Impact of early cyclosporine A levels on acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation using in vivo T-cell depletion.

BACKGROUND AIMS: Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS: To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS: CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS: Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.

The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma.

INTRODUCTION: Despite remarkable therapeutic advances over the last two decades, which have resulted in dramatic improvements in patient survival, multiple myeloma (MM) is still considered an incurable disease. Therefore, there is a high need for new treatment strategies. Genetically engineered/redirected chimeric antigen receptor (CAR) T cells may represent the most compelling modality of immunotherapy for cancer treatment in general, and MM in particular. Indeed, unprecedented response rates have led to the recent approvals of the first two BCMA-targeted CAR T cell products idecabtagene-vicleucel ('Ide-cel') and ciltacabtagene-autoleucel ('Cilta-Cel') for the treatment of heavily pretreated MM patients. In addition, both are emerging as a new standard-of-care also in earlier lines of therapy. AREAS COVERED: This article briefly reviews the history of the preclinical development of CAR T cells, with a particular focus on Cilta-cel. Moreover, it summarizes the newest clinical data on Cilta-cel and discusses strategies to further improve its activity and reduce its toxicity. EXPERT OPINION: Modern next-generation immunotherapy is continuously transforming the MM treatment landscape. Despite several caveats of CAR T cell therapy, including its toxicity, costs, and limited access, prolonged disease-free survival and potential cure of MM are finally within reach.

Allogeneic Stem Cell Transplantation in Multiple Myeloma: Risk Factors and Outcomes in the Era of New Therapeutic Options-A Single-Center Experience.

BACKGROUND: Despite major treatment advances, multiple myeloma remains incurable. The outcome of patients who are refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies is poor, and improved treatment strategies for this difficult-to-treat patient population are an unmet medical need. METHODS: This retrospective, unicentric analysis included 38 patients with relapsed/refractory multiple myeloma or plasma cell leukemia who underwent allogeneic stem cell transplantation (allo-HSCT) between 2013 and 2022. Survival outcomes, relapse incidence, and non-relapse mortality were calculated according to remission status, date of allo-HSCT, cytogenetic risk status, timing, and number of previous autologous HSCTs. RESULTS: The median PFS was 13.6 months (95% CI, 7.7-30.4) and the median OS was 51.4 months (95% CI, 23.5-NA) in the overall cohort. The cumulative incidence of relapse at 3 years was 57%, and non-relapse mortality was 16%. The median PFS and OS were significantly longer in patients with very good partial remission (VGPR) or better compared to patients with less than VGPR at the time of allo-HSCT (mPFS 29.7 months (95% CI, 13.7-NA) vs. 6.5 months (95% CI, 2.6-17.0); p = 0.009 and mOS not reached vs. 18.6 months (95% CI, 7.0-NA); p = 0.006). CONCLUSION: For selected patients, allo-HSCT may result in favorable overall survival, in part by providing an appropriate hemato-immunological basis for subsequent therapies.

Successful SARS-CoV-2 mRNA Vaccination Program in Allogeneic Hematopoietic Stem Cell Transplant Recipients-A Retrospective Single-Center Analysis.

(1) Background: mRNA COVID-19 vaccines are effective but show varied efficacy in immunocompromised patients, including allogeneic hematopoietic stem cell transplant (HSCT) recipients. (2) Methods: A retrospective study on 167 HSCT recipients assessed humoral response to two mRNA vaccine doses, using the manufacturer cut-off of ≥7.1 BAU/mL, and examined factors affecting non-response. (3) Results: Twenty-two percent of HSCT recipients failed humoral response. Non-responders received the first vaccine a median of 10.2 (2.5-88.9) months post-HSCT versus 35.3 (3.0-215.0) months for responders (p < 0.001). Higher CD19 (B cell) counts favored vaccination response (adjusted odds ratio (aOR) 3.3 per 100 B-cells/microliters, p < 0.001), while ongoing mycophenolate mofetil (MMF) immunosuppression hindered it (aOR 0.04, p < 0.001). By multivariable analysis, the time from transplant to first vaccine did not remain a significant risk factor. A total of 92% of non-responders received a third mRNA dose, achieving additional 77% seroconversion. Non-converters mostly received a fourth dose, with an additional 50% success. Overall, a cumulative seroconversion rate of 93% was achieved after up to four doses. (4) Conclusion: mRNA vaccines are promising for HSCT recipients as early as 3 months post-HSCT. A majority seroconverted after four doses. MMF usage and low B cell counts are risk factors for non-response.

Impact of the Recipient's Pre-Treatment Blood Lymphocyte Count on Intended and Unintended Effects of Anti-T-Lymphocyte Globulin in Allogeneic Hematopoietic Stem Cell Transplantation.

Background: In allogeneic hematopoietic stem cell transplantation (HSCT), Anti-T-Lymphocyte Globulin (ATLG) may be used for the prevention of severe graft-versus-host disease (GVHD). ATLG targets both the recipient's lymphocytes and those transferred with the graft. Assuming an inverse relation between the recipient's absolute lymphocyte count (ALC) and exposure of remaining ATLG to the graft, we aim to evaluate the impact of the recipient's ALC before the first ATLG administration on the benefits (prevention of GVHD and GVHD-associated mortality) and potential risks (increased relapse incidence) associated with ATLG. Methods: In recipients of HLA-matched, ATLG-based HSCT (n = 311), we assessed the incidence of acute GVHD, GVHD-related mortality and relapse, as well as other transplant-related outcomes, in relation to the respective ALC (divided into tertiles) before ATLG. Results: The top-tertile ALC group had a significantly increased risk of aGVHD (subhazard ratio (sHR) 1.81; [CI 95%; 1.14-2.88]; p = 0.01) and aGVHD-associated mortality (sHR 1.81; [CI 95%; 1.03-3.19]; p = 0.04). At the highest ATLG dose level (≥45 mg/kg), recipients with lowest-tertile ALC had a trend towards increased relapse incidence (sHR 4.19; [CI 95%; 0.99-17.7]; p = 0.05, n = 32). Conclusions: ATLG dosing based on the recipient's ALC may be required for an optimal balance between GVHD suppression and relapse prevention.

TOP-PIC: a new tool to optimize pharmacotherapy and reduce polypharmacy in patients with incurable cancer.

PURPOSE: Polypharmacy is a significant problem in patients with incurable cancer and a method to optimize pharmacotherapy in this patient group is lacking. Therefore, a drug optimization tool was developed and tested in a pilot test. METHODS: A multidisciplinary team of health professionals developed a "Tool to Optimize Pharmacotherapy in Patients with Incurable Cancer" (TOP-PIC) for patients with a limited life expectancy. The tool consists of five sequential steps to optimize medications, including medication history, screening for medication appropriateness and drug interactions, a benefit-risk assessment using the TOP-PIC Disease-based list, and shared decision-making with the patient. For pilot testing of the tool, 8 patient cases with polypharmacy were analyzed by 11 oncologists before and after training with the TOP-PIC tool. RESULTS: TOP-PIC was considered helpful by all oncologists during the pilot test. The median additional time required to administer the tool was 2 min per patient (P < 0.001). For 17.4% of all medications, different decisions were made by using TOP-PIC. Among possible treatment decisions (discontinuation, reduction, increase, replacement, or addition of a drug), discontinuation of medications was the most common. Without TOP-PIC, physicians were uncertain in 9.3% of medication changes, compared with only 4.8% after using TOP-PIC (P = 0.001). The TOP-PIC Disease-based list was considered helpful by 94.5% of oncologists. CONCLUSIONS: TOP-PIC provides a detailed, disease-based benefit-risk assessment with recommendations specific for cancer patients with limited life expectancy. Based on the results of the pilot study, the tool seems practicable for day-to-day clinical decision-making and provides evidence-based facts to optimize pharmacotherapy.

Attrition Rates in Multiple Myeloma Treatment under Real World Conditions-An Analysis from the Austrian Myeloma Registry (AMR).

Multiple myeloma (MM) is characterized by serial relapses, necessitating the application of sequential lines of therapy (LoT). Reports on attrition rates (ARs) vary widely. The present study analysed ARs from the Austrian Myeloma Registry. Attrition was defined as being either deceased, progressive without having received another LoT, or lack of follow-up for ≥5 years. A total of 571 patients diagnosed between January 2009 and August 2021 were included (median age: 72 years; median follow-up: 50.8 months). Some 507 patients received at least one LoT. Of the total, 43.6% underwent autologous stem cell transplantation (SCT, transplant eligible = TE)) with primarily VRd (Bortezomib/Lenalidomide/Dexamethasone) given as induction (26.5%), followed by lenalidomide maintenance in 55.7% of cases. Transplant-ineligible (NTE) patients were predominantly treated with Vd (Bortezomib/Dexamethasone, 21.6%), receiving maintenance in 27.1%. A total of 37.5% received a second LoT. ARs across one to five LoTs were 16.7-27%. Frontline induction/ SCT followed by maintenance reduced ARs associated with age and achievement of deep remission in the frontline. Deep remission prolongs follow-up and time-to-next-treatment (TTNT), while high-risk-cyctogenetics negatively affected these outcomes. Our results demonstrate considerably lower ARs for MM patients within the AMR data versus other healthcare systems. Young age and the achievement of significant remissions after optimal frontline therapy resulted in particularly low ARs. These promising results support a key role for the ease of drug access and reimbursement policies in governing long-term MM patient outcomes.

The Agony of Choice-Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond.

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody-drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.

Relapse Protection Following Early Cytomegalovirus Reactivation after Hematopoietic Stem Cell Transplantation Is Limited to HLA-C Killer Cell Immunoglobulin-Like Receptor Ligand Homozygous Recipients.

Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P = .002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P = .63). NRM (sHR, 3.31; P < .001) and grade III-IV acute GVHD (sHR, 2.60; P = .04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P = .53; grade III-IV acute GVHD: sHR, 1.40; P = .50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM.

HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation.

Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as "ATG"), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort (n = 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; p = 0.001), and overall mortality (RR, 0.71; p = 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1/1 recipients (n = 291), by reduction of non-relapse (RR, 0.34; p = 0.0002) and overall mortality (RR, 0.50; p = 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; p = 0.036) in HLA-C group 1/2 recipients (n = 364), without significantly influencing overall mortality (RR, 0.70; p = 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; p = 0.019; n = 322) and overall mortality (RR, 0.60; p = 0.018) in C1/2 recipients as well. In both, C1/1 (RR, 1.70; p = 0.10) and particularly in C1/2 recipients (RR, 0.94; p = 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2/2 recipients (n = 121), ATG neither reduced NRM (RR, 1.10; p = 0.82) nor overall mortality (RR, 1.50; p = 0.17), but increased the risk for relapse (RR, 4.38; p = 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk.