Indications (GRAALL ) Donneurs Conditionnements

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1 Indications (GRAALL 2003-2005) Donneurs Conditionnements
Allogreffe de CSH et LAL non Ph de L’ADULTE en RC1 Indications (GRAALL ) Donneurs Conditionnements Stéphanie Nguyen, Service d’Hématologie du Groupe Hospitalier Pitié-Salpêtrière, Paris

2 RBZ/DNR/ADR+AraC+Aspa
LALA-/87 RBZ/DNR+CPM+VCR+PDN RBZ/DNR/ADR+AraC+Aspa 2 (R) + 1 courses CHEMO (20 months) ASCT age≤40y with sibling age>50y age<40y w/o sibling or 40y<age≤50y ALLO IDA/DNR+VCR+CPM+PDN LALA-94 Standard-risk High-risk* (R) Ph- and CNS- age≤50y with sibling (24 months) age≤50y w/o sibling or age>50y Ph+ and/or CNS+ HAM 2 MTX+Aspa Protocoles LALA 87

3 (A Thiebaut Hematology/oncology clinics of north america 2000)
LAL RC1 : LALA 87 Survie à 10 ans (A Thiebaut Hematology/oncology clinics of north america 2000) Bras Allo Bras contrôle Nombre % P Tout risque 116 46 141 31 0,04 Haut risque 41 44 55 11 0,009 Risque standard 75 49 86 43 NS

4 RBZ/DNR/ADR+AraC+Aspa
Protocoles LALA 94 LALA-/87 RBZ/DNR+CPM+VCR+PDN RBZ/DNR/ADR+AraC+Aspa 2 (R) + 1 courses CHEMO (20 months) ASCT age≤40y with sibling age>50y age<40y w/o sibling or 40y<age≤50y ALLO IDA/DNR+VCR+CPM+PDN LALA-94 Standard-risk High-risk* (R) Ph- and CNS- age≤50y with sibling (24 months) age≤50y w/o sibling or age>50y Ph+ and/or CNS+ HAM 2 MTX+Aspa

5 Supériorité de l’allogreffe chez haut risque
LALA 94 N= 129 Thomas JCO 2004 Supériorité de l’allogreffe chez haut risque Haut risque RC en 2 cures LAL B >30 g/l B CD10- CytoG haut risque Immuno ou cytoG inconnue Donor géno Pas de donneur géno

6 MRC UKALL XII/ECOG 2993 N=1929 Goldstone A H –BLOOD 2008
An international collaboration was set up with a donor had a 5-year improved over therapy and considerable survival benefit to prospectively evaluate the role of allo all survival (OS), 53% versus 45% for standard-risk patients. However, the geneic transplantation for adults with (P .01), and the relapse rate was signifi transplantation-related mortality for highacute lymphoblastic leukemia (ALL) and cantlylower(P< .001).Thesurvivaldiffer risk older patients was unacceptably high compare autologous transplantation with ence was significant in standard-risk pa and abrogated the reduction in relapse standardchemotherapy.Patientsreceived tients, but not in high-risk patients with a risk. There is no evidence that a single 2 phases of induction and, if in remission, high nonrelapse mortality rate in the high autologous transplantation can replace were assigned to allogeneic transplanta risk donor group. Patients randomized to consolidation/maintenance in any risk tion if they had a compatible sibling do chemotherapy had a higher 5-year OS group. This study is registered at nor. Other patients were randomized to (46%) than those randomized to autolo clinicaltrials.govasNCT (Blood. chemotherapy for 2.5 years versus an gous transplantation (37%; P .03) ;111: ) autologous transplantation. A donor ver Matched related allogeneic transplantasus no-donor analysis showed that Phila tions for ALL in first complete remission delphia chromosome–negative patients provide the most potent antileukemic © 2008 by The American Society of Hematology Goldstone A H –BLOOD 2008

7 Meta-analyse : LAL de l’adulte en RC1 Donneur familial HLA-identique vs non donneur Survie (n=2962; 13 essais) Hematopoietic cell transplantation (HCT) and prolonged chemotherapy are standard postremission strategies for adult acute lymphoblastic leukemia in first complete remission, but the optimal strategy remains controversial. There are no randomized trials of allogeneic HCT. In the present study, updated individual patient data were collected and analyzed from studies with information on availability of matched sibling donor (used to mimic randomization) and from randomized trials of autograft versus chemotherapy. Data from 13 studies including 2962 patients, excluding Philadelphia chromosome–positive patients, showed a survival benefit for having a matched sibling donor for patients < 35 years of age (OR 0.79; 95% CI, , P ) but not for those > 35 years of age (OR 1.01; 95% CI, , P .9; heterogeneity P .03) because of the higher absolute risk of nonrelapse mortality for older patients. No differences were seen by risk group. There was a trend toward inferior survival for autograft versus chemotherapy (OR 1.18; 95% CI, ; P .06). No beneficial effect of autografting was seen compared with chemotherapy in this analysis. We conclude that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years. Improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future. The place of allogeneic transplantation in adult ALL patients is still difficult to assess In a recent large donor versus no-donor meta-analysis published this year, a significant survival advantage was observed in the donor group, the plateau was reached after 4 years of follow-up. Yet: This survival advantage was only observed in patients under 35 years of age. Autologous transplantations were performed in the no-donor group, associated with a worse outcome. And C) the overall gain in 5-year survival was relatively modest (around 7%) As the results associated with chemotherapy alone are still improving, the place of allogeneic transplantation in first Complete remission is still a matter of debate,. The main issue is how to select those patients who will truly benefit from allogeneic transplantation ? Gupta et al, Blood 2013

8 Progrès de la chimiothérapie :inspiration pédiatrique
GRAALL (Huguet JCO 2009) Pediatric options Steroid prephase High cumulative doses of PDN, VCR, and L-aspa High dose-intensity consolidation Late intensification 2-year maintenance Adult options HyperC sequence CNS irradiation Allogeneic SCT for high-risk patients Early G-CSF

9 place de l’allogreffe dans les protocoles d’inspiration pédiatrique?
relapse Nette amélioration du devenir des patients après intensification des chimiothérapies place de l’allogreffe dans les protocoles d’inspiration pédiatrique?

10 Identification de nouveaux facteurs pronostiques
MRD Délétion focale d’IKZF1 (lignée B) Mutation de NOTCH1/FBXW7, N/K-RAS, et délétion de PTEN (lignée T) (Gökbuget Blood 2012, Trinquand JCO 2013, Kheira Beldjord, Blood 2015) intérêt de ces facteurs pour identifier les patients bénéficiant de l’allogreffe?

11 Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia Thank you Mister/Madam Chair. Good afternoon ladies and gentlemen. I would like to thank the ASH abstract selection committee for giving me the opportunity of presenting our results of allogeneic hematopoietic transplantation in Ph negative ALL patients treated in the GRAALL trials and allografted in first complete remission. Nathalie Dhédin, Anne Huynh, Sébastien Maury, Reza Tabrizi, Xavier Thomas, Patrice Chevallier, Stéphanie Nguyen, Valérie Coiteux, Mathilde Hunault, Stéphane de Botton, Yosr Hichri, Martine Escoffre-Barbe, Oumedaly Reman, Yves Chalandon, Didier Blaise, Nicole Raus, Véronique Lhéritier, Jean-Yves Cahn, Hervé Dombret et Norbert Ifrah. Blood, 2015

12 Intensification retardée
Protocoles GRAALL 2003/2005 * Intensification retardée Maintenance: 24 mois MRD1 (6 Sem) MRD2 (12 Sem) Here is the general schedule of the pediatric inspired GRAALL protocol. As shown, allogeneic transplantation was planned to be performed after the first or second consolidation phase In these trials, only patients aged 55 years or less and presenting at least one conventional high-risk factor were eligible for transplantation in first CR. Allogreffe : après 1 ou 2 consolidations *

13 Indications d’allogreffe Protocoles GRAALL 2003/2005
- LAL à haut risque (HR): Critères de haut risque au diagnostic GB ≥ G/L : LAL B Envahissement du SNC LAL B CD10-négative * t(4;11), MLL-AF4 ou autre réarrangement MLL t(1;19), E2A-PBX1 low hypodiploidie, near triploidie, caryotype complexe (≥ 5 anomalies) * Mauvaise réponse précoce au traitement Corticorésistance à J8 de préphase de stéroides (Blastes sanguins > 1 G/L ) Chimiorésistance: Persistance blastes médullaires > 5% à J8 de la chimiothérapie d’induction Absence de RC après l’induction Maladie résiduelle Ig/TCR ≥ 10-2 ** This slide shows the conventional high-risk factors we used including baseline factors, like white blood cell count and cytogenetics and poor early blast clearance after the steroid prephase in the peripheral blood or during induction course in the bone marrow One risk factor was enough to be classified in the high-risk ALL group. We did not use minimal residual disease in this classification (except very high levels in the first GRAALL-2003 trial), but, as you will see later, we measured it. - Age < 55 ans et RC1 *: critères introduits dans le GRAALL-2005, ** critère présent uniquement dans le GRAALL-2003

14 Modalités d’allogreffe
12Gy ICT - CY MTX + Cyclo Donneur 10/10 HLA MRD or MUD (9/10 HLA MUD*) * t(4;11) et/ou MLL-AF4+ ou autre réarrangement MLL, low hypodiploidie ou near triploidie, absence de RC après la chimiothérapie d’induction

15 Pts éligibles pour la greffe : HR, 15-55 ans
GRAALL 2003/2005 : LAL Ph-, ans N = 955 RC1 N = 880 (92%) Pts éligibles pour la greffe : HR, ans N = 522 Bras greffe N = 283 140 familiales HLA-identiques 143 non apparentées (10/10 HLA: 95; 9/10 HLA: 35; USP: 13) Délai médian : RC- greffe: 106 jours Bras non greffe N = 239 Here is the patient flow chart: Out of 955 pts treated in the GRAALL trials, 92% achieved CR; 522 with high-risk ALL were eligible for allogeneic transplant; and 283 were actually transplanted. Caractéristiques des patients: Pas de différence significative entre les deux bras sauf t(4;11) et d’anomalies de MLL: plus fréquent dans le bras greffe

16 Patient outcome according to the GRAALL-2003/2005 risk classification.
Survie à 5 ans N=221 Standard risk 74% N=522 High risk 58.4% Among 743 classifiable patients aged 55 years old or less with ALL in first CR, 5-year OS from CR was estimated at 58.4% ( ) in the 522 high-risk patients versus 74.0% ( ) in the 221 with standard-risk patients (HR, 1.80 [ ]; P<0.001).

17 Devenir des patients allogreffés
GVH

18 Comparaison greffe vs non greffe
Groupe pts à Haut Risque Survie sans rechute Allogreffe N=283 Pas allogreffe N=239

19 Analyse par sous groupes Comparaison greffe vs non greffe: survie sans rechute
*: HR du bras greffe versus du bras non greffe. **: par le modèle Andersen-Gill.

20 Maladie résiduelle Evaluation en post-induction
Ig/TCR 6 semaines après le début de la chimiothérapie moelle Seuil de 10-3 N= 278 patients testés/522 patients HR We then looked at Minimal Residual Disease. We used the first post-induction MRD1 evaluation in bone marrow samples by Ig/TCR specific PCR, performed 6 weeks after chemotherapy initiation. 278 of the 522 patients had an MRD1 evaluation 55% of them had an MRD1 above 10-4, with no significant difference in MRD response between the transplant and no-transplant cohorts. Allogreffe Non allogreffe Tous MRD1 <10-3 93 77 170 MRD1 ≥10-3 61 (40%) 47 (38%) 108 (39%) p= NS

21 L’allogreffe bénéficie aux MRD1+
MRD1 neg, no SCT MRD1 neg, SCT MRD1 pos, SCT MRD1 pos, no SCT

22 Impact de la MRD Survie sans rechute LAL B LAL T

23 Impact des anomalies oncogénétiques Comparaison greffe vs non greffe: survie sans rechute
LAL B : Délétion IKZF1 LAL T : Classification à 4 gènes* *Absence de mutation NOTCH1/FBXW7 et mutation de N/K-RAS ou délétion de PTEN

24 Allo MAC après chimio d’inspiration pédiatrique sujets “HR”
Conclusions GRAAL Allo MAC après chimio d’inspiration pédiatrique sujets “HR” 3y-OS 69% ; NRM à 15% BONS RESULTATS >45 ans > 3 blocs de consolidation GRAALL 2014 RIC si > 45 ans NRM pas de bénéfice de l’allogreffe chez les patients avec facteurs ‘conventionnels’ de haut risque GRAALL2014 Indication d’allogreffe basée sur la MRD In conclusion: - In adult patients with ALL, good results were observed with transplantation performed after a pediatric-inspired chemotherapy - Conventional high-risk factors do not help to define which patients will benefit from transplantation in first CR - On the contrary, as already reported by the German group, early MRD response appears to be of high prognostic value and even predictive of a Stem Cell Transplantation positive effect So in the next GRAALL trial, indication of transplantation will tbe based on MRD response only, using the VHR MRD definition. Thank you very much for your attention Bénéfice de l’allogreffe en RC1 chez MRD1+ et la dél IKAROS (lignée B)

25 Quels sont les donneurs disponibles ?
Quels donneurs?

26 Dhedin et al, Blood 2014

27 Allogreffe de LAL MUD=MRD
EBMT LAL RC1 Kiel JCO 2004 Apparenté=62 Non apparenté =32

28 survie identique HLA id=USP=mismatch 7/8
LAL en RC1 ou 2 . regression we compared outcomes after 116 mismatched single or double cord blood, 546 peripheral blood progenitor-cells and 140, bone marrow. Patient and disease characteristics of recipients were similar except cord blood recipients were younger, more likely to be non-Caucasians and to have low white blood cell count at diagnosis. Probability of overall survival. The 3-year probabilities of overall survival adjusted for disease status, duration of first complete remission and patient race after cord blood, 8/8 and 7/8 HLA-matched peripheral blood progenitor cell or bone marrow transplants were 44% (95% CI 34 – 54), 44% (95% CI 40 – 48) and 43% (95% CI 35 – 51), respectively Marks, Haematologica 2014

29 Mayumi et al Immunobiology 1996
Donneur haploidentique? Intérêt des greffes haplo non manipulée avec déplétion in vivo des LT alloréactifs par ENDOXAN post-greffe 1)Destruction des LT alloréactifs. 2) Préservation des clones de CTL anti-infectieux 3) Expansion d’autres populations d’intérêt? (NK? NKT? Treg?..) Mayumi et al Immunobiology 1996

30 N=30 haplo CDT TBI 12Gy+Flu + Endoxan post-greffe
Greffon de CSP non manipulé Solomon, BBMT 2015

31 Les Haplo MAC-TBI font au moins aussi bien que les MUD-MAC
Population totale Bas risque-int Rique défav-très défavorable Solomon, BBMT 2015

32 AVEC QUEL CONDITIONNEMENT ?

33 MAC: TBI vs BU - pas d’essais randomisées de qualité
Bunin, BMT 2003 (rando enfants) Granados, Haematologica 2000 Davies, JCO 2000 (IBMTR) Shi Xia leuk lymph 2010 (meta-analyse) Kaleycio, BMT 2011 Eyroglu, Leuk Lymph 2013… - pas d’essais randomisées de qualité - les seules études rétrospectives publiées sont plutôt en faveur de la TBI Dans l’attente d’une grande étude randomisée BU vs TBI Difficile d’abandonner la TBI dans la LAL de l’adulte (problèmes chez l’enfant)

34 Age médian des patients Données ABM (enfants inclus)

35 Age médian des patients allogreffés ( la Pitié Salpetrière )

36 + de rechute dans les RIC
Etude rétrospective EBMT; 186 centres N= 576 malades ( 1-71 ans) Greffes âge médian 52 ans Marks, Blood 2010 Eom, am J hematol 2013 Mohty, Blood + de rechute dans les RIC + de TRM dans les MAC Devenir comparable TRM P=0,03 LFS P=0,07 P=0,6 Survie Relapse P=0,001 Trait plein = MAC Mohty et al; Blood 2010

37 N=30 LAL HR sujets âgés (60 ans)
CDT avec Thiotepa, Fluda, carmustine Intérêt du Thiotepa en remplacement de la TBI? Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days −6 to −4), carmustine (400 mg/m2 on day −6), and thiotepa (5 mg/kg twice daily on days −5 and −4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, years), and the median follow-up was 968 days (range, days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system–active conditioning. Christopoulos, BBMT 2012

38 Critères « classiques » de Haut risque
CONCLUSIONS-PROJECTIONS Critères « classiques » de Haut risque Critère MRD de Haut risque + amélio chimio quel donneur ? Géno 10/10 OK HR 400 Phéno 10/10 OK Haut risque 200 9/10 ? USP ? Haplo? à discuter 600 280 ne rechuteront pas 400 Bas risque 200 Bas risque 120 rechutent 30 HLA géno 45 phéno 10/10 45 9/10, USP, haplo

39 QUEL CONDITIONNEMENT? <45 ans TBI reste de rigueur chez l’adulte >45 ans RIC Chez l’enfant ou si contre indication TBI MAC avec Bu? Thiotepa? Protocole européen TBI vs Thiotepa en cours

40 Remerciements Nathalie Dhédin Jean Paul Vernant
I would also like to thank all the people who collaborated to the study, especially Nathalie Dhédin, Sébastien Maury, as well as the data managers Nicole Raus and Véronique Lhéritier. (And I declare there were No competing interests).