12 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 (?%)
14 What is detection of MRD It is nothing but detection of the clones of cells resistant to the chemotherapy given.
15 MRD: Study of Resistance in ALL Resistance can also be studied by:-(1) MTT in-vitro AssayPred + Asp + VCR Drug resistance profile3 yr DFS 100% Most sensitive profile (20% pts)84% Inter. sensitive profile (40% pts)43% Least sensitive profile (40% pts)
16 MRD: Study of Resistance in ALL Resistance can also be studied in-vivo by:-(2) D7 blast count post exposure toPred + 1 dose of IT-MTX(3) D 15 BM blast %
22 Treatment of Childhood ALL TOP PRIORITYPREVENTION OF RELAPSE
23 ALL-Challenges For Developed Countries Clinical 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 effectsLittle progress has been made in the treatment of certain very high risk groups (Ph+, infants and relapse)Develop new treatment options
26 PEDIATRIC ONCOLOGY : FACTS India U.S.A.New cases / yr , ,400Rx, curative intent <25% %Cure rate, adequ. Rxed % %Overall cure rate % %Rxed on Co-op Groups % %
27 Hematological cancers in India Average Annual Age standardized incidence rate per 100,000 persons ( )Region Lymphoid leukemia Myeloid leukemiaM F M FDelhiMumbaiBangaloreChennaiBhopalBarshiMedical Oncology, vol. 19, , 2002
28 Rx of ALL: THE TMH EXPERIENCE V+P %V+P+Doxo or L-Asp %VACP %1. Advani et al: Am J Hematol 15:35,19832. Advani et al: Ind J Cancer 26:180,19893. Advani et al: Am J Hematol 39:242, 19924. Advani et al: Ann Onc 10:167,1999
32 Clinical characteristics in relationship to event free survival by participating center. Results of multi-variate analysis.CharacteristicDELHIP-ValueCHENNAIIMUMBAINumber accrued228168652Age0.200.0330.74WBC count0.00050.0800.002Platelet count0.0250.0590.011Hemoglobin0.940.380.79LDH--0.470.39Immunophenotype0.990.130.17Lymphadenopathy0.660.830.49Hepatosplenomegaly0.580.92Mediastinal mass0.320.10
34 T- ACUTE LYMPHOBLASTIC LEUKEMIA CHANGING INCIDENCE OVER 3 DECADES
35 Frequencies of the major subgroups of Precursor B cell ALL in Indian children differ from the rest. Siraj AK, et al. Leukemia 2003; 17:n= 259India (%) USA (%) Europe (%)TEL-AMLmBCR-ABL*ELA-PBXMLL-AF*Guiterrez MI, et al. J Mol Diagnostics 2005; 7:40-47
44 Estimation of MRDFlow 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.
47 TDT expression by all ALL blasts Not expressed normally in PB Real Time Analysis of Terminal Deoxy Transferase Gene Expression: A convenient marker for Minimal Residual Leukemia Bu R, Belgaumi A, Timson G, Banavali S, Al Mahir, Bhatia K, Gutierrez MI.TDT expression by all ALL blastsNot expressed normally in PBEstimation of TDT in PB by Real time PCR
50 ALL: “Core Biology” Lab Assessment Of Components Of Cure In Developing Countries Real time reference laboratory system for risk based classification.MRD studies : using single parameter, e.g. TDTUsing PBAt diagnosis ; At week 4 & 6 (8)
51 ALL: “Core Biology” Lab Assessment 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 .Remaining sample to be stored for future studies.
54 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 parameterFunctional assay
55 Management of Childhood ALL Common Standard Rem. Ind ProtocolEstimation of MRD at D29/D43> 1 %< 0.01 %< 0.1 %? Less intensive Rx? Shorter durationD. D. IAllo. BMTInvestigational Therapies
56 CURABLE Childhood Cancers are PROVIDED THEY ARE…. diagnosed early diagnosed properlytreated appropriately
57 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. ParikhDr. R.Bhagwat Dr.S. Barbhaya MSW Dept.Dr. A.Vora Dr.S.Kamath Mr.M.A. PatilSister Asha Dr.P. Kadam Amre Ms. Neelima DalviMs. A. PaesDr. S.Chiplunkar Data ManagersRadiotherapy Dr.J.Khode Ms. B.KolhatkarDr.M.A.Muckaden Ms.M.Patkar Ms.R.HawaldarDr.S.Lashkar Ms. B.TambeDr. N.Nair Mr.R.KadamSurgery Dr. S.GoswamiDr. R.Mistry Dr.N.Merchant