CCO_MDS_2012_Slides

Views:
 
Category: Education
     
 

Presentation Description

No description available.

Comments

Presentation Transcript

Myelodysplastic Syndromes: Updates in Treatment and Supportive Care:

Myelodysplastic Syndromes: Updates in Treatment and Supportive Care This program is supported by an educational grant from

About These Slides:

About These Slides Our thanks to the presenters who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Program Chairs:

Program Chairs Alan F. List, MD Executive Vice President and Physician-in-Chief H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Rami Komrokji, MD Assistant Professor of Oncologic Sciences Oncologic Sciences University of South Florida Clinical Director Hematologic Malignancies H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Malignancies

Faculty Disclosures:

Faculty Disclosures Rami Komrokji, MD, has disclosed that he has received fees for non-CME/CE services from Celgene. Alan F. List, MD, has disclosed that he has received consulting fees and fees for contracted research from Celgene .

Overview:

Overview MDS Classification Criteria and Cytogenetic Abnormalities Current and Evolving Treatment Approaches in MDS Treatment Options for Low- and Intermediate-Risk MDS Role of Lenalidomide in the Treatment of MDS Treatment Options for High-Risk MDS Hypomethylating agents Key Issues in Supportive Care of Patients With MDS

Topic 1: MDS Classification Criteria and Cytogenetic Abnormalities:

Topic 1: MDS Classification Criteria and Cytogenetic Abnormalities

Anemia Management Algorithm 2012: Low-/Intermediate-1 Risk MDS:

Anemia Management Algorithm 2012: Low-/Intermediate-1 Risk MDS Epo > 500 mU/mL RCMD ≥ 2 U RBC/mo del(5q) Lenalidomide Epo < 500 mU/mL < 2 U RBC/mo ESA del(5q) + GCSF HMA Age > 60 yrs ≤ 60 yrs IST NCCN. Clinical practice guidelines in oncology. MDS. v.1.2012.

Erythropoietin in MDS:

Erythropoietin in MDS Response rates to erythropoietin much lower in MDS than in other malignancies Mean response rate: 16% to 20% Predictors for good response were serum EPO level < 500 U/L, nonrefractory anemia with ring sideroblasts subtype, and lack of previous need for transfusion Response rates may improve when given in combination with G-CSF (> 40%) Ludwig H. Semin Oncol. 2002;29(3 suppl 8):45-54. Hellström-Lindberg E. Br J Haematol. 1995;89:67-71. Casadevall N, et al. Blood. 2004;104:321-327.

Predictive Model for Response to Treatment With rhuEPO + G-CSF:

Score > +1 Score -1 to +1 Score < -1 RA, RARS, RAEB Intermediate (23%, n = 31) Poor (7%, n = 29) Good (74%, n = 34) Response Probability Treatment Response Criteria Treatment Response Score Predictive Model for Response to Treatment With rhuEPO + G-CSF CR Stable Hb > 11.5 g/dL PR Increase in Hb with >1.5 g/dL or total stop in RBC transfusions S-EPO U/l < 100 100-500 > 500 +2 +1 -3 Transf U RBC/mos < 2 units/mos ≥ 2 units/mos +2 -2 Hellström-Lindberg E, et al. Br J Hematol. 2003;120:1037-1046.

Role of Lenalidomide in the Treatment of MDS:

Role of Lenalidomide in the Treatment of MDS

Lenalidomide:

Lenalidomide Thalidomide analogue with immunomodulatory, antiangiogenic, and antineoplastic properties Approved for use Transfusion-dependent anemia due to low- or intermediate-1–risk MDS associated with del(5q), with or without additional abnormalities Multiple myeloma in combination with dexamethasone in patients who have received at least 1 previous therapy

Lenalidomide in MDS With 5q Deletion MDS-003 Study Design:

Primary endpoint: transfusion independence Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety Lenalidomide in MDS With 5q Deletion MDS-003 Study Design R E S P O N S E R E G I S T E R Lenalidomide 10 mg PO x 21 days Eligibility IPSS diagnosed low/int-1 MDS del(5q31) ≥ 2 U RBC/8 wks Platelets > 50,000/µ L ANC > 500/µL Yes Continue No Off study Wk Lenalidomide 10 mg/day PO 0 4 8 12 16 20 24 List AF, et al. N Engl J Med. 2006;355:1456-1465.

MDS-003: Response to Lenalidomide Therapy:

MDS-003: Response to Lenalidomide Therapy List AF, et al. N Engl J Med. 2006;355:1456-1465. 38/85 (45%) 62/85 (73%) Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 Erythroid Response Cytogenetic Response TI 99/148 (67%) 112/148 (76%) TI + Minor CCR CCR + PR

MDS-003: Response to Lenalidomide Therapy:

MDS-003: Response to Lenalidomide Therapy Erythroid Response TI 99/148 (67%) 112/148 (76%) TI + Minor Cytogenetic Response List AF, et al. N Engl J Med . 2006;355:1456-1465. Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 CCR CCR + PR 38/85 (45%) 62/85 (73%) Median Hb increase: 5.4 g/dL Time to response: 4.6 wks Duration of response: > 2 yrs

MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS:

Primary endpoint: TI, Hb response Secondary endpoints: cytogenetic response, safety MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS R E S P O N S E R E G I S T E R Lenalidomide 10 mg PO x 21 days Eligibility IPSS diagnosed low/int-1 MDS w/o del(5q) abnormality ≥ 2 U RBC/8 wks Platelets > 50,000/µ L ANC > 500/µL Yes Continue No Off study Wk Lenalidomide 10 mg/day PO 0 4 8 12 16 20 24 Dose reduction 5 mg QD 5 mg QOD Raza A, et a. Blood. 2008;111:86-93.

MDS-002: Clinical and Hematologic Features:

MDS-002: Clinical and Hematologic Features Characteristic Patients (N = 214) Median age, yr (range) 72 (27-94) Male:female 138:75 (38) Median MDS duration, yr (range) 2.2 (0-12.9) Median RBC units/8 wks (range) 4.0 (1-24) Pts receiving ≥ 2 RBC units/mo in mo before study entry, n (%) 175 (82) IPSS score, n (%) Low 92 (43) Int-1 76 (36) Int-2 high 8 (4) Unclassified 38 (18) Neutropenia < 1500/ μ L, n (%) 57 (27) Thrombocytopenia < 100,000/ μ L, n (%) 41 (20) Raza A, et al. Blood. 2008;111:86-93.

MDS-002: Response to Lenalidomide Therapy:

MDS-002: Response to Lenalidomide Therapy 56/214 (26%) 93/214 (43%) Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 Erythroid Response Cytogenetic Response TI TI + Minor 4/47 (9%) 9/47 (19%) CCR CCR + PR Raza A, et al. Blood. 2008;111:86-93.

MDS-002: Response to Lenalidomide Therapy:

Response (%) 0 20 40 70 80 100 Response (%) 0 20 40 70 80 100 MDS-002: Response to Lenalidomide Therapy CCR CCR + PR 4/47 (9%) 9/47 (19%) Erythroid Response Cytogenetic Response TI TI + Minor 56/214 (26%) 93/214 (43%) Median Hb increase: 3.2 g/dL Time to response: 4.8 wks Median duration of response: 41 wks Raza A, et al. Blood. 2008;111:86-93.

MDS-002/003: Treatment-Related Adverse Events:

MDS-002/003: Treatment-Related Adverse Events Grade ≥ 3 Adverse Events, % Non-del(5q) del(5q) Thrombocytopenia 20 44 Neutropenia 25 55 Pruritus 1 3 Rash 4 6 Diarrhea 1 3 Fatigue 4 3 List AF, et al. N Engl J Med . 2006;355:1456-1465. Raza A, et al. Blood. 2008;111:86-93.

MDS-004: Phase III Placebo-Controlled Study of 2 Lenalidomide Doses in del(5q):

MDS-004: Phase III Placebo-Controlled Study of 2 Lenalidomide Doses in del(5q) *Crossover at Week 16. Primary endpoint: transfusion independence ≥ 26 wks Secondary endpoints: duration of transfusion independence, progression to AML, adverse events Eligibility IPSS low/int-1 del(5q31) Transfusion dependent Lenalidomide naive Stratified by IPSS Complexity Continue for 52 wks Open-label treatment S T R A T I F Y A R S E S S E P S O S N S E* R A N D O M I Z E Lenalidomide PO 10 mg/day for 21 days of each 28-day cycle Lenalidomide PO 5 mg/day for 28 days of each 28-day cycle Double blind Wk 0 4 8 12 16 Response No response (Not included in efficacy analysis) Placebo Fenaux P, et al. Blood. 2011;118:3765-3776.

MDS-004: Transfusion Independence:

MDS-004: Transfusion Independence ITT Population Confirmed Low/Int-1 Placebo (n = 51) Len 5 mg (n = 46) Len 10 mg (n = 41) Placebo (n = 51) Len 5 mg (n = 46) Len 10 mg (n = 41) Transfusion independence (8+ wks), % 8 50* 61* 7.8 50.0 61.0 Transfusion independence (26+ wks), % 6 41* 56* 5.9 (1.2-16.1) 41.3* (27.0-56.8) 56.1* (39.7-71.5) Median rise in hemoglobin, g/dL 2.3 5.1 † 6.3 † 2.3 5.1 6.3 * P < 0.001 vs placebo. † P < 0.05 vs placebo. Fenaux P, et al. Blood. 2011;118:3765-3776.

Summary: Lenalidomide in Low-/ Intermediate-1–Risk MDS:

Summary: Lenalidomide in Low-/ Intermediate-1–Risk MDS MDS-004 confirmed results of MDS-003 [1,2] Efficacy of 10 mg comparable between studies Transfusion independence by IWG (61% vs 67%) MDS-004 supports 10 mg as appropriate starting dose Higher TI for 10 mg Mean duration of TI: 106 wks Greater proportion of cytogenetic responses vs 5 mg (41% vs 17%) No significant differences in hematological toxicity The rate of transformation to AML is comparable to the literature MDS-001 and MDS-002 provided evidence that lenalidomide could be a choice for anemia treatment in lower-risk non-del(5q) pts with adequate platelets and neutrophil count [3,4] Lenalidomide mechanism of action is karyotype dependent, suppressing the clone in del(5q) and promoting erythropoiesis in non-del(5q) [5] 1. Fenaux P, et al. Blood. 2011;118:3765-3776. 2. List AF, et al. N Engl J Med. 2006;355:1456-1465. 3. List AF, et al. N Engl J Med. 2005;352:549-557. 4. Raza A, et al. Blood. 2008;111:86-93. 5. Sekeres MA, et al. J Clin Oncol. 2008;26:5943-5949.

Azacitidine for Low-/Intermediate-1–Risk MDS:

Azacitidine for Low-/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:

5-2-2: 75 mg/m 2 5-2-5: 50 mg/m 2 5: 75 mg/m 2 x 6 IWG 2000 HI 12 Cycles AZA x 5 days q4-6 wks Study Design (N = 151) Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. (n = 50) (n = 51) (n = 50) Eligibility All FAB Cytopenia ECOG PS: 0-3 Randomized Phase II Study of Alternative Azacitidine Dose Schedules

Alternate AzaC Dose Schedule Study: Frequency of Major HI in Evaluable Patients (N = 139) :

*IWG 2000 criteria. Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. Alternate AzaC Dose Schedule Study: Frequency of Major HI in Evaluable Patients (N = 139) Lineage HI in Evaluable Pts,* n (%) 5-2-2 (n = 50) 5-2-5 (n = 51) 5d (n = 50) Erythroid Ma 19/43 (44) 19/43 (44) 20/44 (46) RBC-TI 12/24 (50) 12/22 (55) 15/25 (64) Platelet Ma 12/28 (43) 8/30 (27) 11/22 (50) Any HI 22/50 (44) 23/51 (45) 28/50 (56) Neutrophil Ma 4/23 (17) 4/23 (17) 9/24 (38) Heme AEs > grade 3 33/50 (66) 24/48 (50) 17/50 (34) AE Tx delay 34/50 (68) 30/48 (63) 17/50 (34)

Treatment Options for High-Risk MDS:

Treatment Options for High-Risk MDS

Treatment Algorithm 2012: Intermediate-2–/High-Risk MDS:

SCT candidate No donor Allogeneic donor HMA Investigational SCT Favorable Unfavorable Treatment Algorithm 2012: Intermediate-2–/High-Risk MDS Field T, et al. Mediterr J Hematol Infect Dis. 2010;2:e2010019

Pre-Transplant Chemotherapy as a Bridge to Transplant:

Pre-Transplant Chemotherapy as a Bridge to Transplant 1 Nakai K, et al. Leukemia. Mar 2005;19(3):396-401. 2 De Padua Silva, et al. BMT . 2009 June;43(11):839-43 3 Cogle CR, et al. Clin Adv Hematol Oncol . Jan 2010;8(1):40-46. 4 Field T, et al. Bone Marrow Transplant. Feb 2010;45(2):255-260. Retrospective Data 1 No benefit from induction chemotherapy prior to transplant. Caveats: (A) Data from 1990 ’ s, (B) Retrospective, (C) Poor description of chemotherapies used Improved survival in those achieving CR before transplant Feasibility Data 2-4 Feasible to give Vidaza or Dacogen before Transplant Rapid donor cell engraftment Prospective Trials Needed European BMT Group: Allo-MDS2x2 Trial

Approximate Life Expectancy After Ablative Allogeneic Transplantation:

Approximate Life Expectancy After Ablative Allogeneic Transplantation Risk Group, Yrs Transplantation at Diagnosis Transplantation at Yr 2 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 Cutler C, et al. Blood. 2004;104:579-585. Median age: 42 yrs Data precede all FDA-approved drugs for MDS

Hypomethylating Agents:

Hypomethylating Agents

AZA-001: Trial Design:

Azacitidine + BSC (75 mg/m 2 /day x 7 days SC q28 days) Stratified by FAB: RAEB, RAEB-T IPSS: int-2, high (n = 179) (n = 179) Treatment continued until unacceptable toxicity or AML transformation or disease progression CCR R A N D O M I Z E 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) Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001: Trial Design

AZA-001 Trial: Azacitidine Significantly Improves OS:

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

AZA-001: Hematologic Improvement (2000 IWG):

Fenaux P, et al. Lancet Oncol. 2009;10:223-232. AZA-001: Hematologic Improvement (2000 IWG) Patients (%) 0 10 30 40 50 60 Any HI HI-E Major 20 HI-P Major HI-N Major 49.2 28.7 39.5 10.6 32.6 14.0 19.1 18.0 Azacitidine CCR

AZA-001: Grade 3/4 Adverse Events (≥ 2%)*:

AZA-001: Grade 3/4 Adverse Events (≥ 2%)* Adverse Events, n (%) Azacitidine (n = 175) BSC Only (n = 102) Neutropenia 159 (91) 70 (69) Thrombocytopenia 149 (85) 72 (71) Leukopenia 26 (15) 1 (1) Anemia 100 (57) 67 (66) Febrile neutropenia 22 (13) 7 (7) Pyrexia 8 (5) 1 (1) Abdominal pain 7 (4) 0 Dyspnea 6 (3) 2 (2) Fatigue 6 (3) 2 (2) Hematuria 4 (2) 1 (1) Hypertension 2 (1) 2 (2) *When any grade of the reactions occurs in ≥ 5% of azacitidine-treated patients. Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

Outcome After Azanucleoside Failure in MDS and CMML:

Outcome After Azanucleoside Failure in MDS and CMML Institution N AZA Failures, n AML Progression, n (%) Median OS, Mos OS at 12 Mos, % Moffitt [1] 151 59 12 (20.3) 8.4 30 GFM* [2] 341 NR NR 6 29 MDACC † [3] NR 87 25 (29) 4.3 28 † Decitabine only. *Includes AZA001, GFM, and JHU studies. 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.

Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies:

Type of Salvage N ORR Median OS, Mos Unknown 165 NA 3.6 Best supportive care 122 NA 4.1 Low-dose chemotherapy 32 0/18 7.3 Intensive chemotherapy 35 3/22 8.9* Investigational therapy 44 4/36 13.2* † Allogeneic transplantation 37 13/19 19.5* † Prébet T, et al. J Clin Oncol. 2011;29:3332-3327. *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). Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies 100 75 50 25 0 0 365 730 1,095 1,460 OS (%) Time Since AZA Failure (Days) Investigational Allo-SCT

Decitabine Phase III MDS Trial: Study Design:

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 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) Stratification IPSS Type of MDS (primary or secondary) Eligible patients (N = 170) R A N D O M I Z E D Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Decitabine Phase III Trial: Response to Decitabine (ITT):

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. IWG Response Rate, Onset , and Duration,* n (%) Decitabine (n = 89) Supportive Care (n = 81) Overall response rate (CR + PR) 15 (17) † 0 (0) CR 8 (9) 0 (0) PR 7 (8) 0 (0) Hematologic improvement 12 (13) 6 (7) † P value < .001 from 2-sided Fisher’s exact test Onset and duration of response, mos Median time to response (CR + PR) Median duration of response (CR + PR) 3.3 (2.0-9.7) 10.3 (4.1-13.9) ‡ N/A

ADOPT Trial: Study Design:

ADOPT Trial: Study Design Patients (N = 99) with de novo or secondary MDS of any FAB subtype and IPSS score ≥ 0.5 Decitabine 20 mg/m 2 IV daily for 5 days Primary endpoint: ORR by IWG 2006 criteria Secondary endpoints: cytogenetic response, hematologic improvement, response duration, survival, safety Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

ADOPT Trial: Responses :

ADOPT Trial: Responses Response (IWG 2006 Criteria), n (%) Patients (N = 99) Overall complete response rate (CR + mCR) 32 (32) Overall response rate (CR + mCR + PR) 32 (32) Overall improvement rate ( CR + mCR + PR +HI) 50 (51) Rate of SD or better (CR +mCR + PR + HI +SD) 74 (75) CR 17 (17) mCR 15 (15) PR 0 (0) HI 18 (18) SD 24 (24) PD 10 (10) Not assessable 15 (15) Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

ADOPT: Time to First Response:

ADOPT: Time to First Response Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848. 0 20 10 30 50 Cycle 2 3 40 Patients With CR/mCR/HI (%) 1 4 ≥ 5 Time to first response Time to best response

ADOPT: Survival:

ADOPT: Survival Patients stratified by FAB subtype Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848. Patients stratified by IPSS score RA (n = 20) RARS (n = 17) RAEB (n = 45) RAEB-T (n = 6) CMML (n = 11) Survival (%) Time (days) 100 90 80 70 60 50 40 30 20 10 0 1,000 0 100 200 300 400 500 600 800 900 700 A Survival (%) Time (days) 100 90 80 70 60 50 40 30 20 10 0 1,000 0 100 200 300 400 500 600 800 900 700 B Low ( n = 1) Intermediate 1 (n = 52) Intermediate 2 (n = 23) High risk (n = 23)

ADOPT: Adverse Events Reported in ≥ 10% of Patients:

ADOPT: Adverse Events Reported in ≥ 10% of Patients Event, % Patients Grade 1-2 Grade ≥ 3 Hematologic Neutropenia 1 31 Thrombocytopenia 2 18 Febrile neutropenia 3 14 Anemia 5 12 Nonhematologic Fatigue 26 5 Nausea 26 1 Pyrexia 17 0 Diarrhea 12 0 Anorexia 12 0 Constipation 11 0 Pneumonia 1 11 Vomiting 10 1 Chills 10 0 Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.

EORTC-06011 Decitabine Phase III Trial: Study Design:

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 Decitabine 15 mg/m 2 IV x 4 hrs q8h x 3 days q6w (max 8 cycles) (n = 119) Supportive Care (n = 114) Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cycles; Exception: CR – 2 additional cycles. Wijermans P, et al. ASH 2008. Abstract 226.

Best IWG 2000 Response: EORTC-06011:

HI: 3 lineage (n = 7), 2 lineage (n = 5), 1 lineage (n = 6) Median no. courses: 4 Wijermans P, et al. ASH 2008. Abstract 226. Patients (%) 0 5 16 25 10 20 CR PR HI SD 13 6 0 0 15* 2 14 22 Decitabine (n = 119) Supportive care (n = 114) Best IWG 2000 Response: EORTC-06011

Overall Survival: EORTC-06011:

O N Patients at Risk, n 96 114 71 38 22 6 3 99 119 83 53 24 15 4 4 Mos 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 Median (mos): 10.1 vs 8.5 HR: 0.88 (95% CI: 0.66-1.17; log rank P = .38) Decitabine Supportive care Wijermans P, et al. ASH 2008. Abstract 226. 10 Overall Survival: EORTC-06011

Progression-Free Survival: EORTC-06011:

Decitabine Supportive care Wijermans P, et al. ASH 2008. Abstract 226. Median (mos): 6.6 vs 3 HR: 0.68 (95% CI: 0.52-0.88; log rank P = .004) O N Patients at Risk, n 105 114 33 15 7 3 1 113 119 62 32 11 2 0 Mos 0 6 12 18 24 30 36 0 10 20 30 40 50 60 70 80 90 100 Progression-Free Survival: EORTC-06011

Lenalidomide + Azacitidine in Patients With Higher-Risk MDS:

Lenalidomide + Azacitidine in Patients With Higher-Risk MDS Multicenter, single-arm phase II continuation study (N = 36) Patient eligibility Higher-risk MDS: 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/m 2 on Days 1-5 After 7 cycles, patients could continue azacitidine monotherapy off study Median patient follow-up: 15 mos (range: 5-65+) Sekeres MA, et al. ASH 2011. Abstract 607.

Lenalidomide + Azacitidine in Patients With Higher Risk MDS: Results:

Lenalidomide + Azacitidine in Patients With Higher Risk MDS: Results Median CR duration: 16+ mos (range: 3-36+) Median OS among CR: 27+ mos (range: 7-55+) 7 patients evolved to AML at median of 20 mos after CR Treatment well tolerated; FN was most common grade 3/4 AE (31%) Randomized trial planned to compare azacitidine vs lenalidomide/azacitidine vs azacitidine/vorinostat in higher-risk MDS 0 10 20 30 40 50 60 70 80 90 100 Lenalidomide/ Azacitidine (N = 36) Response Rate (%) CR Hematologic improvement Bone marrow CR 42 28 3 Sekeres MA, et al. ASH 2011. Abstract 607.

Azacitidine + Vorinostat for Higher-Risk MDS:

Azacitidine + Vorinostat for Higher-Risk MDS Age ≥ 18 years Untreated MDS (≥ Int-1) or AML And any of the following: Total bilirubin ≥ 2 mg/ dL Creatinine ≥ 2 mg/ dL ECOG performance status > 2 Excluded from all other clinical trials: Presence of other active malignancy Patients with CBF excluded Garcia-Manero et al. Blood 2011;

Azacitidine + Vorinostat: Study Design:

Azacitidine + Vorinostat: Study Design Dose and schedule: AZA 75 mg/m 2 IV QD days 1 to 5 Vorinostat 200 mg PO TID days 1 to 5 Cycles repeated every 28 days Statistical considerations: Maximum sample size N = 30 Stop if N/total patients alive > 60 days: ≤0/3, 2/6, 3/9, 5/12, 6/15, 8/18, 10/21, 11/24, 13/27 Stop if N/total patients with no CR ≥ 6/6, 11/12, 16/18, 21/24, 26/30 Garcia-Manero et al. Blood 2011;

Azacitidine + Vorinostat: Survival:

Azacitidine + Vorinostat: Survival Median follow up: 9.5 months (6.8-15) Number of patients surviving more than 60 days: 24 (80%) Stopping rule met by patient #17 Survival Probability 0.0 0.2 0.6 1.0 0.4 0.8 0 3 Months 12 18 15 9 6 Survival Overall Event-Free Total 30 30 Fair 21 27

Azacitidine + Vorinostat: Response (N=30):

Azacitidine + Vorinostat: Response (N=30) Patients (N) CR (%) CRp (%) ORR ALL 8 (26) 1 (3) 30 Diploid (7) 3 (42) 0 42 -5/-7 (16) 3 (10) 1 (3) 13 +8 (3) 2 (66) 0 66 Median courses to response= 2 (1-9)

Selected Novel Agents :

Selected Novel Agents Agent Patient Population Response Clofarabine HMA failure (n = 32) PO 33% IV-15 26% IV-30 22% Oral azacitidine MDS (n = 29) 34% HMA naïve 54% Rigosertib MDS (n = 51) 38 HMA failure 13/38 (34%) > 50% decrease in blasts Sapcitabine Phase I refractory AML/MDS (n = 47) OR 28% Erlotinib HMA failure higher risk MDS (n = 35) 5/26 (19%) Dasatinib HMA failure higher risk (n = 18) 16% Faderl S, et. al. ASH 2008; Abstract 222. Raza, et al. ASH 2011.Abstract # 3822. Komrokji, et al. ASH 2011. Abstract # 1714. Garcia-Manero G, et al. ASH 2009. Abstract 117. Kantarjian et al, JCO 2010. Vu, et al. ASH 2011.Abstract # 1727.

Topic 3: Key Issues in Supportive Care of Patients With MDS :

Topic 3: Key Issues in Supportive Care of Patients With MDS

Is Transfusion Dependency an Issue in MDS?:

Malcovati L, et. al. J Clin Oncol. 2005;23:7594-7603. Is Transfusion Dependency an Issue in MDS? Transfusion-dependent patients had a significantly shorter OS than transfusion-independent patients (HR: 2.16; P < .001 overall) Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 0 80 140 0.9 0.8 0.6 0.4 0.2 0.1 120 100 60 40 20 *Excludes isolated 5q- Good IPSS Risk* Intermediate IPSS Risk Transfusion independent Transfusion dependent Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 0 80 140 0.9 0.8 0.6 0.4 0.2 0.1 120 100 60 40 20

Serum Ferritin Is Predictive of Survival and Risk of AML in MDS :

Serum Ferritin Is Predictive of Survival and Risk of AML in MDS Development of transfusional iron overload is a significant independent prognostic factor for overall survival and evolution to AML Sanz G, et al. 2008 ASH. Abstract 640. Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0 10 15 20 Ferritin < 1000 µg/L Ferritin ≥ 1000 µg/L P < .0001 OS Time Without AML Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0 10 15 20 P < .0001

Improved Survival in MDS Patients Receiving Iron Chelation Therapy:

0 50 100 150 200 No ICT ICT Median Survival (Mos) 40.1 mos (0.7-224) (Not reached at 160 mos) P < .03 For patients with low and intermediate-1 MDS, iron chelation was associated with a significant improvement in OS Leitch HA. Leuk Res. 2007;31(suppl 3):S7-S9. + Improved Survival in MDS Patients Receiving Iron Chelation Therapy

Iron Chelation Therapy and Survival in MDS:

Iron Chelation Therapy and Survival in MDS Survey of 170 patients with MDS referred for RBC transfusion at 18 French treatment centers during 1-mo period in 2005 Assessments: hematologic data, RBC transfusion requirement, iron chelation therapy, and iron overload Cohort survival prospectively followed and reanalyzed on May 15, 2007 Standard iron chelation therapy Subcutaneous deferoxamine 40 mg/kg/day for 3-5 days/wk: n = 41 Deferiprone 30-75 mg/kg/day: n = 5 Subcutaneous deferoxamine plus deferiprone: n = 5 Deferasirox 20-30 mg/kg/day: n = 6 Low-dose iron chelation therapy Subcutaneous deferoxamine bolus 2-3 g/wk: n = 12 Intravenous deferoxamine 50-100 mg/kg once after RBC transfusion: n = 7 Rose C, et al. ASH 2007. Abstract 249.

Iron Chelation Therapy and Survival in MDS:

Iron Chelation Therapy and Survival in MDS OS significantly better for patients who received iron chelation therapy Results consistent across all subgroups analyzed (IPSS low and intermediate-1, sex, age) Rose C, et al. ASH 2007. Abstract 249. Median survival: 63 mos (whole group) 115 vs 51 mos ( P < .0001) CT No CT Diagnosis to Death Time (Mos) 0 50 100 150 200 250 0 0.25 0.50 0.75 1.00 Survival Distribution Function

Deferasirox in MDS: EPIC and US03 Studies:

Mo Serum Ferritin, ng/mL EPIC (N = 341) US03 (N = 176) 0 2730 3397 3 2358 3057 6 2210 2802 9 2076 2635 12 1904 2501 Deferasirox in MDS: EPIC and US03 Studies US03 results HI by IWG criteria: 8/176 (5%) Erythroid response: 5 Major platelet response: 1 Combined platelet + neutrophil response: 1 Both EPIC [1] and US03 [2] studies required Baseline serum ferritin ≥ 1000 ng/mL > 20 units red blood cell transfusions Treatment: deferasirox 10-30 mg/kg/ day 1. Gattermann N, et al. Leuk Res. 2010;34:1143-1150. 2. List AF, et al. ASH 2008. Abstract 634.

Deferasirox Black Box Warning:

Deferasirox Black Box Warning Deferasirox is contraindicated in patients with: Creatinine clearance < 40 mL/min or serum creatinine > 2 times the age-appropriate upper limit of normal Poor performance score and high-risk MDS or advanced malignancies Platelet counts < 50 x 10 9 /L Known hypersensitivity to deferasirox or any component of drug Deferasirox [package insert]. 2011.

TELESTO Study :

Screening 1 mo 4 yrs 1 yr 2 yrs Randomization (2:1 = Deferasirox /Placebo) 3 yrs 5 yrs Interim analysis: at 50% of primary composite events (~ 3 yrs) at 75% of primary composite events (~ 4 yrs) 54% chance to stop the trial depending on IA results IA IA Placebo (n = 210) 10 mg/kg/day (1st 2 weeks) 20 mg/kg/day (weeks 2-12) Up to 40 mg/kg/day (after 12 weeks) Deferasirox (n = 420) 10 mg/kg/day (first 2 wks) 20 mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12 wks) Expected end of study Low or int-1 risk MDS Serum ferritin > 1000 µg/L and < 2500 µg/L TELESTO Study ClinicalTrials.gov. NCT00940602.

MDS Patients Who Are Likely to Benefit Most From Management Iron Overload:

MDS Patients Who Are Likely to Benefit Most From Management Iron Overload Characteristic NCCN [1] MDS Foundation [2] Transfusion status Received 20-30 packed RBC units Continuing transfusions Transfusion dependent, requiring 2 units/mo for > 1 yr Serum ferritin level > 2500 μ g/L 1000 μ g/L MDS risk IPSS: low or intermediate-1 risk IPSS: Low- or Int-1 WHO: RA, RARS and 5q- Patient profile Candidates for allografts Life expectancy > 1 yr and no comorbidities that limit progress A need to preserve organ function Candidates for allografts 1. NCCN. Clinical practice guidelines in oncology. MDS. 2. Bennett JM. J Hematol. 2008;83:858-861.

Go Online for More CCO Coverage of Myelodysplastic Syndromes:

Go Online for More CCO Coverage of Myelodysplastic Syndromes Interactive Virtual Presentations review and consider challenging patient cases with guidance from expert faculty members Interactive Case Challenges work through challenging patient cases and review the implications of treatment choices Text-Based Modules plus downloadable PowerPoint slides clinicaloptions.com/oncology

authorStream Live Help