Debate: Should ‘pediatric’-like strategies be extended over the age …€¦ · and paired patients treated with EORTC ALL4 protocol. Stratification according to age : P= NS.

Should ‘pediatric’-like strategies be extended over the age of 35?

Jean-Pierre Marie, Ollivier Legrand, Stephanie Haiat, Anne Vekhoff

Department of Hematology, Saint-Antoine Hospital, Paris

University Pierre & Marie Curie

Principles of a « pediatric-like » regimen Example: FRALLE (versus LALA) (Boissel N, JCO 2003, 5: 774)

FRALLE-93 (77 pts) LALA-94 (100pts)Prednisolone: 4.4g/sqm 0.8g/sqm x 5.5VCR/VDS: 19 infusions 6 infusions x 3.2Aspa: 180.000 U 9.000 U x 20DNR: 280mg 150mg x 1.9VP16/CPM: 1.2g/0 0/12.5gDelay induction-conso: 0 5 days

Much more « Non Myelotoxic Drugs » : corticosteroids, VCR, L Asparaginase. No delay nor dose reduction Longer intensive post induction phases (consolidation, intensification, interphase…) 2 year maintenance

Toxicities of the Non Myelotoxic Drugs

Corticosteroids

Asparaginase

Vinca alkaloïds

DIABETIS

INFECTIONS

OSTEONECROSIS NEUROPATHY

DENUTRITION

THROMBOSIS

LIVER/ PANCREATIC TOXICITY

Is an age threshold for « pediatric like » ALL regimen ? Analysis of 3 trials

• FRALLE 2000 faisability: – Monocentric: Hôtel-Dieu Hospital, (40 pts, 18-55y), Leuk Res 2011,

35:66-72

– Multicentric: H70 HOVON phase II trial using FRALLE 2000 (54 pts, 17-40y), Leukemia 2011, 25:1697-1703

• DFCI faisability: – Princess Margaret Hospital (85 pts, 18-60y), Br J Haematol 2009, 146:76-

85

R egis tra tion

P re-phase

Induc tion

C onso lida tion

In tens ifica tion I

In te rphase

In tens ifica tion II

M a in tenance

A llogene ic s tem ce lltransp lan ta tion

1)

1)

1)

1)

1)

1) P atien ts in C R , o the rw ise o ff p ro toco l trea tm ent

Frame of the FRALLE2000 -like faisability trial

7d PDN

PDN, VCR, Aspa, DNR

6TG, VP16, Ara-C,PDN,6MP,HDMe

Dexa, Vind, ADR, Aspa, 6TG, VP16, Ara-C

PDN, VCR, 6MP, HD Me

Dexa, Vind, ADR, Aspa, 6TG, VP16, Ara-C

6MP, Metho, VCR, PDN

(+ IT prophylaxis)

Cortico-sensitivity

Chemo-sensitivity

CR? If NO : HAM

8monthS

2y

Only if bad cytogenetic or high MRD

0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

Months

P(s

urvi

val) Results of

FRALLE2000In children

Grade 3-4 toxicity according to age (Hôtel-Dieu experience)

Haiat et al, Leuk Res. 2011, 35:66-72.

0% 10% 20% 30% 40% 50% 60% 70% 80%

Liver tox

Infections

Thrombosis

Osteonecrosis

Hyperglycemia

Weigh loss

Neuropathy

Reduction of ASPA

>40y<40y

*

***

* p<0.05No toxic deaths (except after allograft)

FRALLE 2000: Time Schedule in adults

D1ConsoD35- 42

D1Intens. 1D95-102

D1InterphaseD155-162

D1Intens. 2D205-212

D1Mainte- nanceD265-272

Median

extremes

38

31-54

102

95-162

164

150-198

242 (+30d)

225-305

306 (+34d)

270-382

0

,2

,4

,6

,8

1

Surv

ie C

um.

0 500 1000 1500 2000 2500 3000 3500 4000

0

,2

,4

,6

,8

1

Surv

ie C

um.

0 250 500 750 1000 1250 1500 1750 2000

P=0.04

79%

44%

50%

41%

Comparison of overal survival in adult ALL treated with FRALLE-like regimen or EORTC-ALL4 regimen

< 40 yo (26 pts) >40 yo (14 pts)

FRALLE 2000 like« classic » adult ALL schedule (EORTC ALL4)

Historical comparison between patients treated with FRALLE 2000 and paired patients treated with EORTC ALL4 protocol

Stratification according to age :

P= NS

HOVON 70: FRALLE 2000 FaisabilityMulticentric phase II faisability of a pediatric protocol (FRALLE2000) in yong adults(17-40y) : 54 pts included, median age 26. 91% CR. Median follow-up 32 months.

% o

f gra

de ¾

toxi

city

0%

10%

20%

30%

40%

50%

60%

Liver tox Infections Neuropathy Thrombosis

INDUCTIONCONSO/INTENS.MAINTENANCE

Only 33 (61%) completed the treatment as scheduled (< 2 months delay until maintenance)

3 (5.5%) toxic death1 pulmonary embolism2 septic shock

2 hip osteonecrosis

The Princess Margaret Hospital (Toronto) experience Storring JM et al, Br J Haematol 2009, 146:76-85

• Between 2000 and 2006, 85 Ph(-)ALL, 18-60 (median 37y) were treated with a « modified » DFCI 91-01 pediatric regimen:

PDN 6-MP

Dexa9

Induction CNS Therapy Intensification maintenance28 days 21 days 21 d cycle 21 d cycle

x 10 cycles x 24 cycles

RxRxRxRxDexa

6

DoxoVCR

Metho 4g 30mgx3

Aspa 25000 U 12500Ux3

78 mg VCR

425 000 U/m2 ASPA

The Princess Margaret Hospital (Toronto) experience Storring JM et al, Br J Haematol 2009, 146:76-85

• Most frequent complications

7 (8.2%) treatment-related deaths, 5 during induction, 2 during intensification20% induction mortality in patients > 50y6/35 (17%) pts over 35 received <80% of the planned dose of ASPA28/85 (33%) pts received vinblastine during intensification, without worse prognosis

DFS according to dose of ASPA received in adult pts treated with DFCI 91-01

• 85 bcr-abl (-) ALL, 18-60 yo

Storring JM et al, Br J Haematol 2009, 146:76-85

In conclusion* The age threshold depends upon the drug intensity

schedule, especially doses of Non Myelotoxic Drugs, and comorbidities (increasing with age)

* If enough drugs cannot be administered, the benefit of the schedule vanishes

• A clear learning effect has to be taken in consideration, with the development of adequate supportive care and drug replacement.

=> When a “pediatric” schedule is introduced, the first age threshold should be 35y, and progressively increased to 40 or 45y according to comorbidities

Comparison of adult vs pediatric regimen in adolescents with ALL

« Pediatric inspired » protocol components:

- Corticoïd prephase, High dose asparaginase during induction- Several blocks of consolidation with re-induction, intensification and HD metho- 2 years maintenance with 1 y of monthly VCR+PDN

Pediatric-based PETHEMA ALL-96

• 81pts, 15-30yo, treated with 5drug/5 w induction, 2 early consolidations and 2 y maintenance

15-18 y

19-30 y)

0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

Months

P(s

urvi

val)

0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

Months

P(n

o ev

ent)

EFS (whole cohort)OS (whole cohort)

• 524 patients • Median follow-up: 28 months

– OS at 3 y : 97.6% (96.0-99.2) – EFS at 3 y : 95.4% (93.2-97.7)– DFS at 3 y : 95.5% (93.0-98.0)

FRALLE 2000: preliminary results in children

• Prevention of infections:– G-CSF if neutrophils<0.5 G/l– AB and antiviral prophylaxie :

• Valaciclovir and Sulfamethoxazone/Trimethoprime from D1 to the end of maintenance

• Cefotaxime during induction• Prevention of clotting

– Prophylactic antithrombotic therapy according to genetic risk factors

– Antithrombine infusion if ATIII rate<60% during L-Asparaginase treatment

• Prevention of hip osteonecrosis– Early detection by Rx- RMI permitted leg discharge

The supportive care: essential for preventing complications

GRALLE-2003 schedule 225 pts ALL Ph(-) patients treated, m= 31y (15-60)

• Induction• Consolidation 1&2

• Late Reinduction• Consolidation #3

• Maintenance

Allograft

MRD detection

Tolerance of GRAALL-2003 according to age

The schedule is not manageable and too toxic after 45y

Outcome after chemotherapy in the GRAAL 2003 protocol according to age. Transplanted patients were censored at D0 Transplant.

Huguet F et al. JCO 2009;27:911-918

©2009 by American Society of Clinical Oncology

cumulative incidence of chemotherapy-related death

58%

46%

23%

5%

P=0.03

P<0.001