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Acute Myeloid Leukemia in Down Syndrome

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Acute Myeloid Leukemia in Down Syndrome Acute Myeloid Leukemia in Down Syndrome Jeffrey W. Taub, M.D. Division of Hematology/Oncology Children’s Hospital of Michigan Wayne State University School of Medicine Detroit, Michigan 1930 1957 Case Study • A newborn baby has dysmorphic facial features, transverse palmar creases, systolic ejection murmur. • A CBC reveals: WBC: 59,000/µl Hemoglobin: 17 gm/dL Platelets: 80,000/µl Peripheral smear: 50% blasts What is the most likely diagnosis ? 1. Infection 2. Leukemoid reaction 3. Infant ALL 4. Transient Myeloproliferative Disorder of DS Transient Myeloproliferative Disorder Transient Myeloproliferative Disorder (TMD)/Transient Abnormal Myelopoiesis • Estimated that 5-10% of DS newborns have a precursor of acute megakaryocytic leukemia (AML-M7; AMkL), TMD, in which blasts in the peripheral blood and/or bone marrow have the same morphology and antigen expression as AMkL. • TMD has also been diagnosed in DS mosaics and in infants with isolated trisomy 21 in blast cells with no other evidence of mosaicism. • Majority of TMD cases can spontaneously regress with supportive care alone, though ~20-30% of patients will subsequently develop AML. • A subset of patients present with high risk features (e.g. high WBC counts, liver dysfunction with hepatic fibrosis) which are associated with high mortality rates. These patients may benefit from early chemotherapy intervention with low dose cytarabine (ara-C). Case Study • A 14 month old male baby with Down syndrome has a past history of TMD [maximum WBC 45,000/µL) which resolved with supportive care alone without the use of chemotherapy treatment. • Ongoing monitoring of the baby’s CBC revealed a slow decrease in the platelet count though he remained clinically asymptomatic. Mild hepatomegaly was present on exam as well as a heart murmur. A CBC revealed: WBC: 18,000/µl Hemoglobin: 10.2 gm/dL; MCV: 83 fl Platelets: 33,000/µl Approximately 5-10% atypical blast-like cells on the peripheral smear. Acute Megakaryocytic Leukemia-AMKL M7 Myeloid Leukemia of Down Syndrome (ML-DS) • 2008 WHO classification of ML-DS encompasses the group of both MDS patients (blasts <30%) as well as AML patients who predominantly have the AMKL phenotype. • Approximately 95% of ML-DS cases diagnosed before the age of 4 years. • Median age of diagnosis 1.8 years vs 7.5 years for non-DS AML (Children’s Cancer Group 2891 study). [Gamis et al., J Clin Oncol 2003] • Down syndrome represent ~15% of total pediatric AML patients. [Nordic Society of Pediatric Hematology and Oncology Zeller et al. Br J Haemat 2005; CCG 2891] Down Syndrome and AML • For AML, most cases in DS children occur under the age of 4 years and a high proportion (>75%) are the acute megakaryocytic leukemia phenotype (M7; AMkL) while AMkL represents ~5-10% of AML cases in non-DS children. • Estimated that DS children have a 500-fold increased risk of developing AMkL compared to non-DS children. [Zipursky et al., Leukemia Research 1994] Characterization of Blast Cells • Immunophenotype: CD41/61 (platelet antigens glycoprotein IIb/IIIa, CD7 (aberrant T-cell antigen expression), CD36 (thrombospondin receptor). • Common cytogenetics abnormalities include trisomies +8, +21, +11 and structural abnormalities dup(1q), del(6q), del(7p), dup(7q), del(16q). [Forestier et al., Blood 2008] • Classic cytogenetic abnormalities detected in pediatric AML cases are extremely rare in DS-AML including t(8;21), inv(16), t(15;17), MLL (11q23) rearrangements or t(1;22) seen in non-DS AMKL cases. • The intensity of AML chemotherapy is adjusted according to the risk of relapse (risk stratification) for all children including those with DS. True or false ? Study Entry Recommended criteria for 4 years of age at diagnosis AAML0431 PROTOCOL proceeding to each cycle of therapy: ANC ≥ 1,000/µL BMA/MRD At and platelets ≥ 100,000/µL. Diagnosis Induction I CI-TAD + IT AraC BMA/MRD Day 14 Cumulative Doses for If cellular, Induction I and II: BMA/MRD Day 28 moderately AraC: 24,800 mg/m2 cellular, ≥ 20% blasts Daunorubicin 160 mg/m2 Induction II Capizzi II Course BMA/MRD Day 14 and 28 if PR or RD after Induction I Day 28 marrow Induction III CI-TAD + IT AraC If RD Induction IV CI-TAD BMA = Bone Marrow Aspirate. MRD = Minimal Residual Disease BMA/MRD CI-TAD: Continuous Infusion Cytarabine (AraC)/Daunorubicin + 6-Thioguanine PR, RD or Relapse CR = Complete Response Intensification I VP/Ara-C PR = Partial Response RD = Refractory Disease Capizzi II: Cytarabine (AraC)/L-asparaginase Off Protocol Therapy VP/Ara-C: Etoposide/Cytarabine (AraC) IT AraC: Intrathecal Cytarabine Intensification II VP/Ara-C BMA/MRD Follow-Up Prognostic value of MRD in DS-AML AAML0431 1 1 MRD-neg (n=123) MRD-neg (n=123) 0.75 0.75 MRD-pos (n=24) MRD-pos (n=24) 0.5 0.5 0.25 DFS 0.25 OS p=0.001 p=0.002 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years (from end of Induction I) (from end of Induction I) Taub, Berman, Hitzler et al., ASH 2014 Challenges in Treating Children with Down Syndrome and Leukemia TOXICITY CURE Down syndrome Study Design < 4 years of age at diagnosis AAML1531 BMA at diagnosis Induction I (all patients) TAD + IT Ara-C Standard Risk MRD Risk Group High Risk (Arm A) Assessment (Arm B) MRD <0.05% BMA MRD >0.05% Induction II TAD Induction II Mitoxantrone/Ara-C Induction III - TAD BMA and MRD Intensification I Intensification I Ara-C/Etoposide HR Ara-C/Etoposide Intensification II Intensification II Ara-C/Etoposide Capizzi II Follow up Follow up BMA, bone marrow Aapirate; MRD , minimal residual disease Induction I (all patients) AD: continuos infusion ytarabine; short infusion Daunorubicin ; oral 6-Thioguanine; intrathecal Cytarabine STANDARD ARM (Arm A) Induction II and III ; TAD, continuos infusion Cytarabine (Ara-C) ; short infusion Daunorubicin ; oral 6-Thioguanine Intensifications I and II : Cytarabine (Ara-C)/Etoposide HIGH RISK ARM (Arm B) Induction II: Mitoxantrone/ Cytarabine (Ara-C) Intensification I: High dose Cytarabine (Ara-C)/Etoposide Intensification II: Capizzi II, High Dose Cytarabine (Ara-C)/L-Asparaginase Why does DS-AML have very high cure rates? 1. Due to a gene(s) on chromosome 21 2. Extraordinary adherence to chemotherapy 3. Very low toxicity 4. Due to a gene not located on chr. 21 Ex Vivo Chemotherapy Sensitivity of DS-AML Blasts Non-Down Down Syndrome Syndrome AML AMKL (n=22) (n=362) Ara-C IC50 (nM) 77.5 350.9 Daunorubicin IC 50 5.8 71.2 (nM) Ara-CTP (pmol/mg 737.3 166.9 prot) (n=11) (n=20) Identification of Somatic GATA1 Mutations in DS-AML A I II III IV V VI GATA1 Chr Xp11.23 Zinc finger domain N-terminus C-terminus Cf chromosome 21 Nf GATA1 (50kDa) GATCN(A/T)GATA(A/G) FOG-1 Normal megakaryocyte and erythroid cell development B I II III IV V VI mutated GATA1 Zinc finger domain C-terminus Nf Cf GATA1s (40kDa) GATCN(A/T)GATA(A/G) FOG-1 trisomy 21 Acute megakaryocytic leukemia transformation Cytidine Deaminase Expression and AML • CDA transcripts were a median 5.1-fold lower in DS AML blasts compared to non-Down syndrome AML blasts. • CDA transcript is transcribed from a CDA “long form” promoter (CDAlf) while a “short form” promoter (CDAsf) acts as an enhancer for the promoter. • GATA1s protein in DS AML cases, results in reduced CDA enhancer activity and decreased CDA expression compared to non-DS AML cases. [Ge et al., Cancer Research 2004] • Is there linkage between chromosome 21 and GATA1 mutations? • True or false. Model: Trisomy 21 accelerates CBS activity and drives mutagenesis of GATA1 toward TMD/AMKL [Cabelof D et al., Blood 2009] Can children with Down syndrome develop leukemia more than once? • A) Yes • B) No Down Syndrome AML/ALL Cases • Patient diagnosed at birth with the transient myeloproliferative disorder (TMD)/transient abnormal myelopoiesis (TAM) which resolved spontaneously with supportive care. • Diagnosed at the age of 18 months with myeloid leukemia of Down syndrome (AMKL phenotype). Treated with chemotherapy on the COG AAML0431 protocol. She received 4 of 6 planned cycles of therapy due to fungal sepsis/pneumonia. • Routine follow-up visit 3.5 years off therapy WBC: 7100/µL; ANC: 700; Hemoglobin: 11 g/dL; Platelets: 112,000/µL and blasts on the peripheral smear • Diagnosed with ETV6-RUNX1 ALL and currently on therapy. • 2/204 patients enrolled on AAML0431 have subsequently developed ALL. Diagnosis of AMkL Uncontrolled proliferation of expression of immature chromosome 21- megakaryocytes/ localized genes GATA1 exon 2 Additional mutations develop unknown genetic prenatally hits Ara-C/ anthracycline LINKAGE OF Expression of therapy GATA1-target LEUKEMOGENESIS AND genes/Chromosome 21-localized gene TREATMENT RESPONSE result in altered IN DS AML activity and increased sensitivity to ara-C/ anthracyclines DS AMkL patients with EFS rates of 80-100% vs. 50% for non-DS AML patients and <35% for non-DS AMkL patients Future Directions • Can the intensity of AML therapy be reduced for children with ML-DS, while maintaining high EFS rates? • Are there biomarkers which may be used to select treatment intensity for ML-DS? • What is the basis for refractory/relapsed ML-DS cases which are outliers from a group who are overall very chemotherapy- responsive? • Identify new therapeutic agents for refractory/relapsed ML-DS cases. Acute Lymphoblastic Leukemia and Down syndrome Johann (Hans) Hitzler, M.D. The Hospital for Sick Children Division of Hematology/Oncology Developmental and Stem Cell Biology Toronto, ON POGO 2016 Multi-Disciplinary Symposium on Childhood Cancer, Nov 4-5 Distribution of Cancers in DS SIR 18 16 14 12 10 8 6 4 2 0 all sites solid tumours leukemia Hasle H 2000 Lancet Increased Risk for Leukemia in DS - Hypotheses • Genes on HSA21 – Gene dosage imbalance, Down syndrome critical region candidate genes (e.g.
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