Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

peer reviewedLate relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity

Development of new tools to determine diagnosis and prognosis of patients with myeloproliferative neoplasms.

Plusieurs scores pronostiques ont été élaboré chez les patients atteints de leucémie myéloïde chronique (LMC) sans qu’un lien n’ait été établi entre ces scores et la biologie de la LMC. Nous montrons que les patients de mauvais pronostic ont une expression accrue de GATA2, en corrélation avec les taux de basophiles et de plaquettes au diagnostic, paramètres utilisés dans le calcul des scores pronostiques, et à l’expression de gènes impliqués dans le fonctionnement des basophiles. Cette expression augmente lors de la transformation sur un versant myéloïde. Alors qu’un certain nombre de patients peuvent désormais tenter un arrêt de traitement avec un succès dans 50% des cas, il apparaît essentiel de revoir notre manière d’évaluer le pronostic. Ainsi, l’obtention d’une réponse moléculaire optimale dès 6 mois est associée avec une tentative ultérieure d’arrêt de traitement dans notre cohorte. Alors que le diagnostic de la LMC est relativement aisé, il est parfois difficile de différencier thrombocytémie essentielle (TE), pré-myélofibrose et myélofibrose. Nous réévaluons l’intérêt de la numération des cellules CD34+ circulantes: un nombre de cellules CD34+ circulantes < 10/μl permet d’exclure le diagnostic de myélofibrose avec une très bonne sensibilité (97%) et spécificité (90%). Dans une cohorte de patients atteints de TE avec mutation CALR, nous montrons que l’augmentation de sa charge allélique, et non la présence de mutations additionnelles, est associée à un risque accru de progression. L’ensemble de ces paramètres sera étudié dans une étude prospective multicentrique visant à établir un score diagnostique non invasif permettant de différencier TE, pré-myélofibrose et myélofibrose.Various scoring systems have been successively elaborated to predict outcome of patients with chronic myeloid leukemia (CML). However, no link has been identified between those scores and CML biology. We show that high-risk patients have high GATA2 levels, in correlation with higher baseline basophil and platelet counts, two parameters used to calculate prognostic scores, and expression of genes involved in basophils. GATA2 expression increases in accelerated and myeloidblast-phase. Since some patients can now stop treatment, with a near 50% success rate, it is necessary to reevaluate the way we assess prognosis. A 6-month optimal molecular response was associated with an increased discontinuation attempt rate in our cohort. While the diagnosis of CML is fairly easy, it is often difficult to distinguish essential thrombocythemia (ET), pre-myelofibrosis and myelofibrosis. The numeration of CD34+ circulating cells is of interest in this setting : we show that a number < 10/μ excludes the diagnosis of myelofibrosis with a very good sensitivity (97%) and good specificity (90%). In a cohort of patients with ET and CALR mutation, We show that an increase in allele burden, and not additional mutations at diagnosis or during follow-up,is associated with an increased risk of progression. All of these parameters will be evaluated in a prospective multicentric study in order to elaborate a non-invasive diagnostic score to distinguish TE, pre-myélofibrosis, and myelofibrosis

Hb Angers: A new α2‐globin variant [α2 (140)(HC2) Tyr → Ser; HBA2 : C.422 A>C] with increased oxygen affinity leading to erythrocytosis

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Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis

International audienceMyelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors-ruxolitinib, fedratinib, pacritinib, momelotinib-or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia

Severe Viral Hepatitis in a Patient with Chronic Lymphocytic Leukemia (CLL) Complicated with Autoimmune Haemolytic Anemia (AIAH), Treated with Steroids

International audienceInfectious complications are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL) due to impaired immunity secondary to the disease itself and to the immunosuppressive therapies administered to these patients. We report a 78-year-old woman with CLL who was treated with steroids for autoimmune hemolytic anemia (AIHA). A few weeks later, she was admitted for severe acute hepatitis with disseminated intravascular coagulation (DIC). Despite the symptomatic treatment of DIC, standard reanimation and probabilistic antibiotics, the patient died within 24h with severe hepatic failure. Autopsy was in favor of a disseminated viral infection with esophageal, hepatic and pulmonary cytopathologic lesions with acidophilic intranuclear inclusions suggestive of herpes virus, even though HSV 1 and 2, CMV and HHV6 PCRs were negative. This case of severe viral hepatitis with esophagitis occurring three weeks after the introduction of high-dose steroid treatment for AIHA in a CLL patient calls for anti-herpetic prophylaxis in such patients, immunodepressed by their diseases and the treatment they receive

Progressive multifocal leukoencephalopathy after durvalumab treatment for acute myeloid leukemia: A consequence of an immune reconstitution inflammatory syndrome?

Abstract Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system resulting from the reactivation of the John Cunningham virus (JCV). PML occurs almost exclusively during profound immune suppression but it can also be observed in immunocompromised subjects as part of an inflammatory immune reconstitution syndrome (IRIS) in patients receiving antiviral therapy. We report a case of PML in a 61‐year‐old patient with acute myeloid leukemia who had developed after discontinuation of durvalumab (anti‐PD‐L1) therapy initiated after multiple treatments. Results suggest that PML may result from two nonexclusive mechanisms: (i) an inhibition of the protective response of JCV‐specific T cells as a consequence of the blockade of the PD1‐PDL1 pathway, associated with a lack of compensatory expression of other inhibitory receptors by T cells and (ii) a neuroinflammatory response (PML‐IRIS) that may have contributed to virus reactivation

Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia

(1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary AML is now considered a diagnostic qualifier rather than a separate disease entity. (2) Methods: To assess the association between clinical history and AML outcomes in the context of allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 759 patients with de novo AML, 115 with AHD AML, and 105 with therapy-related AML who received first allografts while in first or second remission. (3) Results: At the time of HCT, these three cohorts differed significantly regarding many patient and disease-specific characteristics, including age (p p p = 0.005), HCT-CI score (p p = 0.003), first vs. second remission (p p p p p = 0.7) and therapy-related AML (HR = 0.86, p = 0.4) after multivariable adjustment, as were relapse-free survival (HR = 1.20, p = 0.2, and HR = 0.89, p = 0.5) and overall survival (HR = 1.19, p = 0.2, and HR = 0.93, p = 0.6). Non-relapse mortality was higher for AHD AML (HR = 1.59, p = 0.047). (4) Conclusions: These data suggest that the clinical history by itself contains limited prognostic value for adults with AML undergoing allografting, supporting the most recent approach to use this information as a diagnostic qualifier rather than a disease entity

Diagnostic approach to hemoglobins with high oxygen affinity: experience from France and Belgium and review of the literature.

International audienc

Serum phosphate level and its kinetic as an early marker of acute kidney injury in tumor lysis syndrome

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No detection of atypical one-base deletion of CALR exon 9 with fragment analysis: A molecular trap to avoid

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