Semen Cryopreservation in Adolescents and Young Adults with Hematologic Diseases: from Bed to Benchside

International audiencePurpose: Infertility in adolescents and young adult (AYA) survivors of malignant disease remains a major long-term adverse effect, but semen collection for fertility preservation in fertility centers is not always feasible and makes AYAs uncomfortable. We evaluated the feasibility of collecting sperm samples on the ward versus in fertility centers. Methods: Consecutive hospitalized AYA-aged male patients in the Hematology AYA unit (Saint-Louis Hospital, France) between August 2010 and June 2016 with hematological disease and indication of semen collection (n = 95) were included in this retrospective study. Semen quality was analyzed according to World Health Organization guidelines and was compared according to semen collection place: on the ward (n = 46) or in fertility center (n = 49). Results: The median age was median age 19.1 years (range: 13.7-33.3; interquartile range: 17.1-22.8) and 85 patients successfully collected semen. Sperm collection failure was ∼11% and was comparable between the two modalities as were main sperm quality characteristics (semen volume, sperm concentration, total sperm count, progressive motility and vitality, sperm morphology, and multiple anomalies index). Oligospermia was significantly higher in the samples obtained in fertility center (47.7%) than on the ward (26.8%), p = 0.047. Average frozen straws were comparable, 12.2 ± 6.4 on the ward versus 11.9 ± 6.3 in fertility center. Conclusion: Semen collection on the ward is feasible and would be particularly interesting for AYA male patients without altering semen quality characteristics

PHF6-altered T-ALL harbored epigenetic repressive switch at bivalent promoters and respond to 5-azacitidine and venetoclax

Purpose: To assess the impact of PHF6 alterations on clinical outcome andtherapeutical actionability in T cells acute lymphoblastic leukemia (T-ALL).Experimental Design: We described PHF6 alterations in an adult cohort of T-ALL fromthe French trial GRAALL 2003/2005 and retrospectively analyzed clinical outcomesbetween PHF6-altered (PHF6ALT) and wild-type patients. We also used EPIC andChIP-seq data of patient samples to analyze the epigenetic landscape of PHF6ALT T-ALLs. We consecutively evaluated 5-azacitidine efficacy, alone or combine withvenetoclax, in PHF6ALT T-ALL.Results: We show that PHF6 alterations account for 47% of cases in our cohort anddemonstrate that PHF6ALT T-ALL presented significantly better clinical outcomes.Integrative analysis of DNA methylation and histone marks shows that PHF6ALT arecharacterized by DNA hypermethylation and H3K27me3 loss at promotersphysiologically bivalent in thymocytes. Using patient-derived xenografts (PDX), weshow that PHF6ALT T-ALL respond to the 5-azacytidine alone. Finally, synergism withthe BCL2-inhibitor venetoclax was demonstrated in refractory/relapsing PHF6ALT T-ALL using fresh samples. Importantly, we report three cases of refractory/relapsed(R/R) PHF6ALT patients who were successfully treated with this combination.Conclusions: Overall, our study supports the use of PHF6 alterations as a biomarkerof sensitivity to 5-azacytidine and venetoclax combination in R/R T-ALL

IL-7 receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK inhibition

International audienceT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted therapies. Activating mutations of interleukin-7–receptor pathway genes (IL-7Rp) play a proven leukemia-supportive role in T-ALL. JAK inhibitors, such as ruxolitinib, have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK inhibitors are still lacking. Herein, we show that IL-7R (CD127) expression is more frequent (∼70%) than IL-7Rp mutations in T-ALL (∼30%). We compared the so-called nonexpressers (no IL-7R expression/IL-7Rp mutation), expressers (IL7R expression without IL-7Rp mutation), and mutants (IL-7Rp mutations). Integrative multiomics analysis outlined IL-7R deregulation in virtually all T-ALL subtypes, at the epigenetic level in nonexpressers, genetic level in mutants, and posttranscriptional level in expressers. Ex vivo data using primary-derived xenografts support that IL-7Rp is functional whenever the IL-7R is expressed, regardless of the IL-7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL-7R expression and IL-7Rp addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, the combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting the achievement of complete remission in 2 patients with refractory/relapsed T-ALL. This provides proof of concept for translation of this strategy into clinics as a bridge-to-transplantation therapy. IL7R expression can be used as a biomarker for sensitivity to JAK inhibition, thereby expanding the fraction of patients with T-ALL eligible for ruxolitinib up to nearly ∼70% of T-ALL cases

Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies

International audienc