Childhood Acute

Lymphoblastic Leukemia: Risk Stratification in

Developing Countries

Shripad BanavaliMD(Med;Bom), BC(Ped;USA), BE(Hem-Onc;USA)

Tata Memorial Hospital

banavali_2000@yahoo.com

Acute Lymphoblastic Leukemia

• Most common form of childhood cancer.

• Treatment of ALL is true success story of modern oncology.

Key Components of Successful Therapy

• Clinical trials; Co-operative groups• Empiric multi-agent CNS therapy• Pre-symptomatic CNS therapy• Post-induction intensification

– Anti-metabolite therapy– Re-induction/re-consolidation

Risk adapted therapy

ALL: L1, L2, L3, PAS

Multiplex RT-PCR in B lineage ALL

MORPHOLOGICAL REMISSION (98%)

• Morphology cannot discriminate between patients with HR or LR of relapse.

• More sensitive techniques needed to detect small numbers of malignant cells during and after treatment.

• Detection of MRD (IP and RT-PCR).

MOLECULAR REMISSION (?%)

What is detection of MRD

What is detection of MRD

It is nothing but detection of the clones of cells resistant to the chemotherapy given.

MRD: Study of Resistance in ALL

Resistance can also be studied by:-

(1) MTT in-vitro Assay

Pred + Asp + VCR Drug resistance profile

3 yr DFS 100% Most sensitive profile (20% pts)

84% Inter. sensitive profile (40% pts)

43% Least sensitive profile (40% pts)

MRD: Study of Resistance in ALL

Resistance can also be studied in-vivo by:-

(2) D7 blast count post exposure to

Pred + 1 dose of IT-MTX

(3) D 15 BM blast %

Estimation of MRD

(1) Flow cytometry :

(2) RT-PCR:

Treatment of Childhood ALL

TOP PRIORITY

PREVENTION OF RELAPSE

ALL-Challenges For Developed CountriesClinical trials

• Despite success, 25% of children relapse. Intensify therapy for those who need or will benefit from it.

• Many of those who are cured are over-treated Minimize side effects

• Little progress has been made in the treatment of certain very high risk groups (Ph+, infants and relapse)

Develop new treatment options

PEDIATRIC ONCOLOGY : FACTS

India U.S.A.

• New cases / yr 44,000 12,400

• Rx, curative intent <25% 100%

• Cure rate, adequ. Rxed 50% 70%

• Overall cure rate 12% 70%

• Rxed on Co-op Groups 1% 98%

Hematological cancers in IndiaAverage Annual Age standardized incidence rate per

100,000 persons (1990-1996)

Region Lymphoid leukemia Myeloid leukemia

M F M F

Delhi 2.3 1.2 2.3 1.9

Mumbai 1.8 1.1 2.0 1.6

Bangalore 1.2 0.8 1.8 1.7

Chennai 1.7 1.0 1.4 1.2

Bhopal 1.4 0.3 1.8 1.4

Barshi 1.0 0.5 1.4 0.7

Medical Oncology, vol. 19, 141-150, 2002

Rx of ALL: THE TMH EXPERIENCE

V+P1 -------------------------------22%

V+P+Doxo or L-Asp2-------------32%

VACP3------------------------------30%

1. Advani et al: Am J Hematol 15:35,1983

2. Advani et al: Ind J Cancer 26:180,1989

3. Advani et al: Am J Hematol 39:242, 1992

4. Advani et al: Ann Onc 10:167,1999

Acute Lymphoblastic Leukemia (MCP 841)

DFS 1986-89

YEARS

14121086420

Su

rviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

DFS 47.4 %

Acute Lymphoblastic Leukemia (MCP 841)

DFS 1990-94

YEARS

121086420

Su

rviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

DFS 54.18 %

Acute Lymphoblastic Leukemia (MCP 841)

DFS 1995-98

YEARS

76543210

Su

rviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

DFS 58.2 %

Acute Lymphoblastic Leukemia (MCP 841)

DFS (1986-98)

YEARS

14121086420

Su

rviv

al

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

DFS 54.0 %

Advani et al. Ann Oncol 1999

Advani et al. Ann Oncol 1999

Clinical characteristics in relationship to event free survival by participating center. Results of multi-variate analysis.

Characteristic DELHI

P-Value

CHENNAII

P-Value

MUMBAI

P-Value

Number accrued 228 168 652

Age 0.20 0.033 0.74

WBC count 0.0005 0.080 0.002

Platelet count 0.025 0.059 0.011

Hemoglobin 0.94 0.38 0.79

LDH -- 0.47 0.39

Immunophenotype 0.99 0.13 0.17

Lymphadenopathy 0.66 0.83 0.49

Hepatosplenomegaly 0.58 0.13 0.92

Mediastinal mass 0.32 0.10 0.92

CALLA + ACUTE LYMPHOBLASTIC LEUKEMIA

CHANGING INCIDENCE OVER 3 DECADES

0%

10%

20%

30%

40%

50%

60%

70%

80%

Mumbai Delhi Chennai

1980s

1990s

2000s

T- ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADES

33%

25%22%

38%

32%

65%

37%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MUMBAI DELHI CHENNAI

1980S

1990S

2000S

Frequencies of the major subgroups of Precursor B cell ALL in Indian children

differ from the rest.Siraj AK, et al. Leukemia 2003; 17:1192-93

n= 259 India (%) USA (%) Europe (%)

TEL-AML-1 7 22 23mBCR-ABL* 5 2.2 1.8ELA-PBX1 7 3.8 1.6MLL-AF4 0 1.2 1.6

*Guiterrez MI, et al. J Mol Diagnostics 2005; 7:40-47

• CHENNAI

o DELHI

x MUMBAI

Childhood Acute Lymphoblastic Leukemia Results of MCP-841 in other Centres

Bangalore Trivandrum Jaipur

Total number 127 66 49

CR (%) 96 83 90

TRM(%) 2.4 24.2 16.3

Relapse(%) - 21.8 22.4

CCR(%) 53 57 53

F Up(months) 96 36 38

ALL : FUTURE PLANSCLINICAL

New ALL protocol

Collaboration with INCTR

Salient features

• More Continuous CT

• More Chemo in 1st year

• Both Inj. & oral CT during Maintenance

• Less RT (1260 cGy)

THE PROBLEM

Limited Resources Lack of Appropriate

(Financial and Human Capital) Research

High

Low capacity to treat Poor Access to therapy Mortality Rate

Late Presentation

&

Late Detection

THE SOLUTION

Limited Resources Appropriate

(Financial and Human Capital) Research

Best

Low capacity to treat Rx Pts. ĉ Best Prognosis Value for Money

Low Intensity Rx

Appropriate Rx

SEEDBiology of

Leukemic cells

SOILGenotype

ALLRx

Outcome

PharmacogeneticsPharmakokinetics

NutritionSupportive

care ComplianceDrug quality

What is detection of MRD

It is nothing but detection of the clones of cells resistant to the chemotherapy given.

“Functional Assay”

Appropriate Rx

SEEDBiology of

Leukemic cells

SOILGenotype

ALLRx

Outcome

PharmacogeneticsPharmakokinetics

NutritionSupportive

care ComplianceDrug quality

Estimation of MRD

(1) Flow cytometry : 2-3 laser Flow-cytometer many antibodiestime consuming expensive

(2) RT-PCR: by TCR receptor; Ig gene rearrangements; known translocations. Individual primers.Expertise not available at all centres.

Can there be a simple way to estimate MRD?

Real Time Analysis of Terminal Deoxy Transferase Gene Expression: A convenient marker for Minimal

Residual LeukemiaBu R, Belgaumi A, Timson G, Banavali S, Al Mahir,

Bhatia K, Gutierrez MI.

• TDT expression by all ALL blasts

• Not expressed normally in PB

• Estimation of TDT in PB by Real time PCR

ALL: “Core Biology” LabAssessment Of Components Of Cure In

Developing Countries

Real time reference laboratory system for risk based classification.

• MRD studies : using single parameter, e.g. TDT

• Using PB

• At diagnosis ; At week 4 & 6 (8)

ALL: “Core Biology” LabAssessment Of Components Of Cure In

Developing Countries

• All samples to be sent to a central lab by courier.

• MRD studies based on single parameter, e.g. TDT.

• 5-7 day turnaround time.• Results sent by e-mail.• Remaining sample to be stored for future

studies.

What Is The Best Way To Risk Stratify Children With ALL In

Developing Countries?

One parameter (Not multiple like clinical, IP, DI, Cytogen, Mol, MRD)

MRD EstimationSimplest version using single parameter

Functional assay

Management of Childhood ALL

Common Standard Rem. Ind Protocol

Estimation of MRD at D29/D43

< 0.01 % < 0.1 % > 1 %

? Less intensive Rx? Shorter duration

D. D. I Allo. BMTInvestigational Therapies

Childhood Cancers are

CURABLE

PROVIDED THEY ARE…. diagnosed earlydiagnosed properlytreated appropriately

ALL TEAM

Clinical Lab Studies INCTR Collaboration

Dr. S.D.Banavali Dr.C.N.Nair Dr. Ian MagrathDr. P.A.Kurkure Dr. Ashok Kumar Ms. Melissa AddeDr. B.Arora Mr. Sashikant Dr. Kishore BhatiaDr. S.K.Pai Dr. A.Chougule Dr. Marina GutierrezDr. P.M.Parikh Dr. P.M. Parikh Dr. R.Bhagwat Dr.S. Barbhaya MSW Dept.Dr. A.Vora Dr.S.Kamath Mr.M.A. PatilSister Asha Dr.P. Kadam Amre Ms. Neelima Dalvi

Ms. A. Paes Dr. S.Chiplunkar Data Managers

Radiotherapy Dr.J.Khode Ms. B.KolhatkarDr.M.A.Muckaden Ms.M.Patkar Ms.R.HawaldarDr.S.Lashkar Ms. B.Tambe Dr. N.Nair Mr.R.KadamSurgery Dr. S.GoswamiDr. R.Mistry Dr.N.Merchant