Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high ...mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Mesenchymal stem cells have been shown to mediate immunomodulatory effects. They have been used in patients with steroid-refractory acute GVHD (aGVHD), but their relevance as a therapeutic agent ...targeting aGVHD has still to be defined. In this case series, we report 13 patients with steroid-refractory aGVHD who received BM-derived MSC expanded in platelet lysate-containing medium from unrelated HLA disparate donors. MSC were characterized by their morphological, phenotypical and functional properties. All tested preparations suppressed the proliferation of in vitro activated CD4+ T cells. MSC were transfused at a median dosage of 0.9 x 10(6)/kg (range 0.6-1.1). The median number of MSC applications was 2 (range 1-5). Only two patients (15%) responded and did not require any further escalation of immunosuppressive therapy. Eleven patients received additional salvage immunosuppressive therapy concomitant to further MSC transfusions, and after 28 days, five of them (45%) showed a response. Four patients (31%) are alive after a median follow-up of 257 days, including one patient who initially responded to MSC treatment. In our patient cohort, response to MSC transfusion was lower than in the series reported earlier. However, our experience supports the potential efficacy of MSC in the treatment of steroid-refractory aGVHD.
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net ...classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ⩾4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the ...safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.
The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, ...biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1).
We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18-60 years.
In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3-0.9, P = 0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3-1.1, P = 0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37-0.9, P = 0.02) and relapse-free survival (HR 0.51, 95% CI 0.34-0.76; P = 0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer.
Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1.
NCT00180115, NCT00180102.
To predict the need of intensive care unit admission with organ support during the transplantation hospital stay in 101 consecutives allogeneic hematopoietic cell transplantation (allo-HCT) ...recipients the added predictive utility of three times per week Copeptin, MR-proADM, MR-proANP, NT-proBNP, IL-6, Procalcitonin, D-dimer and three times per week bed-sided pulmonary function test was determined in comparison with an index model. The index model was calculated by multivariate regression analysis out of the patients' routine laboratory parameters. To calculate the added predictive utility of the investigated markers the Δ-AUC and the continuous net reclassification improvement (cNRI + 2 to - 2), splitted for events and non-events were calculated for each marker in comparison with the index model. According to the Δ-AUC, none of the parameters improved risk prediction. In contrast, the cNRI was significantly improved for events and non-events by Copeptin (event 0.75, p value 0.0013; non-event 0.4, p value 0.000079) and for events by NT-proBNP (0.6, p value 0.018). D-dimer and PCT significantly predicted the non-event. Of the spirometry parameters, the FEF
improved prediction of event and non-event according to the cNRI model. Our data support the additional serial analysis of Copeptin and NT-proBNP in allo-HCT recipients during the transplantation hospital stay.
The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) withoutFLT3-ITD, ...biallelicCEBPA-, orNPM1 mutations (here referred to asNPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1).
We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. TheNPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18–60years.
In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3–0.9,P=0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3–1.1,P=0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37–0.9,P=0.02) and relapse-free survival (HR 0.51, 95% CI 0.34–0.76;P=0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer.
Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate riskNPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1.
NCT00180115, NCT00180102
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