Impact of central nervous system involvement in adult patients with Philadelphia-negative acute lymphoblastic leukemia: a GRAALL-2005 study.

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT.

Grade 2 acute GVHD is a factor of good prognosis in patients receiving peripheral blood stem cells haplo-transplant with post-transplant cyclophosphamide.

BACKGROUND: The impact of acute graft versus host disease (GVHD) on survivals for patients receiving a haploidentical allogeneic stem-cell transplant (Allo-SCT) with peripheral blood stem-cells (PBSC) complemented by post-transplant cyclophosphamide (PTCY) is ill-known. MATERIAL AND METHODS: This retrospective study included 131 patients who received a PBSC haplograft in order to precise the impact of acute GVHD on outcomes. There were 78 males and 53 females and the median age for the whole cohort was 59 years (range: 20-71). Thirty-five patients were allografted for a lymphoid disease and 96 for a myeloid malignancy, including 67 patients with acute myeloid leukemia (AML). RESULTS: The cumulative incidence (CI) of day 100 grade 2-4 and 3-4 acute GVHD was 43.4 + 4.6% and 16.7 + 3.4%, respectively. The 2-year CI of moderate/severe chronic GVHD was 10.1 + 2.8%. The only factor affecting the occurrence of GVHD was GVHD prophylaxis. Indeed, CI of day 100 grade 2-4 (but not grade 3-4) acute GVHD was significantly reduced when adding anti-thymoglobulin (ATG) to PTCY. However, in multivariate analysis, grade 2 acute GVHD was significantly associated with better disease-free (HR: 0.36; 95%CI: 0.19-0.69, p = .002) and overall (HR: 0.35; 95%CI: 0.1-0.70, p = .003) survivals. The same results were observed when considering only AML patients. CONCLUSION: Acute grade 2 GVHD is a factor of good prognosis after PBSC haplotransplant with PTCY. Further and larger studies are needed to clarify the complex question of GVHD prophylaxis in the setting of haplo-transplant, especially that of combining ATG and PTCY.

Invasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients.

We present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole-resistant Aspergillus fumigatus isolate and the other a Rhizomucor-A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.

Posaconazole prophylaxis in neutropenic patients with hematological malignancies: limits in clinical practice.

Posaconazole (PSZ) is being used for prophylaxis in hematological patients who are at high risk for invasive fungal disease (IFD), but absorption limitations have been reported. Our objective was to assess both the feasibility and the efficacy of PSZ prophylaxis in clinical practice. From March 2010 to September 2010, all patients admitted to our unit for chemotherapy for acute leukemia or hematopoietic stem cell transplantation received optimized PSZ prophylaxis 200 mg four times daily with cola soda. PSZ trough concentrations (Cmin) were monitored at days 5, 7, 14, and 21. The incidence of IFDs was determined and compared to that of a historical control group. Thirty-five consecutive patients were prospectively included. PSZ prophylaxis was interrupted for 29% of them at day 14 and 51% of them at day 21. The main limitations were impracticality of oral feeding (29%) and occurrence of suspected IFDs (23%). PSZ median Cmin were 0.47, 0.40, 0.24, 0.36 µg/mL at days 5, 7, 14, and 21, respectively. Eighty percent of patient results were lower than the target Cmin of 0.5 µg/ml on day 14, the higher-risk period associated with neutropenia. Four probable breakthrough IFDs (11%) were diagnosed in 2010; no clear association between PSZ Cmin and occurrence of infection was observed. The incidence of IFDs was unchanged (historical control group: 9.7%; P = 0.72). Implementation of systematic PSZ prophylaxis did not significantly decrease the incidence of IFDs at our center. PSZ interruptions related to mucositis and too low Cmin were the main limitations to its use.

[Secondary cancers following allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Cancers secondaires après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held the 13th edition of the Clinical Practices Harmonization Workshops. Our workgroup reviewed the current data on the incidence, screening methods and international guidelines for the prevention of secondary solid cancers following allogeneic hematopoietic stem cell transplantation. The purpose of this workshop was to provide recommendations for the screening and prevention of secondary malignancies to Francophone transplantation centers.

[Haemorrhagic cystitis following hematopoietic stem cell transplantation: Prophylaxis, diagnosis, and treatment. Guidelines from the SFGM-TC]. / La cystite hémorragique après allogreffe de cellules souches hématopoïétiques : prophylaxie, diagnostic, et traitement. Recommandations de la SFGM-TC.

Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic cell transplantation (allo-HCT). Its manifestations range from microscopic hematuria without urinary symptoms to extensive and prolonged macroscopic hemorrhage requiring invasive interventions that can often prolong the duration of hospitalization and result in significant morbidity. The early onset of HC is related to allo-HCT conditioning regimen, whereas the late onset form is secondary to viral infection, most commonly due to BK virus. In the framework of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) practice harmonization workshops held in Lille in September 2021, the prophylaxis, the diagnostic approach and the treatments of HC following allografting were reviewed after analysis of published studies.

Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) remains a very difficult disease to cure due to the persistence of leukemic stem cells (LSCs), which are resistant to different lines of chemotherapy and are the basis of refractory/relapsed (R/R) disease in 80% of patients with AML not receiving allogeneic transplantation. METHODS: In this study, we showed that the interleukin-1 receptor accessory protein (IL-1RAP) protein is overexpressed on the cell surface of LSCs in all subtypes of AML and confirmed it as an interesting and promising target in AML compared with the most common potential AML targets, since it is not expressed by the normal hematopoietic stem cell. After establishing the proof of concept for the efficacy of chimeric antigen receptor (CAR) T-cells targeting IL-1RAP in chronic myeloid leukemia, we hypothesized that third-generation IL-1RAP CAR T-cells could eliminate AML LSCs, where the medical need is not covered. RESULTS: We first demonstrated that IL-1RAP CAR T-cells can be produced from AML T-cells at the time of diagnosis and at relapse. In vitro and in vivo, we showed the effectiveness of IL-1RAP CAR T-cells against AML cell lines expressing different levels of IL-1RAP and the cytotoxicity of autologous IL-1RAP CAR T-cells against primary cells from patients with AML at diagnosis or at relapse. In patient-derived relapsed AML xenograft models, we confirmed that IL-1RAP CAR T-cells are able to circulate in peripheral blood and to migrate in the bone marrow and spleen, are cytotoxic against primary AML cells and increased overall survival. CONCLUSION: In conclusion, our preclinical results suggest that IL-1RAP CAR T-based adoptive therapy could be a promising strategy in AML treatment and it warrants the clinical investigation of this CAR T-cell therapy.

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics.

Recent studies have provided several insights into acute myeloid leukemia. Studies based on molecular biology have identified eight functional mutations involved in leukemogenesis, including driver and passenger mutations. Insight into Leukemia stem cells (LSCs) and assessment of cell surface markers have enabled characterization of LSCs from hematopoietic stem and progenitor cells. Clonal evolution has been described as having an effect similar to that of microenvironment alterations. Such biological findings have enabled the development of new targeted drugs, including drug inhibitors and monoclonal antibodies with blockage functions. Some recently approved targeted drugs have resulted in new therapeutic strategies that enhance standard intensive chemotherapy regimens as well as supportive care regimens. Besides the progress made in adoptive immunotherapy, since allogenic hematopoietic stem cell transplantation enabled the development of new T-cell transfer therapies, such as chimeric antigen receptor T-cell and transgenic TCR T-cell engineering, new promising strategies that are investigated.

Arsenic Trioxide Treatment during Pregnancy for Acute Promyelocytic Leukemia in a 22-Year-Old Woman.

Acute leukemia during pregnancy is rare (1 for 100000 pregnancies). The association of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is known as the best therapy in standard-risk acute promyelocytic leukemia (APL). We describe the first case of a pregnancy with ATRA and ATO reported in the literature. In March 2018 at the University Hospital of Besançon, a 22-year-old woman was diagnosed with APL at 14 weeks of gestation (WG). She received a total of 2160 mg of ATRA and 930 mg of ATO between 14 and 35 WG. The mother's cytological remission was very fast. No maternal or fetal complications occurred during pregnancy. The pediatrics outcomes were good. Many case reports about ATRA exposure during the second and third trimesters report no serious adverse effect for pregnancy. ATO is teratogenic, genotoxic, and carcinogenic and passes through the placenta. Fetal exposure seems to be associated with bad pregnancy outcomes (preterm delivery, decreased birth weight, and fetal loss) and with lung diseases in young adults. No clinical trial is obviously possible, and the only data available are environmental exposure or animal studies. This case report may help medical teams to make hard decision for a treatment of APL during pregnancy.

[Related donors follow-up: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Suivi des donneurs apparentés : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Since 2010 there has been an exponential increase of the number of transplants performed from related donors. The development of haploidentical transplants increases the resort to related-donation, which presents two main advantages: a less important financial cost and a faster availability of the graft. Standards for mandatory accreditation exist, but the adherence to these recommendations is not optimal: currently, different practices regarding the organizational modalities of care, recruitment criteria, qualification and follow-up of related donors have been observed among French transplant centers. The Francophone Society of Marrow Transplant and Cellular Therapy (SFGM-TC) has developed guidelines for the consent and the non-eligibility criteria for hematopoietic stem cell donors. A multidisciplinary group has devised a booklet as a medium to inform donors about hematopoietic cell donation and transplantation in a clear and accessible language. This paper provides recommendations on post-donation follow-up, taking into account both medical standards and organizational constraints of French centers. Some tools are proposed.

Altered thymic CD4+ T-cell recovery after allogeneic hematopoietic stem cell transplantation is critical for nocardiosis.

PURPOSE OF THE STUDY: Nocardia affects immunocompromised human host exhibiting an altered cell-mediated immunity. Infectious risk after allogeneic hematopoietic cell transplantation (AHCT) is significantly correlated to the recovery status of donor-derived immune system, especially CD4+ T-cells reconstitution and thymopoiesis. The purpose of this paper is to highlight a lack of cell-mediated immunity recovery for patients presenting a nocardiosis compared to a control cohort. PATIENTS AND METHODS: This is a case control retrospective monocentric study. We retrospectively analyzed a monocentric cohort of 15 cases of nocardiosis after AHCT and we explored the degree of patients' immunosuppression by phenotyping circulating lymphoid subpopulations, including NK cells, CD8+ T-cells, CD4+ T-cells and CD19+ B-cells. We focused on CD4+ T-cell subsets to appreciate thymic output, especially on naive CD4+ T-cells (NTE, CD45RA+/RO- CD4+ T-cells) and recent thymic emigrants (RTE, CD4+CD45RA+/RO-/CD31+). Infected patients were paired with a control cohort of patients with identical transplantation characteristics screened on hematological disease, AHCT conditioning, primary graft-versus-host disease (GHVD) prophylaxis, graft type, sex, age, and season at the AHCT and data concerning immunological reconstitution were compared. RESULTS: At onset of nocardiosis, circulating lymphocytes and CD4+ T-cells means count were respectively 730/µL and 162/µL. CD8+ T-cells, CD56+ NK cells and CD19+ B-cells means count were respectively 362/µL, 160/µL, 112/µL. CD4+ T-cells subpopulations, naïve CD4+ T-cells production was impaired with NTE and RTE means count at 26/µL and 11/µL respectively. Comparison between nocardiosis cohort and control cohort over time highlight significant lower cellular count for lymphocytes, CD4+ T-cells, NTE and RTE with p = 0.001, p < 0.001, p < 0.001, p < 0.001 respectively. CONCLUSION: Immune recovery monitoring follow-up after AHCT is of particular importance to identify patients susceptible to develop Nocardiosis. Efficient microbiological investigations toward Nocardia such PCR should be used in case of compatible clinical presentation.

[Transfusion in autologous and allogenic hematopoietic stem cell transplant: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Transfusion dans l'autogreffe et l'allogreffe de cellules souches hématopoïétiques chez l'adulte et l'enfant : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The recommendations of the French Health and Drug Safety Authorities (HAS/ANSM-Haute Autorité de santé/Agence nationale de sécurité du médicament) are known, but there are always new developments underway. With regards to CMV suppression, there is the introduction of platelet glycoprotein Ia and the Intercept (Amotosalem+UVA) inactivation method which addresses bacterial risk. The irradiation of platelets is included in the recommendations to ensure HEV-negative plasma post allograft. In terms of blood transfusion safety, these measures as well as the broader spectrum of Ia, particularly for arboviruses, are a real breakthrough. The survey conducted in clinical services and the services providing blood products for transfusion along with a literature review have shown that several improvements need to be made. The first is a reduction of transfusions of concentrated red blood cells with introduction at a threshold of 7g/dL during hospitalization of patients without a fragile clinical status. The second improvement would address transfusion of refractory thrombocytopenia, encouraging an increase in discussion between clinicians and those conducting the transfusion in order to consider different etiologies and to identify appropriate care protocols. Third would be the need for the transmission of information between the transplantation doctors and blood transfusion specialists in order to define an approach to transfusion care adapted to the patient's situation. It is important to inform and educate patients about transfusion protocols post allotransplant or autotransplant. It must be clearly communicated to patients that they should always have on their person their blood group documentation. This is especially true when receiving care for a hemopathy or an autologous transplant. If undergoing an allogeneic transplant, patients should also carry transfusion guidelines post autotransplant or post allotransplant along with the phone numbers for the stem cell transplantation department and the blood transfusion center responsible for their care.

Scoring System Based on Post-Transplant Complications in Patients after Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Study from the SFGM-TC.

PURPOSE: We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). PATIENTS AND METHODS: We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. RESULTS: Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. CONCLUSION: This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies.

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.