We performed a retrospective analysis of all patients undergoing ALOTH in our adult transplant program from 2010 to 2018. For this purpose, we reviewed the database of our program and medical records, obtaining data on clinical and laboratory characteristics, survival rates and transplant-related morbidity and mortality.

Our program performs a standardized pretransplant evaluation and intrahospital transplantation process, as previously reported. Briefly, our program uses sources from identical, unrelated, and haploidentical related donors. Currently, we do not use umbilical cord blood in adults. The conditioning treatment is intensity-adjusted depending on the underlying disease and functional state, with myeloablative conditionings for patients under 40 years of age or older with good physiological reserve and reduced intensity conditioning for people over 40 years of age or under this age with significant comorbidities. The process of infusion of stem cells, apheresis and post-transplant care is also described in a previous report.10

In patients with identical family donor transplants, prophylaxis with endovenous (EV) methotrexate 15mg/m2 day +1, followed by 10mg/m2 on days 3, 6, 9 and 12 and cyclosporine 3mg/kg every 12h EV, following which oral (PO) administration was used for therapeutic serum levels. In patients with unrelated and haploidentical donors, the prophylaxis was with tacrolimus 0.03mg/kg EV, followed by PO, mycophenolate 1g every 8h PO and post-transplant cyclophosphamide 50mg/kg/day +3 and +4, with an equivalent dose of mesna. In the absence of manifestations of GVHD, the immunosuppressive treatment was gradually interrupted after 180 post-transplant days. According to the time of the onset of clinical features, acute GVHD was defined in patients with symptoms or signs in the first 100 days post-transplant and as chronic GVHD in those who had symptoms after that period. The diagnosis was made with a cutaneous, surgical or endoscopic digestive biopsy when possible. In the presence of hepatic GVHD, the diagnosis was presumptive, given the risk of percutaneous liver biopsies. The disease was graded according to standard classifications: Gluksberg for acute and Seattle for chronic GVHD.11,12 The GVHD treatment protocol of our program in mild acute or chronic cases includes symptomatic relief treatment, with topical clobetasol propionate ointments, budesonide PO/enemas for gastrointestinal manifestations and corticoid mouthwashes for oropharyngeal manifestations. In cases of severe acute or chronic GVHD, the first-line treatment was prednisone 1–2mg/kg day for 2 weeks, with gradual tapering. If there was a failure in the corticosteroid treatment, a second-line treatment with ruxolitinib or extracorporeal photopheresis was started. In cases of refractoriness to any treatment, our algorithm includes the use of ibrutinib, rituximab, infliximab and rapamycin in combinations, methotrexate, and mesenchymal stem cells. In those patients without corticoid response, the treatment was de-escalated promptly to avoid corticoid-related adverse effects.

Complete remission of GVHD was established with complete resolution of clinical and laboratory manifestations at 4 weeks from the first dose of the treatment. The partial remission was defined with the improvement without resolution, nor worsening of the manifestations, and without involvement of other organs; the absence of response was established with persistence of the disease. Mortality was classified among those directly associated with GVHD and complications associated with treatment and deaths caused by progression of the underlying disease and other causes.

The demographic and baseline characteristics are presented with descriptive statistics. The comparisons between the variables were made with the Chi-square method. The relapse and GVHD analyses were performed in a competitive risk framework, using the non-parametric estimator of cumulative incidence, and as a time-dependent covariate. The software used was the SPSS.V.15 (IBM Software, USA) and Prisma Software V 6.0.1 (GraphPad software, USA).

As shown in Table 1, during the 10 years of the analysis period, 156 allogeneic transplants were performed, of which 46% were in women. The average age of the patients at the time of transplant was 45 (17–69). During this period, 74 transplants from an identical familial donor, 15 from identical unrelated human leucocyte antigen (HLA) donors, and 67 haploidenticals were made. Basal diseases were: 30% acute lymphoid leukemia, 40% acute myeloid leukemia, 10% myelodysplasia, 15% aggressive lymphoma, and 5% acquired aplastic anemia.

The cumulative incidence of acute GVHD was 36% and chronic GVHD was 42%. The majority of patients had favorable response to first-line treatment and 40% had refractory corticoid treatment and required other treatments. Of these, 11% (17 patients) had refractory corticosteroid and second-line therapy and were treated with ruxolitinib. The average of previous treatments was 3 (range 1–5). Table 2 summarizes the characteristics of the patients treated with ruxolitinib and Figure 1 shows the treatments prior to ruxolitinib.

Figure 1.

Treatments prior to ruxolitinib.

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The median initial dose of ruxolitinib was 5mg twice daily for all patients. According to the hematologic tolerance, doses were increased and 40% of the patients reached full doses of 25mg twice daily, 40% of the patients just tolerated doses of 10mg twice daily and 20% could not tolerate increased ruxolitinib dosing. We found no association between the doses and the response obtained. Thus, patients who received low doses had similar responses to those who received higher doses.

The overall response to treatment was 80%. As shown in Table 3, the overall response was similar in patients with acute or chronic manifestations of the disease. The complete response rate in acute GVHD was 40%, and in chronic GVHD, 23%. The partial response rate for acute and chronic GVHD was 40 and 56%, respectively. Figure 2 shows response rates in several types of GVHD. Due to the failure in corticosteroid treatment, in all refractory patients with or without response to ruxolinitib, corticosteroids were de-escalated. Ruxolinib was tapered in all patients with acute GVHD and, in 2 of them, was restarted due to the cutaneous GVHD relapse. In chronic patients who obtained response, ruxolitinib treatment was continued.

Figure 2.

GVHD response to ruxolitinib, according to affected organ.

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A total of 90% of the patients presented cytopenias associated with the treatment, mostly mild. The most frequent finding was leukopenia, followed by thrombocytopenia. There were no serious adverse events associated with ruxolitinib. The incidence of reactivation of cytomegalovirus (CMV) in patients with acute refractory GVHD was 80%, mostly in HAPLO, a finding similar to the incidence in non-refractory patients (data not shown). In patients with chronic GVHD treated with ruxolitinib, we did not observe CMV reactivation events. A 50% seasonal incidence of viral respiratory infections was observed in patients with acute and chronic GVHD. Most infections were limited, except for one patient with acute GVHD, who developed pulmonary distress that caused his death.

It was observed that 40% of the patients with acute refractory GVHD died because of uncontrollable disease, with severe manifestations of central nervous system (n=1), liver (n=1) and severe infections (n=2). We did not find patients with chronic GVHD whose death was attributable to GVHD.