Persistent Impairment in Immune Reconstitution and Worse Survival Outcomes in Allogeneic Stem Cell Transplantation Patients with Early Coronavirus Disease 2019 Infection.

Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplantation-related complications in the first year post-transplantation, owing in part to the profound immune dysregulation with T cell and B cell lymphopenia and functional impairment. Although several large studies have reported higher mortality rates from Coronavirus disease 2019 (COVID-19) in HSCT recipients, to date no study has focused on the impact of early COVID-19 infection on immune reconstitution post-transplantation and the correlation with transplantation outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection, with a median time to diagnosis of 100 days post-transplantation. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% confidence interval [CI], 1.26 to 13.05; P = .019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P = .001). This was attributed mainly to higher nonrelapse mortality (NRM) among early COVID-19 patients (P = .042). Allogeneic HSCT recipients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P = .021), CD3+CD4+ cell (95% CI, -105.35 to -11.59; P = .042), CD3+CD8+ cell (95% CI, -324.55 to -57.13; P = .038), and CD3-CD56+ cell (95% CI, -193.51 to -47.31; P = .014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impaired immune reconstitution post-transplantation.

Adoptive cellular therapy after hematopoietic stem cell transplantation.

Effective cellular therapy using CD19 chimeric antigen receptor T-cells for the treatment of advanced B-cell malignancies raises the question of whether the administration of adoptive cellular therapy (ACT) posttransplant could reduce relapse and improve survival. Moreover, several early phase clinical studies have shown the potential beneficial effects of administration of tumor-associated antigen-specific T-cells and natural killer cells posttransplant for high-risk patients, aiming to decrease relapse and possibly improve survival. In this article, we present an in-depth review of ACT after transplantation, which has the potential to significantly improve the efficacy of this procedure and revolutionize this field.

Strategies to Mitigate the Drug-Drug Interaction between Nirmatrelvir/Ritonavir and Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Azole Antifungals: Results of a Case Series.

INTRODUCTION: Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals. CASE PRESENTATIONS: We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations. CONCLUSION: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.

Autologous hematopoietic stem cell transplantation for a patient with multiple autoimmune diseases.

Level of autoantibodies after autologous hematopoietic stem cell transplantation. AGA, antigliadin antibody; AHSCT, autologous hematopoietic stem cell transplantation; Anti-GAD65, Ab anti-glutamic acid decarboxylase epitope 65 antibody; Anti-TPO, anti-thyroid peroxidase antibody; CU, chemiluminescent unit.

Anakinra versus etoposide-based therapy added to high-dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome usually treated with high-dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH-94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide-based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. METHODS: We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH-94 protocol, HDS alone, or supportive care. RESULTS: Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH-94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH-94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH-94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). CONCLUSION: Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.

Once-Daily Foscarnet Is Effective for Human Herpesvirus 6 Reactivation after Hematopoietic Stem Cell Transplantation.

Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3,100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.

Allogeneic stem cell transplantation for patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell neoplasms primarily affecting older persons, associated with dysplastic changes of bone marrow cells, peripheral cytopenias, and various risk of leukemic transformation. Although treatment with several drugs has shown improved disease control, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for MDS. The number of patients receiving a transplant, as well as survival, have increased past years because of the use of reduce-intensity conditioning regimens (RIC) as well as the use of haploidentical donors for transplantation. With treatment-related mortality as main limitation, pre-transplant evaluation is essential to assess risks for this older group of patients. In a recent randomized study, allo-HSCT with RIC for patients >50 years old with higher-risk MDS demonstrated superiority in survival compared with hypomethylating agents. Genetic mutations have been shown to significantly impact treatment outcomes including after transplant. Recently, a transplant-specific risk score (which includes age, donor type, performance status, cytogenetic category, recipient's cytomegalovirus status, percentage of blasts, and platelet count) has shown superiority in transplantation outcome prediction, compared with previous scoring systems. Survival remains low for most patients with TP53 mutations and novel treatment strategies are needed, such as administration of natural killer cells post-transplant, as there is no clear evidence that maintenance therapy after transplantation can improve outcomes.

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis.

Acute myeloid leukemia (AML) with mutated RUNX1 (RUNX1mut) is considered to have an unfavorable prognosis. However, recent studies have reported comparable survival outcomes with wild-type RUNX1 (RUNX1wt). To assess the clinical outcomes of AML with and without RUNX1mut, we performed a prospective cohort study and systematic review and meta-analysis. The study enrolled 135 patients (27 with RUNX1mut; 108 with RUNX1wt). There were no significant differences in the median OS and RFS of the RUNX1mut and RUNX1wt groups (9.1 vs. 12.2 months; p = 0.268 and 7.8 vs. 14.6 months; p = 0.481, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics showed similar outcomes. Our meta-analysis pooled data from 23 studies and our study. The complete remission rate was significantly lower in the RUNX1mut group (pooled odds ratio: 0.42). The OS, RFS, and event-free survival rates also favored the RUNX1wt group (pooled risk ratios: 1.36, 1.37, and 1.37, respectively). A subgroup analysis of de novo AML patients with intermediate-risk cytogenetics demonstrated nearly identical OS and RFS outcomes. This study confirms that patients with AML and RUNX1mut had poor prognoses. Nonetheless, in de novo AML with intermediate-risk cytogenetics, the survival outcomes of both groups were comparable.

Efficacy of Targeted Immunotherapy as Induction or Salvage Therapy in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Monoclonal antibodies targeting cluster of differentiation (CD) proteins have been incorporated into standard treatments for multiple types of hematologic malignancies, including acute lymphoblastic leukemia (ALL). This systematic review and meta-analysis investigated the efficacy of using CD-targeted antibodies for ALL. MATERIALS AND METHODS: The EMBASE and MEDLINE databases were searched for research papers using immunotherapy- and ALL-related terms from inception to July 2021. Eligible studies were randomized, controlled trials (RCTs) or cohort studies in which ALL patients received CD-targeted immunotherapy or conventional chemotherapy as the induction or salvage therapy. The reports had to report our primary outcomes of interest: overall survival (OS), relapse-free survival (RFS), or complete remission (CR), with the patient number for each outcome. The effect estimates with 95% confidence interval (CI) from each study were combined to calculate the pooled-effect estimate, using the Hantel-Maenszel method. RESULTS: Five RCTs and 9 retrospective cohort studies were eligible for the meta-analysis. ALL patients given CD-targeted immunotherapy in the induction or salvage therapy had significantly higher OS and RFS rates than those administered conventional chemotherapy only, with pooled odds ratios (OR) of 2.11 (95% CI, 1.76-2.53; I2, 0%) and 2.25 (95% CI, 1.62-3.14; I2, 61%), respectively. The rates of achieving CR and minimal residual disease negativity were also higher for the immunotherapy group, with pooled ORs of 1.70 (95% CI, 1.07-2.69; I2, 79%) and 2.98 (95% CI, 1.17-7.58; I2, 90%), while developing less risk for febrile neutropenia (pooled OR, 0.22; 95% CI, 0.08-0.58; I2, 84%). Subgroup analyses revealed that all antibody types yielded dramatically better OS rates than those for patients administered chemotherapy alone. CONCLUSIONS: The ALL patients receiving CD-targeted immunotherapy as induction or salvage therapy had significantly higher response rates and survival outcomes, as well as lower odds of acquiring febrile neutropenia, than the patients given conventional chemotherapy.

A five-year retrospective study of treatment outcomes using the L-asparaginase-based regimen as a first-line chemotherapy protocol for patients diagnosed with extranodal NK/T-cell lymphoma, nasal-type, in Thailand.

OBJECTIVE: To assess clinical outcomes of newly diagnosed extranodal NK/T-cell lymphoma nasal-type (ENKTL) patients treated with L-asparaginase-containing chemotherapy as first-line chemotherapy. MATERIALS AND METHODS: We retrospectively reviewed data of new ENKTL patients in Siriraj Hospital, Thailand during 2012-2016. RESULTS: Among 27 patients, 16 were men and 11 were women, and their median age was 52 (range, 25-83) years. The primary sites were the aero-nasal area (23) and skin (4). Clinical stages of ENKTL were I, II, III and IV in 10, 8, 1 and 8 patients, respectively. Patients classified according to the NK cell-lymphoma prognostic index with PINK (27) and PINK-E (19) as low, intermediate, and high were 14, 8, 5, respectively and 11, 4, and 4, respectively. Chemotherapy regimens used were SMILE (24) and AspaMetDex (3). Fourteen patients received post- chemotherapy local radiation. The overall response rate for 26 assessable patients was 69%, with complete response in 14 patients (52%). Median progression-free and overall survival were 32 and 33 months, respectively. The most common L-asparaginase regimen related complications were hypofibrinogenemia (24) and hypersensitivity (9). The overall mortality at follow-up was 14/27 (52%) owing to sepsis (11) and disease progression (3). DISCUSSION: L-asparaginase-based regimens showed similar results as other study results. including those in which hematopoietic stem cell transplantation was performed, suggesting that transplantation can be avoided if it is unaffordable. Thrombosis or bleeding, the regimen side effects, should be carefully monitored during treatment. CONCLUSIONS: L-asparaginase-based regimens offer a good outcome as a front-line treatment for ENKTL.