How Do You Measure Success in ALL?: Assessment of MRD

Transcription

1 How Do You Measure Success in ALL?: Assessment of MD Martin Schrappe, MD, PhD University Medical Center Schleswig-Holstein Christian-Albrechts-University Kiel, Germany

2 Topics Current risk classification in ALL MD response Treatment and endpoints AIEOP-BFM ALL 2000 AIEOP-BFM ALL 2009 Perspectives ALL, acute lymphoblastic leukemia; MD, minimal residual disease.

3 Topics Current risk classification in ALL Based on immunphenotype, genetics, and clinical factors (eg, age, WBC) esponse to (early) treatment: Prednisone response in PB Cytomorphology: BM analysis on days 8, 15, and EoI MD by FCM and PC Combination of the two principles BM, bone marrow; EoI, extensions of indication; FCM, flow cytometry; PB, peripheral blood; PC, polymerase chain reaction; WBC, white blood cell/count

4 van Dongen JJ, et al. Lancet. 1998;352(9142):

5 elapse-free Survival in I-BFM-SG Study According to the Combined MD Information at Timepoints 1 and 2 (n = 129) 43% of patients 4% of relapses 43% of patients 42% of relapses 14% of patients 54% of relapses van Dongen JJ, et al. Lancet. 1998;352(9142): van Dongen JJ, et al. Blood. 2015;125(26):

6 MD Timepoints 1a I A -D + I A -P + AIEOP-BFM ALL 2000: Treatment and MD 1 1b 2 day 33 day 78 I B H: PED-P t(9;22) t(4;11) N d33 M H: MD level at tp. 2 >=10-3 H - 1 H 3' S : no H criteria MD neg. at tps. 1+2 M: no H criteria no S-criteria H 2' H 1' S S - 2 M M - 2 (3) (4) (5) I I 12 Gy* only T-ALL 10 weeks interim maintenance with 6-MP / MTX 12 Gy* only T-ALL 12Gy* I 6-MP/MTX 6-MP/MTX I I I 4 Wks. 4 Wks. 3 H - 2 H 1' H 2' H 3' AIEOP BFM H 1' H 2' 18Gy* H 3' 12Gy* 0 BM sampling G-CSF I A -D: Protocol I, Phase A with DEXA I A -P: Protocol I, Phase A with PED 22 S C T # * presymptomatic cranial irradiation (18[24] Gy for CNS pos. pts only) # selected indications for allo-sct (in all strata of H) S: 2 molecular marker with a sensitivity of =<10-4 available (obligatory) W. 6-MP, 6-mercaptopurine; CNS, central nervous system; DEXA, dexamethasone; G-CSF, granulocyte-colony stimulating factor; Gy, Gray; H, high-risk; MD, medium-risk; MTX, methotrexate; N, non-responder; PED, prednisone;, randomization; SCT, stem-cell transplantation; S, standard-risk; tp, timepoint. Conter V, et al. Blood. 2010;115(16): Moricke A, et al. Blood. 2016;127(17): Schrappe M, et al. Blood. 2011;118(8):

7 pcb- and T-ALL in AIEOP-BFM ALL 2000: Distribution of Patients in MD isk Groups Distribution (%) pcb-all T-ALL 0 MD-S MD-I MD-H MD isk Groups AIEOP-BFM ALL 2000 I, intermediate-risk; pcb, precursor B-cell, T-ALL, T-cell ALL Conter V, et al. Blood. 2010;115(16): Schrappe M, et al. Blood. 2011;118(8):

8 AIEOP-BFM ALL 2000: Treatment and MD (3) (4) (5) MD Timepoints 1a I A -D + I A -P + 1 1b 2 day 33 day 78 I B H: PED-P t(9;22) t(4;11) N d33 M H: MD level at tp. 2 >=10-3 H - 1 H 3' S : no H criteria MD neg. at tps. 1+2 M: no H criteria no S-criteria H 2' H 1' S S - 2 M M - 2 I I 12 Gy* only T-ALL 10 weeks interim maintenance with 6-MP / MTX 12 Gy* only T-ALL 12Gy* I 6-MP/MTX 6-MP/MTX I I I 4 Wks. 4 Wks. 0 BM sampling H - 2 H 1' 20 H 2' + I A -D: Protocol I, Phase A with DEXA I A -P: Protocol I, Phase A with PED H 3' AIEOP BFM 22 H 1' H 2' S C T # Gy* H 3' 12Gy* W. Conter V, et al. Blood. 2010;115(16): Moricke A, et al. Blood. 2016;127(17): Schrappe M, et al. Blood. 2011;118(8):

9 Moricke A, et al. Blood. 2016;127(17):

10 AIEOP-BFM ALL 2000 MD Timepoints Day 33 Day 78 S S-1 1 I DXM p.o. (21d+) 10 mg/m²/day S-2 PDN p.o. (21d+) 60 mg/m²/day pct (in selected subgroups) MT MT IA-D IA-P IB VC i.v. 1.5 mg/m²/dose max. 2 mg M M M-1 2 DN p.i. (1 h) 30 mg/m²/dose M-2 I E.coli L-ASP p.i.(1 h)/i.m. 5,000 IU/m²/dose Int MT pct (in selected subgroups) I MT MT H H-1 3 H-2 MTX IT H H H 3 G-CSF 2 G-CSF 1 G-CSF H 1 G-CSF H 2 G-CSF H 3 G-CSF I Int MT I Int MT I BMP/ MD Days H H H 1 G-CSF 2 G-CSF 3 G-CSF allohsct pct MD pct MT MT wks BMP, bone marrow puncture; DN, daunorubicin; DXM, dexamethasone; L-ASP, L-asparaginase; PDN, prednisone; VC, vincristine Conter V, et al. Blood. 2010;115(16): Moricke A, et al. Blood. 2016;127(17): Schrappe M, et al. Blood. 2011;118(8):

11 P AIEOP-BFM ALL 2000: CI of elapse (5 Years) DXM n (%) PDN n (%) P (X²) TM (related to Prot. IA) 42 (2.4%) 19 (1.0%).001 infection-related 29 (1.6%) 13 (0.6%).008 other 13 (0.7%) 6 (0.4%) , SE = , SE =.007P(Gray) < DXM (N=1853) CI-el, 229 relapses years PDN (N=1867) CI-el, 323 relapses CI-el, cumulative incidence of relapse; SE, standard error; TM, transplantation-related morbidity/mortality. Moricke A, et al. Blood. 2016;127(17):

12 P dexa_pred10.tab 06SEP13 AIEOP-BFM ALL 2000: CI of elapse and EFS (5 Years) , SE= , SE= P(Log-ank)= P(Gray) < , SE= , SE= years DXM (N = 1853) EFS, 341 events CI-el, 229 relapses PDN (N = 1867) EFS, 401 events CI-el, 323 relapses EFS, event-free survival. Moricke A, et al. Blood. 2016;127(17):

13 AIEOP-BFM ALL 2000, Survival (5 Years) dexa_pred10.tab 06SEP13 P , SE = , SE = P(Log-ank)= DXM (N = 1853) SU, 216 deaths years SU, survival PDN (N = 1867) Moricke A, et al. Blood. 2016;127(17): SU, 209 deaths

14 Is MD a suitable endpoint in a (large) clinical trial (n = 3740)??? Moricke A, et al. Blood. 2016;127(17):

15 250 no data TEL-AML1 positive TEL-AML1 negative AIEOP-BFM ALL 2000: DEXA vs PED Composition of elapses pb-all, Pred Good-esponse TEL-AML1 elapse risk group MD response d S1/S2 S3/S4 250 no data good poor Dexa Pred 0 Dexa Pred 0 Dexa Dexamethasone mainly prevented those relapses that would have had a good chance of cure with relapse treatment. Therefore, PED-treated patients had superior survival after Moricke A, et al. Blood. 2016;127(17): treatment of recurrence. Pred

16 Definition of Standard isk ALL in Trial AIEOP-BFM ALL 2000

17 elapse-free Survival in I-BFM-SG Study According to the Combined MD Information at Time Points 1 and 2 (n = 129) 43% of patients 4% of relapses 43% of patients 42% of relapses 14% of patients 54% of relapses van Dongen JJ, et al. Lancet. 1998;352(9142): van Dongen JJ, et al. Blood. 2015;125(26):

18 Trial AIEOP-BFM ALL 2000: isk Stratification Standard isk (S) MD negative with 2 PC markers for IgH and T-cell receptor rearrangements in week 5 and week 12 after induction and consolidation therapy, respectively Marker sensitivity at least 10-4 No clinical/biologic H criteria M MD positive at w5 a./o. w12 and MD at w12 <10-3 with 2 markers or MD not classifiable; no clinical/biological H criteria H MD 10-3 at w12 or Prednisone-Poor-esponse, or Non-emission end of induction, or t(9;22) or t(4;11) IgH, immunoglobulin heavy chain. Schrappe M, et al. Blood. 2011;118(8):

19 ALL-BFM 83 pefs (10 Years) andomization S-Low With vs Without einduction 0.81, SE = 0.05 P (log-rank) =.002 with reinduction pefs , SE = 0.06 without reinduction years S-L/1, without reinduction (N = 66, 29 events) S-L/2, with reinduction (N = 60, 11 events) Möricke A, et al. Leukemia. 2010;24(2):

20 AIEOP-BFM ALL 2000 S-1 I MT MD Timepoints Week 5 Week 12 S 1 S-2 MT IA-D IA-P IB Controlled treatment M-1 I reduction in I patients M selected M by 2 early MD negativity M-2 MT MT H H-1 3 H-2 H 3 H 1 H 2 H 2 H 1 H 3 AIEOP BFM H 1 I I I I H 2 H 3 MT MT pct MT wks Conter V, et al. Blood. 2010;115(16): Moricke A, et al. Blood. 2016;127(17): Schrappe M, et al. Blood. 2011;118(8):

21 educed Intensity Delayed Intensification Protocol I Standard Intensity Delayed Intensification Protocol DEXA 10 mg/m 2 /d VC 1.5 mg/m 2 /d DOX 30 mg/m 2 /d L-ASP 10,000 U/m 2 /d (E.coli- MEDAC/KYOWA) CPM 500 mg/m 2 /d CPM 1000 mg/m 2 /d AA-C 75 mg/m 2 /d TG 60 mg/m 2 /d MTX IT BM/MD Day AA-C, cytosine arabinoside; CPM, cyclophosphamide; DOX, doxorubicin; TG, thioguanine Schrappe M, et al. Blood. 2011;118(8):

22 educed Intensity Delayed Intensification Protocol I Standard Intensity Delayed Intensification Protocol eduction of treatment DEXA 10 mg/m 2 /d VC 1.5 mg/m 2 /d DOX 30 mg/m 2 /d L-ASP 10,000 U/m 2 /d (E.coli- MEDAC/KYOWA) CPM 500 mg/m 2 /d AA-C 75 mg/m 2 /d TG 60 mg/m 2 /d DEX: by 30% VC: by 50% DOX: by 50% CPM: by 50% Duration minus 3 weeks CPM 1000 mg/m 2 /d MTX IT BM/MD Day Schrappe M, et al. Blood. 2011;118(8):

23 AIEOP-BFM ALL 2000 andomization in Standard isk (S) ALL 4937 pts registered in trial AIEOP-BFM ALL pts eligible for trial 1346 eligible for randomization in S 64 S not eligible due to early events etc; 182 refused randomization 1164 randomized in S (= 86.5% of eligible and accessible pts) Schrappe M, et al. Blood. 2016;128: Abstract 4.

24 100 AIEOP-BFM ALL 2000: S - Intent-to-Treat Event-Free Survival (EFS) at 5 Years (%) 40 median FU: 8.6 years rand_sr.tab 16NOV Log-ank P = years Experimental Arm: educed intensity (Protocol I): EFS 90.7% (SE = 1.2), N = 581, 60 events Control arm: egular DI (Protocol ): EFS 94.7% (SE = 0.9), N = 583, 45 events DI, delayed intensification. Schrappe M, et al. Blood. 2016;128: Abstract 4.

25 AIEOP-BFM ALL 2000 educed intensity delayed intensification (Prot. I) vs Standard delayed intensification (Prot. ) Analyzed per treatment given

26 100 AIEOP-BFM ALL 2000: S - As Treated Event-Free Survival (EFS) at 5 Years (%) Log-ank p = years educed intensity (Protocol I), EFS 90.6% (SE = 1.2), N = 584, 62 events Control: egular DI (Protocol ), EFS 94.9% (SE = 0.9), N = 579, 42 events Schrappe M, et al. Blood. 2016;128: Abstract 4.

27 30 25 AIEOP-BFM ALL 2000: S - As Treated Cumulative Incidence of elapse at 5 Years rand_sr.tab 16NOV16 Cum. Incidence elapse P(Gray)= years educed intensity (Protocol I): CI 7.5% (SE = 1.1), N = 584, 50 events Control: egular DI (Protocol ): CI 4.1% (SE = 0.8), N = 579, 35 events Schrappe M, et al. Blood. 2016;128: Abstract 4.

28 AIEOP-BFM ALL 2000: S, pb, ETV6/UNX1 Negative - As Treated 100 EFS (at 5 Year) rand_sr.tab 16NOV16 (%) Log-ank P = years educed intensity (Protocol I): EFS 87.7% (SE = 1.8), N = 325, 43 events Control: egular DI (Protocol ): EFS 94.2% (SE = 1.3), N = 316, 25 events Schrappe M, et al. Blood. 2016;128: Abstract 4.

29 AIEOP-BFM ALL 2000: S (Age 10 Years) As Treated EFS (5 years) (%) 40 rand_sr.tab 28NOV Log-ank P = years educed intensity (Protocol I): EFS 81.6% (SE = 4.0), N = 96, 17 events Control: egular DI (Protocol ): EFS 95.2% (SE = 2.4), N = 84, 6 events Schrappe M, et al. Blood. 2016;128: Abstract 4.

30 AIEOP-BFM ALL 2000: S (Age 10 Years ) As Treated 30 Cumulative Incidence of elapse at 5 Years 25 Cum. Incidence rand_sr.tab 28NOV P(Gray)= educed intensity (Protocol I): CI 14.1% (SE = 3.7), N = 96, 13 events Control: egular DI (Protocol ): CI 1.2% (SE = 1.2), N = 84, 3 events Schrappe M, et al. Blood. 2016;128: Abstract 4. years

31 AIEOP-BFM ALL 2009 ecruitment: ecruitment of new pts closed Dec 31, eligible pts before (please see details in AIEOP-BFM ALL 2009 report) ClinicalTrials.gov Identifier: NCT ( EudraCT Number: (

32 S: AIEOP-BFM ALL 2009 isk Stratification (new) * No H criteria and PC-MD-S (new: with at least one sensitive marker) or Not stratifiable by PC-MD, and FCM-MD on day 15 <0.1% M: No S criteria; no H criteria Not stratifiable by any MD method H: Prednisone Poor-esponse Non-emission at day 33 (induction failure) MLL/AF4-positive Hypodiploidy <45 Chromosomes PC-MD-H: PC-MD >10-3 at week 12 PC-MD-M SE in non-t-all: PC-MD >10-3 at d33 and still positive at week 12 FCM-MD d15 >10% * Age <365 days: not eligible for AIEOP-BFM ALL 2009 but eligible for Interfant-06 ClinicalTrials.gov Identifier: NCT ( EudraCT Number: (

33 AIEOP-BFM ALL 2009: Current Treatment Strategy in T-ALL MD Timepoints d15 TP1 TP2 d 33 d 78 T - non-h IA D IB M MD-H: PC at TP2 >= 5x10-4 (>= 0.05%) Ind Failure FCM d15 >10% T - H IB H H H IA CPM H I I I IB + SCT Exp. window + SCT w ClinicalTrials.gov Identifier: NCT ( EudraCT Number: (

34 andomized Treatment Questions 1 : eduction of induction related toxicity in pb VL patients 2 : Late intensification in pb M patients H : Early intensification in all H patients: Primary endpoint - MD VL, very low-risk

35 MD Timepoints Immunology unknown or pb-all + TEL/AML1 neg + FCM-MD d15 >=0.1% pb/non-h TEL/AML1 pos and/or FCM-MD d15 <0.1% AIEOP-BFM ALL 2009: Treatment Strategy in Bpc-ALL d15 IA IA 1 IA IB w IA Prot. IA with 4 DN doses (day 8, 15, 22 and 29) IA Prot. IA with 2 DN doses (day 8 and 15) * in patients with CNS disease (CNS 3) tct with 12 Gy/18 Gy (dose age-adapted)) & since 2010: lipos. DN + FLA CT, cranial radiotherapy; FLA, fluradabine and cytarabine

36 MD Timepoints Immunology unknown or pb-all + TEL/AML1 neg + FCM-MD d15 >=0.1% pb/non-h TEL/AML1 pos and/or FCM-MD d15 <0.1% AIEOP-BFM ALL 2009: Treatment Strategy in Bpc-ALL d15 IA IA 1 IA IB M S M w IA Prot. IA with 4 DN doses (day 8, 15, 22 and 29) IA Prot. IA with 2 DN doses (day 8 and 15) * in patients with CNS disease (CNS 3) tct with 12 Gy/18 Gy (dose age-adapted)) & since 2010: lipos. DN + FLA

37 Pieters, et al. Cancer. 2011;117(2):

38 andomization PEG-L-Asparaginase in M pb-all Monitoring of Enzyme Activity, ASN Depletion (CSF), and Antibody Formation Protocol A B Maintenance Protocol -ASP+ A B Maintenance weeks PEG-L-ASP (2,500 IU/m 2 ) Analysis of ASP activity and antibodies in serum Analysis of ASP activity and antibodies in serum, asparagine in CSF LP, intrathecal MTX ASN, asparaginase; CSF, cerebrospinal fluid; LP, lumbar puncture; PEG-L-ASP, pegylated L-asparaginase

39 AIEOP-BFM ALL 2009: Treatment with pegaspase IV T/non-H IA D IB M pct 12 Gy if age 2 yrs* / in selected subgroups no CT + 6x IT MTX Immunology unknown or pb-all + TEL/AML1 neg + FCM-MD d15 >0.1% IA S pb # /non-h TEL/AML1 pos and/or FCM-MD d15 <0.1% IA 1 IA IB M M MD-M SE MD-H only Nd33 only FCM d15 10% 2 H T-ALL pb-all # IA CPM IA pct 12 Gy if age 2 yrs* / in selected subgroups no CT + 6x IT MTX IB H H H H I I I IB + SCT DNX-FLA + SCT PEG L-asparaginase (2500 IU/m²) IV IA Prot. IA with 4 DN doses (day 8, 15, 22 and 29) IA Prot. IA with 2 DN doses (day 8 and 15) # or immunophenotype unknown * in patients with CNS disease (CNS 3) tct with 12 Gy/18 Gy (dose age-adapted)) w PEG-ASP 2500 IU/m 2 every 2 weeks, over 20 weeks in total PEG-ASP 4 x 2500 IU/m 2 over 4 weeks

40 MD in H Patients Strategy in AIEOP-BFM ALL 2009

41 Intensification of Consolidation Phase in the H group andomization H andomization of 4 Weeks (4 doses) vs No Additional PEG-L-ASP in Prot. IB

42 andomization PEG-L-ASP in H (done with weekly ASP enzyme monitoring) Prot. IA / IB IA IB Prot. IA / IB-ASP+ IA IB weeks PEG-L-ASP (2500 IU/m 2 )

43 andomization PEG-L-ASP in H (done with weekly ASP enzyme monitoring) Prot. IA / IB Prot. IA / IB-ASP+ IA IB IA IB weeks MD at week 12 = primary endpoint PEG-L-ASP (2500 IU/m 2 )

44 AIEOP-BFM ALL 2009 T/non-H IA D IB M pct 12 Gy if age > 2 yrs* / in selected subgroups no CT + 6x IT MTX Immunology unknown or pb-all + TEL/AML1 neg + FCM-MD d15 >0.1% IA S pb # /non-h TEL/AML1 pos and/or FCM-MD d15 <0.1% IA 1 IA IB M M MD-M SE MD-H only Nd33 only FCM d15 >10% 2 H T-ALL pb-all # IA CPM IA pct 12 Gy if age 2 yrs* / in selected subgroups no CT + 6x IT MTX IB H H H H I I I IB + SCT DNX-FLA + SCT w IA Prot. IA with 4 DN doses (day 8, 15, 22 and 29) IA Prot. IA with 2 DN doses (day 8 and 15) PEG-ASP 2500 IU/m 2 every 2 weeks, over 20 weeks in total # or immunophenotype unknown * in patients with CNS disease (CNS 3) tct with 12 Gy/18 Gy (dose age-adapted)) PEG-ASP 4 x 2500 IU/m 2 over 4 weeks

45 Target Population: MD High-isk Group TP1 TP2 MD Timepoints H P IA IB H 1' H 2' H 3' P: (4y-pEFS) MD neg. 0.70, SE = 0.08 (N = 42) Years MD < , SE = 0.10 (N = 27) MD , SE = 0.10 (N = 25) H 1' H 2' H 3' 6-MP/ MTX MD-H-only : SCT VHL : Experimental therapy VHL, very high-risk leukemia

46 Patients MD-esponse After DNX/FLA MD after DNX/FLA (log-step) -6 negative Immunephenotyp e T pb T T pb T T pb T pb T T pb pb pb pb T

47 Perspectives Genetics and esponse

48 10-Year Survival in the 624 Study Patients With Induction Failure Who Had Genetic Data, According to Genetic Abnormality Schrappe M, et al. N Engl J Med. 2012;366(15):

49 New Candidate Prognostic Factors: CLF2 and IKZF1: BFM Data CLF2/P2Y8 + IKZF1 del + Cario G, et al. Blood. 2010;115(26): Dörge P, et al. Haematologica Aug 8 [Epub ahead of print]

50 New Candidate Prognostic Factors: CLF2 and IKZF1 CLF2/P2Y8 + IKZF1 del + 5-y OS: IKZF1 not del. 0.92, SE = 0.01 IKZF1 del. 0.82, SE = 0.04 Independent confirmation of prognostic impact in AIEOP patients with ALL. Limited clinical utility as prognostic impact on overall survival is limited. Del., deleted; OS, overall survival Cario G, et al. Blood. 2010;115(26): Dörge P, et al. Haematologica Aug 8 [Epub ahead of print]

51 Treatment Outcome of IKZF1del-Negative and Positive Childhood ALL Patients by EG Deletion IKZF1del EFS (5 years) , SE = , SE = 0.04 P Combination with other factors can refine prognostic potential Log-ank P = EGwt (N = 138, 54 events) years EGdel (N = 26, 5 events) Zaliova M, et al. Leukemia. 2014;28(1):

52 IKZF1 Screening by MLPA MLPA kit P335-A3 (MC-Holland): Analysis of additional genes*, e.g. CDKN2A, CDKN2B, PAX5, and PA1 (=CLF2) Testing of all single deletions and all possible deletion combinations for effect on outcome MLPA, Multiplex ligation-dependent probe amplification. *associated with GATA3 alleles variants.

53 Definition: IKZF1 plus Deletion of IKZF1 and: PAX5 and/or CDKN2A and/or CDKN2B and/or CLF2 (PA) and Negativity for EG deletion

54 Conclusions evision of stratification systems needed by incorporating newly defined high-risk subgroups Combining validated genetic profiles and MD results may allow novel approaches (Example IKZF1 or IKZF1 plus ) The role of intensified L-ASPase therapy not yet clear (ongoing randomizations in trial 2009) Treatment intensity should not be increased but rather be reduced in well-controlled clinical trials Potentially, acute toxicity can be reduced by controlled introduction of new alternative treatment modalities