High versus low dose cyclosporine‐A, after allogeneic marrow transplantation in leukemia: Long‐term follow‐up of a randomized study
Authors: Andrea Bacigalupo, Maria Teresa Van Lint, Simona Sica, Luca Laurenti, Maria Belen Rosales, Alida Dominietto, Carmen di Grazia, Emanuele Angelucci
Journal: American Journal of Hematology (2018)

To the Editor: Leukemia relapse remains a major problem in patient with acute leukemia, undergoing allogeneic hemopoietic stem cell transplant (HSCT), and has not been reduced over the past 3 decades.1 Efforts to reduce leukemia relapse by increasing the intensity of the conditioning regimen have not resulted in improved survival, due to increased toxicity of intensified regimens.2 On the other hand, the graft versus leukemia effect (GvL) is known to play an important role in allogeneic HSCT, both in the preclinical setting,3 as well as in the clinic.4, 5 Reduced GvL has been reported when the graft is depleted of T cells.5 In 1991, we reported the results of a randomized trial of low versus high dose Cyclosporine A (CsA), following an allogeneic HSCT in patients with acute leukemia.6 All patients received a myeloablative conditioning regimen with cyclophosphamide 60 mg/kg×2 and fractionated total body irradiation (9.9–12 Gy).6 The hypothesis, of that trial, was that a lower dose of CsA would reduce the risk of leukemia relapse by increasing the GvL effect. The actuarial 2 year disease-free survival (DFS) of patients randomized to receive CsA 1 mg/kg/day (CsA1) was 71% versus 35% for patients randomized to receive CsA 5 mg/kg (CsA5).6 Of interest is the fact that the dose of CsA received and the CsA serum levels were significantly different only in the first 10 days after HSCT: this is due to the fact that on days 11–20, patients randomized to CsA5 had to reduce the dose, due to increasing creatinine levels, and patients randomized to CsA1 had to increase the dose due to graft versus host disease (GvHD). Average CsA serum levels on days 1–10 were 295 versus 686 ng/mL (P = .004) for CsA1 versus CsA5 respectively; CsA serum levels on days 11–20 were 465 versus 650 ng/mL (P = .1).6 Relapse at 2 years was 20% versus 52% (P = .001). This observation was confirmed in a pediatric population of acute leukemia, comparing CsA 1 mg/kg versus CsA 3 mg/kg, with a relapse risk of 15% versus 41% for the two arms, and an event-free survival at 5 years of 70% versus 51% (P = .1).7 More recently CsA exposure, as identified as area under the curve in the first 21 days post-HSCT, has been shown to correlate with the risk of relapse8; similarly tacrolimus exposure, in the first 11 days post-HSCT, was predictive of survival in patients with refractory AML.9 One question is whether the GvL effect induced by low CsA/tacrolimus exposure early after HSCT is long lasting. To answer this question we have updated our randomized study, with a minimum follow up of 15 years and are reporting the results of the update. Of the original 81 patients 27 patients are alive: 18/41 patients randomized to the CsA1 arm, compared to 9/40 in the CsA5 arm (P = .04). Patients in the CsA1 arm had more moderate/severe chronic GvHD (29%) compared to patients in the CsA5 arm (17%), but this did not reach statistical significance (P = .2). The cumulative incidence of transplant related mortality (TRM), at 27 years, is 45% (95% CI 32%-64%) for CsA1, and 32% (95% CI 20%-51%) for CsA5 (P = .3 Grays test). The 27-year cumulative incidence of relapse is 10% (95% CI 4%-24%) for CsA1, and 45% (95% CI 32%-63%) for CsA5 (P = .0004 Grays test) (Figure 1A). It is 4% versus 40% for patients in first remission (P = .001) and 21% versus 53% for patients with disease beyond first remission (P = .08). The actuarial DFS at 27 years post HSCT is 43% versus 22% for CsA1 versus CsA5 respectively (P = .04) (Figure 1B). Causes of death were as follows in the CsA1 versus the CsA5 arm: leukemia relapse 5 and 18 patients, GvHD 10 and 5, second tumor 2 and 1, toxicity 5 and 7 (P = .005). The dose of TBI delivered in the two arms was, 1008 rads (836–1341) for the CsA1 arm, and 1006 rads (802–1318) for the CsA5 arm (P = 0.35 -T test). This observation is relevant, since we had previously shown, in a larger group of patients, receiving low dose CsA, also outside this randomized trial, that the dose of TBI received was a predictive factor for relapse.10 A, Cumulative incidence of relapse in patients randomized to receive CsA 1 mg/kg/day or CsA 5 mg/kg/day, in the first 10 days post-HSCT. B, Disease-free survival of patients randomized to receive CsA 1 mg/kg/day or CsA 5 mg/kg/day, in the first 10 days post-HSCT In conclusion, we confirm that a lower dose of CsA in the first 10 days after HSCT, significantly protects patients given the same dose of TBI, from leukemia relapse. The effect is long lasting and can be seen 27 years later. There was more chronic GvHD in the low CsA arm, and more GvHD related deaths (10 vs. 5), although one should consider that these patients received CsA alone for GvHD prophylaxis, in the late eighties. However, the protective effect on leukemia relapse and leukemia related death (5 vs. 18) was so strong, to improve disease-free survival. Several post-transplant approaches, including maintenance therapy,11, 12 with or without cellular therapy,10 have been described to control leukemia relapse after transplant. One additional feasible intervention is the prospective use of low dose CsA/tacrolimus post-HSCT, which has been shown to protect from leukemia relapse in four independent studies,6-9 two of which were prospective randomized trials, and may be considered in the first 10 days post-HSCT. This study was funded by Associazione Italiana Ricerca contro il Cancro Milano, Italy and FARITMO Genova. AB designed the study, analyzed the data and wrote the manuscript together with SS, LL, and MBR; AD, CDG, MTVL, EA, AB contributed patients. Authors declare no conflict of interest.