Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, ...high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future.
The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field.
Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues.
We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.
Inotuzumab ozogamicin (InO; CD22-directed antibody–drug conjugate indicated for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia ALL) has been associated with ...hepatotoxicity/hepatic veno-occlusive disease (VOD), particularly after HSCT.
Post-HSCT outcomes in patients who received InO before first HSCT.
Observational, post-authorization safety study; final analysis, 5-year (y) data (Aug 2017–Aug 2022).
United States, with B-cell precursor ALL.
Overall survival (OS), non-relapse mortality (NRM), relapse, adverse events (AEs). Multivariate analyses examined prognostic factors for NRM/VOD and outcomes in patients (≥18 y) with ALL and the subset with R/R ALL.
261 patients with ALL (median age 39 y): 36% in first complete remission (CR1), 46% in CR2, 11% in CR≥3, 4% in first relapse, 1% in ≥third relapse, 2% with primary induction failure. CR/CRi and minimal residual disease negativity achieved in 80% and 64% of patients, respectively, after InO. Median (range) time from last InO dose to HSCT, 2.4 months (0.6–26.2). Post-HSCT OS at 18 months: patients with ALL, 54%, patients with R/R ALL, 50%. NRM within 18 months in 22% and 25%, respectively; most common causes were VOD (26%, 24%) and graft-versus-host disease (GVHD; 22%, 19%). Relapse within 18 months in 40% of both sets of patients. AEs occurring in ≥30% of patients with ALL and R/R ALL, respectively, within 100 days post-HSCT: bacterial infection (51%, 56%), viral infection (44%, 44%), and acute GVHD (grades II–IV, 43%, 41%). Of 35 patients who developed VOD, 15 cases were mild, 20 severe. Multivariate analyses (204 patients with ALL): Karnofsky score <90 or unknown vs 90–100 (HR, 3.00, 7.55; P=0.0010, <0.0001) and dual alkylators (compared by myeloablative conditioning (MAC)/no dual alkylators and reduced-intensity conditioning (RIC)/non-MAC: HR, 0.15, 0.26; P=<0.0001, 0.0027) were negative prognostic factors for NRM at 18 months. Dual alkylators were a negative prognostic factor for VOD at 100 days (compared by MAC/no dual alkylators and RIC/non-MAC: odds ratio, 0.26, 0.15; P=0.0275, 0.0032).
VOD incidence was consistent with previous reports. Dual alkylators should be avoided, when possible, in this patient subset. These patients should be considered for clinical trials testing novel prophylactic treatments for VOD.
Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, ...and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
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•A selective, orally bioavailable Menin-MLL inhibitor, VTP50469, is developed•Displacement of Menin from chromatin leads to loss of MLL from specific loci•Treatment with VTP50469 leads to suppression of a subset of MLL fusion target genes•Treatment with VTP50469 improves survival in PDX models of MLL-r ALL
Krivtsov et al. develop a selective and orally bioavailable small-molecule inhibitor targeting the Menin-MLL interaction, which suppresses a subset of MLL fusion target genes and significantly improves survival in PDX models of MLL-rearranged leukemia.
While PAX5 is an important tumor suppressor gene in B‐cell acute lymphoblastic leukemia (B‐ALL), it is also involved in oncogenic translocations coding for diverse PAX5 fusion proteins. PAX5‐JAK2 ...encodes a protein consisting of the PAX5 DNA‐binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of the PAX5‐JAK2 fusion protein in a mouse model expressing it from the endogenous Pax5 locus, resulting in inactivation of one of the two Pax5 alleles. Pax5Jak2/+ mice rapidly developed an aggressive B‐ALL in the absence of another cooperating exogenous gene mutation. The DNA‐binding function and kinase activity of Pax5‐Jak2 as well as IL‐7 signaling contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the remaining wild‐type Pax5 allele, allowing efficient DNA‐binding of Pax5‐Jak2. While we could not find evidence for a nuclear role of Pax5‐Jak2 as an epigenetic regulator, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5Jak2/+ B‐ALL tumors, implying that nuclear Pax5‐Jak2 phosphorylates STAT5. Together, these data reveal Pax5‐Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus.
Synopsis
The oncogenic human PAX5‐JAK2 translocation encodes a protein consisting of the PAX5 DNA‐binding region fused to the constitutively active JAK2 kinase domain. A mouse model shows how this translocation promotes rapid development of aggressive B‐cell acute lymphoblastic leukemia (B‐ALL) in the absence of other exogenous mutations.
Leukemogenesis in Pax5Jak2/+ mice depends on the DNA‐binding function and kinase activity of PAX5‐JAK2 and on IL‐7 signaling.
Rapid tumorigenesis onset correlates with, and is accelerated by, loss of the wild‐type Pax5 allele.
Loss of Pax5 facilitates DNA binding of PAX5‐JAK2.
PAX5‐JAK2 does not act as a transcriptional or epigenetic regulator in the nucleus.
PAX5‐JAK2 is a constitutively‐active nuclear kinase maintaining activation of the transcriptional leukemogenesis driver STAT5.
A mouse model of the oncogenic PAX5‐JAK2 translocation reveals promotion of aggressive B‐ALL not via transcriptional or epigenetic alterations, but via increased phosphorylation and activation of the JAK2 target STAT5.
This single‐center, retrospective study evaluated age as a risk factor for relapsed/refractory disease and/or death in 153 children with B‐cell acute lymphoblastic leukemia. The study sample included ...children near the 10‐year age cutoff for high‐risk disease (6.0‐13.9 years at diagnosis) and without other high‐risk features (high white cell count, unfavorable cytogenetics). Children 10.0‐13.9 years treated per high‐risk protocols did not have inferior outcomes compared with children aged 6.0‐9.9 years initiating treatment per standard‐risk protocols. The study indicates that, in the era of cytogenetics, an age threshold of 10 years might not be an independent prognostic marker. Multicenter analyses are needed.
This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses ...were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval CI: 49.9–55.5) versus 46.8% (95% CI: 43.8–49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio HR: 0.81 95% CI: 0.72–0.92, P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61–0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48–0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% 95% CI: 56.2–62.7 vs. 54.9% 95% CI: 51.3–58.3, P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.
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•Center effect influences survival in Ph-negative, not Ph-positive, B-ALL cases post allo-HSCT.•Elderly and CBT patients show a pronounced center effect in Ph-negative cases.
Chemoresistance often causes treatment failure of B‐cell acute lymphoblastic leukemia (B‐ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase‐1 (HO‐1) was ...found in the bone marrow stromal cells (BMSCs) from B‐ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B‐ALL cell lines Super B15 and CCRF‐SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO‐1. Silencing HO‐1 expression in BMSCs increased the apoptotic rates of B‐ALL cell lines induced by VCR, whereas upregulating HO‐1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B‐ALL cells were arrested in the G0/G1 phase due to HO‐1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment‐associated chemoresistance, was also positively coexpressed with HO‐1. VEGF secretion was markedly increased in BMSCs with HO‐1 upregulation but decreased in BMSCs with HO‐1 silencing. B‐ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO‐1 expression may promote the VCR resistance of B‐ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO‐1. In conclusion, this study clarifies a mechanism by which B‐ALL is induced to resist VCR through HO‐1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice.
Overexpression of heme oxygenase‐1 (HO‐1) in bone marrow stromal cells (BMSCs) mediates B‐cell acute lymphoblastic leukemia cells resistant to vincristine which may occur via the promotion of vascular endothelial growth factor secretion in BMSCs‐conditioned medium, and HO‐1 overexpression regulated VEGF in BMSCs via activating PI3K/Akt pathways.
Patients often undergo consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT) to maintain long-term remission following chimeric antigen receptor (CAR) T-cell therapy. ...Comparisons of safety and efficacy of allo-HSCT following complete remission (CR) achieved by CAR-T therapy
versus
by chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL) has not been reported. We performed a parallel comparison of transplant outcomes in 105 consecutive B-ALL patients who received allo-HSCT after achieving CR with CAR-T therapy (n=27) or with chemotherapy (n=78). The CAR-T-allo-HSCT group had more patients in second CR compared to the chemotherapy-allo-HSCT group (78%
vs.
37%; p<0.01) and more with complex cytogenetics (44%
vs.
6%; p<0.001) but the proportion of patients with pre-transplant minimal residual disease (MRD) was similar. The median follow-up time was 49 months (range: 25-54 months). The CAR-T cohort had a higher incidence of Grade II-IV acute graft-
versus
-host disease (aGVHD 48.1% 95% CI: 46.1-50.1%
vs.
25.6% 95%CI: 25.2-26.0%; p=0.016). The incidence of Grade III-IV aGVHD was similar in both groups (11.1%
vs.
11.5%, p=0.945). The overall incidence of chronic GVHD in the CAR-T group was higher compared to the chemotherapy group (73.3% 95%CI: 71.3-75.3%
vs.
55.0% 95%CI: 54.2-55.8%, p=0.107), but the rate of extensive chronic GVHD was similar (11.1%
vs.
11.9%, p=0.964). Efficacy measures 4 years following transplant were all similar in the CAR-T
vs.
the chemotherapy groups: cumulative incidences of relapse (CIR; 11.1% vs.12.8%; p=0.84), cumulative incidences of non-relapse mortality (NRM; 18.7%
vs.
23.1%; p=0.641) leukemia-free survival (LFS; 70.2%
vs.
64.1%; p=0.63) and overall survival (OS; 70.2%
vs.
65.4%; p=0.681). We found that pre-transplant MRD-negative CR predicted a lower CIR and a higher LFS compared with MRD-positive CR. In conclusion, our data indicate that, in B-ALL patients, similar clinical safety outcomes could be achieved with either CD19 CAR T-cell therapy followed by allo-HSCT or chemotherapy followed by allo-HSCT. Despite the inclusion of more patients with advanced diseases in the CAR-T group, the 4-year LFS and OS achieved with CAR T-cells followed by allo-HSCT were as remarkable as those achieved with chemotherapy followed by allo-HSCT. Further confirmation of these results requires larger, randomized clinical trials.
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