salvage Platzbecker U. et al. Leukemia 2012;26:381-389 Major R Minor R no Response Relapse no Relapse Relapse Response: 16/20 (80%) Hematologic Relapse: 65% Relapse was delayed median 231 days after initial decrease of CD34+ chimerism to <80% Preemptive AZA: acceptable safety & prevent or delay hematologic relapse

Post-transplant Salvage Azacitidine + DLI in AML (28) or MDS (2) relapsing after allosct (AZARELAR trial) AZA: 8 cycles, D1-5 (median 3) DLI: every 2 nd AZA cycle ORR: 30% (CR 23%, 2 PR) agvhd 37%, cgvhd 17% CR or CRi : longer OS Schroeder et al. Leukemia 2013

감사합니다!!