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

peer reviewedThe 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

BackgroundThe 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.MethodsTo 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.Results206 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 &lt;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.ConclusionThe 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.</jats:sec

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

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.</jats:p

Eltrombopag in Chronic Myelomonocytic Leukemia (CMML) with Severe Thrombocytopenia: Final Results of a Multicenter Phase II Study

Context: Thrombocytopenia (&amp;lt;50 x109/L) is seen in 10-30% of CMML and is associated with worse prognosis (Itzykson JCO 2013, Patnaik Leukemia 2013). It may have a central and/or a peripheral mechanism. Eltrombopag (ELT), an oral TPO analog, has shown efficacy in low risk MDS with no increased risk of disease progression (Oliva Lancet Hematol 2017) but data is limited in CMML and disease progression has been seen in patients with high risk features (Ramadan Clin Lymphoma Myeloma Leuk 2016). We report the final results of a multicenter phase 2 study investigating ELT efficacy, toxicity and biomarkers in CMML pts with platelets (PLT) &amp;lt;50 x109/L (NCT02323178). Methods: In this a phase I/II, open-label, single arm, multicenter study, key inclusion criteria were: WHO 2008 defined HMA-naive CMML, PLT &amp;lt; 50 x109/L, marrow blasts ≤ 5%, IPSS low/int-1 in MD-CMML, and in MP-CMML no or only 1 severity criteria (Hb &amp;lt; 10 g/dL, ANC &amp;gt; 16 x109/L, abnormal karyotype, extramedullary disease), spleen size &amp;lt; 16 cm. ELT was started at 100mg/d (amended to 50 mg/d) with escalating dose up to 300mg/d for at least 12 weeks. Primary endpoint was Platelet Response (HI-P) at 12 weeks, according to IWG 2006 criteria. Responders could continue ELT until protocol-defined progression, loss of response or toxicity. Results: Between August 2014 and September 2018, 30 pts (median age 77.5 years; M/F 22/8) including 21 MD-CMML and 9 MP-CMML were enrolled. 19 pts had CMML-0 and 11 pts CMML-1 with median PLT count of 32 x109/L (IQR 21-43 x109/L). 12 pts were PLT transfusion dependent (PLT-TD). In the 28 pts sequenced, TET2 mutation (mut) was found in 26 pts, RUNX1mut in 16 pts, SRSF2mut in 11 pts, ASXL1mut in 9 pts, signaling mut in 10 pts and PHF6mut in 5 pts. Median ELT dose at 12 weeks was 150 mg/d (IQR 100-262.5 mg/d). At 12 weeks, 14 pts (46.7%) achieved HI-P (95%CI 28 ; 66%) including 10 MD-CMML and 4 MP-CMML irrespective of PLT-TD status (p=0.46). Responders and non-responders mutational profile was comparable except that none of the 5 PHF6mut pts responded (p=0.06). Responders received ELT for a median of 33 weeks (IQR 17.3-49.5 weeks) with one responder still on therapy at 24 months. Median duration of response was 3.4 months (95%CI: 1.7-11.6 months). Loss of response were due to PLT decrease (11 pts) or transfusion (5 pts) and disease progression (3 pts). At 12 weeks, bleeding symptoms (all grades) were present in 3 (38%) non-responders and 4 (29%) responders. Clinical and biological grade≥ 3 adverse events (AE) were reported in 15 pts each. Before 12 weeks, 24 clinical and 16 biological AE occurred in 7 and 10 pts resp. Toxicity was cardiovascular, pulmonary or gastro intestinal in 2 pts each resp., hepatic and musculo-skeletal in 1 pt each and others in 3 pts. Biological toxicity was hepatic in 4 pts, electrolytic in 4 pts and others in 3 pts. Five pts discontinued ELT due to persistent drug related toxicity. No therapy-related deaths were reported. With a median follow-up of 17 months, 14 pts progressed (including 4 AML transformations) and 17 died. The12-month cumulative incidence of AML was 7% (95%CI: 1-21%). No factors were associated with risk of transformation in univariate analysis (neither WBC nor molecular mutational profile). Two-years OS and PFS were 47% (95%CI: 31-71%) and 28% (95%CI: 15-52%) respectively. Splice mutations were associated with better PFS in univariate analysis (HR=0.29, (95%CI: 0.11-0.76%); p=0.012). In the 21 CMML pts with PLT &amp;lt; 50 x109/L and ≤5% BM blasts from our previous CMML cohort (Itzykson JCO 2013) who were not exposed to ELT, the 12-month estimates cumulative incidence of AML was 10% (95%CI: 0-23%). Comparison with a larger historical cohort not exposed to ELT is ongoing. Conclusion: In CMML patients with severe thrombocytopenia and no marrow blast excess, treatment with ELT is safe and induces frequent but mostly transient responses without increasing the risk of CMML progression. ELT could thus help manage a situation at risk of bleeding such as a scheduled surgical procedure. Phase III studies may be useful to confirm the role of ELT in CMML patients with thrombocytopenia. Disclosures Rabian: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Braun:Daiichi Sankyo: Honoraria; Servier: Research Funding. Ades:jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Celgene/BMS: Research Funding. Solary:Janssen: Research Funding. Itzykson:Oncoethix (now Merck): Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Abbvie: Honoraria; Stemline: Membership on an entity's Board of Directors or advisory committees. </jats:sec

Eltrombopag in chronic myelomonocytic leukemia with severe thrombocytopenia. A Groupe Francophone des Myélodysplasies (GFM) study

International audienc

APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

Introduction : TP53 mutated (TP53m) MDS and AML have very poor outcome irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months (Bejar, Blood 2014). APR-246 is a prodrug spontaneously converted to methylene quinuclidinone (MQ), a Michael acceptor that binds covalently to cysteines in mutant p53, leading to protein reconformation that reactivates its pro apoptotic and cell cycle arrest functions. The combination of AZA and APR 246 showed promising results in a phase Ib study in TP53m MDS (Sallman, ASH 2018). We report interim results of a GFM phase 2 study of AZA+ APR-246 in TP53m MDS and AML, conducted in parallel with a similar US MDS consortium study. Patients and Methods : The study included hypomethylating agent (HMA) naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV /d (6 hour infusions) (days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles, and treatment with reduced APR 246 and AZA doses could be continued after allo-SCT. Results : 53 patients were enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 73 years (range 44-87), and M/F: 28/25. 34 patients had MDS (including 74% very high IPSS-R) and 19 had AML. IPSS-R cytogenetic risk was very poor in 30/34 MDS, and unfavorable in 18/19 AML, complex in 89% of the patients. Median baseline mutated TP53 VAF was 21% (range 3-76). Nineteen of the 53 patients had been included at least 7 months before date of analysis (25 July 2019), had received protocol treatment and were thus potentially evaluable for response after 6 treatment cycles (ITT population). One of them died after only one cycle from an unrelated cause (cerebral ischemic stroke), and 2 during the third cycle (from bleeding and sepsis, respectively). In the remaining 16 patients (evaluable population per protocol), the response rate was 75% including 9 (56%) CR, 3 (19%) marrow CR or stable disease with hematological improvement (HI), and 4 treatment resistance. In the ITT population, the response rate was 63%, including 47% CR, and 16% stable or marrow CR+ HI. Among CR patients, complete cytogenetic CR and negative NGS for TP53 mutation (VAF cutoff of 2%) were achieved in 7/9 (78%) and 8/8 (100%), respectively. So far, 1 patient has undergone allo-SCT. All 53 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of the patients. The latter, reviewed with a neurological team, were mainly grade 1 or 2 and consisted of ataxia (n=13), sometimes associated with cognitive impairment (n=4), suggesting a cerebellar origin. Other patients experienced acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1). Neurological AEs reached grade III in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p&amp;lt;0.01) and higher age (p=0.05). Neurological symptoms spontaneously regressed within 5 days of drug discontinuation (after a median of 1 day). They did not recur in the following cycles after per protocol APR 246 dose reductions. Conclusion : In this very high-risk elderly population of TP53m MDS and AML, generally with complex karyotype, a promising 56% CR rate at 6 cycles was reached in the evaluable population with AZA+ APR 246 combination, with deep molecular remission in all CR patients. We observed manageable neurologic AEs, mainly in elderly patients with reduced renal function, who therefore require close monitoring and dose reduction if necessary. An update regarding safety and efficacy in the 53 patients, including survival data, will be available at the meeting. A phase III international trial comparing AZA alone and AZA+ APR 246 in TP53m MDS is ongoing. Disclosures Cluzeau: Abbvie: Consultancy; Jazz Pharma: Consultancy; Menarini: Consultancy. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Recher:Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; chugai: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stamatoullas:Celgene: Honoraria; Takeda: Consultancy. Berthon:JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD; PFIZER: Other: DISCLOSURE BOARD. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Ades:Amgen: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. </jats:sec

A randomized controlled trial of antibiotics targeting adherent and invasive Escherichia coli versus placebo in Crohn’s disease: the TEOREM trial

International audienceAbstract Background A subset of patients with ileal Crohn’s disease (CD) are colonized with adherent–invasive Escherichia coli (AIEC). Objective This prospective trial tested the efficacy of antibiotics for endoscopic response in CD patients colonized with AIEC. Design Patients with endoscopically active, ileal CD, colonized with AIEC, were randomized to receive oral ciprofloxacin and rifaximin or double placebo for 12 weeks. AIEC was detected in ileal biopsies, by phenotypic analysis. The primary endpoint was endoscopic overall response, as defined by a CD endoscopic index of severity adapted to patients with ileal CD. Central readers blinded to the treatment scored video recordings of colonoscopies at preinclusion and week 12. We expected a strong signal of efficacy for antibiotics in this subgroup of patients. Results Between May 2016 and June 2021, 155 patients were screened, and 24 patients were randomized, 12 in each arm. All patients’ AIEC were sensitive to ciprofloxacin and rifaximin in vitro. There was no statistical difference between the 2 arms for endoscopic overall response (50% in the Cipro–Rifa group vs 33% in the placebo group, estimated difference 17%; 95% CI, −23% to 51%). Within the antibiotics arm, 7/10 patients became AIEC− and 3/10 patients remained AIEC+ (and acquired resistance to ciprofloxacin), as compared to 7/12 AIEC− and 5/12 AIEC+ in the placebo arm, respectively. There was no association between AIEC clearance and endoscopic endpoints. Conclusions A combination of ciprofloxacin and rifaximin was not superior to placebo to achieve endoscopic endpoints in patients with ileal CD colonized with AIEC

Eprenetapopt Plus Azacitidine in <i>TP53</i>-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 &lt; 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 &lt; .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. </jats:sec

Blood Adv

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