Ph+ALL : a new era. Said Y Mohamed KFSHRC, Riyadh Ain Shams University, Cairo, Egypt

Transcription

1 Ph+ALL : a new era Said Y Mohamed KFSHRC, Riyadh Ain Shams University, Cairo, Egypt

2 A 30 Y/O patient with Ph+ ALL What would you start as an induction? 1. BFM/CALGB/UKALL Plus TKI? 2. Some chemo + TKI. How much is his chance to survive to have a job, get married, have kids if sperm banking succeeds in 100%? What consolidation you offer if he achieved CR1 HIDMTX/HIDAC Allo-MSD vs. Auto-SCT (availability) MRD-ve achieving Chemo. + TKI and Stop??

3 Pre-Imatinib Era Dying while on chemotherapy Death Death Long term survivors Long term survivors Dombret H et a;, 2002 Arico M et., 2000

4 MRC-ECOG- Ph+ ALL Actual treatment given after CR-1 Treatment assigned upfront according to HLA-typing done

5 Outcome of adult Ph+ ALL was one of the worst Pullarkat V et al., Blood Oct SWOG 2008 UKALL-ECOG 2993

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7 Ph+ was bad even in China Allo-HSCT Auto-HSCT Zhang YR et al Jun 14, 2013;

8 How much is his chance to survive : pre TKI era % SCT CT SCT CT SCT CT > 1/4??? CT 60-3/4 1/2 2/ < 3/4 1/4 1/2 1/5 1/3 Children AYA Adult Age 1/6 Elderly

9 Ph+ ALL is very bad. An old man with ALL is palliative especially if Ph+ Ph+ ALL is not very bad. An old man with ALL is palliative unless he s Ph+

10 Why Ph+ ALL was a bad disease? Clinical factors Age: 25-50% of ALL above 50 are Ph+ Higher WBCS at presentation Biological factors Multilineage disease Involvement of Src kinases A disease of genetic instability and mutations Therapeutic factors Age vs. intensity match There was no TKI

11 More common in kids but kills more in the old!

12 Schenk TM et al., 1998

13 Rate of KD mutations in elderly with Ph+ ALL (GMALL trial ADE10) 80% % At diagnosis Upfront mutation Concordance probably contributes between mutations to Dx relapse is 90% At relapse Pfeifer H et al., Blood 2007

14 Pfeifer H et al., Blood 2007

15 Mutations and response Ponatinib T315I Dasatinib Y253H E255K/V Nilotinib V299L T315A High dose I/N/D V299L T315A CP AP BC F359V/CI F317L/V/C/I F317L/V/C/I ALL Reference. blood

16 Transplanting Src-knock outs (-/-)into wild type animals does not kill. Hu Y. et al.,

17 Can Imatinib prevent relapse post BMT? A. Yes for sometime Q. Why for sometime only? A. Does Not do well with mutations

18 Apoptosis

19 How is the prognosis of Ph+ ALL NOW??? Power and riches are in a continuous recycling among human beings and nations. The powerful will not remain powerful for ever and the weak will one day gain his power Ghazaly M. 1974

20 Sequential use of TKI, chemo- + HSCT (allo and Auto) high CR rates DFS and OS in Adult Ph+ ALL. GIMEMA 0904 Protocol. HAM HAM IMATINIB 50 d Pre 7-31 Prednisone d+50 HAM 23 (20 Allo and 3 Auto) 20 No SCT 96% CHR 2%PR 2% NR Total 51 ; 2 withdrew for medical reasons 49 started the algorithm 43 only received HAM 100% CHR Median age 45.9 Y ( ) Chiaretti (Poster 618) EBMT OS DFS

21 The historical pessimism with Ph+ ALL If they don t have a donor, the majority will die shortly after Diagnosis. Optimism in TKI era Even if they don t have a donor, they can still survive and we still can transplant Ph+ ALL.

22 Management of Ph+ ALL in TKI era Paradigm shift of management Induction, consolidation and maintenance 1. Chemo-free to chemo-combined induction 2. Outpatient management. 3. Intensity paradox in Ph+ ALL induction Rt shift of age for curative intent Transplantation 1. More realization 2. RIC realization although MAC is still the standard 3. Autologous SCT with Peri-SCT TKI use 4. Post-SCT TKI use (pre-emptive or prophylactic) Outcome DFS OS Pattern of relapse: late vs. early when compared to non-tki Better salvage rate

23 Be simple: Can we de-escalate chemotherapy? No chemo-induction(tki-steroids) Chemolite+ TKI (Intensity paradox)(nilg) Can we de-escalate transplant? TRANSPLANT: Keep ALLo: RIC not MAC No Allo but AUTO.(NILG) NO Allo- NO Auto i.e. NONE TRANSPLANT

24 Can we de-escalate chemotherapy induction with a good remission rate CR-1?

25 Sequential use of TKI, chemo- + HSCT (allo and Auto) high CR rates DFS and OS in Adult Ph+ ALL. GIMEMA 0904 Protocol. HAM HAM IMATINIB 50 d Pre 7-31 Prednisone d+50 HAM 23 (20 Allo and 3 Auto) 20 No SCT 96% CHR 2%PR 2% NR Total 51 ; 2 withdrew for medical reasons 49 started the algorithm 43 only received HAM 100% CHR Median age 45.9 Y ( ) Chiaretti (Poster 618) EBMT OS DFS

26 Study* n Induction regimen CR I- TRM PCR negativity HSCT MDACC 20 HyperCVAD 93 NR m GMALL 92 Dex.Cy.V.DNR Asp. AraC.MP GRAAL L 45 IMATINIB + CHEMOTHERAPY INDUCTION OS DNR,Cy,V, Asp,P,MtX, AraC, 96 5 Dex y PETHEMA 32 V, DNR, P y NILG 59 VCR, IDR, Asp, P 92 (100) y GIMEMA 51 PDN HAM ?? 76? KOREA 20 DNR,V, P, Asp y JALSG 80 Cy, DNR, VCR, P y *: numbers represent percentage (%)., all used imatinib doses IM dose : 600mg except GMALL (400mg) and PETHEMA (400mg)

27 Can we de-escalate transplant in Ph+ ALL? DO Allo-HSCT with RIC not MAC? NO Allo-HSCT but AUTO-HSCT? NO Allo- NO Auto: continue chemo Yes, we can but! Small studies or Short F/U!

28 RIC for HR-ALL (Ph+ ALL) OS DFS Ram R et al., Hematologica 2011

29 3y-OS 47% in Ph+ ALL in CR1 given IM after HCT. OS was 73% for CR1 without MRD at HCT. Relapse was increased in Ph+ patients: (i) With Ad. CyGA (ii) Beyond CR1 (iii) CR1 with MRD + at HCT. What is the best thing you can do for Ph+ ALL going for RIC Age did not limit the feasibility of ttt protocol. Ph+ ALL > 60 years had 3-Y OS = 57%. PRE-HSCT: Don t send for RIC with MRD+. Post-HSCT: Don t forget to add TKI.! Ram R et al., Hematologica 2011

30 RIC PB HSCT for Adult Patients with High-Risk ALL Anthony S. Stein, et al., 2009 BBMT A retrospective, 24 HR-adult ALL (Ph+ ALL) Age 47.5y, F/U: 28.5 mos and CHH RIC: Flu/Mel. Indications for the RIC regimen: (1)> 50 y (42%), (2) Compromised organ function (54%) (3) Previous HCT (37.5%). No significant impact of Age, Ph+ chromosome, Donor source, or Prior HCT. Both OS & DFS at 2 Y was 61.5%. Relapse rate: 21.1% NRM: 21.5% at 2 years. C-GVHD: 86% of evaluable patients.

31 No significant impact of Age, Ph+ chromosome, Donor source, or Prior HCT. nthony S. Stein, et al., 2009 BBMT

32 DFS and Relapse nthony S. Stein, et al., 2009 BBMT

33 Allo-SCT for Ph+ ALL : Impact of Conditioning Intensity, TKI & MRD- 197 adults with Ph+ ALL in CR1 - CIBMTR RIC RIC were matched with 130 MAC (for age, donor type and SCT year). Median age RIC 54 y & MAC 50 y. The RIC gr :sicker ( IFI and a longer time from Dx to CR). TKI pre-sct (RIC: 76% vs MA: 78%). TKI post-sct 31% (RIC) and 17% (MA) TRM at 1 y: RIC vs MA (13% vs 36%; p<0.001). 3-yr relapse rate (49% vs 28%; p=0.058) Similar Survivals: RIC vs MAC OS: 39% vs 35%, p=0.62; DFS: 26% vs. 28%, p=0.75). Post-transplant TKI use & young age (< 40 years) lower TRM and better OS. II-IV agvhd : RIC 30% and MAC 47% (p=0.014). C-GVHD: no relation Pre-transplant TKI therapy 153 pre-hct TKI, pre-hct TKI 2-fold reduction in relapse (HR 0.49; p=0.003). RIC HCT yields similar survival of adults with Ph+ALL in CR1 compared to MA allografts. Bachanova V. ET AL., Tandem 2013 IBMT Abstract 22

34 TKIs Improved remission Quality

35 Can we de-escalate transplant? TRANSPLANT: Keep ALLo: RIC not MAC No Allo but AUTO: ( GRAAPH 2003, NILG)

36 Allo- Auto vs. Chemo in children pre-tki ARICÒ M. et al., NEJM 2000

37 Allo- Auto vs. Chemo in children pre-tki CHEMO 1/2 ¼ 1/5 ARICÒ M. et al., NEJM 2000

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39 Long Term impact of Imatinib on Outcome of adults with Ph+ ALL-GRAAPH+2003 Allo-sib Autologous Allo-sib OS No SCT Allo-URD DFS Autologous No SCT Allo-URD

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41 Auto-HSCT MRD+ vs ve <0.001 <0.001 <0.001 <0.001 Auto- vs. Allo DFS OS 58 pts who received 3-4 courses of imatinib (400 mg twice daily) plus sequential chemotherapy followed either by TBI, 1320 cgy)/etoposide (60 mg/kg) and aallo) SCT from MSD or by TBI/etoposide/cyclo (100 mg/kg) and auto-sct. Fifteen had an allo-sct on study using MSD ; others MUD or received alternative ttt. 19 auto-sct. Wetzler M et al. ASH 2012 Abstract 816

42 Autologous HSCT for Ph+ ALL : A Curative Option in the Era of TKI? an Analysis From the ALWP- EBMT Actuarial LFS All patients? N: 171 patients In CR1 Median age 48.3 (19 65) y 2 Y- OS 45% (+4%) 2y- LFS 32% (+4%). 2 Y-LFS probability increased from 22% between (n=70) 32% between (n=61) 54% between (n=40) p<0.001 We conclude that results of autologous HSCT for Ph+ ALL improved markedly in recent period with more than half of patients being alive and leukemia-free at 2 years. Therefore, it appears than in the era of TKIs autologous HSCT may be considered potentially curative option. Sebastian Giebel, ASH 2012 Abstract 233

43 NILG (northern Italian Leukemia gr) JCO 2010 SCT realization better with IM (72% vs. 54%) Allo 39 % vs. 61% URD 1% vs. 31% Auto both after no TKI or after TKI is feasible After TKI: 6/9 DFS for 5 years No Imatinib: 2/4 had 5 y DFS Allo transplant

44 Now you can do Auto-SCT in Ph+ ALL? Auto

45 Why all data are good now??? TKIs

46 Values of TKIs (Imatinib) in Ph+ ALL 1. Simpler Induction More curative intent therapy 2. Higher CR and less TRM. 3. Higher SCT realization. 4. RIC expansion/ plausibility. 5. Expansion of Allo-HSCT for a larger group. 6. Use of autologous. 7. Better prognosis. 8. Reduced post-bmt relapse. 9. Easier and more successful ttt of post-sct relapse 10.No transplant is an option.

47 Better outcome of pediatric Ph+ ALL with CT + Imatinib COG 2009 IM No IM Continuous IM was better > intermittent/interrupted Schultz KR et al., JCO 2009

48 Schultz KR et al., JCO 2009

49 The impact of MRD status may be less evident with continuous use of Imatinib Even if the the patient had induction failure (IF), he/she would still be able to enjoy a good survival 4 y Schultz KR et al., JCO 2009

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53 Imatinib increased SCT rate (Allo/Auto) in MRC/ECOG study (157/1760) (181/267) (96/176) 50 BMT-consider in CR (95/267) Received SCT in CR Considered=after CR become eligible for allo SCT if available donor Auto if no available donor Pre-IM Post-IM

54 Post-HSCT IM China Total n= 82 Age 28.5 Y (3-51) between May 2005-March 2010 IM + (n: 62) at a median of 70 d post-hct & IM-ve (n:20) Start IM if: Plt >50, ANC >1k or BCR rising x2 or > Y Disease-free survival (DFS) Cumulative incidence of relapse (CIR) 81.5% p= % 33% 10% P=0.016 Was it Safe? Grade 3 4 Aes: in only 17.7%. 10 pts (16.1%) terminated IM 2ry AEs. Chen et al., J Hematol Oncol. 2012; 5: 29

55 Multivariate analysis associated with OS and DFS What is the best thing a hematologist can do to a Ph+ ALL Chen et al., J Hematol Oncol. 2012; 5: 29 PRE-HSCT: to put BCR/ABL down Post-HSCT: to put some TKI in.!

56 New algorithm (suggested Said Y) Go GO Slow GO No GO Some Chemo+ TKI Pred+ TKI Pred+ TKI (reduced) Deep MRD Then add Some chemo MSD Auto-SCT Deep MRD No MRD - VCR. Pred.TKI TKI TKI Post- Transplantation TKI

57 Future directions TKI-intense/Chemolite therapy 3 rd generations TKI (Mutational Blockers) Individual care management Liberal care therapy No transplant Auto-SCT with post-sct TKI and MB Allo: RTC/RIC CBT