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Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic stem cell transplantation (allo-SCT). Comparisons of different ATG formulations are lacking, however. Our aim was to synthesize all published efficacy evidence to enable a comparison of all available formulations of rabbit ATG in the allo-SCT setting. We performed a systematic literature review to identify all available phase III RCT evidence. We searched the Cochrane Library, MEDLINE, MEDLINE In-Process, and the website www.ClinicalTrials.gov . In addition, a trial presented at the Annual Meeting of the American Society of Hematology 2016 was added to include the most recent evidence. We identified a total of 6 RCTs, including 2 formulations: anti–T lymphocyte globulin (ATLG; Grafalon, Neovii Biotech, Lexington, MA) and polyclonal globulin immunized with human thymocytes (Thymoglobulin [Thymo]; Genzyme-Sanofi, Cambridge, MA). The evidence was synthesized using a conventional network meta-analysis (NMA). The best treatment for preventing graft-versus-host disease (GVHD) was ATLG, which had a more favorable hazard ratio (HR) compared with standard treatment (chronic GVHD: HR, .42; 95% confidence interval [CI], .31 to .56; acute GVHD grade II-IV: HR, .54; 95% CI, .39 to .73; acute GVHD grade III-IV: HR, .50; 95% CI, .29 to .86), whereas both ATLG and Thymo were at least similarly effective in terms of transplantation-related mortality (TRM) (ATLG: HR, .90; 95% CI, .61 to 1.32; Thymo: HR, .90; 95% CI, .56 to 1.44). Thymo tended to be the better treatment option regarding overall survival (OS) (HR, .86; 95% CI, .59 to 1.26). Our NMA provides the first report of the relative efficacy of all available rabbit ATG formulations in patients undergoing allo-SCT. Until additional data from randomized head-to-head comparisons are available, based on the present analysis, ATLG seems to be the best option to prevent chronic and acute GVHD. Both formulations show similar efficacy in terms of TRM, whereas Thymo appears to be the better treatment option in terms of OS. [ABSTRACT FROM AUTHOR]

• Late relapse after 5 years occurs in about 14% of myelofibrosis patients after allogeneic stem cell transplantation (allo-SCT). • For detection, chimerism and minimal residual disease monitoring should be performed even beyond 5 years after allo-SCT. • Most relapses can be successfully salvaged by donor lymphocyte infusion and/or second allo-SCT. In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P =.13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT. [ABSTRACT FROM AUTHOR]

The article discusses a study on the outcome of patients with recurring myeloma after reduced-intensity conditioning (RIT) allogeneic hematopoietic stem cell transplantation (SCT). The long-term results of 50 patients with refractory or recurrent multiply myeloma who were given allogeneic SCT between January 2001 and June 2004 were analyzed. It concludes that RIC allogeneic SCT can result in a long-term progression-free survival (PFS) in patients with multiple myeloma with best results attained when given early in disease course and in remission.

• Allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) resulted in very good outcomes. • Transplantation from a matched donor was a significant factor in survival. • The risk of relapse risk is <10% in patients with lower-risk MDS after allogeneic SCT. The indication for allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) is controversial. Here we report 60 patients with a low risk (n = 32) or intermediate risk (n = 28) classification according to the revised International Prognostic Scoring System (IPSS-R) who underwent allogeneic SCT with a reduced-intensity conditioning (n = 45) or myeloablative conditioning (n = 15) regimen from an HLA-identical sibling (n = 9), a matched unrelated donor (n = 36), or a mismatched unrelated donor (n = 15). The rates of grade II-IV and grade III-IV acute graft-versus-host disease were 32% and 7%, respectively, resulting in a transplantation-related mortality (TRM) of 17% at 3 years. The cumulative incidence of relapse at 5 years was only 7%, resulting in a 5-year disease-free survival of 72% and overall survival (OS) of 79%. Transplantation from a fully matched donor resulted in significantly improved OS at 5 years (91% versus 70%). Allogeneic SCT in lower-risk MDS (IPSS-R low or intermediate risk) from an HLA-matched donor resulted in excellent OS with a low risk of relapse. [ABSTRACT FROM AUTHOR]

Objectives: During allogeneic hematopoietic stem cell transplantation (allo‐SCT), infections significantly contribute to morbidity and mortality. A monocentric prospective analysis was performed to assess epidemiology, risk factors, and outcomes of infections during the peri‐transplant period. Methods: Data were recorded prospectively using a predefined questionnaire. Results: In 2015, 163 consecutive patients, 37.4% female, median age 59 (range 18‐79) years received 166 allo‐SCT. Median duration of leukopenia <109/L was 14.5 days (range 4‐43 days). Fever of unknown origin (FUO) occurred in 118/166 patients (71.1%). Severe sepsis developed in 95, and septic shock developed in 26 patients. Intensive diagnostic workup helped to identify causative microorganisms only in a small number of infectious courses. All but 13 patients needed antibiotic therapy, each according to the standard operating procedures of the department. Cumulative incidence of death by infection after 1 year was 16.6% (95% CI: 11.3‐22.7). The only risk factor for FUO in neutropenia was duration of neutropenia

• Overall outcomes of patients allografted for BC CML remain poor in the TKI era. • Survival after alloSCT for BC CML depends on the pretransplant remission status. • Conventional prognostic factors remain outcome determinants for BC CML in remission. • UD transplant is associated with better LFS in patients with active BC at alloSCT. The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry-based study of adult patients allografted for BC CML, focusing on patients with active disease at transplant and pretransplant prognostic factors. One hundred seventy patients allografted for BC CML after tyrosine kinase inhibitor pretreatment between 2004 and 2016 were analyzed. Before transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (hazrd ratio, 1.87; P =.010) and shorter leukemia-free survival (LFS; hazard ratio, 1.69; P =.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended toward improved overall survival. In summary, survival of patients allografted for BC CML was strongly dependent on pretransplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplant was associated with prolonged LFS in our study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Abstract JAK inhibition by ruxolitinib is approved for treating myelofibrosis and also has shown efficacy in treating steroid-resistant acute and chronic graft-versus-host disease (GVHD). In 12 patients with myelofibrosis (median age, 63 years; range, 43 to 71 years) who were treated with ruxolitinib and underwent allogeneic stem cell transplantation (ASCT), ruxolitinib was continued (2 × 5 mg daily) until stable engraftment. No graft failure was observed, and leukocyte engraftment was achieved after a median of 12 days (range, 11 to 18 days). One patient developed fever of unknown origin after discontinuation of ruxolitinib; otherwise, no withdrawal syndrome was observed. Overall, only 1 patient each experienced acute GVHD grade I or II, resulting in an 8% incidence of acute GVHD grade II-IV at day +100, with no nonrelapse mortality. Complete chimerism was achieved in 11 patients after a median of 40 days, and molecular clearance of the underlying driver mutation was noted in 10 patients after a median of 32 days. Cytomegalovirus (CMV) reactivation occurred in 5 patients (41%), 1 of whom had CMV colitis as well, but all resolved after ganciclovir treatment. In 2 patients, ruxolitinib had to be discontinued on day 17 and day 18 after ASCT due to cytopenia after engraftment. Levels of inflammatory cytokines IL-8, IL-10, IL-6, TNFR2, INF-α, and INF-β were reduced after ruxolitinib treatment. After day +100, 4 patients developed acute GVHD (1 with grade I, 2 with grade II, and 1 with grade III) after tapering of cyclosporine, and all patients were alive at a median follow-up of 17 months (range, 12 to 18 months). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P  = .05), improved PFS (HR, .393; P  = .01), and OS (HR, .448; P  = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [ P  = .008], and HR, 5.451 [ P  = .002], respectively), whereas no impact was observed for “triple negative” patients. Molecular genetics, especially CALR , IDH2 , and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo- HSCT) is a curative treatment option for myelodysplastic syndromes ( MDS). Little is known about the prognostic impact of mutations, for example, in TP53 specifically after allo- HSCT. We here describe the prognostic impact of mutations in a panel of 19 genes analyzed by amplicon-based next-generation-sequencing in a uniformly treated patient cohort. Sixty-two patients with a median age of 61 yr suffered from MDS with 0-20% bone marrow blasts. International Prognostic Score was intermediate 1 (15%) and higher (79%). Conditioning uniformly was performed using a sequential approach in which FLAMSA chemotherapy was followed by Busulfan-based conditioning. Patients mostly were transplanted from an unrelated donor (77%), and 36% of patients received a graft from a mismatched donor. Median number of mutations was 2 (range 0-6). RUNX1, GATA2, TET2, and CEBPA were the genes most frequently found mutated. TP53, a factor previously reported to confer adverse prognostic impact after allogeneic stem cell transplantation, was mutated in samples from eight patients, one of which showed a silent mutation. With an estimated 5-yr overall/disease-free survival of 48 ± 7%/41 ± 7%, none of the mutations analyzed showed a prognostic impact in this analysis of the largest uniformly treated cohort thus far. This especially holds true for patients with a mutation in TP53. [ABSTRACT FROM AUTHOR]

We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post–essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation. [ABSTRACT FROM AUTHOR]

The close association of the myeloproliferative neoplasms with the activating non-receptor tyrosine kinase JAK2V617F mutation is well established. To further clarify the pathomechanisms of this mutation in patients with myelofibrosis, we performed screening with quantitative real-time PCR for the respective mutation in in vitro expanded bone marrow (BM) mesenchymal stromal cells (MSCs) and compared the results with BM/peripheral blood (PB). Eight patients with primary/secondary myelofibrosis were investigated before ( n = 4) or after allogeneic stem cell transplantation ( n = 4). All patients had systemic evidence of the JAK2V617F mutation in BM/PB (mutation ratios 0.2–23.5) at the time of investigation in contrast to negative results in the MSCs ( n = 7) or a very low (0.004) mutation ratio ( n = 1) which was probably due to hematopoietic contamination. The four patients post-transplant had systemic donor chimerism between 96.5 and 100% in BM/PB, while MSCs showed no evidence of donor-specific alleles. In conclusion, in myelofibrosis, the JAK2V617F mutation is restricted to hematopoietic cells, and cannot explain the stromal alterations being observed in this disorder. Further, the MSCs remain of recipient origin after allogeneic SCT, which might contribute to the increased risk of graft dysfunction or failure in myelofibrosis patients after allogeneic transplantation. [ABSTRACT FROM AUTHOR]

Recently, higher extramedullary relapse rates following allogeneic stem cell transplantation (SCT) in myeloid malignancies were reported e.g. because of selection of poor-risk patients. We analysed five consecutive patients with post-transplant extramedullary relapse of chronic myeloid leukemia (CML) out of a total of 24 patients (21%) undergoing allo-SCT. All five patients with extramedullary relapse had clonal evolution and a history of blast phase (BP). In particular, 56% of the patients in BP had extramedullary relapse with no extramedullary relapse in patients with chronic/accelerated phase. Most frequent manifestation sites were the skeletal system, the muscles/subcutaneous tissue and the central nervous system. In one case chloroma was mimicking myositis of the lower limbs. Combined approaches were performed including irradiation (n = 4), chemotherapy (n = 2), IM (n = 2), dasatinib (n = 4), nilotinib (n = 1), a novel aurora-kinase-inhibitor (n = 1), donor lymphocytes (n = 2) or a second allo-SCT (n = 2). Transient response was achieved in one case, stable partial remissions in two cases, whereas two cases were refractory. Research should focus on prospective studies aiming to improve treatment of extramedullary relapse in stem cell recipients with CML with a special focus on the role of second generation tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0·001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0·001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0·03) and platelets (P = 0·02) and in a lower incidence of acute graftversushost disease (GvHD) grades II–IV (24% vs. 47%,P = 0·06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%,P = 0·001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12–37%] for ATG vs. 28% (95% CI = 15–55%) for alemtuzumab,P = 0·7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39–75%) vs. 45% (95% CI: 28–73%) and 30% (95% CI: 16–55%) vs. 36% (95% CI: 20–62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2·37;P = 0·05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0·0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma. [ABSTRACT FROM AUTHOR]

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%–28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16–6.74; P = .02), relapse (HR, 4.14; 95% CI, 2.04–8.38; P < .001), event-free survival (HR, 3.11; 95% CI, 1.77–5.46; P < .001), and overall survival (HR, 2.69; 95% CI, 1.35–5.35; P = .005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16–0.87; P = .02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%–54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%–78%) and 75% (95% CI, 59%–91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%–100%) and 92% (95% CI, 76%–100%), respectively, for unrelated donors (n = 12). [Copyright &y& Elsevier]

Summary. Three patients with myelofibrosis received allogeneic stem cell transplantation after a dose-reduced conditioning regimen of busulphan (8 mg/kg), fludarabine (180 mg/m2 ) and antithymocyte globulin (4 × 10 mg/kg). The median age at transplantation was 51 years (range 44–58). All patients engrafted with a leucocyte count > 1·0 × 109 /l after a median of 18 d (range 16–20). Grade II acute skin graft-versus-host disease (GvHD) occurred in one patient. One limited and one extensive chronic GvHD was observed. All patients achieved complete haematological remission. In one patient the fibrosis resolved completely 180 d post transplant. All patients are alive 126, 466 and 764 d after transplantation. [ABSTRACT FROM AUTHOR]