Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft-versus-host disease prophylaxis following allogeneic haemopoietic cell transplantation.

BACKGROUND: Concern regarding dose-related toxicities of methotrexate (MTX) and cyclosporin (CYA) graft-versus-host disease (GVHD) prophylaxis occasionally leads to dose alterations post allogeneic haemopoietic cell transplant (alloHCT). AIMS: To clarify causes of MTX and CYA dose alteration and assess impact on patient outcomes, including GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS). METHODS: Analysis of retrospective data was performed in a single tertiary centre of patients who underwent alloHCT for any indication and who received GVHD prophylaxis with CYA and MTX between the years 2011 and 2015. Univariate analysis was conducted using the log-rank test for OS and using competing risk regression for NRM, relapse and GVHD. Fisher exact tests were used to determine if an association existed between each of the pre-transplant variables and MTX alteration. Multivariate models for OS and NRM were constructed using Cox proportional hazards modelling and competing risk regression respectively. RESULTS: Fifty-four (28%) of 196 had MTX alterations and 61/187 (33%) had CYA alterations. Reasons for MTX alteration included mucositis, renal or liver impairment, fluid overload and sepsis. Causes of CYA alteration were numerous, but most commonly due to acute kidney impairment. MTX alteration was associated with inferior OS (hazard ratio 2.4; P = <0.001) and higher NRM (odds ratio (OR) 4.6; P < 0.001) at 6 years post-landmark. CYA alteration was associated with greater NRM (OR 2.7; P = 0.0137) at 6 years. GVHD rates were unaffected by dose alteration. CONCLUSIONS: Our findings suggest dose alteration in MTX and CYA GVHD prophylaxis is associated with adverse survival outcomes in alloHCT, without a significant impact on GVHD rates.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Validating the allogeneic stem cell transplantation disease risk index: sample size, follow-up, and local data are important.

BACKGROUND: Reporting allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes by disease and disease stage can limit statistical power. Recently, the disease risk index (DRI) was developed and validated to stratify clusters of patients with various combinations of disease and stage for overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR). However, the DRI has not been tested for smaller cohorts or cohorts with shorter follow-up. METHODS: Data from recipients of a first alloHSCT between 2000 and 2011 (n=466; median follow-up, 55.2 months) were extracted from our database. Each patient was assigned to one of four risk categories according to the DRI. RESULTS: The DRI was validated as being significantly predictive of OS, PFS, and CIR (P<0.001 for all). The OS, PFS, and CIR from a contemporaneous cohort (n=324) from our institution were superior to the original training cohort. Using randomized patient subsets, the DRI stratified a cohort of 100 patients (OS, P=0.010; PFS, P=0.016; CIR, P=0.027), but failed to stratify a cohort of 50 patients (OS, P=0.385; PFS, P=0.167; CIR, P=0.026). When simulating shorter follow-up, the DRI stratified a cohort (n=322) with a median follow-up of 40.6 months for OS and PFS, but failed to stratify a cohort (n=242) with a median follow-up of 33.1 months. CONCLUSION: The DRI is a simple, robust pre-alloHSCT risk stratification tool. However, users should calibrate with local data before using the DRI to estimate absolute OS, PFS, and CIR and understand its limitations when applied to smaller cohorts or cohorts with shorter follow-up.