Cecile Bally

Resistance to therapy in acute promyelocytic leukemia.

Resistance to treatment in patients with acute promyelocytic leukemia is rare. The authors describe the development of resistance to arsenic through a mutation in the allele of PML that is not rearranged as the PML-RARA oncogenic driver.

Outcome of Acute Promyelocytic Leukemia (APL) in Children and Adolescents: An Analysis in Two Consecutive Trials of the European APL Group

PURPOSE Acute promyelocytic leukemia (APL) is rare in children. All-trans-retinoic acid (ATRA) combined with chemotherapy, the reference treatment of APL, is generally considered to produce similar results in children and adults. However, previously published childhood APL studies have generally analyzed all patients age < 18 years as a group, without further dividing according to age. PATIENTS AND METHODS We compared disease characteristics and outcomes of children (age ≤ 12 years), adolescents (13 to 18 years), and adults (> 18 years) included in two multicenter APL clinical trials (APL 93 and 2000 trials). RESULTS Of the 833 patients age ≤ 60 years included in the two trials, 26 (3%), 58 (7%), and 749 (90%) were children, adolescents, and adults, respectively. Children had significantly higher baseline WBC counts (P < .001). The complete remission (CR) rate (92%, 100%, and 94.5%, respectively) and 5-year cumulative incidence of relapse (CIR; 28%, 20%, and 23%, respectively) did not differ between children, adolescents, and adults, whereas adolescents had significantly better overall survival (OS; 5-year OS, 93.6% v 80.4% in adults and 80.4% in children; P = .03). However, in children age ≤ 4 years, the 5-year CIR was 52%, compared with 17.6% in children age 5 to 12 years (P = .006), although most of the younger children who relapsed experienced durable salvage with autologous or allogeneic stem-cell transplantation. CONCLUSION Adolescents and children age > 4 years with APL treated with ATRA and chemotherapy have outcomes at least as favorable as those of adults. Younger children seem to experience more relapses and may require reinforcement of first-line treatment.

Genetic analysis of therapy-related myeloid neoplasms occurring after intensive treatment for acute promyelocytic leukemia

Therapy-related myeloid neoplasms (t-MN) are severe longterm consequences of cytotoxic therapies, associated with a dismal prognosis. These disorders have been recognized by the World Health Organization classification as a specific subset of myeloid neoplasms, comprising acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients who were exposed to cytotoxic or radiation therapy for an unrelated malignancy or auto-immune disease [1]. Historically, t-MN have been considered as a consequence of DNA damage and oncogenic abnormalities directly induced by cytotoxic therapy in normal hematopoietic stem and progenitor cells [2]. Recent advances in DNA sequencing technologies have considerably improved our understanding of t-MN pathogenesis and provided new insights into t-MN biology. One of the major novel findings that emerged from next-generation sequencing (NGS) studies was that chemotherapy also promotes clonal selection of pre-existing mutant hematopoietic stem cells. This mechanism has been highlighted by Wong et al. for TP53 mutations [3], most of them being loss-of-function mutations that are associated with resistance to chemotherapy. Acute promyelocytic leukemia (APL) represent 5–10% of all AML, and are characterized by a chromosomal rearrangement involving the retinoic acid receptor alpha (RARA). With the incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the treatment paradigm of APL, this disease has become the most curable subtype of adult AML [4]. However, 1 to 2% of APL treated with ATRA and intensive chemotherapy subsequently develop a t-MN (different from APL), a serious late side effect of this treatment. In this study, we specifically focused on t-MN occurring during the evolution of a primary APL. Since cases of APL secondary to MDS or myeloproliferative disorders have also been reported [5], we investigated whether there was a genetic relationship between these two myeloid malignancies, and whether some genetic alterations were shared by both the primary APL (sub)clones and the secondary tMN (sub)clones. Between 2006 and 2015, 956 patients with newly diagnosed APL were included in the French-Belgian-Swiss APL 2006 trial (ClinicalTrials.gov Identifier: NCT00378365)

Favorable evolution of lung interstitial disease in a patient with chronic myelomonocytic leukemia treated with azacitidine

Dear Editor, We report a rare case of chronic myelomonocytic leukemia (CMML) with interstitial lung disease (ILD) responding remarkably well to azacitidine treatment. ILD associated with CMML has already been described with pulmonary Langerhans cell histiocytosis [1], Sweet’s syndrome [2], and pulmonary proteinosis [3]. A 59-year-old man with a 20-pack-year smoking history was evaluated in 2014 for a 2-year history of progressive dyspnea associated with chronic blood monocytosis lasting for more than 5 years. The patient had mild splenomegaly without any other clinical symptoms. Echocardiography was normal and pulmonary function tests revealed an obstructive ventilatory disorder with impaired carbon monoxide diffusing capacity. Lung high resolution computed tomography (HRCT) scan revealed a crazy-paving pattern (Fig. 1a). Laboratory tests revealed significant monocytosis (3 × 10/L) in 2014 (pre-existing in 2011) and a 6% left shift. White blood cell (WBC) count, hemoglobin, and platelet count were 16.8 × 10/L, 12.1 g/dl, and 424 × 10/L, respectively. There were no other biological abnormalities. Bone marrow aspiration revealed 9% of monocytes associated with dysgranulopoiesis without excess of blasts (4%). Karyotype revealed trisomy 8. These results confirmed CMML 0 and a watch and wait approach was decided. During follow-up, dyspnea increased and the patient progressively required oxygen. He was admitted in 2016 for acute respiratory distress. Laboratory tests revealed 13.5 × 10/L WBC including ×10/L monocytes, anemia (10.6 g/dL), and thrombocytopenia (86 × 10/L). A new bone marrow aspiration showed similar results to those of 2014. Lung HRCT scan showed a significant worsening of the ILD and bronchoalveolar lavage (BAL) revealed neutrophilic alveolitis. An extensive search for infection was negative. Sweet’s syndrome was ruled out and PAS staining ruled out alveolar proteinosis. Microbial and autoimmune assays were normal. Treatment as an idiopathic ILC with both hydroxycarbamide (1000 mg/day) and prednisone (1 mg/kg/day) was started with no effect on the pulmonary disease after 1 month. At this time, the patient needed 4 L/min of oxygen flow. Given steroid resistance of ILD in the context of evolving CMML, the patient was referred to our center and treatment with azacitidine was started in January 2017 at the EMA/FDA approved dose. After the second course, lung HRCT scan showed a major improvement of ILD (Fig. 1b). After three courses, the patient became oxygen independent while complete remission of CMML was achieved. After 10 cycles, the patient was still alive without any ILD recurrence. The limitation of this case report is that we did not perform a lung biopsy to confirm the cause of ILD. Notwithstanding complementary exams ruled out many differential diagnoses. Hence, the most probable hypothesis is ILD as an inflammatory disease associated with CMML. Noteworthy, the treatment by azacitidine worked remarkably well and fast on the ILD. ILD is a * Lionel Ades Lionel.ades@aphp.fr

Comparison of TP53 mutations screening by functional assay of separated allele in yeast and next-generation sequencing in myelodysplastic syndromes.

TP53 mutations are major prognostic factors in many hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Next-generation sequencing (NGS) has improved the detection of such mutations by identifying small mutated clones but functional method like FASAY (functional assay of separated allele in yeast) may prove interesting. We compared the detection of TP53 mutations by FASAY and NGS in 91 patients with AML or MDS. By FASAY, 91% of assays were evaluable and 47 patients (57%) had a functional and 36 (43%) a non-functional p53 protein. FASAY could not conclude in 8 cases (9%), mainly because of poor RNA quality. No TP53 mutation was found using NGS in 50 cases (55%), and at least one mutation was detected in 41 cases (45%). The p53 status was concordant between FASAY and NGS in 95% (79/83) of cases. The four discordances included mutations detected by FASAY only in two cases, and by NGS only in two cases. Mutations not detected by NGS consisted of insertions in intronic regions, which were not analyzed by this assay. Mutations not detected by FASAY were mutations for which the percentage of mutated allele was less than 10%, including one mutation reported as non-deleterious in the IARC database. Overall, our data suggest that FASAY is an effective and reliable method to detect TP53 mutations in AML and MDS, which allows the assessment of the protein functionality, contrary to a sequencing approach.