Post on 26-Mar-2015
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