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.
Improvements in the treatment of children with ALL have resulted in 5-year OS approaching 90%.1 However, those with relapsed disease continue to respond poorly to traditional salvage approaches, with survival rates hovering around 35–40%.2 Although allogeneic hematopoietic cell transplantation (HCT) in children with relapsed ALL has the ability to overcome resistant disease and cure some patients, relapse remains a significant barrier to success. Recent studies show that identifying minimal residual disease (MRD) prior to HCT is the strongest predictor of treatment failure.3, 4, 5, 6, 7, 8 Whether eliminating MRD prior to HCT will influence post-HCT outcomes, particularly with regard to reducing relapse, has not yet been established. However, this approach is not without risks, as additional chemotherapy in patients who have already achieved remission could lead to toxic complications that may preclude proceeding to HCT or increase peri-transplant toxicity. Also, in prolonging the time to HCT for further chemotherapy, patients may lose their state of remission and increase their disease burden, rather than decrease it. Despite these uncertainties, there is a strong sense among the pediatric oncology and transplant communities that attempts to eliminate MRD prior to HCT are warranted.9
Clofarabine, a novel purine nucleoside analog granted accelerated FDA approval in 2004 for pediatric relapsed/refractory ALL, has reported promising results as a single agent or part of a multidrug regimen with cyclophosphamide (CY) and etoposide.10, 11, 12 Although clofarabine combinations have shown encouraging rates of CR in heavily pre-treated relapsed/refractory patients,11, 12 significant toxicities exist that appear to be dose dependent.13 In an attempt to reduce and/or eliminate pre-HCT MRD without inducing significant toxicities, we treated eight consecutive patients with reduced dosing of clofarabine, CY and etoposide. The goal of this therapy was to ‘bridge’ patients to HCT. This case series describes the impact of this bridging therapy approach on toxicity, clearance of MRD and transplantation outcomes in children with relapsed ALL and pre-HCT MRD.
Materials and methods
This bridging regimen was selected specifically for patients with relapsed or very high-risk ALL who had received a median of 3 (range, 2–3) blocks of prior re-induction/consolidation therapy and were proceeding to HCT in morphologic remission but with persistent disease identified by multiparameter flow cytometry (>0.01% leukemia). This report of a case series as determined by the participating institution’s review boards did not meet the regulatory definition of research and institution’s review board’s review as it is a discussion of a course of therapy for a small group of patients with all data de-identified and therefore the patient’s permission to use the data was not required. The goal of the therapy was to safely reduce or eliminate MRD in patients without causing significant toxicity and with all patients proceeding to HCT following this course of therapy. Eight patients meeting the above characteristics were treated at our institutions between 2011 and 2013 (Table 1). The median age was 12.5 years (range, 23 months to 20 years). Three patients were evaluated for HCT in CR1 for persistent MRD (Patients 2, 3, 6), three patients had early BM relapses and were in CR2 at the time of HCT with persistent MRD (Patients 1, 4, 5), one patient had a late marrow relapse and in CR2 at the time of HCT with persistent MRD (Patient 8) and the remaining patient (Patient 7) had Ph chromosome positive ALL (CR2) with persistent MRD after failing a prior HCT in CR1.
The bridging regimen was developed to reduce the overall toxicity that had been previously reported using clofarabine at 40 mg/m2 and CY at 440 mg/m211 through a dose reduction of both of these agents to 30 and 300 mg/m2, respectively and yet retain the efficacy of this three-drug regimen. While there were mild variations in the bridging therapy dosing based on treating physician discretion, all patients received the three-drug regimen of clofarabine (20–30 mg/m2 i.v.), CY (300–340 mg/m2 i.v.) and etoposide (100 mg/m2 i.v.) for days 1–5. Treatment-related toxicities were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0.
This bridging regimen was well tolerated overall with 8/8 patients able to proceed to HCT within a median of 53 days (range, 41–201) from completing the five-day cycle. All patients had evidence of MRD (>0.01%, flow cytometry) prior to bridging treatment. Six (75%) patients became MRD-negative (<0.01% leukemia) after a single course of treatment with the remaining two patients achieving significant reduction of their MRD (0.28%→0.02% and 0.14%→0.07%, respectively). There were seven grade 3/4 toxicities occurring among four patients: one grade 4 (mandibular osteomyelitis) and six grade 3 toxicities (sinusitis, rash, fever/neutropenia, achilles tenosynovitis, zoster and transient renal insufficiency). Importantly, none of the toxicities precluded patients from ultimately proceeding to HCT, however the patient who developed zoster (Patient #8) was delayed due to this infection after achieving MRD negativity with the bridging treatment and received oral chemotherapy (6-mercaptopurine and MTX) while awaiting recovery of the zoster. The median time to neutrophil recovery (ANC >500/μL) for the eight patients was 23.5 days (range, 16–37) from the start of the clofarabine-based regimen and a median of 33 days (range, 17–45) to achieve an ANC >1000/μL.
At the time of this report, four patients (50%) are alive without disease with a median of 217 days from HCT (range, 84 to 360), two patients died without disease (day 37 and 140), one patient died of disease (day 94) and one patient relapsed (day 106) but remains alive. EFS at 1 year for the eight patients was 44% (95% CI 6–81) (Figure 1) with a median EFS time of 140 days post HCT.
There have been two cases of relapse in this cohort of patients. One occurred in a Ph chromosome positive patient (Patient 7) who received the bridging therapy, but remained with persistent MRD prior to HCT, which incidentally was a reduced intensity conditioning regimen and the patient’s second HCT. The second relapse occurred in a patient with MLL gene rearrangement (Patient 4) who achieved MRD negativity post bridging therapy but subsequently relapsed 106 days post HCT. This patient then received another course of the clofarabine-based bridging regimen resulting in elimination of his disease becoming MRD-negative (4%→<0.01% by flow cytometry) and proceeded to chimeric Ag receptor T-cell therapy.
Outcomes for patients with relapsed ALL continue to be poor, particularly for patients who have MRD prior to allogeneic-HCT.3, 4, 5, 6, 7, 8 Although consolidative therapy with HCT can cure some patients with persistent MRD,7, 14, 15 most studies suggest that the majority of these patients will relapse post HCT.3, 6, 7, 8 The idea that leukemia-free survival would be improved if pre-transplant MRD can be eliminated has scientific rationale, but the theory has not been formally tested. Whether pre-HCT MRD represents a patient who is inadequately treated, or one who has underlying high-risk biology that is predetermined to fail HCT, is currently unknown. In this case series, we demonstrate that lower doses of clofarabine, CY and etoposide can reduce pre-HCT MRD (eliminating MRD in 75% of patients), maintaining a limited toxicity profile, and successfully bridge patients to allogeneic-HCT. Alternative approaches to bridging therapies may include immunotoxins (for example, moxetumomab pasudotox targeting CD22) or bi-specific T-cell engagers (for example, blinatumomab targeting CD19/CD3) which would be more selective and potentially more tolerable than traditional chemotherapy options.
Although this report is small in scope but typical for a case series, the results are promising and show the possibility of MRD being a reversible risk factor and less of a biomarker for predefined treatment failure since our pre-HCT MRD-positive patients behaved more like MRD-negative patients after receiving bridging therapy with a relatively low relapse rate of 25%. This relapse rate is strikingly less than what would be predicted for pre-HCT MRD positive patients (relapse rate of 50–60%), and more in line with patients who were MRD-negative.3, 4, 6, 7, 8 Further study of this bridging therapy combination is necessary to characterize the toxicities, as well as the ability to reduce/eliminate MRD prior to HCT and ensure that leukemia-free survival remains improved. Based on this anecdotal experience, a pilot study using this bridging regimen has been opened at the University of Minnesota for patients (ages 0–60 years) with ALL or AML proceeding to HCT who are in morphologic remission but have evidence of persistent disease identified by flow cytometry. Results from this study as well as others will be critical in providing further data regarding the feasibility and efficacy of this approach for patients with acute leukemia and persistent MRD prior to HCT.
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.
Children’s Cancer Research Fund (MJB, MRV) and the University of Minnesota Pediatric Leukemia Program supported this work.
The authors declare no conflict of interest.
About this article
Cite this article
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
Journal of Oncology Pharmacy Practice (2020)
Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia
Cancer Letters (2018)
When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia
Journal of Clinical Medicine (2017)
Combination of clofarabine, cyclophosphamide, and etoposide for relapsed or refractory childhood and adolescent acute myeloid leukemia
Pediatric Hematology and Oncology (2017)
Impact of pretransplant minimal residual disease on the post-transplant outcome of pediatric acute lymphoblastic leukemia
Pediatric Transplantation (2016)