Real-Life Data on the Efficacy and Safety of Letermovir for Primary Prophylaxis of Cytomegalovirus in Allogeneic Hematopoietic Stem Cell Recipients: A Single-Center Analysis

Objective: Cytomegalovirus (CMV) reactivation is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Introduction of letermovir (LMV) seems to improve post-transplant outcomes, but delayed-onset CMV reactivation still remains a challenge. In this study, we report on our first experience with LMV prophylaxis in 93 CMV-seropositive adult patients receiving HSCT in our center. Materials and Methods: We retrospectively analyzed the data of 93 adult CMV-seropositive recipients receiving LMV as CMV prophylaxis after HSCT for hematological malignancies between 2019 and 2023. The starting LMV dose was 480 mg daily, reduced to 240 mg daily for those receiving cyclosporin A co-administration. CMV DNA in the blood was measured by real-time polymerase chain reaction weekly for the first 2 months after transplantation, then every other week until the end of immunosuppressive treatment. LMV was continued to day +100 or to CMV reactivation. Results: The median recipient age at the time of transplant was 51 (range: 20-71) years. All patients received grafts from peripheral blood, mostly for acute myeloid leukemia (60%). The median time from transplantation to LMV initiation was 3 (range: 0-24) days. While 55% of patients were transplanted from matched related donors, 32% had unrelated donors and 13% underwent haploidentical HSCT. Four patients (4%) had CMV "blips" while on LMV, but the drug was continued and repeated assays were negative. Only 2 patients (2%) experienced CMV reactivation while on LMV, on days 48 and 34 after HSCT, respectively. Seven patients (7%) developed late-onset CMV reactivation after a median of 124 days after HSCT (range: 118-152 days) and they were successfully treated with ganciclovir. CMV disease was not observed. Grade III-IV acute graft-versus-host disease occurred in 6 patients (6%) during LMV treatment. LMV treatment was free of side effects. Conclusion: LMV prophylaxis was effective in preventing CMV reactivation with a favorable safety profile. CMV reactivation occurred mostly after LMV discontinuation; thus, extending the duration of prophylaxis beyond 100 days could be beneficial.

Allogeneic hematopoietic stem cell transplantation for acquired severe aplastic anemia: a summary of a 20-year experience.

INTRODUCTION: Severe aplastic anemia (SAA) is a rare but potentially fatal disorder characterized by hypocellular bone marrow and resulting in pancytopenia. It can be cured with allogeneic hematopoietic stem cell transplantation (allo­HSCT), especially in young individuals. OBJECTIVES: The main objective of the study was to assess the safety of the procedure and to identify the factors influencing long­term post­transplant outcome. PATIENTS AND METHODS: Using our institutional database, we performed a retrospective analysis of the patients with SAA allotransplanted in the years 2001-2021. RESULTS: Seventy patients (49 men) at a median age of 25 years at transplantation underwent allo­HSCT. Thirty-eight patients received immunosuppressive treatment (IST) before transplantation. Twenty-one patients received grafts from human leukocyte antigen-matched sibling, 44 from unrelated donors, and 5 from haploidentical related donors. Peripheral blood remained the source of stem cells in the majority of patients. Primary graft failure was observed in 2 cases. The incidence of acute graft­versus­host disease (GVHD) was 44%, whereas chronic GVHD was observed only in 4 patients. Median follow­up was 3 years (interquartile range, 0.45-11.5). Post­transplant outcome was comparable between patients with upfront allo­HSCT and those who relapsed after IST. In the univariable analysis, only a higher Eastern Cooperative Oncology Group (ECOG) score at transplantation and infections in the post­transplant period were found to be associated with unfavorable outcome. Fifty­three patients were alive at last contact. Most transplanted patients died due to infectious complications. A 2­year overall survival was 73%. CONCLUSIONS: The results of allo­HSCT in SAA are satisfactory and offer long­term survival and good quality of life. Higher ECOG score and the presence of infections are associated with poor post­transplant outcome.

Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be related to the occurrence of complications, including graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is connected with T lymphocytes, which identify alloantigens on host's antigen-presenting cells, activate production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and act on the immune effector cells and damage tissues and organs. AIM: The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT. METHODS: We enrolled 62 patients, i.e., 30 (48%) male and 32 (52%) female subjects [median age 49.5 (19-68) years], after allo-HSCT from siblings (n = 12) or unrelated donors (n = 50) due to acute myeloid leukemia with myeloablative conditioning (n = 26; 42%) and with non-myeloablative conditioning (n = 36; 58%). All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting. Blood samples were collected pre-transplant before and after (on day -1) the conditioning therapy and on days +2,+4, +6, +10, +20, and +30 after allo-HSCT. Serum levels of IL-2 and IFN-gamma were determined using ELISA. RESULTS: Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection. Group I included patients with neither acute GvHD nor infections [n = 15 (24%)], group II consisted of patients with infections without acute GvHD [n = 17 (27%)], group III was comprised of patients with acute GvHD without infections [n = 9 (15%)], and group IV included patients with both acute GvHD and infections [n = 21 (34%)]. IFN-gamma concentrations were higher in Group II than in other groups on days +20 (P = 0.014) and +30 (P = 0.008). Post-hoc tests showed lower concentrations of IFN-gamma on day +30 in groups I (P = 0.039) and IV (P = 0.017) compared to group II. The levels of IL-2 were mostly undetectable. CONCLUSION: Serum levels of IFN-gamma following allo-HSCT progressively escalate. High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD. Serum concentrations of IL-2 in most patients are undetectable.

Proinflammatory cytokines as potential risk factors of acute graft-versus-host disease and infectious complications after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with a risk of graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is related to T-lymphocytes, which identify alloantigens on host antigen-presenting cells, induce production of interferon (IFN) gamma and interleukin (IL)-2, recruit immune effector cells and destroy tissues and organs. MATERIAL AND METHODS: The study involved 62 patients, 30 (48%) men and 32 (52%) women [median age 49.5; (19-68) years] after myeloablative conditioning (MAC) n = 26 (42%) or reduced intensity conditioning (RIC) n = 36 (58%) therapy before allo-HSCT from a sibling (n = 12) or unrelated (n = 50) donor due to acute myeloid leukemia (AML). All patients received standard immunosuppressive therapy with cyclosporine A and methotrexate plus pre-transplant anti-thymocyte globulin in the unrelated transplant setting. Blood samples were collected pre-transplant before the start of and after conditioning therapy (1 day pre-transplant) and 2, 4, 6, 10, 20, 30 days following allo-HSCT. The analysis of potential risk factors included IL-2 and IFN-gamma concentrations, patients' age, the use of MAC/RIC and CR/non-CR status before transplantation. RESULTS: The statistical analysis revealed that independent risk factors for aGvHD included non-CR status before allo-HSCT [odds ratio (OR) = 10.52, P = 0.040], the use of MAC [hazard ratio (HR) = 4.80, P = 0.007] and a high level of IFN-gamma on day 6 post-transplant (HR = 1.03, P = 0.032). MAC was also the independent risk factor for infectious complications (OR = 4.04, P = 0.024). CONCLUSION: A high level of IFN-gamma on day 6 post-transplant, non-CR status before allo-HSCT and the use of MAC are independent risk factors for aGvHD. MAC is also the independent risk factor of infectious complications.

Splenic irradiation before allogeneic stem cell transplantation for myelofibrosis.

Splenectomy before allogeneic stem cell transplantation (ASCT) for patients with myelofibrosis (MF) remains a matter of debate, and conflicting results have been reported to date. The procedure seems to fasten post-transplant hematological recovery, but it does not have an impact on survival. The role of pre-transplant splenic irradiation (SI) is much more difficult to evaluate. Forty-four patients (25 males and 19 females) with MF at median age of 49 years at diagnosis (range 14-67) underwent ASCT. The post-transplant outcome was compared between irradiated and non-irradiated patients. Eleven patients received irradiation before transplantation. Median dose of radiation was 1000 cGy (range 600-2400). There was no difference in median time to engraftment between patients with and without previous radiotherapy. Acute and chronic graft versus host disease (GVHD) occurred in 47% and 36% of patients, respectively. There was no difference in GVHD incidence between groups. Eight patients relapsed/progressed in irradiated group versus 17 in non-irradiated (70% vs. 51%; p = 0.3). Transformation to acute myeloid leukemia was observed in 3 patients: 2 in irradiated and 1 in non-irradiated group. In total, 22 patients died with no statistical difference in death rate between irradiated and non-irradiated subjects. The probability of overall survival after transplant for the entire cohort at 2 years was 54% (72% for irradiated and 48% for non-irradiated patients; p = 0.25). Splenic irradiation prior to ASCT for myelofibrosis has not beneficial effect on post-transplant outcome.

Safety and outcome of allogeneic stem cell transplantation in myelofibrosis.

OBJECTIVES: We evaluated the safety and outcome of allo-HSCTs in myelofibrosis (MF). METHODS: A total of 27 patients with primary (n = 20) or secondary (n = 7) MF, aged 51 (21-63) yr, transplanted from HLA-matched related (59%) or unrelated (41%) donors were analyzed. Conditioning was reduced in 26 and myeloablative in one patient; and ATG was used in 25. Sources of stem cells were as follows: peripheral blood (21), bone marrow (4) or both (2). RESULTS: Prognostic factors that adversely affected overall survival (OS) in the multivariate analysis were as follows: recipient age >45 yr (HR = 10.55, P = 0.025) and unrelated donor (HR=3.73, P = 0.026). Post-transplant transfusion dependence adversely affected OS in the univariate analysis: dependence from either both RBCs and platelets (HR = 33.26, P = 0.001) or from either of them (HR = 10.53, P = 0.043). Of 16 JAK2V617F-positive patients evaluated post-transplant, it was eradicated in 69% and decreased in 25%. Acute GVHD III-IV developed in 19% and extensive chronic GVHD in 26% of patients; the relapse in four patients was treated with second allo-HSCT. Spleen decreased in all evaluated patients (n = 24). Fibrotic changes improved or disappeared in 80% of evaluated patients (n = 10). CONCLUSIONS: Allo-HSCT may prolong survival, provide disease regression and improve quality of life in MF, especially in patients ≤ 45 yr transplanted from matched related donors. Achieving transfusion independence post-transplant indicates the favorable outcome.