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Introduction: Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in clinical studies for relapsed/refractory multiple myeloma (RRMM). We performed a systematic literature review to summarize the current body of evidence on the role of anti‐BCMA CAR T cells for RRMM. Objectives and Methods: Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included using a conventional meta‐analysis. Main efficacy outcomes were response, relapse, and survival. Safety outcomes were cytokine release syndrome (CRS) and neurotoxicity. Results: Anti‐BCMA CAR T cells resulted in a pooled overall response of 82% (95% confidence interval [CI], 74%‐88%) and complete response of 36% (24%‐50%). Higher CAR+ cell doses were associated with higher response rates. The pooled relapse rate of responders was 45% (27%‐64%), and median progression‐free survival was 10 months. Present extramedullary disease did not show worse outcome. Severe CRS grades 3‐4 and neurotoxicity occurred in 15% (10%‐23%) and 18% (10%‐31%). Conclusion: Anti‐BCMA CAR T cells showed high response rates, even in patients with present extramedullary disease, while relapse occurred in half of the patients who achieved a response. Larger studies with longer follow‐up especially evaluating the association of response and survival are needed. [ABSTRACT FROM AUTHOR]

Objective: Allogeneic stem cell transplantation (allo‐SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between refractory‐T‐NHL (ref‐NHL) and Chemosensitive‐T‐NHL (CS‐T‐NHL). Materials and Methods: We retrospectively reviewed the records of 26 ref‐NHL and 29 CS‐T‐NHL consecutive patients who underwent allo‐SCT at our center and compared the transplant outcomes between the groups. Results: All patients were heavily pretreated with 27% of patients relapsing post‐auto‐SCT and two patients in the ref‐T‐NHL post‐allo‐SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref‐TNHL and 19% in CS‐TNHL (p =.33), with non‐relapse mortality rates of 28% and 22%, respectively (p =.52). Female patients and those with a previous auto‐SCT had lower relapse incidence (p =.045, p =.003). The 3‐year overall survival was 39% in Ref‐TNHL and 56% in CS‐TNHL (p =.15). Trends for improved progression‐free survival (PFS) and graft‐versus‐host disease relapse‐free survival (GRFS) were observed in the CS‐TNHL group (PFS: 60% vs. 30%, p =.075; GRFS: 38% vs. 21%, p =.1). Conclusion: Acknowledging the retrospective nature of our study, our results indicate that allo‐SCT has a curative potential in patients with T‐NHL even in refractory status. [ABSTRACT FROM AUTHOR]

Summary: Acute graft‐versus‐host disease (aGVHD) is a life‐threatening complication after allogeneic haematopoietic cell transplantation, with gastrointestinal (GI) tract involvement (GI aGVHD) being one of the leading causes of morbidity and mortality. Whilst systemic steroids are the standard first‐line treatment for aGVHD, approximately 50% of patients become steroid refractory (SR), which is associated with poor outcomes. Existing options for SR‐GVHD are limited, and there is a significant unmet need for new non‐immunosuppressive treatment approaches in patients with GI aGVHD. Here, we review newer concepts in the pathogenesis of GI aGVHD and present the evidence for the role of glucagon‐like peptide 2 (GLP‐2) in maintaining and protecting GI epithelial cells, including the enterocytes, intestinal stem cells and Paneth cells, which are direct targets of aGVHD. Finally, we discuss the therapeutic rationale for GLP‐2 treatment as a tissue regeneration approach and the potential use of the novel GLP‐2 analogue apraglutide as an adjunctive treatment for GI aGVHD. [ABSTRACT FROM AUTHOR]

Pre‐transplant minimal residual disease (MRD) impacts negatively on post‐transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post‐transplant outcomes after individualized versus fixed busulfan dosage in intermediate‐risk AML who achieved CR prior to allograft focusing on pre‐transplant flow‐MRD. Eighty‐seven patients (median, 56 years) with intermediate‐risk AML and pre‐transplant flow‐MRD ("different from normal") were included. Thirty‐two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow‐up of 27 months, we observed lower 3‐year relapses (6%, 2%–19% vs. 35%, 23%–49% p = 0.02), improved 3‐year leukemia‐free survival (LFS) (78%, 54%–91% vs. 55%, 40%–70% p = 0.009) and − overall survival (OS) (82%, 60%–93% vs. 69%, 54%–81% p = 0.05) after individualized compared to fixed Bu. Non‐relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1–12.6, p = 0.041) in pre‐transplant MRD‐positive patients. Individualized, AUC‐based, busulfan is associated with lower relapses in intermediate‐risk AML patients allografted in CR and may overcome pre‐transplant MRD‐positivity. [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.

Objectives: Major complications affecting the central nervous system (CNS) present a challenge after allogeneic stem cell transplantation (allo‐SCT). Methods: Incidence, risk factors, and outcome were retrospectively analyzed in 888 patients in a monocentric study. Results: Cumulative incidence (CI) of major CNS complications at 1 year was 14.8% (95%CI 12.3%‐17.2%). Median follow‐up is 11 months. CNS complications were documented in 132 patients: in 36 cases, classified metabolic; 26, drug‐related neurotoxicity (14 attributed to cyclosporine A, 4 to antilymphocyte globulin); 11, cerebrovascular (ischemic n = 8, bleeding n = 3); 9, infections; 9, psychiatric; and 9, malignant. The cause of CNS symptoms remained unclear for 37 patients (28%). Multivariate analysis demonstrated an association of CNS complication with patient age (P <.001). The estimated OS of patients with any CNS complication was significantly lower than in patients without neurological complications (P <.001), and the CI of non‐relapse mortality (NRM) was higher for patients with CNS complication (P <.001). A significant negative impact on survival can only be demonstrated for metabolic CNS complications and CNS infections (NRM, P <.0001 and P =.0003, respectively), and relapse (P <.0001). Conclusion: CNS complications after allo‐SCT are frequent events with a major contribution to morbidity and mortality. In particular, the situations of unclear neurological complications need to be clarified by intensive research. [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

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: Introduction: Ruxolitinib is the first approved drug for treatment of myelofibrosis, but its impact of outcome after allogeneic stem cell transplantation (ASCT) is unknown. Patients and methods: We reported on 159 myelofibrosis patients (pts) with a median age of 59 years (r: 28‐74) who received reduced intensity ASCT between 2000 and 2015 in eight German centers from related (n = 23), matched (n = 86) or mismatched (n = 50) unrelated donors. Forty‐six (29%) patients received ruxolitinib at any time point prior to ASCT. The median daily dose of ruxolitinib was 30 mg (range 10‐40 mg) and the median duration of treatment was 4.9 months (range 0.4‐39.1 months). Results: Primary graft failure was seen in 2 pts (4%) in the ruxolitinib and 3 (2%) in the non‐ruxolitinib group. Engraftment and incidence of acute GVHD grade II to IV and III/IV did not differ between groups (37% vs 39% and 19% vs 28%, respectively), nor did the non‐relapse mortality at 2 years (23% vs 23%). A trend for lower risk of relapse was seen in the ruxolitinib group (9% vs 17%, P = .2), resulting in a similar 2 year DFS and OS (68% vs 60% and 73% vs 70%, respectively). No difference in any outcome variable could be seen between ruxolitinib responders and those who failed or lost response to ruxolitinib. Conclusions: These results suggest that ruxolitinib pretreatment in myelofibrosis patient does not negatively influence outcome after allogeneic stem cell transplantation. [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]

Relapse is the major cause of treatment failure after allogeneic stem-cell transplantation ( AHSCT) for patients with myelodysplastic syndrome/myeloproliferative syndrome neoplasms ( MDS/ MPN). We evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post-transplantation. We screened 45 patients with chronic myelomonocytic leukemia ( n = 39 patients, including seven with transformed-acute myeloid leukemia), MDS/ MPN unclassifiable ( n = 5), and atypical BCR- ABL1-negative CML ( n = 1) for mutations in ASXL1, CBL, NRAS, and TET2 genes by molecular genetics including a sensitive next-generation sequencing ( NGS) technique. In 36 patients, sufficient DNA was available for molecular analyses. In particular, TET2 and CBL mutations were screened applying amplicon deep sequencing. In 89% of cases, at least one mutation could be detected: ASXL1: n = 18 (50%); CBL: n = 7 (19%); TET2: n = 15 (42%); and NRAS: n = 11 (32%). Survival after AHSCT at 5 yr was 46% (95% CI 28-64%) and was not influenced by any mutation. After a median of 6 months after AHSCT in 33% of the patients, one of the molecular markers was still detectable, resulting in a higher incidence of relapse than in patients with undetectable mutations (50% vs. 15%, P = 0.04). In conclusion, pretransplant molecular mutation analysis can help to detect biomarkers in patients with MPN/ MDS, which may be subsequently used as minimal residual disease markers after AHSCT. [ABSTRACT FROM AUTHOR]

Summary To define a prognostic model for predicting outcome of reduced-intensity allogeneic stem cell transplantation (RIC-ASCT) for myelofibrosis we evaluated 150 homogenously treated patients and developed a new risk score for overall survival (OS). In a multivariate Cox model for OS, only JAK2 V617F wild-type, age ≥57 years and constitutional symptoms were independently predictive for OS (Hazard Ratio: 2·02; 2·43 and 2·80 respectively). Depending on the presence of one, two or all of these factors, HR of death was 3·08; 4·70 and 16·61 respectively ( P < 0·001). This score was compared to the Lille, Cervantes, International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS) and modified European Blood and Marrow Transplantation Group (EBMT) scores. Lille score correlated significantly with OS but discriminated poorly between the intermediate and high-risk groups (5-year OS 56% and 51% respectively). IPSS and DIPSS correlated significantly with OS but differences between intermediate-1 and intermediate-2 groups were not significant (5-year OS 78% vs. 78% and 70%, 60% respectively). Modified EBMT and Cervantes models did not predict OS post-ASCT. In conclusion, a simple model which includes: age, JAK2 V617F-status and constitutional symptoms can clearly separate distinct risk groups and can be used in addition to the Lille model to predict OS after RIC-ASCT for myelofibrosis. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment. [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]

A prospective pilot study was performed to evaluate the effect of reduced-intensity conditioning with busulphan (10 mg/kg), fludarabine (180 mg/qm) and anti-thymocyte globulin followed by allogeneic stem cell transplantation from related (n = 8) and unrelated donors (n = 13) in 21 patients with myelofibrosis. The median age of the patients was 53 years (range, 32–63). No primary graft failure occurred. The median time until leucocyte (>1·0 × 109/l) and platelet (>20 × 109/l) engraftment was 16 (range, 11–26) and 23 d (range, 9–139) respectively. Complete donor chimaerism on day 100 was seen in 20 patients (95%). Acute graft-versus-host disease (GvHD) grades II–IV and III/IV occurred in 48% and 19% of cases and 55% of the patients had chronic GvHD. Treatment-related mortality was 0% at day 100 and 16% [95% confidence interval (CI): 0–32%] at 1 year. Haematological response was seen in 100% and complete histopathological remission was observed in 75% of the patients and 25% of the patients showed partial histopathological remission with a continuing decline in the grade of fibrosis. After a median follow-up of 22 months (range, 4–59), the 3-year estimated overall and disease-free survival was 84% (95% CI: 67–100%). [ABSTRACT FROM AUTHOR]

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]