Factors Associated With Treatment Pathways in Early Axial Spondyloarthritis: A Multistate Analysis of the 10-Year Follow-Up of the DESIR Cohort.

OBJECTIVE: Current recommendations for the management of patients with axial spondyloarthritis (axSpA) emphasize the need of an individualized strategy in therapeutic decision-making. The study objectives were to describe therapeutic strategies observed in axSpA, and to assess the factors associated with treatment intensification over time. METHODS: We included patients with axSpA from the French prospective cohort DESIR (Devenir des Spondylarthropathies Indifférenciées Récentes), with a scheduled 10-year follow-up. A multistate model with 4 ordered treatment states (no treatment, nonsteroidal antiinflammatory drugs [NSAIDs], conventional synthetic disease-modifying antirheumatic drugs [csDMARDs], and tumor necrosis factor inhibitors [TNFi]) was defined, with 6 possible transitions. Restricted mean sojourn times in each state were estimated. Then, predictors of those transitions were assessed by multivariable Cox models. RESULTS: A total of 686/708 (96.9%) patients who had > 1 visit were analyzed. At cohort entry, 199 (29%) were untreated, 427 (62.2%) were receiving NSAIDs, 60 (8.7%) csDMARDs, and none were receiving TNFi. Over the follow-up period, patients mostly (46.4% of the time) received NSAIDs, followed by TNFi (24.4% of the time). The presence of sacroiliitis on radiographs, inflammatory bowel disease, and articular index were jointly associated with the transition to NSAIDs. Longer duration in the previous state often decreased the hazard of the transition to csDMARDs or TNFi. Worse disease activity outcomes increased the hazard of most transitions. CONCLUSION: To our knowledge, this was the first study using a multistate model to easily represent different treatment states, detailing the transitions across them and their associated factors. Different time profiles for the management of patients with axSpA were identified, including in those abstaining from treatment up to a significant proportion of patients treated with csDMARDs.

Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.

The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012).

Long-term outcomes of adult pulmonary Langerhans cell histiocytosis: a prospective cohort.

BACKGROUND: The long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience. METHODS: To address this issue, all patients with newly diagnosed PLCH referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases and extrapulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan-Meier method. RESULTS: 206 patients (mean age 39±13 years, 60% female, 95% current smokers) were prospectively followed for a median duration of 5.1 years (IQR 3.2-7.6 years). Of these, 12 patients (6%) died. The estimated rate of survival at 10 years was 93% (95% CI 89-97%). The cumulative incidences of CRF and/or PH were <5% at both 5 and 10 years, and 58% of these patients died. 27 malignancies were observed in 23 patients. The estimated standardised incidence ratio of lung carcinoma was 17.0 (95% CI 7.45-38.7) compared to an age- and sex-matched French population. Eight (5.1%) of the 157 patients with isolated PLCH developed extrapulmonary involvement. CONCLUSION: The long-term prognosis of PLCH is significantly more favourable than has previously been reported. Patients must be closely monitored after diagnosis to detect severe complications early.

Long-Term Outcome of Neoadjuvant Tyrosine Kinase Inhibitors Followed by Complete Surgery in Locally Advanced Dermatofibrosarcoma Protuberans.

In locally advanced dermatofibrosarcoma protuberans (DFSP), imatinib mesylate has been described as an efficient neoadjuvant therapy. This retrospective study included patients with locally advanced DFSP who received neoadjuvant TKI (imatinib or pazopanib) from 2007 to 2017 at Saint Louis Hospital, Paris. The primary endpoint was the evaluation of the long-term status. A total of 27 patients were included, of whom nine had fibrosarcomatous transformation. The median duration of treatment was 7 months. The best response to TKI treatment before surgery, evaluated according to RECIST1.1 on MRI, consisted of complete/partial response (38.5%) or stability (46.2%). DFSP was surgically removed in 24 (89%) patients. A total of 23 patients (85%) were disease-free after 64.8 months of median follow-up (95% confidence interval 47.8; 109.3). One patient developed distant metastases 37 months after surgical tumor resection and finally died. Two patients (7%) did not get surgery because of metastatic progression during TKI treatment, and one patient refused surgery even though the tumor decreased by 30%. Treatment-related adverse events (AE) occurred in 23 patients (85%). Only four patients (imatinib: n = 3, pazopanib: n = 1) had grade ≥3 AE requiring temporary treatment disruption. Neoadjuvant TKI followed by complete surgery with micrographic analysis is an effective strategy for locally advanced and unresectable DFSP, with durable local recurrence disease-free survival.

Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

PURPOSE: TP53-mutated (TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset (P < .01) and higher age (P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.