Abstract
In patients with relapsed ALL, minimal residual disease (MRD) identified prior to allogeneic hematopoietic cell transplantation (HCT) is a strong predictor of relapse. We report our experience using a combination of reduced-dosing clofarabine, CY and etoposide as a ‘bridge’ to HCT in eight patients with high risk or relapsed ALL and pre-HCT MRD. All patients had detectable MRD (>0.01%, flow cytometry) at the start of therapy with all eight achieving MRD reduction following one cycle. The regimen was well tolerated with seven grade 3/4 toxicities occurring among four of the eight patients. Five patients (62.5%) are alive, one died from relapse (12.5%) and two from transplant-related mortality (25%). The combination of reduced-dose clofarabine, CY and etoposide as bridging therapy appears to be well tolerated in patients with relapsed ALL and is effective in reducing pre-HCT MRD.
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References
Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M et al. Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer 2012; 60: 957–963.
Raetz EA, Bhatla T . Where do we stand in the treatment of relapsed acute lymphoblastic leukemia? Hematol Am Soc Hematol Educ Program 2012; 2012: 129–136.
Ruggeri A, Michel G, Dalle JH, Caniglia M, Locatelli F, Campos A et al. Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP-EBMT analysis. Leukemia 2012; 26: 2455–2461.
Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP et al. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant 2012; 18: 963–968.
Pulsipher MA, Bader P, Klingebiel T, Cooper LJ . Allogeneic transplantation for pediatric acute lymphoblastic leukemia: the emerging role of peritransplantation minimal residual disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches aimed at preventing relapse. Biol Blood Marrow Transplant 2009; 15: 62–71.
Elorza I, Palacio C, Dapena JL, Gallur L, de Toledo JS, de Heredia CD . Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia. Haematologica 2010; 95: 936–941.
Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 2009; 27: 377–384.
Foster JH, Hawkins DS, Loken MR, Wells DA, Thomson B . Minimal residual disease detected prior to hematopoietic cell transplantation. Pediatr Blood Cancer 2011; 57: 163–165.
Burke MJ, Lindgen B, Verneris MR . Treatment of relapsed acute lymphoblastic leukemia: approaches used by pediatric oncologists and bone marrow transplant physicians. Pediatr Blood Cancer 2012; 58: 840–845.
Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004; 103: 784–789.
Hijiya N, Thomson B, Isakoff MS, Silverman LB, Steinherz PG, Borowitz MJ et al. Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood 2011; 118: 6043–6049.
Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol 2009; 147: 371–378.
Hijiya N, Gaynon P, Barry E, Silverman LB, Thomson B, Chu R et al. A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia 2009; 23: 2259–2264.
Leung W, Pui CH, Coustan-Smith E, Yang J, Pei D, Gan K et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood 2012; 120: 468–472.
Wayne AS, Radich JP . Pretransplant MRD: the light is yellow, not red. Blood 2012; 120: 244–246.
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Children’s Cancer Research Fund (MJB, MRV) and the University of Minnesota Pediatric Leukemia Program supported this work.
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Gossai, N., Verneris, M., Karras, N. et al. A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD). Bone Marrow Transplant 49, 440–442 (2014). https://doi.org/10.1038/bmt.2013.195
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DOI: https://doi.org/10.1038/bmt.2013.195
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