The different cell subsets of the immune system express the vitamin D receptor (VDR). Through the VDR, vitamin D exerts different functions that influence immune responses, as previously shown in ...different preclinical models. Based on this background, retrospective studies explored the impacts of vitamin D levels on the outcomes of patients undergoing allogeneic hematopoietic stem-cell transplantation, showing that vitamin D deficiency is related to an increased risk of complications, especially graft-versus-host disease. These results were confirmed in a prospective cohort trial, although further studies are required to confirm this data. In addition, the role of vitamin D on the treatment of hematologic malignancies was also explored. Considering this dual effect on both the immune systems and tumor cells of patients with hematologic malignancies, vitamin D might be useful in this setting to decrease both graft-versus-host disease and relapse rates.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, ...particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.
We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling ...in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P = .008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.
The outcome of 29 multiple myeloma patients receiving fludarabine and melphalan‐based non‐myeloablative allogeneic transplant (NMT) was evaluated. Event‐free survival (EFS) at 24 months was 33%, ...being significantly higher for patients who developed chronic graft‐versus‐host disease (cGVHD) when compared with those who did not 51%vs 0% respectively, P = 0·02; hazard rate = 3·16 (95% confidence interval = 1·09–9·15, P = 0·03) as well as for patients transplanted in complete remission/partial response (CR/PR) or stable disease (SD), compared with those with refractory/progressive disease (43%vs 0% respectively, P = 0·02). Overall survival (OS) at 24 months was 60%72%vs 42% for patients who did and did not develop cGVHD respectively (P = 0·1); 63%vs 41% for patients in CR/PR or SD vs refractory/progressive disease at transplant respectively (P = 0·013). At a median follow‐up of 366 d, 13 patients remained in CR/PR (45% overall response rate). Nine patients have died, three of them as a result of disease progression and six (21%) as a result of transplant‐related mortality (TRM). Actuarial incidence of TRM was 37% for patients who developed acute GVHD vs 13% for those who did not (log rank, P = 0·04). The present study suggests that graft‐versus‐myeloma effect is the main weapon for disease control after NMT in MM patients and the efficacy of this immune effect depends on tumour burden before transplant.
We analyzed the impact of CD34+ cell dose on the outcome of 86 patients undergoing reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation. The RIC was based on ...fludarabine 150 mg/m2 and melphalan 140 mg/m2 or busulphan 10 mg/kg. A median of 5.68 × 106 CD34+ cells/kg and 2.86 × 108 CD3+ cells/kg were infused. All patients receiving more than percentile 75 (p75) of CD34+ cells reached complete chimerism in T lymphocytes by days 21 to 28, compared with 44β among those receiving p75 or fewer cells (P = .046). Overall, 30.3β patients developed grade 2 to 4 acute graft-versus-host disease (aGVHD). Among 83 evaluable patients, 55.8β developed chronic GVHD (cGVHD). The dose of CD34+ cells infused did influence the development of cGVHD, with a cumulative incidence of extensive cGVHD of 74β vs 47β (P = .02) among patients receiving more than p75 CD34+ cells vs those receiving p75 or fewer. Projected overall survival (OS) and event-free survival (EFS) at 43 months were 60β and 46β, respectively. Neither the dose of CD34+ cells nor the dose of CD3+ cells infused significantly influenced OS and EFS, although among patients categorized as high-risk, 36β of those receiving p75 or fewer CD34+ cells relapsed or progressed, compared with only 9β among those receiving more than p75 CD34+ cells (P = .07). Among patients receiving p75 or fewer CD34+ cells, 36β of high-risk patients relapsed, compared with 10β of low- and intermediate-risk patients (P = .004), while relapse rates were not significantly different between both subgroups when we infused more than p75 CD34+ cells, thus indicating that infusing high doses of CD34+ cells ameliorates the negative effect of advanced disease status at transplantation. cGVHD was associated with better EFS (63β vs 16β at 43 months for patients with and without cGVHD; P < .0001) and better OS (78β vs 28β for patients with and without cGHVD; P < .001). The number of CD34+ cells infused should be tailored to prevent extensive cGVHD among patients categorized as low-risk, while high-risk patients, in whom the graft-versus-leukemia effect may determine disease outcome, should receive high doses of CD34+ cells.
•Tisagenlecleucel responses in patients with r/r FL remain highly durable a year after primary analysis; no new safety signals were observed.•Low levels of LAG3+CD3+ exhausted T cells and higher ...levels of naïve CD8+ T cells were significantly associated with improved outcomes.
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Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor–positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval CI, 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.
Dreyling et al report on longer-term follow-up of the phase 2 ELARA trial of tisagenlecleucel (tisa-cel) for treatment of relapsed/refractory (R/R) follicular lymphoma (FL) in third-line or later therapy. They report on 97 patients treated with tisa-cel for R/R FL that relapsed after autologous transplantation. Median progression-free survival, duration of response, and overall survival were not reached after a median follow-up of 29 months, confirming durable efficacy, especially in patients achieving complete remission. Low levels of exhausted T cells and high levels of naïve CD8+ T cells predicted better outcomes.
Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use ...of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.
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