英Acute Lymphoblastic Leukemia

1、Childhood Acute Lymphoblastic Leukemia: Risk Stratification in Developing Countries Shripad BanavaliMD(Med;Bom), BC(Ped;USA), BE(Hem-Onc;USA) Tata Memorial Hospital banavali_Acute Lymphoblastic Leukemia Most common form of childhood cancer. Treatment of ALL is true success story of modern oncology.K

2、ey 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-consolidationRisk adapted therapyALL: L1, L2, L3, PASMultiplex RT-PCR in B lineage ALLMORPHOLOGI

3、CAL 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 MRDWhat is detection of

4、 MRDIt is nothing but detection of the clones of cells resistant to the chemotherapy given.MRD: Study of Resistance in ALLResistance 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

5、% pts) 43% Least sensitive profile (40% pts)MRD: Study of Resistance in ALLResistance 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 ALLTOP PRIORITYPREVENTION OF RE

6、LAPSEALL-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 ri

7、sk groups (Ph+, infants and relapse) Develop new treatment optionsPEDIATRIC 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 st

8、andardized incidence rate per 100,000 persons (1990-1996)RegionLymphoid leukemia Myeloid leukemia M F M FDelhi 2.3 1.2 2.3 1.9Mumbai 1.8 1.1 2.0 1.6Bangalore 1.2 0.8 1.8 1.7Chennai 1.7 1.0 1.4 1.2Bhopal 1.4 0.3 1.8 1.4Barshi 1.0 0.5 1.4 0.7Medical Oncology, vol. 19, 141-150, 2002Rx of ALL: THE TMH E

9、XPERIENCEV+P1 -22%V+P+Doxo or L-Asp2-32%VACP3-30%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 10:167,1999Acute Lymphoblastic Leukemia (MCP 841)DFS 1986-89YEARurvival1.0.9.8.7.6.5.4.3.2

10、.10.0DFS 47.4 %Acute Lymphoblastic Leukemia (MCP 841)DFS 1990-94YEARS121086420Survival1.0.9.8.7.6.5.4.3.2.10.0DFS 54.18 %Acute Lymphoblastic Leukemia (MCP 841)DFS 1995-98YEARS76543210Survival1.0.9.8.7.6.5.4.3.2.10.0DFS 58.2 %Acute Lymphoblastic Leukemia (MCP 841)DFS (1986-98)YEARurvival

11、1.0.9.8.7.6.5.4.3.2.10.0DFS 54.0 %Advani et al. Ann Oncol 1999Advani et al. Ann Oncol 1999 Clinical characteristics in relationship to event free survival by participating center. Results of multi-variate analysis. CharacteristicDELHIP-ValueCHENNAII P-ValueMUMBAI P-ValueNumber accrued228168652Age0.2

12、00.0330.74WBC count0.00050.0800.002Platelet count 0.0250.0590.011Hemoglobin0.940.380.79LDH-0.470.39Immunophenotype0.990.130.17Lymphadenopathy0.660.830.49Hepatosplenomegaly0.580.130.92Mediastinal mass0.320.100.92CALLA + ACUTE LYMPHOBLASTIC LEUKEMIACHANGING INCIDENCE OVER 3 DECADEST- ACUTE LYMPHOBLAST

13、IC LEUKEMIACHANGING INCIDENCE OVER 3 DECADESFrequencies of the major subgroups of Precursor B cell ALL in Indian children differ from the rest.Siraj AK, et al. Leukemia 2003; 17:1192-93n= 259 India (%) USA (%) Europe (%)TEL-AML-172223mBCR-ABL*52.21.8ELA-PBX173.81.6MLL-AF401.21.6* *GuiterrezGuiterrez

14、 MI, et al. J Mol Diagnostics 2005; 7:40-47 MI, et al. J Mol Diagnostics 2005; 7:40-47 CHENNAIo DELHI x MUMBAIChildhood Acute Lymphoblastic Leukemia Results of MCP-841 in other CentresBangaloreTrivandrumJaipurTotal number1276649CR (%)968390TRM(%)2.424.216.3Relapse(%)-21.822.4CCR(%)535753F Up(months)

15、963638ALL : FUTURE PLANSCLINICALNew ALL protocolCollaboration with INCTRSalient features More Continuous CT More Chemo in 1st year Both Inj. & oral CT during Maintenance Less RT (1260 cGy) THE PROBLEMLimited Resources Lack of Appropriate(Financial and Human Capital) Research HighLow capacity to trea

16、t Poor Access to therapy Mortality RateLate Presentation&Late DetectionTHE SOLUTIONLimited Resources Appropriate(Financial and Human Capital) Research BestLow capacity to treat Rx Pts. Best Prognosis Value for MoneyLow Intensity RxAppropriate RxSEEDBiology ofLeukemic cells SOILGenotype ALLRxOutcomeP

17、harmacogeneticsPharmakokineticsNutritionSupportive care ComplianceDrug qualityWhat is detection of MRDIt is nothing but detection of the clones of cells resistant to the chemotherapy given. “Functional Assay”Appropriate RxSEEDBiology ofLeukemic cells SOILGenotype ALLRxOutcomePharmacogeneticsPharmako

18、kineticsNutritionSupportive care ComplianceDrug qualityEstimation 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

19、 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 TD

20、T in PB by Real time PCRALL: “Core Biology” LabAssessment Of Components Of Cure In Developing CountriesReal 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 Com

21、ponents 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 parameterFunctional assayManagement of Childhood ALLCommon Standard Rem. Ind ProtocolEstimation of MRD at D29/D43 0.01 % 1 %? Less intensive Rx? Shorter durati