Faecal microbiota transplantation to prevent complications after allogeneic stem cell transplantation for haematological malignancies: a study protocol for a randomised controlled phase-II trial (the FMT-allo study).

INTRODUCTION: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to graft-versus-host disease (GvHD) and infectious complications. Alterations of the intestinal microbiota plays a major role in the development of allo-HSCT complications. The gut microbiota could be restored by faecal microbiota transplantation (FMT). However, there are no published randomised studies assessing the efficacy of FMT for GvHD prophylaxis. METHODS AND ANALYSIS: This prospective, open-label, multi-centre, parallel-group, randomised phase-II clinical trial has been designed to assess the effect of FMT on toxicity in patients treated with myeloablative allo-HSCT for haematological malignancy. Based on Fleming's single-stage sample size estimation procedure, the design plans to include 60 male and female patients aged 18 or over per arm, to be randomly assigned to two groups, one with and one without (control group) FMT. The primary endpoint is GvHD-free relapse-free survival rate at 1 year after allo-HSCT. Secondary endpoints are outcome measures of the impact of FMT on allo-HSCT-related morbidity and mortality (overall survival and progression-free survival at 1 and 2 years, haematological parameters, infectious complications, tolerance and safety of FMT). The primary endpoint will be evaluated according to assumptions of the single-stage Fleming design, compared between groups by a log-rank test and further investigated in a multivariate marginal structural Cox model taking into account centre effect. The proportional-hazard hypothesis will be verified using Schoenfeld's test and by plotting residuals. ETHICS AND DISSEMINATION: The local institutional review board (CPP Sud-Est II, France) issued approval on 27 January 2021. The French national authorities issued approval on 15 April 2021. The outcome of the study will be disseminated via peer-reviewed publications and at congresses. TRIAL REGISTRATION NUMBER: NCT04935684.

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia.

Cytogenetic aberrations are found in 65% of adults and 75% of children with acute leukemia. Specific aberrations are used as markers for the prognostic stratification of patients. The current standard cytogenetic procedure for acute leukemias is karyotyping in combination with FISH and RT-PCR. Optical genome mapping (OGM) is a new technology providing a precise identification of chromosomal abnormalities in a single approach. In our prospective study, the results obtained using OGM and standard techniques were compared in 29 cases of acute myeloid (AML) or lymphoblastic leukemia (ALL). OGM detected 73% (53/73) of abnormalities identified by standard methods. In AML cases, two single clones and three subclones were missed by OGM, but the assignment of patients to cytogenetic risk groups was concordant in all patients. OGM identified additional abnormalities in six cases, including one cryptic structural variant of clinical interest and two subclones. In B-ALL cases, OGM correctly detected all relevant aberrations and revealed additional potentially targetable alterations. In T-ALL cases, OGM characterized a complex karyotype in one case and identified additional abnormalities in two others. In conclusion, OGM is an attractive alternative to current multiple cytogenetic testing in acute leukemia that simplifies the procedure and reduces costs.

Salvage haploidentical or cord-blood allogeneic stem cell transplantation after a prior alternative allograft in hematologic malignancies: A retrospective study from the SFGM-TC.

BACKGROUND: Haploidentical (haplo-) donors and cord-blood (CB) stem cells provide alternative transplant options in patients lacking an HLA-matched donor. In case of relapse or graft failure after a first alternative allogeneic hematopoietic stem cell transplant (HSCT), a second alternative HSCT (HSCT2) is rarely considered due to a high risk of toxicity. METHODS: A retrospective French multicentre study was performed, including patients with hematologic malignancies who underwent two consecutive HSCT from alternative donors. All data were exported from the national ProMISE database between 2000 and 2016. RESULTS: Forty-three patients (61.4%) received a CB-HSCT2 and 27 (38.6%) a haplo-HSCT2. Indications for HSCT were graft failure (51.4%) or disease progression (48.6%). Two-years probabilities of overall survival, progression-free survival and toxicity-related mortality were 18.5%, 17.8% and 55.8%, respectively. In multivariate analysis, complete remission status at HSCT2 and year of HSCT2 ≥ 2012 were significantly associated with a better outcome (with respectively hazard ratio [HR] = 0.42, p = .002 and HR = 0.5, p = .051). CONCLUSIONS: Neither the indication of HSCT2 nor the source of stem cell was more advantageous towards overall patient survival. A salvage haploidentical or cord-blood stem cell transplantation is a high-risk procedure, that may be considered for patients achieving a complete remission before receiving the second HSCT.

[Cardiac complications following allogeneic hematopoietic stem cell transplantation: Recommendations of the SFGM-TC]. / Complications cardiaques de la greffe de cellules souches hématopoïétiques : recommandations de la SFGM-TC.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can lead to early cardiac complications as well as late sequelae. A cardiac evaluation is essential in the pre-transplant assessment given the patient's comorbidities and previous chemotherapy treatments received. Various thresholds of cardiac function are recommended as eligibility criteria. The rise of haplo-identical transplantation with the use of post-transplant high-dose cyclophosphamide (PT-Cy) as a prophylaxis against graft-versus-host disease (GVHD) is accompanied by a resurgence of cardiological concerns. Arrhythmias are also a concern and the list of drugs implicated in this complication is growing. The rare occurrence of cardiac GVHD has been reported, although the entity is not well defined. Finally, although long-term follow-up recommendations exist, they are not accompanied by specific targets for cardiovascular risk factors, the presence of which is nevertheless increased after HSCT. In the framework of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) practice harmonization workshops held in Lille in September 2019, the prophylaxis, the diagnostic approach and the treatments of cardiac complication following HSCT were reviewed after analysis of published studies.

COVID-19 systematic screening of asymptomatic haematopoietic stem cell donors: Less if often more.

From COVID pandemic spread until now, many HSCT unrelated donor registries recommend as a precaution a systematic COVID-19 testing for all donors during the precollection time. Literature is quite poor to support this systematic attitude. We report one sibling allogeneic HSCT which we proceeded despite a positive COVID test on related asymptomatic donor and summarize the all seven cases reported until now. We suggest to question this systematic COVID testing, two years after pandemic began, when there is no systematic testing on other blood products received during all the haematological malignancies treatment process.

[Hematopoietic stem cell transplantation ocular complications: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge des complications ophtalmologiques de l'allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

INTRODUCTION: Allogeneic stem cell transplantation is currently the only curative therapy for hematological disorders. This treatment can lead to complications, of which ophtalmological involvement. METHODS: We reviewed the literature and established accessible and convenient recommendations for hematologists and ophthalmologists. RESULTS: Ophtalmological follow-up should be done in every patient having had an allogeneic transplantation, by the hematologist questioning and by the ophthalmologist physical exam. Complications due to graft-versus-host disease (GVHD) or not due to GVHD are cited, as well as therapeutic options. DISCUSSION: Screening and treatment of ophthalmologic complications in allogeneic stem cells transplantation recipients requires a close collaboration between hematologists and ophthalmologists. The management of these patients by caregivers trained in these questions is encouraged.

[Oral complications following allogeneic hematopoietic cell transplantation: Recommendations of the Francophone Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)]. / Complications stomatologiques dans le contexte de l'allogreffe de cellules hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Stomatological complications of allogeneic hematopoietic stem cell transplantation (HSCT) are frequent and very uncomfortable for patients. The primary complication is the graft versus host disease reaction. Other side effects of the procedure include infections, taste disorders and carcinogenic risks. Various local treatments are used but remain imperfect. Within the framework of the 10th workshop of practice harmonization of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held in Lille in September 2019, diagnostic approaches and treatments of tongue and oral complications following allogeneic HSCT were reviewed according to the analysis of published studies.

[Intestinal microbiota and allogeneic stem cell transplantation]. / Microbiote intestinal et allogreffe de cellules souches hématopoïétiques.

Allogeneic hematopoïetic stem cell transplantation is one of the most efficient curative treatment for acute leukemia. But it is also a heavy process with an important risk of complications, particularly infection and graft versus host disease. Increasing data in literature show that an alteration of the intestinal microbiota of allogeneic stem cell recipients is associated with these complications. Indeed, treatments used during conditioning regimen lead to an impaired microbiota, which cannot fulfill its protective functions anymore. To limit this microbiota impairment, we could restore a healthy microbiota by a fecal microbiota transplantation, which has already shown its efficiency in the treatment of Clostridium difficile infection. The aim of this review is to describe the intestinal microbiota, the link between microbiota and complications of allogeneic stem cells transplantation, and the recent published data on fecal microbiota transplantation in this field.

Prevalence of malnutrition in adult patients previously treated with allogeneic hematopoietic stem-cell transplantation.

INTRODUCTION: Malnutrition is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is a well-known prognostic factor for survival. The nutritional status of patients in a long term after allo-HSCT is less well documented. The main objective of this study was to evaluate the prevalence of malnutrition in adult patients who underwent allo-HSCT more than one year ago. Secondary objectives were to assess body composition, muscle strength, and factors associated with malnutrition. PATIENTS & METHODS: All allo-HSCT patients admitted into the University Hospital of Clermont-Ferrand between 1st January 1985 and 31st December 2012 were screened. Clinical and biological nutritional assessments included anthropometric measurements, serum nutritional proteins, body composition assessed by bioelectrical impedance, and upper-limb muscle strength (MS) measured by dynamometry. Hematological and nutritional data during and after hospital stay for allo-HSCT were retrospectively collected. RESULTS: Eighty four allo-HSCT patients (52% men; mean age 54.4 ± 12.5 years) were enrolled. Average follow-up after allo-HSCT was 56.4 ± 47.5 months. Prevalence of malnutrition at the end of follow-up was 20%. Compared to well-nourished patients (WN group), undernourished patients (UN group) at the end of follow-up were significantly more likely to be undernourished (50% vs. 21%, p = 0.04) at hospital admission, and to have a Nutritional Risk Index of <97.5 (47% vs. 20%, p = 0.004). Compared to a reference population, mid-arm muscle circumference and MS were significantly more likely to be decreased in the UN group than in the WN group (35.3% vs. 8.9%, p = 0.017; 24% vs. 3%, p = 0.005, respectively); fat-free mass index and appendicular skeletal muscle mass index were decreased in 30.5% and 36.6% of all patients, respectively, with no difference between UN and WN groups. Chronic graft-versus-host disease was more frequent, although not significantly in the UN group (76% vs. 52%, p = 0.071). In multivariate analyses, the presence of malnutrition at hospital admission for allo-HSCT trended towards an increased risk of longer-term malnutrition (OR = 3.60 [0.95; 13.67], p = 0.06). CONCLUSION: Malnutrition is a frequent consequence of allo-HSCT, and may occur several months or years after allo-HSCT, particularly if malnutrition existed before allo-HSCT. Our findings support the need for specialized nutritional care for both before and after allo-HSCT. Furthermore, assessment of muscle mass may be a pertinent parameter of malnutrition in this instance.

[Preventative and therapeutic relapse strategies after allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Stratégies préventives et thérapeutiques de la rechute après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7th annual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT. For high risk AML and MDS, a post transplant maintenance strategy is possible, using hypomethylating agents or TKI anti-FLT3 when the target is present. For Philadelphia positive ALL, there was a consensus for the use of post-transplant TKI maintenance. For lymphomas, there are no strong data on the use of post-transplant maintenance, and hence a preemptive strategy is recommended based on modulation of immunosuppression, close follow-up of donor chimerism, and donor lymphocytes infusion. For multiple myeloma, even though the indication of allo-HCT is controversial, our recommendation is post transplant maintenance using bortezomib, due to its a good toxicity profile without increasing the risk of GVHD.

[Polymorphism in HLA and KIR genes and the impact on hematopoietic stem cell transplantation outcomes and unrelated donor selection: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Polymorphisme des gènes HLA et KIR et l'impact sur le devenir de la greffe et le choix du donneur non apparenté de cellules souche hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

[Ibrutinib prescription in B-cell lymphoid neoplasms]. / Rationnel et modalités de prescription de l'ibrutinib dans les hémopathies lymphoïdes B.

Ibrutinib is a new-targeted therapy that irreversibly and specifically inhibits the Bruton's Tyrosine Kinase (BTK), a key component of the signaling pathways of B cells. The results are very encouraging as monotherapy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström's macroglobulinemia. Following the results of recent studies, ibrutinib is now available in France for these three diseases.

Impact of Thymoglobulin by Stem Cell Source (Peripheral Blood Stem Cell or Bone Marrow) After Myeloablative Stem Cell Transplantation From HLA 10/10-Matched Unrelated Donors: A Report From the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: The impact of antithymocyte globulin (ATG) in the setting of a myeloablative conditioning transplantation remains controversial, especially when using bone marrow (BM) as the stem cell source. METHODS: We therefore conducted a retrospective analysis to investigate the impact of ATG in patients with acute myeloid leukemia or myelodysplastic syndrome receiving myeloablative conditioning followed by a matched 10 of 10 unrelated donor transplant from BM or peripheral blood stem cells (PBSCs). Our study included 356 patients conditioned with cyclophosphamide associated with fractionated total body irradiation or busulfan. RESULTS: Median follow-up was 17.6 months (range, 0-156). The ATG and PBSCs were the only variables that independently decreased the cumulative incidence (CI) of chronic graft-versus-host disease (GvHD) (hazards ratio [HR], 0.4; 95% CI, 0.21-0.73; P < 0.01; and HR, 0.53; 95% CI, 0.30-0.90; P = 0.02, respectively). The ATG had no impact on overall survival, disease-free survival, relapse, and nonrelapse mortality. In the PBSC group (n = 139), ATG was associated with a lower CI of both grades III to IV acute GvHD (HR, 0.17; 95% CI, 0.03-0.91; P = 0.04), chronic GvHD (HR, 0.31; 95% CI, 0.11-0.87; P = 0.03), and GvHD-free/relapse-free survival (HR, 0.48; 95% CI, 0.29-0.80; P < 0.01), whereas these correlations were not significant in the group of patients (n = 217) receiving BM (HR, 0.36; 95% CI, 0.11-1.93; P = 0.06 for grade III-IV acute GvHD; HR, 0.49; 95% CI, 0.22-1.06; P = 0.08 for chronic GvHD; and HR, 0.69; 95% CI, 0.46-1.01; P = 0.06 for GvHD-free/relapse-free survival). CONCLUSIONS: Although our results confirm the recommendation for ATG to be added after PBSC transplantation, no obvious benefit was identified using this approach in the setting of BM transplantation. Only prospective studies may yield definitive answers to this question.

TCL1 expression patterns in Waldenström macroglobulinemia.

The oncogenic role of TCL1 in chronic lymphocytic leukemia is well established in transgenic mice. TCL1 expression in other B-cell malignancies has been also described: post-germinal center-derived malignancies, such as multiple myeloma, classically do not express TCL1. Waldenström macroglobulinemia is a post-germinal center malignancy that is known to be similar to chronic lymphocytic leukemia in terms of its gene expression profile. TCL1 expression has not been so far assessed in Waldenström macroglobulinemia. Transcriptomic explorations show that TCL1A expression is linked to signaling pathways and biological functions that are known to be involved in Waldenström macroglobulinemia as well as to gene signatures of interest in B-cell malignancies. We investigated TCL1 expression at the protein level in the bone marrow of a series of 59 patients with Waldenström macroglobulinemia: 76% of patients expressed TCL1, which appeared to be associated with a pejorative prognostic impact. TCL1 could have an oncogenic role in Waldenström macroglobulinemia, and deserves further exploration.

Could enteral nutrition improve the outcome of patients with haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation? A study protocol for a randomized controlled trial (the NEPHA study).

BACKGROUND: Myeloablative allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a major procedure usually accompanied by multifactorial malnutrition, prompting the recommendation of systematic artificial nutritional support. Parenteral nutrition (PN) is usually administered during allo-HSCT, essentially for practical reasons. Recently published data suggest that enteral nutrition (EN), given as systematic artificial nutrition support, could decrease grade III-IV graft-versus-host disease (GVHD) and infectious events, which are associated with early toxicity after allo-HSCT and then have an impact on early transplant-related mortality (D100 mortality). METHODS/DESIGN: We report on the NEPHA trial: an open-label, prospective, randomised, multi-centre study on two parallel groups, which has been designed to evaluate the effect of EN compared to PN on early toxicity after an allo-HSCT procedure. Two hundred forty patients treated with allo-HSCT for a haematological malignancy will be randomly assigned to two groups to receive either EN or PN. The primary endpoint will assess the effect of EN on D100 mortality. Secondary endpoints will compare EN and PN with regards to the main haematological, infectious and nutritional outcomes. DISCUSSION: The impacts of nutritional support should exceed the limits of nutritional status improvement: EN may directly reduce immunological and infectious events, as well as decrease early transplant-related morbidity and mortality. EN and PN need to be prospectively compared in order to assess their impacts and to provide treatment guidelines. (Clinical trials gov number: NCT01955772; registration: July 19th, 2013).

[Plasma cell leukemia]. / La leucémie à plasmocytes.

Plasma cell leukemia (PCL) is a rare disorder which develops spontaneously (primary PCL) or evolves in patients with multiple myeloma (secondary PCL). It is defined by the presence of 2 × 10(9)/L peripheral blood plasma cells or plasmacytosis accounting for more than 20 % of the differential white cell count. PCL presents more often extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, as well as impaired renal function. Cytogenetic abnormalities and mutations observed in PCL lead to escape from immune surveillance and independence from the bone marrow microenvironment with changes in expression of adhesion molecules or chemokines receptors. The outcome of PCL has improved with combination approaches with novel agents (including bortezomib and immunomodulatory drugs, such as lenalidomide) and with autologous stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is currently available for young patients. This article is an overview of this rare and severe disease and the different therapeutics options that are recommended.

Lung postmortem autopsy revealing extramedullary involvement in multiple myeloma causing acute respiratory distress syndrome.

Pulmonary involvement with multiple myeloma is rare. We report the case of a 61-year-old man with past medical history of chronic respiratory failure with emphysema, and a known multiple myeloma (Durie and Salmon stage III B and t(4;14) translocation). Six months after diagnosis and first line of treatment, he presented acute dyspnea with interstitial lung disease. Computed tomography showed severe bullous emphysema and diffuse, patchy, multifocal infiltrations bilaterally with nodular character, small bilateral pleural effusions, mediastinal lymphadenopathy, and a known lytic lesion of the 12th vertebra. He was treated with piperacillin-tazobactam, amikacin, oseltamivir, and methylprednisolone. Finally, outcome was unfavourable. Postmortem analysis revealed diffuse and nodular infracentimetric infiltration of the lung parenchyma by neoplastic plasma cells. Physicians should be aware that acute respiratory distress syndrome not responding to treatment of common causes could be a manifestation of the disease, even with negative BAL or biopsy and could be promptly treated with salvage therapy.

Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas.

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.