Treatment of newly diagnosed moderate or severe chronic graft-versus-host disease with prednisone and everolimus (PredEver first): a prospective multicenter phase IIA study.

Although most patients with chronic graft-versus-host disease (cGVHD) show initial response to first-line therapy, long-term clinically meaningful success of first-line treatment remains rare. In a prospective multicentre phase II trial in 6 German centers, patients with newly diagnosed moderate or severe cGVHD received prednisone and everolimus for 12 months followed by a 1-year follow-up period. Primary endpoint was treatment success (TS) at 6 months defined as patient being alive, achieving PR or CR of cGVHD, having no relapse of underlying disease and requiring no secondary treatment for cGVHD. Of the 34 patients evaluable for efficacy, 19 (56%) had TS at 6 months with 22 and 52% of the patients in a CR and PR respectively. Overall 30 patients (88%) had a CR or PR as best response, nearly all responses (29/30) occurring within the first 6 weeks of treatment. The cumulative incidence of treatment failure at 1 year was 63%, corresponding to 37% TS. Predefined safety endpoint (thrombotic microangiopathy, pneumonitis, and avascular necrosis) were not observed in any patient. Addition of everolimus to prednisolone is well tolerated and may improve long-term treatment success. Larger studies are necessary to ascertain the possible role of everolimus in first-line treatment of cGVHD.

Role of pre-transplant MRD level detected by flow cytometry in recipients of allogeneic stem cell transplantation with AML.

OBJECTIVES AND METHODS: We analyzed the impact of pretransplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80) years). All patients were subdivided into negative (n = 96), "low" (0.1%-0.5%, n = 32), and "high" MRD (>0.5%, n = 61) groups. RESULTS: In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, P < .001) and 5.4 (95% CI 2.1-14, P = .0058) for relapse; 2.3 (95% CI 1.3-4.1, P = .006) and 1.6 (95% CI 0.82-3.3, P = .16) for OS; and 2.8 (95% CI 1.7-4.7, P < .001) and 2.2 (95% CI 1.1-4.2, P = .02) for LFS, respectively. We found no significant impact of "low" MRD level on relapses (0.68, 95% CI 0.33-1.4, P = .30), OS (0.72, 95% CI: 0.36-1.5, P = .36) and LFS (0.79, 95% CI: 0.42-1.5, P = .46) related to "high" MRD group. CONCLUSIONS: Presence of detectable MRD was indicative for a high relapse risk, low LFS and OS. "Low" MRD level showed no significant impact on relapse, LFS and OS related to "high" MRD group.

Ruxolitinib plus extracorporeal photopheresis (ECP) for steroid refractory acute graft-versus-host disease of lower GI-tract after allogeneic stem cell transplantation leads to increased regulatory T cell level.

Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.

Allogeneic stem cell transplantation for myelofibrosis patients aged ≥65 years.

INTRODUCTION: Myelofibrosis (MF) is a disease of elderly with median age of 65 years at diagnosis. Allogeneic stem cell transplantation (ASCT) currently is the only potentially curative option, although associated with treatment-related morbidity and mortality. Development of reduced intensity conditioning (RIC) regimens enabled transplant to be performed successfully in older patients. OBJECTIVES AND METHODS: To evaluate outcome of transplantation among elderly patients (≥65 years), we conducted retrospective analysis of results in 45 patients transplanted between 2002 and 2018 at the University Medical Center Hamburg. Median age at ASCT was 67 years (r: 65-74). The majority of patients (n = 43) received busulfan plus fludarabine RIC regimen and were classified as DIPSS intermediate-2 or high risk at time of transplantation. RESULTS: After a median follow-up of 4 years, 6-year estimated progression-free survival and overall survival were 60% and 64%, respectively. Cumulative incidence of non-relapse mortality was 21% at 1 year. Cumulative incidence of relapse at 6 years was 10%. Patients with Sorror score 3 or less had a significant better survival (73% vs 25%, P = .009). CONCLUSION: Reduced intensity conditioning regimen followed by ASCT in older patients with myelofibrosis is a curative treatment option. Outcome is more favorable in patients with no or minimal comorbidities.

Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis.

Allogeneic stem cell transplantation (alloSCT) is a curative procedure for myelofibrosis. Elderly people are mainly affected, limiting the feasibility of myeloablative regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible for older patients. Nevertheless, the incidence of myelofibrosis is not negligible in young patients, who are theoretically able to tolerate high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in younger myelofibrosis patients. This study included 56 transplanted patients aged <55 years. Only 30% had a human leucocyte antigen (HLA)-matched sibling donor, the others were transplanted from a fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the European Society for Blood and Marrow Transplantation protocol: busulfan-fludarabine + anti-thymocyte globulin, followed by ciclosporin and mycophenolate. One patient experienced primary graft failure. Incidence of graft-versus-host disease grade II-IV was 44% (grade III/IV 23%). One-year non-relapse mortality was 7% and the 5-year cumulative incidence of relapse was 19%. After a median follow-up of 8·6 years, the estimated 5-year progression-free survival and overall survival (OS) was 68% and 82%, respectively. Patients with fully-matched donor had a 5-year OS of 92%, in contrast to 68% for those with a mismatched donor (P = 0·03). The most important outcome-determining factor is donor HLA-matching. In conclusion, RIC-alloSCT ensures optimal engraftment and low relapse rate in younger myelofibrosis patients, enabling the possibility of cure in this group.

Long-Term Results of Prophylactic Donor Lymphocyte Infusions for Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation.

The major reason for treatment failure after allografting in multiple myeloma (MM) is relapse. Donor lymphocyte infusions (DLIs) are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been reported rarely. In the present study, we examined the efficacy of prophylactic DLIs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in myeloma patients with a long-term follow-up of more than 5 years. A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse. Overall response rate to DLI was 77%. Thirty-three patients (54%) upgraded their remission status, 41 patients (67%) achieved or maintained complete remission, and 26% achieved a molecular remission. Incidence of acute graft-versus-host disease (GVHD) grade II to IV was 33% and no DLI-related mortality was noted. After a median follow-up of 68.7 months from first DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43% (95% confidence interval [CI], 28% to 57%) and 67% (95% CI, 53% to 82%), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62% and 8-year OS was 83%). Prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved.

Acute hepatitis as a prequel to very severe aplastic anemia.

Severe aplastic anemia is a rare and potentially life-threatening disease of the bone marrow often requiring allogeneic hematopoietic stem cell transplantation. Pathogenesis of the disease can vary and often remains enigmatic. Occasionally, severe aplastic anemia is associated with prior severe acute hepatitis. Differential diagnosis of acute non-viral hepatitis challenges the physician as pathogenesis remains unclear.We here present a case of a young patient presenting with acute hepatitis followed by severe aplastic anemia successfully treated with allogeneic hematopoietic stem cell transplantation. Due to immunosuppressive treatment with azathioprine for acute hepatitis of putative autoimmune pathogenesis and coincident infection with parvovirus B19, diagnosis of the sequential disease of acute hepatitis followed by severe aplastic anemia was complicated. We discuss the caveats and present a review of the literature.

A transplant "immunome" screening platform defines a targetable epitope fingerprint of multiple myeloma.

Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and next-generation sequencing-assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy.