Childhood Acute Lymphoblastic Leukemia R...

Childhood Acute Lymphoblastic Leukemia: Risk Stratification in Developing Countries : 

Childhood Acute Lymphoblastic Leukemia: Risk Stratification in Developing Countries Shripad Banavali MD(Med;Bom), BC(Ped;USA), BE(Hem-Onc;USA) Tata Memorial Hospital banavali_2000@yahoo.com

Acute Lymphoblastic Leukemia : 

Acute Lymphoblastic Leukemia Most common form of childhood cancer. Treatment of ALL is true success story of modern oncology.

Key Components of Successful Therapy : 

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

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ALL: L1, L2, L3, PAS

Multiplex RT-PCR in B lineage ALL : 

Multiplex RT-PCR in B lineage ALL

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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

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 : 

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 : 

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 : 

Estimation of MRD Flow cytometry : (2) RT-PCR:

Treatment of Childhood ALL : 

Treatment of Childhood ALL TOP PRIORITY PREVENTION OF RELAPSE

ALL-Challenges For Developed CountriesClinical trials : 

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 : 

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%

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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 : 

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

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Advani et al. Ann Oncol 1999

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Advani et al. Ann Oncol 1999

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

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

CALLA + ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADES : 

CALLA + ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADES

T- ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADES : 

T- ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADES

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 : 

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 23 mBCR-ABL* 5 2.2 1.8 ELA-PBX1 7 3.8 1.6 MLL-AF4 0 1.2 1.6 *Guiterrez MI, et al. J Mol Diagnostics 2005; 7:40-47

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CHENNAI DELHI x MUMBAI

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

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

ALL : FUTURE PLANSCLINICAL : 

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 : 

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 : 

THE SOLUTION Limited Resources Appropriate (Financial and Human Capital) Research Best Low capacity to treat Rx Pts. c Best Prognosis Value for Money Low Intensity Rx

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Appropriate Rx SEED Biology of Leukemic cells SOIL Genotype ALL Rx Outcome Pharmacogenetics Pharmakokinetics Nutrition Supportive care Compliance Drug quality

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. “Functional Assay”

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Appropriate Rx SEED Biology of Leukemic cells SOIL Genotype ALL Rx Outcome Pharmacogenetics Pharmakokinetics Nutrition Supportive care Compliance Drug quality

Estimation of MRD : 

Estimation of MRD Flow cytometry : 2-3 laser Flow-cytometer many antibodies time 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? : 

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. : 

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 : 

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: “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? : 

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 Estimation Simplest version using single parameter Functional assay

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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. BMT Investigational Therapies ? ?

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Childhood Cancers are CURABLE PROVIDED THEY ARE…. diagnosed early diagnosed properly treated appropriately

ALL TEAM : 

ALL TEAM Clinical Lab Studies INCTR Collaboration Dr. S.D.Banavali Dr.C.N.Nair Dr. Ian Magrath Dr. P.A.Kurkure Dr. Ashok Kumar Ms. Melissa Adde Dr. B.Arora Mr. Sashikant Dr. Kishore Bhatia Dr. S.K.Pai Dr. A.Chougule Dr. Marina Gutierrez Dr. P.M.Parikh Dr. P.M. Parikh Dr. R.Bhagwat Dr.S. Barbhaya MSW Dept. Dr. A.Vora Dr.S.Kamath Mr.M.A. Patil Sister Asha Dr.P. Kadam Amre Ms. Neelima Dalvi Ms. A. Paes Dr. S.Chiplunkar Data Managers Radiotherapy Dr.J.Khode Ms. B.Kolhatkar Dr.M.A.Muckaden Ms.M.Patkar Ms.R.Hawaldar Dr.S.Lashkar Ms. B.Tambe Dr. N.Nair Mr.R.Kadam Surgery Dr. S.Goswami Dr. R.Mistry Dr.N.Merchant