Pacharapan Surapolchai, MD Associate Professor Department of Pediatrics, Faculty of Medicine, Thammasat University, Thailand October 2018
Outline Case study Introduction of Current management of infantile leukemia New treatment strategies of infantile leukemia Prognostic outcomes of infantile leukemia Conclusion
Case study: Part I Thai F 1+mo presented with red spots at buttock. PE: afebrile, petechial rash, erythematous plaques at scalp and buttock with hepatosplenomegaly. CBC: Hb 9.8 g/dl, WBC 244,410/cu.mm. (N 2, L 1, blast 98%), platelet 19,000/cu.mm. BMA: lymphoblast 85% with positive for CD19, PAX5, CD34, TdT, HLA-DR with aberrant expression of CD33 Cytogenetics: 46, XX, t(4;11)(q21;q23) [30] Multiplex RT-PCR: positive for MLL/AF4 Diagnosis: MLL rearranged infantile ALL Unpublished data; courtesy of Division of Pediatric Hematology-Oncology, Ramathibodi.
Case study: Part I Which plan of management should be proposed for this infant? A. Chemotherapy alone B. HSCT after first CR C. HSCT when relapse
Definition: Leukemia (ALL and AML) in infants diagnosed before one year of age Leukemia in infants has unique epidemiological, biological, and clinical characteristics Biondi A, et al. Blood. 2000;96:24-33. Silverman LB. Pediatr Blood Cancer. 2007;49 (7 Suppl):1070-3.
Incidence: US: 30-40 cases per million live births (approx.160 cases per year with ALL:AML = 1.3:1) Thailand (ThaiPOG): 82 case (ALL 42 cases [51%]; AML 35 cases [43%]) during 2003-2005 Infantile ALL approx. 2.5% to 5% of pediatric ALL Infantile AML comprises 6% to 14% of pediatric AML Wiangnon S, et al. Asian Pac J Cancer Prev. 2011;12(9):2215-20. SEER Cancer Statistics Review, 1975-2015, National Cancer Institute. Bethesda, MD.
Pathogenesis: Prenatal origin and chemical exposure in mother Few studies found an increased risk of infantile leukemia after in utero exposure to household pesticides, dipyrone, bioflavonoids, estrogens which might be due to genotoxic effects to fetus was associated with the mixed lineage leukemia (MLL) gene fusion, likely as a result of topoisomerase II inhibition Hernández AF, et al. Int J Mol Sci. 2016;17(461):1-16.;
Characteristics: Presentations tend to be more aggressive: hepatosplenomegaly, extramedullary involvement (i.e. skin; leukemia cutis), CNS involvement, hyperleucocytosis Infants with ALL have a particularly high risk of treatment failure and early relapse Biondi A, et al. Blood. 2000;96:24-33. Silverman LB. Pediatr Blood Cancer. 2007;49 (7 Suppl):1070-3.
Diagnosis: by clinical and bone marrow studies Blast morphology and flow cytometry: Infantile ALL-mostly pre B-cell phenotype with aberrant co-expression of myeloid markers Lymphoblasts from infants with MLL rearrangements (MLL-r) are often CD10 negative and express high levels of FLT3 Infantile AML-mostly FAB M4/M5 and M7 Biondi A, et al. Blood. 2000;96:24-33. Silverman LB. Pediatr Blood Cancer. 2007;49 (7 Suppl):1070-3. Masetti R, et al. Front Pediatr. 2015;3:37.
Diagnosis: Cytogenetics and molecular genetics: Chromosomal and molecular aberrations of leukemia in infants are markedly different from those in children Another distinctive trait of infantile leukemia is the low frequency of favorable cytogenetic and molecular features Infantile ALL rarely found ETV6/RUNX1; ALL with MLL-r commonly found overexpression of FLT3 Infantile AML rarely found NPM1 or CEBPA mutations; And, FLT3-ITD mutation is significantly lower in infantile AML Biondi A, et al. Blood. 2000;96:24-33. Masetti R, et al. Front Pediatr. 2015;3:37.
Diagnosis: Cytogenetics and molecular genetics: Balanced chromosomal translocations involving 11q23 or MLL-r (MLL1 or KMT2A rearrangements) are found in 70-80% of infantile ALL and 35-50% of infantile AML** Infantile ALL mostly found MLL-AF4 (KMT2A-AFF1); t (4;11)(q21;q23) Infantile AML mostly found MLL-AF9; t(9;11)(p23;q23) and MLL-AF10; t(10;11)(p12;q23) **MLL-r have also been reported with increased frequency in mixed phenotypic leukemias and therapy-related leukemias after topoisomerase II inhibitor therapy Winters AC, Bernt KM. Front Pediatr. 2017;5:4.
Winters AC, Bernt KM. Front Pediatr. 2017;5:4.
Diagnosis: Cytogenetics and molecular genetics: Detection of MLL (KMT2A)-r might be high variety and not be available in some particular institutes Cytogenetics* Fluorescence in situ hybridization (FISH)* Southern blot Long-distance inverse (LDI) PCR Multiplex PCR for MLL-AF4 (KMT2A-AFF1)** Next-Gen sequencing
Management Treatment for infantile AML: not different from older children Treatment for infantile ALL: Chemotherapy HSCT New treatment strategies (e.g. epigenetic targeted therapy, immunotherapy)
Management for infantile ALL Intensive chemotherapy regimens: Using agents not typically incorporated into frontline therapy for older children with ALL Postinduction intensification courses with high doses of cytarabine and methotrexate Triple IT to prevent CNS relapse Balancing between Intensity, Relapse and Toxicity With current approaches, treatment-related mortality reported up to 10% of infants Hilden JM, et al. Blood. 2006; 108(2):441 51. Pieters R, et al. Lancet. 2007;370(9583):240-50. Dreyer ZE, et al. Pediatr Blood Cancer. 2015;62(3):419-26.
Management for infantile ALL The current THREE collaborative clinical trials 1. Children's Oncology Group (COG) 2. Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) 3. Interfant Study Group
Kotecha RS, et al. Blood cancer J. 2014;4:e200.
Management for infantile ALL:
Management for infantile ALL Treatment for ALL infants with MLL-r Treatment for ALL infants without MLL-r New treatment strategies for ALL and AML infants
Management for infantile ALL Treatment for ALL infants with MLL-r Intensive chemotherapy 1. Interfant: cytarabine-intensive chemotherapy (lowand high-dose cytarabine) 5-yr EFS 37% 2. COG: multiple doses of high-dose MTX, CTX, Eto 5-yr EFS 37% On COG P9407 (NCT00002756) trial: shortened (46- week) intensive chemotherapy 5-yr EFS 36% Hilden JM, et al. Blood. 2006; 108(2):441 51. Pieters R, et al. Lancet. 2007;370(9583):240-50. Dreyer ZE, et al. Pediatr Blood Cancer. 2015;62(3):419-26.
Management for infantile ALL Treatment for ALL infants with MLL-r HSCT: HSCT in first CR remains controversial!! 1. COG: no difference in EFS between patients underwent HSCT in first CR and received chemotherapy 2. Japanese trial: all infants proceeded to HSCT 3 to 5 months after diagnosis (1998-2002) 3-yr EFS 34% with 27% relapsed before transplant Kato M, et al. Br J Haematol. 2015;168(4):564-70. Kosaka Y, et al. Blood. 2004;104(12):3527-34. Dreyer ZE, et al. J Clin Oncol. 2011;29(2):214-22
Management for infantile ALL Treatment for ALL infants with MLL-r HSCT: HSCT in first CR remains controversial!! 3. Interfant-99: no difference in DFS in high-risk infants (defined by prednisone response) with either HSCT in first CR or chemotherapy alone** **In a subset analysis, HSCT in first CR was associated with a significantly better DFS for <6 mo-old infants with MLL-r and had either a poor prednisone response or leukocyte counts >300,000/µL (64% reduction) Pieters R, et al. Lancet. 2007;370(9583):240-50. Mann G, et al. Blood. 2010;116(15):2644-50.
Yoshimi A, et al. Pediatr Transplant. 2017;21:e12918.
Management for infantile ALL Treatment for ALL infants without MLL-r Intensive chemotherapy 1. COG: P9407 (NCT00002756) trial 5-yr EFS 70% 2. Interfant-99: cytarabine-intensive treatment regimen 4-yrs EFS 74% 3. Japanese trial: subgroup analysis (n = 22, 91% males) favorable outcome comparable to older children with ALL 5-yr EFS 95.5% Pieters R, et al. Lancet. 2007;370(9583):240-50. Dreyer ZE, et al. Pediatr Blood Cancer. 2015;62(3):419-26. Tomizawa D, et al. Leukemia. 2007;21(11):2258-63.
MLL fusion protein involved histone modifications and transcription elongations in hematopoiesis **Promoter hypermethylation **Disruption of HOX gene expression Winters AC, Bernt KM. Front Pediatr. 2017;5:4.
Management for infantile ALL New treatment strategies for ALL infants FLT3 inhibitors in MLL-r ALL TACL study: phase I trial quizartinib (AC220) in relapsed acute leukemia (status: completed in 2017, unpublished) Midostaurin (PKC412) (NCT00866281) for relapsed/refractory FLT3-mutated AML and MLL-r ALL (status: terminated due to low No. of participants) www.clinicaltrials.gov.
Management for infantile ALL New treatment strategies for ALL infants FLT3 inhibitors in MLL-r ALL COG: phase III trial of intensive chemotherapy backbone (AALL0631) +/- Lestaurtinib (CEP-701) (NCT00557193) for MLL-r ALL (status: completed in 2017, unpublished) www.clinicaltrials.gov.
Management for infantile ALL New treatment strategies for ALL infants Hypomethylating agents AALL15P1 (NCT02828358): phase II trial adding azacitidine to the Interfant chemotherapy backbone in MLL-r ALL infants (status: recruiting) www.clinicaltrials.gov.
Management for infantile ALL New treatment strategies for ALL infants Proteasome and HDAC inhibitors: SJCRH (NCT02419755): adding bortezomib and vorinostat into backbone regimens for MLL-r hematologic malignancies (status: terminated*) SJCRH (NCT02553460): phase I/II trial incorporating bortezomib and vorinostat into an ALL chemotherapy backbone (Total therapy for infant ALL I) for newly diagnosed infants with ALL (status: recruiting) *Terminated early, because accrual goals were no longer feasible based on restrictions imposed by DSMB www.clinicaltrials.gov.
Stackelberg AV, et al. J Clin Oncol. 2016;34(36):4381 9. Gardner R, et al. Blood. 2016;127:2406-10. Rayes A, et al. Pediatr Blood Cancer. 2016;63:1113 5. Management for infantile ALL New treatment strategies for ALL infants Immunotherapy: CD19-directed CAR-T Blinatumomab (bidirectional antibody targeting CD19) **Theoretical concerns about the immaturity of T-cell responses **Relapses with myeloid leukemia after treatment?lineage plasticity of MLL-r blasts
Management for infantile ALL MLL specific pathways and targeted inhibitors DOT1L inhibitor NCT02828358: phase I trial of pinometostat (EPZ- 5676) in the treatment of pediatric relapsed/refractory MLL-r Leukemia (status: completed in 2016, unpublished) www.clinicaltrials.gov.
Management for infantile ALL MLL specific pathways and targeted inhibitors BCL-2 inhibitor NCT01150656: studying the effects of BCL-2 inhibitor, obatoclax in cell samples from patients with infantile AML (status: completed in 2016, unpublished) www.clinicaltrials.gov.
Prognosis Prognostic factors for infantile AML: unremarkable Poor prognostic factors for infantile ALL: A very young age (<6 mo and poorer in 90 days) Extremely high presenting leukocyte count ( 200,000 300,000/μL) MLL-r CD10 negativity Poor early response, as reflected by a poor response to a prednisone prophase or high levels of MRD at the end of induction and consolidation phases Hilden JM, et al. Blood. 2006; 108(2):441 51. Pieters R, et al. Lancet. 2007;370(9583):240-50. Dreyer ZE, et al. Pediatr Blood Cancer. 2015;62(3):419-26.
ThaiPOG protocol (Updated in 2016)
Pediatric ALL survival in 2006-2008 (ThaiPOG-ALL-01-05&-02-05) 5-yr OS 67.2% 5-yr EFS 58.7% Seksarn P, et al. Asian Pac J Cancer Prev. 2015;16(11):4609-14.
Conclusion Leukemia in infants is an infrequent but very challenging disease because of the high rate of toxicities and relapses The outcome of infantile ALL is inferior to the outcome of childhood ALL, whereas infantile AML cure rates are comparable to these of older children Because of the rarity of the disease, the complexity of treatment protocols and clinical management, and the high rate of toxic complications, treatment of these patients should be reserved to experienced sites
Conclusion The issue whether HSCT should be largely employed in infants with leukemia in CR1 or rather mainly reserved to relapsing patients remains individualized (beneficial in high-risk status) and needs to be addressed in future For further outcome improvement, particularly in infantile ALL, new treatment modalities (i.e. epigenetic treatment and immunotherapy) should be incorporated into the treatment protocols Long-term follow-up for survivors is crucial to monitor and overcome any long-lasting toxic complications
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