Risk Stratification in Childhood Leukemia

Transcription

1 Risk Stratification in Childhood Leukemia Why is risk stratification important? Toxicities Deepa Bhojwani, MD May 11, 2018 To determine intensity of therapy - When to intensify therapy - When to de-intensify therapy Without compromising cure Cumulative burden of chronic toxicities N=39,697 Risk stratification Intensification CNS prophylaxis Supportive care Combination therapy 96.1% of individuals in this cohort of >5000 patients had developed a severe (grade 3), life-threatening (grade 4), or fatal (grade 5) condition by the age of 50 years Bhakta N et al, Lancet 2017 Dec 9;390(10112): Hunger SP, Mullighan CG. N Engl J Med 2015;373: History 1966: Sidney Farber described 15 survivors out of 1445 children with ALL treated with chemotherapy..it is still impossible to differentiate, at the time of diagnosis, the 99% whose lives will be prolonged by months or one or 2 years and the 1% who will survive 5 years or longer. Age After significant cure.. search for prognostic factors Presenting white blood cell count Gender Immunophenotype (T-cell) Cytogenetics Poor prognosis in Philadelphia chromosome positive ALL (POG) Good prognosis in hyperdiploid ALL (POG) Early response to therapy 1986: Day 8 peripheral blood response (BFM) 1988: Day 8 bone marrow response (CCG) 1998: Significance of minimal residual disease 1

2 Outline 1 2 Presenting clinical features Biological features of the leukemia Acute lymphoblastic leukemia - B-ALL - T-ALL - Infant ALL - Relapsed ALL Acute myeloid leukemia Mixed phenotype acute leukemia 3 Response to treatment Modified from slideshare.net Chemotherapy regimen Refining treatment (1): Presenting clinical features Refining treatment by biology(2) Karyotype 1985: Rome workshop All reports should use two well established and readily available prognostic factors to describe high-risk ALL (5-year EFS <40%) Initial peripheral WBC 50,000 Age at diagnosis 10 years Clinical trials should prospectively and uniformly collect certain clinical and biologic data Statistical reporting of results should include standardized methods 1993: NCI workshop Similar presenting features May modify risk group by including cytogenetics 54,XY,+X,+4,+6,+8,+14,+17,t(17;19)(q22;p13),+21,+21. Fluorescent in situ hybridization Molecular subtypes Split signal probe: MLL-rearrangements Dual-fusion probe: BCR-ABL1 BCR-ABL1 3% E2A-PBX1 6% ETV6-RUNX1 25% Hypodiploid 1% MLL-R 9% MYC 2% NOS 22% MEF2D-R ZNF384-R NOS 4.5% TCF3-HLF 0.5% Dic (9;20) 2% iamp21 2% ERG 3% CRLF2 4% Hyperdiploid 28% Ph-like 9% Bhojwani D et al. PCNA 2015; 62(1):47-60, modified 2

3 Prognostic impact of molecular subtypes Intrachromosomal amplification of chr. 21 (iamp21) Red = RUNX1 (chr. 21); Green = ETV6 (chr. 12) Loh M et al. ASH 2016, abstract # 451 Risk stratification is important Ph-like ALL Genetic changes resulting in constitutive activation of cytokine receptor and/or tyrosine kinase signaling 19% of HR B-ALL Spectrum of alterations in Ph-like ALL Various rearrangements Response to tyrosine kinase inhibitors Gene expression changes similar to Ph-positive ALL Inferior outcome Den Boer ML et al Lancet Oncology 2009; 10(2): Roberts K et al, Cancer Cell 2012; Aug 14;22(2): COG approach to Ph-like ALL 2008 WHO classification of ALL Screening algorithm Therapeutic study B-lymphoblastic leukemia/lymphoma B-lymphoblastic leukemia/lymphoma, NOS B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities LDA card Ph-like expression Yes CRLF2 expression High Low mpcr/ sequencing ABL1 class fusion AALL dasatinib B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);bcr-abl1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);kmt2a rearranged B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy CRLF2-IGH (FISH) or P2RY8-CRLF2 (LDA) +/- JAK sequencing JAK pathway mutant or CRLF2-R AALL1521 (ruxolitinib) B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);tcf3-pbx1 Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1 like* Provisional entity: B-lymphoblastic leukemia/lymphoma with iamp21* T-lymphoblastic leukemia/lymphoma Provisional entity: Early T-cell precursor lymphoblastic leukemia* Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma* *2016 revision 3

4 Refining Treatment (3): Response to therapy Minimal Residual Disease..finding needles in the haystack effectively Morphologic remission MRD Prognostic impact of MRD in ALL POG 9900 January 2000-March 2005 N=1971 Leukemia at diagnosis Recovering bone marrow Methods: Flow cytometry: aberrant immunophenotypes (~0.01%) PCR: Ig and TCR genes or fusion transcripts ( %) Next generation massive parallel sequencing (~0.0001%) Campana D, BJH 2003; 121(6): Borowitz M J et al. Blood 2008;111: MRD by high-throughput sequencing Current COG classification: AALL08B1 Pre-transplant N=41 End-induction N=619 Pulsipher M et al. Blood 2015;125: Wood B et al, ASH 2016, abstract # 618 Risk stratification by other cooperative groups Risk-based therapy to reduce toxicity UKALL2003: Randomized trial of treatment reduction for children and young adults with low-risk ALL defined by minimal residual disease and cytogenetics MRD low-risk: Undetectable at end-induction or end-consolidation No adverse cytogenetics: MLL-R, hypodiploid, iamp21 No difference between one verses two courses of delayed intensification Alexander S. Hematology 2014 Vora A et al. Lancet Oncology 2013; 14(3):

5 Examples of reducing therapy for Additional potential prognostic features lower-risk ALL Host Sentinal lesion Secondary lesions AALL0932: - Reduce frequency of VCR/Dex pulses UKALL2011: - Decrease induction dexamethasone from 28 to 14 days - Maintenance without VCR/Dex pulses - Maintenance without intrathecal therapy Bhojwani D et al. PCNA 2015; 62(1):47-60 Host: Germline SNPS associated with response 2535 children with newly diagnosed ALL SNPs interrogated 133 SNPs were prognostic for response after adjusting for risk factors including MRD Many SNPs influenced host disposition of anti leukemia drugs Higher risk of relapse in patients with Native American Ancestry European African Asian Native American Ex. PYGL SNP Without delayed intensification POG 9904/05 With delayed intensification POG 9904/05 All patients MRD negative patients Yang JJ et al. Nature Genetics 2011; 43(3): Secondary genomic lesions in ALL Whites Asians Blacks 9p13.3 PAX5 Hispanics Deletions, amplifications, point mutations and structural rearrangements in genes encoding principal regulators of B- lymphocyte development in 40% of B-ALL Ex. PAX5, E2A, EBF1, LEF1, IKZF1 Mullighan CG et al. Nature 2007 Apr 12;446(7173):

6 IKAROS alterations in ALL T-ALL IKZF1 deletions are a hallmark of Ph+ ALL Associated with poor prognosis in Ph- ALL Detected in approximately 30% of HR ALL Mullighan C et al. NEJM 2009; 360 (5): Collins-Underwood R and Mullighan C. Leukemia 2010; 24(10): Not age and WBC Biology of T-ALL Infant ALL Not MLL-rearranged MLL-rearranged, age < 6 months and WBC >300,000 MRD Litzow MR and Ferrando AA; Blood 2015; 126: Interfant-99: Lancet 2007 and Leukemia 2009 Relapsed ALL AML Timing of relapse Low Intermediate High Late(M) Early/late (IEM) Late (M) Early/late (IEM) End-induction MRD < 0.1% 0.1% Any Very early/early (M) Very early (IEM) M = marrow IEM = Isolated extra-medullary Very early relapse: Less than 18 months from initial diagnosis Early relapse: months from initial diagnosis Late relapse: More than 36 months from initial diagnosis APL Standard risk: Initial WBC < 10,000 High risk: Initial WBC 10,000 AAML1031 and AAML1331 6

7 Mixed phenotype acute leukemia (MPAL) Current risk stratification Approximately 3% of childhood leukemia Subtypes: B/myeloid, T/myeloid, B/T Often treated with hybrid ALL/AML therapy Prognostic factors are unknown (possibly MRD) Better outcome with ALL-type therapy Should we treat like high-risk ALL? Plan for a separate stratification of MPAL in AALL1732 Toxicities Goal Thank you 7