Metronomic Maintenance With Weekly Vinblastine After Induction With Bevacizumab-Irinotecan in Children With Low-grade Glioma Prevents Early Relapse.

BACKGROUND: Pediatric low-grade glioma (pLGG) represents the most common brain tumor in childhood. Previous studies have reported that a therapeutic strategy on the basis of the association of bevacizumab alone (B) or in combination with irinotecan (BI) could produce rapid tumor response and clinical improvement in children with pLGG. Nevertheless, a majority of patients relapses shortly (median, 5 mo) after stopping B or BI treatment. We proposed metronomic maintenance with weekly vinblastine added after a 6 months induction of B/BI to prevent early relapse. PATIENTS AND METHODS: Monocentric retrospective analysis of a patient with pLGG treated with B or BI for 6 months followed by a 12-month maintenance with weekly vinblastine (6 mg/m²) from October 2012 to September 2019 in a single institution. RESULTS: In total, 18 patients (7 males and 11 females) were identified. Because of progression during the B or BI induction 2/18 children were excluded. In total, 16 patients were analyzed with a median age of 10 years (range, 4 to 16 y). A total of 13 patients received BI and 3 patients received B alone. The mean duration of induction was 6.2 months (range, 2 to 12 mo). After induction 5/16 patients had a partial radiologic response, 11/16 patients had stable disease. All patients started maintenance (median duration, 12 mo; range, 3 to 12 mo). With a median follow-up of 3.9 years after the end of B or BI (range, 11 mo to 7.2 y), 15/16 patients were alive and 9/16 patients were progression-free. Seven of 16 children progressed with a median time to progression of 23 months (ranges, 5 to 39 mo). Three of 16 (18%) children progressed during vinblastine maintenance and 4/16 (25%) patients after the end of maintenance. After the total duration of treatment, clinical improvement was noted in 4 patients, 9 patients had stable symptoms, and only 3 patients progressed. One and 2-year event-free survival were, respectively, 81.2% and 56.2%. Two-year overall survival was 93.7%. CONCLUSIONS: We report here, the potential benefit and the improvement of progression-free survival by adding metronomic maintenance with weekly vinblastine after initial induction with B or BI in children with low-grade glioma.

Single-Unit versus Double-Unit Umbilical Cord Blood Transplantation in Children and Young Adults with Residual Leukemic Disease.

We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 unit does not decrease the risk of transplantation failure but may enhance alloreactivity. Here we evaluated the influence of pretransplantation minimal residual disease (MRD) on leukemia relapse and survival after single- versus double-UCB transplantation (UCBT). Among 137 children and young adults who underwent UCBT in this randomized study, 115 had available data on MRD assessment done immediately before initiation of the pretransplantation conditioning regimen. MRD was considered positive at a level of ≥10-4, which was the case of 43 out of 115 patients. Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level: 70.7 ± 5.4% in MRD-negative (<10-4) patients (n = 72), 71.1 ± 9.4% in MRD-positive patients with 10-4 ≤ MRD <10-3 (n = 26) and 58.8 ± 11.9% in MRD-positive patients with ≥10-3 (n = 17). In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P = .025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P = .031). This difference was observed only in patients who had not received antithymocyte globulin during their conditioning regimen. In the MRD-negative group, there was no differencebetween the single- and the double-UCBT arms. We conclude that even in cases of positive pretransplantation MRD, UCBT in children and young adults with acute leukemia yields a high cure rate, and that a double-unit strategy may enhance the graft-versus-leukemia effect and survival in these patients.

Mutational and cytogenetic analyses of 188 CLL patients with trisomy 12: A retrospective study from the French Innovative Leukemia Organization (FILO) working group.

Trisomy 12 (tri12) is the second most frequent chromosomal aberration (15%-20%) in chronic lymphocytic leukemia (CLL). Tri12 confers an intermediate prognosis but is a heterogeneous entity. We examined whether additional mutational or chromosomal alterations might impact tri12 patient outcomes. This retrospective study, carried out by the French Innovative Leukemia Organization, included 188 tri12 patients with comprehensive information on immunoglobulin heavy chain (IGHV) gene status, karyotypic/FISH abnormalities, and NOTCH1, TP53, SF3B1, and MYD88 mutations. The main cytogenetic abnormalities associated with tri12 were del(13q) (25%), additional trisomies (14%) (including tri19 (10%) and tri18 (4%)), 14q32 translocations (10%), del(17p) (6.5%), del(14q) (4%), and del(11q) (4%). Unmutated (UM) IGHV, NOTCH1, and TP53, mutations were identified in respectively 66%, 25%, and 8.5% of cases. Multivariate analyses showed that additional trisomies (HR = 0.43, 95% CI = 0.23-0.78, P = .01) were associated with a significantly longer time to first treatment in Binet stage A patients and with a lower risk of relapse (HR = 0.37, 95% CI = 0.15-0.9, P = .03) in the overall tri12 population. Binet stage B/C, TP53 disruption, and UM IGHV status were associated with a shorter time to next treatment, while Binet stage B/C (HR = 4, 95% CI = 1.6-4.9, P = .002) and TP53 disruption (HR = 5, 95% CI = 1.94-12.66, P = .001) conferred shorter overall survival in multivariate comparisons. These data indicate that additional cytogenetic and mutational abnormalities, and particularly additional trisomies, IGHV status, and TP53 disruption, influence tri12 patient outcomes and could improve risk stratification in this population.

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo.

Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4+ FoxP3+ regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3+-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance.