[Second allogeneic (update). Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Deuxième allogreffe (mise à jour). Recommandations de la Société francophone de greffe de moelle osseuse et de thérapie cellulaire (SFGM-TC).

Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains a major concern because it is associated with poor survival. A second allo-HCT is a valid option in this situation. During the 13th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to update the second allo-HCT recommendations elaborated during the previous workshop (2016). The main indication for a second allo-HCT remains relapse of initial hematologic malignancy. Disease status; complete remission (CR), and relapse time after the first allo-HCT>6 months impact positively the overall survival of patients after the second allo-HCT. Donor change is a valid option, particularly if there is HLA loss on leukemic cells after a first haploidentical or following a mismatched allo-HCT is documented. Reduced intensity conditioning is recommended, while a sequential protocol is a reasonable option in patients with proliferative disease. A post-transplant maintenance strategy after hematological recovery is recommended as soon as day 60, even if the immunosuppressive treatment has not yet been stopped. Hypomethylating agents, and targeted therapies such as anti FLT3, anti BCL2, anti-IDH1/2, TKI, anti-TP53, anti-CD33, anti-CD19, anti-CD22, anti-CD30, check point inhibitors, and CAR-T cells can be used as a bridge to transplant or as an alternative treatment to the second allo-HCT.

[Management of genetic predisposition to hematologic malignancies in patients undergoing allogeneic hematopoietic cell transplantation (HCT): Guidelines from the SFGM-TC]. / Conduite à tenir devant une prédisposition génétique aux hémopathies malignes chez un patient candidat à l'allogreffe de cellules souches hématopoïétiques (CSH) : recommandations de la SFGM-TC.

The advent of new technologies has made it possible to identify genetic predispositions to myelodysplastic syndromes (MDS) and acute leukemias (AL) more frequently. The most frequent and best characterized at present are mutations in CEBPA, RUNX1, GATA2, ETV6 and DDX41 and, either in the presence of one of these mutations with a high allelic frequency, or in the case of a personal or family history suggestive of blood abnormalities such as non-immune thrombocytopenia, it is recommended to look for the possibility of a hereditary hematological malignancy (HHM). Indeed, early recognition of these HHMs allows better adaptation of the management of patients and their relatives, as allogeneic hematopoietic stem cell transplantation (HSCT) is very often proposed for these pathologies. According to current data, with the exception of the GATA2 mutation, the constitutional or somatic nature of the mutations does not seem to influence the prognosis of hematological diseases. Therefore, the indication for an allograft will be determined according to the usual criteria. However, when searching for a family donor, it is important to ensure that there is no hereditary disease in the donor. In order to guarantee the possibility of performing the HSC allograft within a short period of time, it may be necessary to initiate a parallel procedure to find an unrelated donor. Given the limited information on the modalities of HSC transplantation in this setting, it is important to assess the benefit/risk of the disease and the procedure to decide on the type of conditioning (myeloablative or reduced intensity). In view of the limited experience with the risk of secondary cancers in the medium and long-term, it may be appropriate to recommend reduced intensity conditioning, as in the case of better characterized syndromic hematological diseases such as Fanconi anemia or telomere diseases. In summary, it seems important to evoke HHM more frequently, particularly in the presence of a family history, certain mutations or persistent blood abnormalities, in order to discuss the specific modalities of HSC allografting, particularly with regard to the search for a donor and the evaluation of certain modalities of the procedure, such as conditioning. It should be noted that the discovery of HHM, especially if the indication of an allogeneic HSC transplant is retained, will raise ethical and psychological considerations not only for the patient, but also for his family. A multidisciplinary approach involving molecular biologists, geneticists, hematologists and psychologists is essential.

Changes on chest HRCT in systemic sclerosis-related interstitial lung disease after autologous haematopoietic stem cell transplantation.

OBJECTIVE: To evaluate extent of interstitial lung disease (ILD) and oesophageal involvement using high-resolution computed tomography (HRCT) in early diffuse SSc patients after autologous haematopoietic stem cell transplantation (aHSCT). METHODS: Overall chest HRCT, lung function and skin score changes were evaluated in 33 consecutive diffuse SSc patients before and after aHSCT during yearly routine follow-up visits between January 2000 and September 2016. Two independent radiologists blindly assessed the ILD extent using semi-quantitative Goh and Wells method, the widest oesophageal diameter (WOD) and the oesophageal volume (OV) on HRCT. Patients were retrospectively classified as radiological responders or non-responders, based on achieved stability or a decrease of 5% or more of HRCT-ILD at 24 months post-aHSCT. RESULTS: Using a linear mixed model, the regressions of the extent of ILD and of ground glass opacities were significant at 12 months (ILD P = 0.001; ground glass opacities P = 0.0001) and at 24 months (ILD P = 0.007; ground glass opacities P = 0.0008) after aHSCT, with 18 patients classified as radiological responders (probability of response 0.78 [95% CI 0.58, 0.90]). Meanwhile the WOD and the OV increased significantly at 12 months (WOD P = 0.03; OV P = 0.34) and at 24 months (WOD P = 0.002; OV P = 0.007). Kaplan-Meier analyses showed a trend towards better 5-year survival rates (100% vs 60%; hazard ratio 0.23 [95% CI 0.03, 1.62], P = 0.11) among radiological responders vs non-responders at 24 month follow-up after aHSCT. CONCLUSION: Real-world data analysis confirmed significant improvement in extent of HRCT SSc-ILD 24 months after aHSCT, although oesophageal dilatation worsened requiring specific attention.

Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial.

PURPOSE: The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979). METHODS: BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD. RESULTS: Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; P < .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively. CONCLUSION: BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.

[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.

Final results of brentuximab vedotin combined with ifosfamide-carboplatin-etoposide in first refractory/relapsed Hodgkin lymphoma: a lymphoma study association phase I/II study.

This phase I/II study assessed the combination of brentuximab vedotin (BV) with ifosfamide-carboplatin-etoposide (ICE) as a second-line therapy in refractory/relapsed (R/R) classical Hodgkin lymphoma (cHL) patients. Phase I study was designed to determine the maximum tolerated dose (MTD) of BV (10 patients) and phase II evaluated the rate of complete metabolic response (CMR) after 2 cycles of BV-ICE (42 patients). There were no dose-limiting toxicities (DLT) during phase I recommending BV 1.8 mg/kg for phase II. Twenty-six patients (61.9%) achieved CMR after 2 cycles of BV-ICE and 37 patients (88%) were transplanted. With a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) rate were 64.3% and 100%, respectively. Hematological toxicities (81%) and infections (21%) were the most frequent adverse event encountered BV-ICE regimen is feasible with manageable toxicities and could be an alternative to other salvage treatments. Trial Registration: ClinicalTrials.gov identifier: NCT02686346.

Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study.

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

Brachytherapy for uterine cervix-limited acute myeloid leukemia relapse.

Acute myeloid leukemia (AML) may extend to extra-medullary sites at diagnosis or at relapse, either isolated or associated with bone marrow disease. Granulocytic sarcoma of uterine cervix is rare, and there is no established treatment for this disease. Two cases of uterine cervix-limited AML relapse showed that brachytherapy may be an effective therapeutic option in this setting along with chemotherapy, with good tolerance.

[Palliative care in hematopoietic stem-cell transplanted patients: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge palliative des patients allogreffés : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic cell transplantation (allo-HCT), the only curative therapy for numerous hematological malignancies, carries a significant risk of morbidity and mortality. The patients and families' expectations regarding the procedure, the prognosis uncertainties, as well as the existence of potential new therapeutic possibilities, lead to frequent use of intensive care. Even though the transplant physicians are highly skilled in acute care, their knowledge of palliative approach is limited, making the use of palliative care insufficient and often late. By promoting reflection on the proportionality of care and the patients' quality of life, palliative care may contribute to the allo-HCT patients management. Nevertheless, obstacles to this approach remain. The objective of this work is to propose recommendations to promote the implementation of palliative care into transplant units.

Bronchoscopic Treatment of Endobronchial Inflammatory Myofibroblastic Tumors.

Endobronchial localizations of inflammatory myofibroblastic tumors are very unusual. We report the multimodal, bronchoscopic management of 3 cases, offering durable local control in all cases (including 2 patients who were definitively cured). Although surgery is usually considered the gold standard, therapeutic bronchoscopy should probably be considered as a frontline option for proximal lesions with limited base (< 10 mm2) because of uncommon metastatic spread and delayed local recurrence. Of note, 1 of our cases is a rare airway case after allograft hematopoietic stem cell transplant.

Brentuximab vedotin in real life, a seven year experience in patients with refractory/relapsed CD30+ T cell lymphoma.

INTRODUCTION: Brentuximab vedotin (Bv) has been approved for the treatment of Refractory/Relapsed (R/R) Anaplastic Large Cell Lymphomas (ALCL) and cutaneous T-Cell Lymphomas, but is also effective in other CD30+ malignancies. We report here the outcomes of patients with various R/R Peripheral T Cell Lymphoma (PTCL) treated with Bv in real life practice. METHOD: This was a retrospective, single-center study based on medical records of patients with R/R PTCL treated either with Bv alone or in combination with chemotherapy. RESULTS: Among 27 patients treated with Bv, neutropenia was the main serious adverse event observed in particular when Bv was used as combination treatment. The complete Response Rates (CRR) was 40.7%; it was significantly improved when Bv was used as combination treatment. The majority of eligible patients (7/10) underwent Stem Cell Transplantation. Median Progression Free Survival (PFS) and Overall Survival (OS) were 5.2 months and 12.5 months respectively. CONCLUSION: Our current study shows that Bv used in combination with chemotherapy provides a high CRR and thereby allows SCT in R/R PTCL. The use of Bv treatments in this setting warrants further investigation.

Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p<0.005) and overall (HR: 0.18 [0.03-0.98], p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.

Oral acute graft versus host disease after donor lymphocyte infusions: Clinicopathological characterization in a monocenter cohort.

Donor lymphocyte infusions (DLI) are used after hematopoietic stem cell transplant (HSCT) in order to boost the graft-versus-tumor effect. The most significant toxicity is acute or chronic graft-versus-host disease (GVHD), whose clinical symptoms mirror those occurring after HSCT. By contrast, oral acute GVHD lesions have been exceptionally described post-DLI. We report on a monocenter cohort of 12 adult patients that developed oral acute GVHD after DLI. The majority was treated for acute myeloid leukemia. A total of 29 DLI treatments were applied and the median time between the last DLI and the oral mucosal lesions was 42 days. Most patients presented these oral lesions concomitant with skin lesions and none of them had exclusive oral involvement. Oral lichenoid changes were observed in 11 patients, including plaque-like lesions and/or reticulated white streaks consistent with Wickham's striae, affecting mainly the buccal mucosa and dorsal or lateral aspects of the tongue. Mucosal histopathological findings showed a patchy-to-florid lichenoid interface dermatitis for 3 biopsied patients. Eight patients also experienced salivary gland changes. The treatment of oral lesions included high- to very high-potency topical corticosteroids in the majority of patients. Oral GVHD lesions have seldom been described after DLI, and only exceptionally in an acute setting. Our results are not consistent with those reported in the literature evaluating GVHD after DLI. In fact, oral acute GVHD lesions post-DLI appeared very common and similar to the oral lichenoid reactions of chronic GVHD following HSCT. The main limitations of this work are its retrospective design and the relatively small sample size.

Pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis: A case report.

RATIONALE: The use of autologous hematopoietic stem cell transplantation (AHSCT) for autoimmune diseases has become the first indication for transplant in nonmalignant disease. Mucormycosis is a rare invasive infection with increasing incidence in patients treated with AHSCT. We report the first case of pulmonary mucormycosis following AHSCT for systemic sclerosis (SSc). PATIENT CONCERNS: A 24-year-old woman with rapidly progressive diffuse cutaneous SSc presented with an acute respiratory distress syndrome 6 days after AHSCT. DIAGNOSES: The results of clinical and computed tomography scan were consistent with pulmonary mucormycosis and the diagnosis was confirmed by a positive Mucorales Polymerase Chain Reaction on a peripheral blood sample. INTERVENTIONS AND OUTCOMES: Early antifungal therapy by intravenous amphotericin B provided rapid improvement within 4 days and sustained recovery after 2 years of follow-up. LESSONS: With the progressively increasing use of AHSCT and other stem cell therapy for treatment of severe SSc and other autoimmune diseases, the potential onset of rare post-transplant fungal infections, such as mucormycosis, requires careful patient monitoring and better awareness of early initiation of adequate therapy.

[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.