Long-term outcome after allogeneic stem cell transplantation for GATA2 deficiency: An analysis of 67 adults and children from France and Belgium.

Modalities and timing of haematopoietic stem cell transplant (HSCT) in patients with GATA2 deficiency are still subject to debate. On June 2022, 67 patients (median age 20.6 years) underwent a first allogeneic HSCT among 21 centres. Indications for HSCT were myelodysplastic syndrome (MDS) ≤5% blasts ± immunodeficiency (66%), MDS >5% blasts (15%), acute myeloid leukaemia (19%). Conditioning regimen was myeloablative in 85% and anti-thymocyte globulins were used in 67%. The cumulative incidence (CInc) of acute graft versus host disease (GvHD) grade II-IV and III-IV at day 100 were 42% and 13%, and CInc of chronic and extensive chronic GvHD at 2 years were 42% and 23%. CInc of relapses was 3% and 11% at 1 and 5 years. Overall survival (OS) at 1 and 5 years was 83% and 72% (median follow-up 5.6 years). The factors associated with worse OS in multivariable analysis were the year of HSCT, a history of excess blasts before transplant and peripheral blood stem cell (PBSC) grafts. Age at HSCT, non-myeloablative conditioning and PBSC grafts were associated with increased non-relapse mortality. In conclusion, bone marrow monitoring to identify clonal evolution and perform HSCT before the appearance of excess blast is mandatory.

Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.

While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.

Childhood myelodysplastic syndromes: Is cytoreductive therapy useful before allogeneic hematopoietic stem cell transplantation?

For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In the case of increased blasts (cMDS-IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo-HSCT for cMDS reported in the SFGM-TC registry between 2000 and 2020 were analyzed (n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty-eight percent of patients presented with cMDS-IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five-year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six-month cumulative incidence of grade II-IV acute graft-versus-host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5-year OS. In the cMDS-IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRM since no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS-IB. They need to be confirmed on a larger scale and prospectively.

Impact of Graft Function on Health Status and Quality of Life in Very Long-Term Survivors Who Received an HSCT for Inborn Errors of Immunity, a Prospective Study of the CEREDIH.

The overall survival rate after hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI) has improved considerably, and its indications have broadened. As a consequence, addressing the issue of long-term health-related quality of life (HRQoL) has become crucial. Our study focuses on the health and HRQoL of post-HSCT survivors. We conducted a multicenter prospective follow-up study enrolling IEI patients who underwent transplantation in childhood before 2009. Self-reported data from the French Childhood Immune Deficiency Long-term Cohort and the 36-item Short Form questionnaires were compiled. One hundred twelve survivors were included with a median duration period from HSCT of 15 years (range 5-37), of whom 55 underwent transplantation for a combined immunodeficiency. We show that in patients evaluated at least 5 years after HSCT, 55% are still affected by a poor or very poor health status. Poor and very poor health status correlated with an abnormal graft function, defined as host or mixed chimerism, abnormal CD3+ count, or diagnosis of chronic graft-versus-host disease (poor health: odds ratio [OR] = 2.6, 95% confidence interval [CI], 1.1-5.9, P = .028; very poor health: OR = 3.6, 95% CI, 1.1-13, P = .049). Poor health was directly linked to a poorer HRQoL. Significant improvements in graft procedures have translated into better survival rates, but we show here that about half of the transplanted patients remain affected by an altered health status with a correlation to both abnormal graft function and impaired HRQoL. Additional studies are needed to confirm the impact of those improvements on long-term health status and HRQoL.

[Management of cytokine release syndrome and macrophage activation syndrome following CAR-T cell therapy: Guidelines from the SFGM-TC]. / Prise en charge du syndrome de relargage cytokinique et du syndrome d'activation macrophagique après traitement par CAR-T cells : recommandations de la SFGM-TC.

The use of chimeric antigen receptor T cells (CAR-T) has increased since their approval in the treatment of several relapsed/refractory B cell malignancies. The management of their specific toxicities, such as cytokine release syndrome (CRS), tends to be better understood and well-defined. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on the management of patients developing CRS following CAR-T cell therapy. A special chapter has been allocated to macrophage activation syndrome (MAS), a rare but life-threatening complication post-CAR-T. In addition to symptomatic measures and preemptive broad-spectrum antibiotics, immunomodulators such as tocilizumab and corticosteroids remain the corner stone for the treatment of CRS. Tocilizumab/corticosteroids-resistant CRS associated with haemophagocytosis markers (spleen and liver enlargement, hyperferritinaemia>10,000ng/mL, hypofibrinogenemia…) should direct the diagnosis towards an overlapping CRS/MAS. An adapted treatment will be based on high-dose IV anakinra and corticosteroids and chemotherapy with etoposide at late refractory stages. These complications and others delignate the need of close collaboration with an intensive care unit.

[Management of neurotoxicity following CAR-T cell therapy: Recommendations of the SFGM-TC]. / Prise en charge du syndrome de neurotoxicité associée au traitement par cellules CAR-T chez l'adulte et l'enfant : recommandations de la SFGM-TC.

The immune effector cell-associated syndrome (ICANS) has been described as the second most frequent specific complication following CAR-T cell therapy. The median time to the onset of neurological symptoms is five days after CAR-T infusion. ICANS can be concomitant to cytokine release syndrome but often follows the resolution of the latter. However, 10 % of patients experience delayed onset after 3 weeks of CAR-T cell infusion. The duration of symptoms is usually short, around five days if an early appropriate treatment is given. Symptoms are heterogeneous, ranging from mild symptoms quickly reversible (alterations of consciousness, deterioration in handwriting) to more serious forms with seizures or even a coma. The ICANS severity is currently based on the ASTCT score. The diagnosis of ICANS is clinical but EEG, MRI and lumbar punction can help ruling out alternative diagnoses. The first line treatment consists of high-dose corticosteroids. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on updating the SFGM-TC recommendations on the management of ICANS. In this review we discuss the management of ICANS and other neurological toxicities in patients undergoing of CAR-T cell therapy. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management neurological complications associated with this new therapeutic approach.

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX).

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Disseminated Cryptosporidium infection in an infant with CD40L deficiency.

The protozoan Cryptosporidium affects the digestive tract of humans and animals. Cryptosporidiosis leads to diarrhoea mimicking a cholera-like course with dehydration and may even result in death in immunodeficient patients, as patients with hyper-IgM syndrome. We describe a rare case of disseminated Cryptosporidium infection in a seven- year-old boy with CD40 L deficiency. During the pre-graft phase, the patient presented an intestinal cryptosporidiosis which became complicated few days later during the aplasia period with a cholangitis and pulmonary cryptosporidiosis. Cryptosporidium hominis was identified. After treatment with nitazoxanide and azithromycine the patient was doing well.

[Complications other than infections, CRS and ICANS following CAR T-cells therapy: Recommendations of the Francophone Society of bone marrow transplantation and cell therapy (SFGM-TC)]. / Complications des cellules CAR-T autres que les infections, CRS et ICANS : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

CAR-T cells are an innovative treatment for an increasing number of patients, particularly since the extension of their indication to mantle lymphoma and multiple myeloma. Several complications of CAR T-cell therapy, that were first described as exceptional, have now been reported in series of patients, since its first clinical use in 2011. Among them, cardiac complications, delayed cytopenias, acute and chronic Graft versus Host Disease, and tumoral lysis syndrome are recognized as specific potent complications following CAR T-cells infusion. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of these complications with focuses the epidemiology, the physiopathology and the risk factors of these 4 side effects. Our recommendations apply to commercial CAR-T cells, in order to guide strategies for the management of complications associated with this new therapeutic approach.

[Prevention and management of infections in patients undergoing CAR T-cell therapy: Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge prophylactique, thérapeutique des complications infectieuses et vaccination des patients traités par CAR-T cells : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Infections occurring after CAR T-cells are a common complication. At the acute phase of treatment following CAR T-cell infusion, the exact incidence of infections is unknown given the overlapping symptoms with cytokine release syndrome. The risk factors for infection include the malignant underlying disease and its multiple treatments, and an immunosuppressive state induced by CAR-T cells themselves and the treatment of their complications. During the twelfth edition of practice harmonization workshops of the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC), a working group focused its work on the management of post-CAR infectious complications. In this review we discuss anti-infection prophylaxis and vaccination of patients undergoing CAR T-cell therapy as well as a special chapter for the specific case of COVID-19. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management and prevention of infectious complications associated with this new therapeutic approach.

Therapy-related acute myeloid leukemia following treatment of lymphoid malignancies.

Therapy-related acute myeloid leukemia (t-AML) is a heterogeneous entity most frequently related to breast cancer or lymphoproliferative diseases (LD). Population-based studies have reported an increased risk of t-AML after treatment of lymphomas. The aim of this study was to describe the characteristics and outcome of 80 consecutive cases of t-AML following treatment of LD. t-AML accounted for 2.3% of all AML cases, occurred 60 months after LD diagnosis, and were characterized by a high frequency of FAB M6 AML and poor-risk cytogenetic abnormalities. Time to t-AML diagnosis was influenced by patient age, type of LD, and treatment. Among the 48 t-AML patients treated with intensive chemotherapy, median overall survival (OS) was 7.7 months compared to 26.1 months in de novo, 4.2 months in post-myeloproliferative neoplasm, 9.4 months in post-myelodysplastic syndrome, 8.6 months in post-chronic myelomonocytic leukemia AML, 13.4 months in t-AML secondary to the treatment of solid cancer, and 14.7 months in breast cancer only. OS of post-LD t-AML patients was significantly influenced by age, performance status, myelodysplastic syndrome prior to LD/t-AML, and treatment regimen for LD. Thus, t-AML following lymphoid malignancies treatment should be considered as very high-risk secondary AML. New treatment strategies in patients with LD/t-AML are needed urgently.