Relapsed or Refractory Adult Acute Lymphoblastic Leukemia (ALL): Distinct Patient Populations With Significant Unmet Medical Need

Transcription

1 Relapsed or Refractory Adult Acute Lymphoblastic Leukemia (ALL): Distinct Patient Populations With Significant Unmet Medical Need Hagop M. Kantarjian, MD Chairman, Leukemia Department Department of Hematology The University of Texas M. D. Anderson Cancer Center

2 Overview Distinct subsets of patients with adult ALL exist with high unmet medical need Primary resistance to frontline Rx Early relapse; CRD1 < 12 months Second salvage Rx (Salvage 2) CRD, duration of complete remission. 2

3 Probability of complete remission duration Relapse Following Frontline ALL Therapy: Complete Remission is Not Durable for Most Patients Total Fail Prognostic Median CR Score No. patients (%) model risk duration (months) Low (37) Intermediate (36) High 4 62 (27) Good Intermediate Poor (P<0.0001) 5-Yr CR duration (%) For those who do achieve CR, responses are not durable in the majority of patients and overall survival (OS) is poor following relapse Kantarjian H, et al. Cancer. 2004;101(12):

4 Outcomes Are Poor For Adults With Refractory or Relapsed ALL (< 1 Year of CR) Following Frontline Therapy (MDACC) In 245 relapsed/refractory ALL patients, only 31% achieved CR CRs were not durable (median 5 months) Median OS was 4.7 months 12% of patients died during induction therapy or within the first 2 weeks of therapy This study established baseline expectations against which new approaches should be compared Novel treatment strategies are needed for this difficult to treat patient population Survival Probability Tota l Events Median (mos) CR duration Overall Months Kantarjian H, et al. Cancer. 2010;116:

5 Outcomes Are Poor For Adults With Relapsed ALL Following Frontline Therapy (PETHEMA) In 263 relapsed/refractory ALL patients the median OS after relapse was 4.5 months; 1-year OS was 24%, death during induction occurred in 17% of patients Median DFS after second remission (CR2) was 6 months; 1-year DFS probability was 34% Patient age and the time from CR1 were both factors associated 1.0 with OS and DFS 1.0 Proportion alive P<0.001 Relapse > 2 years after CR1, N=49 Relapse 1 to 2 years after CR1, N=61 Relapse <1 years after CR1, N= Years from relapse Proportion alive and in CR P<0.001 Relapse > 2 years after CR1, N=309 Relapse 1 to 2 years after CR1, N=31 Relapse <1 years after CR1, N= Years from second complete remission DFS, disease-free survival. Oriol A, et al. Haematologica. 2010;98(4):

6 Outcomes Are Poor For Adults With Relapsed ALL Following Frontline Therapy (MRC UKALL/ECOG 2993) Median OS after relapse was 4.6 months; 1-year OS was 22% With nearly 4.5 years of follow-up, only 42/609 (7%) patients are alive and disease free; 5% of patients died during induction therapy Patient age, sex, time to relapse (below), site of relapse, and type of therapy in CR1 were associated with OS 100 Percent P< > 2 years 11% At risk: Time (years) yrs 5% 6 mo. 1 yrs 6% > 6 mo. 5% <6 months 6 m 1 yr 1-2 yrs > 2 yrs Fielding A, et al. Blood. 2007;109(3):

7 Outcomes After SCT Are Poor For Adults With Refractory or Relapsed ALL Without CR Of 582 ALL patients who underwent SCT and were not in CR, OS at 3 years was 16% OS was worse with the following risk factors: First refractory or second or greater relapse 25% marrow blasts Cytomegalovirus-seropositive donor Age of 10 years or older SCT is only an option for patients in CR or those with no risk factors if not in CR SCT, stem cell transplant. Duval M, et al. J Clin Oncol. 2010;28(23):

8 Poor Outcome of Adults With Refractory or Relapsed ALL Who Undergo Third-line (Second Salvage) Therapy In 288 relapsed/refractory ALL patients treated with second salvage therapy, only 18% achieved CR CRs were not durable (median 7 months) Median OS was dismal at only 3 months Only 8% of patients were able to undergo allogeneic-sct as second salvage therapy; 1-year survival rate was only 18% 23% of patients died during induction therapy or within the first 2 weeks of therapy Survival Probability Survival Tota l Events Overall CR duration Months O Brien S, et al. Cancer. 2008;113:

9 Novel Therapies and Combinations Have Failed to Provide Benefit in This Patient Population SWOG Study S0530: phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukemia (N=37) Median age was 41 years, 44% of patients were either in 2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics Six of 36 patients (17%) achieved CR; median OS was 3 months This regimen lacked sufficient activity to warrant further testing Advani AS, et al. Br J Haematol. 2010;151(5):430. 9

10 Novel Therapies and Combinations Are Needed For These Distinct ALL Patient Populations Ideal therapies for relapsed/refractory ALL would provide one or more of the following: Increase the number of patients who achieve CR Increase the duration of CR Increase OS Decrease treatment related mortality Increase the number of patients who can achieve SCT 10