allosct and CLL in the BCRi era time for a study

Transcription

1 allosct and CLL in the BCRi era time for a study

2 Patient characteristics in BCRi studies and allosct candidates DIFFER

3 Facts on BCRi no Cure Risk factors for shorter BCRi efficacy in MV analysis? PA-refractory (Complex Cytogenetics?) Being a European? Being an European Byrd 2014

4 What do we know from allosct? Slides with courtesy of Mauricette Michallet

5 TP53 mutation has no impact on clinical outcome after allosct Dreger P et al. Blood 2013;121:3284

6 Percent OS Percent Survival Patients in Remission have Better Survival after allosct 70% RIC, 30% MAC FLU-cyclophosphamide 100 CR/PR (42) 50 HR 2.74 ( ); CR/PR (68) p 0.02 SD/PD (21) Months from SCT Active disease (34) Courtesy of J Brown and H Kim p= % RIC, 28% MAC CR(43) (43) 50 5y 67% (50, 85) PR(160) 5y 41% (4, 78) HR 0.20 ( ); CR/PR (52) p 0.02 <PR (14) < PR (147) p<0.001 Months from SCT Dreger Blood 2013, Brown Leukemia 2013, Hahn iwcll 2013, Michallet Leukemia 2010

7 The better the HLA-matching the lower the NRM and the better the survival n=368 72% RIC, 28%MAC MM : mis-matched (n=131) WMUD : HLA compatibility 8/8 (n=39) Sibling (n=181) NRM OS Michallet et al Leukemia 2010

8 Younger patients have lower hazard of death after allosct Van Gelder, de Wreede, Schetelig et al., poster # 2561 ASH 2014

9 Conclusions allosct allosct can overcome poor prognostic impact of del(17p) / TP53 mutation Patients in remission fare better after allosct good transplant candidates are patients with lower age no or with minor co-morbidity well HLA-matched donors responsive disease

10 Proposed Randomized Study Poor risk CLL Good risk SCT Ibr+ anti- CD20 CR PR SD * PD/S D R Ibr until relapse Allo SCT + Ibr until MRD- off study Part 1 Part 2

11 Reasons why we halted the RCT Unlikely to end successfully Skepticism about inclusion rate (CMWP EBMT, ERIC, ) Skepticism as this would then be the 1 st successful transplant RCT It becomes more clear that subgroups of the BCRi studies do worse, and need alternative therapies Transplant candidates are likely among these Pharmaceutical companies recognize this

12 2 Study proposals : HOVON or GIMEMA Exploration of BCRi + anticd20 +/- Bcl2i followed by allosct +/- maintenance until MRD-negativity

13 Results of the Dutch-Belgian Prospective Multicenter HOVON88 Trial R-DHAP before allosct in high risk CLL

14 Results - 2 Proceeding to allosct after R-DHAP (52% overall response) 61% of R-DHAP treated patients proceeded to allosct; 55% MRD at 1 year after allosct Similar results in. Reasons for no transplant: progression NRM poor performance

15 Aims of a new study 1. Improve % of transplanted patients with a 10/10 HLA-matched donor from 60% to 80% 2. Minimum of 60% MRD- at 1 year after allosct

16 Inclusion Criteria EBMT criteria for allogeneic HCT Non-response or early relapse (< 12 months) after PA therapy Relapse (< 24 months) after PA-combination therapy Any relapse of CLL with p53 deletion/mutation del 17p- age <60 years or age >60 years and HCT-CI score of 0 medically fit

17 ChemoNo Remission Induction for Refractory CLL prior to allogeneic stem cell transplantation Fludarabine Refractory < 1 year, or Fludarabine + MoAb Refractory < 2 years, or TP53 mutation/del(17p) from 2nd line on Registration, Start Donor Search Modern no chemo induction Responsive or Stable Disease and 10/10 HLA-matched Donor Available? Yes No RIC AlloSCT (+ maintenance until MRD-) Maintenance until progression or alternative therapy

18 Treatments Induction BCRi Ibrutinib Idelalisib After allosct No maintenance Anti-CD20 maintenance until MRD- Plus / minus anti-cd20 Rituximab Ofatumumab Obinatuzumab

19 Power calculation Study aim Improve % of transplanted patients with a 10/10 HLA-matched donor from 60% to 80% 35 needed Interim after 13 Correction factor for those not having a 10/10 HLAmatched donor 35/0.55=64 maximal needed May be too pessimistic accrual stops when for 35 a 10/10 HLA-matched donor is available

20 SIMILAR STUDY GIMEMA

21 GIMEMA Ofatumumab + Ibrutinib induction, followed by allosct if 10/10 HLA-matched donor available High risk TP53 mutation / del(17p) Fludarabine refractory < 12 months year Exclusion: anti-cd20/anti-cd52 MoAb <3 months before inclusion

22 GIMEMA Induction: 7x28 days Ibrutinib ofatumumab

23 GIMEMA Induction: 7x28 days Ibrutinib ofatumumab Time of primary endpoint: CR rate Aim: increase CR rate from 17% after Benda-ritiximab to 32% with Ibr-Ofa

24 GIMEMA Induction: 7x28 days Ibrutinib ofatumumab maintenance allohsct Responsive patients with 10/10 HLA-matched donor may proceed to allosct Time of primary endpoint: CR rate Aim: increase CR rate from 17% after Benda-ritiximab to 32% with Ibr-Ofa

25 GIMEMA Induction: 7x28 days Ibrutinib ofatumumab maintenance allohsct Patients with 10/10 HLA-matched donor proceed to allosct primary endpoint: 80% with 10/10 HLA-matched donor make it to allohsct Aims: 1. increase 10/10 HLA-matched allohsct rate from 60% to 80% 2. Minimal 60% MRD- PFS at 1 year after allohsct

26 allosct and CLL in the BCRi era Who wants to join the writing cie.?