Acute lymphoblastic leukemia

FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631

Abstract

Infants with KMT2A‐rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy‐induced cytotoxicity in preclinical models. Children’s Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post‐induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.

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Fig. 1: CONSORT diagram: the flow of patients from enrollment to treatment assignment.
Fig. 2: Survival and cumulative incidence of events from study entry by risk group.
Fig. 3: Survival and cumulative incidence of events from post-induction treatment assignment by treatment arm.
Fig. 4: Survival according to results of FLT3 inhibitor laboratory correlative assays for patients treated with lestaurtinib (Arm C).

References

  1. 1.

    Brown P, Pieters R, Biondi A. How I treat infant leukemia. Blood. 2019;133:205–14.

    CAS  Article  Google Scholar 

  2. 2.

    Brown P. Treatment of infant leukemias: challenge and promise. Hematol Am Soc Hematol Educ Program. 2013;2013:596–600.

    Article  Google Scholar 

  3. 3.

    Hilden JM, Dinndorf PA, Meerbaum SO, Sather H, Villaluna D, Heerema NA, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the children’s oncology group. Blood. 2006;108:441–51.

    CAS  Article  Google Scholar 

  4. 4.

    Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370:240–50.

    CAS  Article  Google Scholar 

  5. 5.

    Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (cohort 3). Pediatr Blood Cancer. 2015;62:419–26.

    Article  Google Scholar 

  6. 6.

    Pieters R, De Lorenzo P, Ancliffe P, Aversa LA, Brethon B, Biondi A, et al. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the Interfant-06 protocol: results from an international phase III randomized study. J Clin Oncol. 2019;37:2246–56.

    CAS  Article  Google Scholar 

  7. 7.

    Salzer WL, Jones TL, Devidas M, Dreyer ZE, Gore L, Winick NJ, et al. Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the children’s oncology group. Pediatr Blood Cancer. 2015;62:414–8.

    Article  Google Scholar 

  8. 8.

    Sison EA, Brown P. Does hematopoietic stem cell transplantation benefit infants with acute leukemia? Hematol Am Soc Hematol Educ Program. 2013;2013:601–4.

    Article  Google Scholar 

  9. 9.

    Dreyer ZE, Dinndorf PA, Camitta B, Sather H, La MK, Devidas M, et al. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the children’s oncology group. J Clin Oncol. 2011;29:214–22.

    CAS  Article  Google Scholar 

  10. 10.

    Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 study. Blood. 2010;116:2644–50.

    CAS  Article  Google Scholar 

  11. 11.

    Van der Velden VHJ, Corral L, Valsecchi MG, Jansen MWJC, De Lorenzo P, Cazzaniga G. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23:1073–9.

    Article  Google Scholar 

  12. 12.

    Kang H, Wilson CS, Harvey RC, Chen IM, Murphy MH, Atlas SR, et al. Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a children’s oncology group study. Blood. 2012;119:1872–81.

    CAS  Article  Google Scholar 

  13. 13.

    Stam RW, Schneider P, Hagelstein JAP, Van der Linden MH, Stumpel DJPM, de Menezes RX. et al. Gene expression profiling-based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants. Blood. 2010;115:2835–44.

    CAS  Article  Google Scholar 

  14. 14.

    Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–7.

    CAS  Article  Google Scholar 

  15. 15.

    Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173–83.

    CAS  Article  Google Scholar 

  16. 16.

    Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085–8.

    CAS  Article  Google Scholar 

  17. 17.

    Brown P, Levis M, Shurtleff S, Campana D, Downing J, Small D. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood. 2005;105:812–20.

    CAS  Article  Google Scholar 

  18. 18.

    Chillon MC, Gomez-Casares M, Lopez-Jorge C, Rodriguez-Medina C, Molines A, Sarasquete ME, et al. Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia. Leukemia. 2012;26:2360–6.

    CAS  Article  Google Scholar 

  19. 19.

    Stam RW, Schneider P, de Lorenzo P, Valsecchi MG, den Boer ML, Pieters R. Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia. Blood. 2007;110:2774–5.

    CAS  Article  Google Scholar 

  20. 20.

    Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia. 2006;20:1368–76.

    CAS  Article  Google Scholar 

  21. 21.

    Stam RW, den Boer ML, Schneider P, Nollau P, Horstmann M, Beverloo HB, et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia. Blood. 2005;106:2484–90.

    CAS  Article  Google Scholar 

  22. 22.

    Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood. 2006;108:3477–83.

    CAS  Article  Google Scholar 

  23. 23.

    Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117:3294–301.

    CAS  Article  Google Scholar 

  24. 24.

    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  25. 25.

    Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer. 1977;35:1–39.

    CAS  Article  Google Scholar 

  26. 26.

    Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.

    Article  Google Scholar 

  27. 27.

    Schultz KR, Pullen DJ, Sather HN, Shuster JJ, Devidas M, Borowitz MJ, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the pediatric oncology group (POG) and children’s cancer group (CCG). Blood. 2007;109:926–35.

    CAS  Article  Google Scholar 

  28. 28.

    Brown P, Meshinchi S, Levis M, Alonzo TA, Gerbing R, Lange B, et al. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood. 2004;104:1841–9.

    CAS  Article  Google Scholar 

  29. 29.

    Horton TM, Sposto R, Brown P, Reynolds CP, Hunger SP, Winick NJ, et al. Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference. Pediatr Blood Cancer. 2010;54:872–8.

    Article  Google Scholar 

  30. 30.

    Knapper S, Russell N, Gilkes A, Hills RK, Gale RE, Cavenagh JD, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129:1143–54.

    CAS  Article  Google Scholar 

  31. 31.

    Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104:1145–50.

    CAS  Article  Google Scholar 

  32. 32.

    Zwaan CM, Soderhall S, Brethon B, Luciani M, Rizzari C, Stam RW, et al. A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia. Br J Haematol. 2019;185:623–7.

    Article  Google Scholar 

  33. 33.

    Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40.

    CAS  Article  Google Scholar 

  34. 34.

    Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20:984–97.

    CAS  Article  Google Scholar 

  35. 35.

    Cooper TM, Cassar J, Eckroth E, Malvar J, Sposto R, Gaynon P, et al. A phase I study of quizartinib combined with chemotherapy in relapsed childhood leukemia: a therapeutic advances in childhood leukemia & lymphoma (TACL) study. Clin Cancer Res. 2016;22:4014–22.

    CAS  Article  Google Scholar 

  36. 36.

    Krivtsov AV, Evans K, Gadrey JY, Eschle BK, Hatton C, Uckelmann HJ, et al. A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell. 2019;36:660.673.e11.

    CAS  Article  Google Scholar 

  37. 37.

    Tomizawa D, Miyamura T, Imamura T, Watanabe T, Moriya Saito A, Ogawa A, et al. A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial. Blood. 2020;136:1813–23.

    CAS  Article  Google Scholar 

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Acknowledgements

The correlative laboratory studies were funded by grants NIH/NCI (K23 CA111728; PAB), Damon Runyon Cancer Research Foundation (CIA 30-06; PAB), Leukemia and Lymphoma Society (SCOR 7327–07 to DS and PAB, and LLS Scholar 2365–12 to PAB), and Children’s Cancer Foundation (PAB). The clinical trial was funded by grants to the children’s oncology group from the National Institutes of Health/National Cancer Institute (U10CA098543, U10CA098413, U10CA180886, and U10CA180899) and the St. Baldrick’s Foundation. Lestaurtinib was provided to study participants by Teva via a Collaborative Research and Development Agreement with the National Institutes of Health/National Cancer Institute/Cancer Therapy and Evaluation Program.

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PAB and DS conceived of the clinical trial and correlative laboratory studies; PAB conducted the correlative laboratory studies; PAB, SPH, WLC, MD, JAK, JMH, ZED, LG, WLS, NJW, EAR, and MLL designed and executed the clinical trial; AJC and NAH performed a central review of cytogenetics and FISH data for risk stratification; MJB performed immunophenotyping for eligibility; JAK and CW performed statistical analyses. PAB and JAK wrote the paper. All authors reviewed, edited, and approved the paper.

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Correspondence to Patrick A. Brown.

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The authors report the following potential conflicts of interest: PAB: Scientific Advisory Committees for Novartis, Servier, Jazz, and Janssen. LG: Consultancy for Amgen, Novartis, Roche/Genentech; Equity Ownership for Amgen, Anchiano, Blueprint Medicines, Celgene, Clovis, Mirati, Sanofi Paris; Honoraria for Amgen, Roche/Genentech; Scientific Advisory Committee for Amgen; Data Safety and Monitoring Committee member for Novartis and Celgene. EAR: Research Funding from Pfizer; Data Safety and Monitoring Committee member for Celgene. MJB: Honoraria from Beckman Coulter. MLL: Scientific Advisory Committee for Medisix Therapeutics. SPH: Consultancy for Amgen, Bristol Myers Squibb,, and Novartis; Equity Ownership for Amgen; Honoraria for Jazz.

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Brown, P.A., Kairalla, J.A., Hilden, J.M. et al. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631. Leukemia (2021). https://doi.org/10.1038/s41375-021-01177-6

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