GVHD prophylaxis using low‐dose cyclosporine improves survival in leukaemic recipients of HLA‐identical sibling transplants

Abstract

Graft-versus-host disease (GVHD) prophylaxis of short duration (6 months) with low-dose cyclosporine A (CsA) starting at 1 mg/kg per day i.v. and four doses of methotrexate (MTX) were given to 171 consecutive leukaemic recipients of HLA-identical sibling transplants. In contrast, apart from MTX, retrospective controls received high-dose CsA, starting at 5-7.5 mg/kg per day i.v. and discontinued 1 yr post-transplant. In the low-dose CsA group, the probability of acute GVHD grades I-II (70% vs. 53%, P < 0.01), and chronic GVHD were increased (58% vs. 25%, P < 0.01), whereas the incidences of acute GVHD grades III-IV (9% vs. 5%, P = 0.62), and non-relapse mortality (20% vs. 22%, P = 0.58) were similar. Moreover, the probability of relapse was decreased (31% vs. 54%, P < 0.01), and both relapse-free (56% vs. 38%, P = 0.04) and overall survival (61% vs. 40%, P = 0.04) were markedly improved using the low-dose CsA regimen. In multivariate analyses, low-dose CsA was strongly associated with chronic GVHD [relative hazard (RH) 2.56, P < 0.01], which decreased the risk of relapse (RH 0.46, P < 0.01) and improved the probability of survival (RH 1.84, P < 0.01). In conclusion, a low-dose CsA regimen in leukaemic recipients of HLA-identical sibling transplants increases the rate of chronic GVHD, which seems to attenuate the risk of relapse, thereby improving patient survival owing to enhanced graft-versus-leukaemia effect.

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…[31][32][33][34][35][36] and despite first-line prophylaxis usually consisting of CsA and MTX, GvHD still occurs in 10-50% of patients depending on the HLA disparity between host and donor. 29,52 Although CsA is considered a cornerstone in GvHD prophylaxis, we showed that its reduction of GvHD-related mortality was comparable to that observed by IVIG in our model. In a clinical setting, IVIG are used with CsA and other immunosuppressive drugs, although in our model IVIG and CsA were used alone.…”

“…We also tested whether OKT3 and CsA could inhibit GvHD in this model. CsA is a key drug used in GvHD prophylaxis in humans [27][28][29][30] and OKT3 is used for steroid-refractory GvHD. [31][32][33][34][35][36] We showed that OKT3 and CsA significantly prevented GvHD-related mortality ( Figure 1), with a greater efficacy for OKT3.…”

Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan‐Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation

“…GVHD prophylaxis with sirolimus and tacrolimus was given to 12 patients . During the first month, blood CsA levels were kept at 100 or 200 ng/mL when a sibling donor or unrelated donor was used, respectively . Patients with nonmalignant diseases were also kept at the higher CsA level of 200 ng/mL.…”

“…20 During the first month, blood CsA levels were kept at 100 or 200 ng/ mL when a sibling donor or unrelated donor was used, respectively. 21 Patients with nonmalignant diseases were also kept at the higher CsA level of 200 ng/mL. In the absence of GVHD, patients with malignant diseases discontinued CsA after tapering at 34 months in HLA-identical transplants, and at 6 months in unrelated donor transplants, whereas it was discontinued after 12-24 months in patients with nonmalignant disorders.…”

Mild chronic graft‐versus‐host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

“…The FLT3 mutation is undetectable by PCR at pre-or post-transplant time points in patients with many AML who have been FLT3-ITD positive at diagnosis and subsequently relapsed after transplant. Grunwald et al reported that application of a new, sensitive technique -tandem duplication PCR (TD-PCR) for detecting MRD in FLT3-ITD AML patients (30)-may provide an opportunity for early clinical intervention (31), for example the triggering of GvHD and GvL effect as a result of the discontinuation of immunosuppresive therapy (32,33), DLI (34), or administration of FLT3-ITD inhibitors which may also have immunomodulatory potential (e.g., sorafenib) (24,35). Studies are underway to incorporate all of these strategies in a clinical setting to determine their impact on relapse and survival after HSCT.…”