Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Sexuality- and Fertility-Related Issues in Women after Allogeneic Hematopoietic Stem Cell Transplantation.

Sexual dysfunction and fertility related issues appear as major post-allogeneic hematopoietic stem cell transplantation (HSCT) late effects in young women, with a heavy impact on quality of life. The objective of the present study was to evaluate the impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of allogeneic HSCT. Between January 2014 and January 2016, adult female patients who underwent HSCT before age 35 and had been followed for more than 2 years in our center were offered participation in the study through a self-reported survey and/or ovarian function assessment if age <40 at inclusion. A total of 63 patients were included, with a median age of 23.4 years at transplantation and 30.9 years at inclusion. Twenty-nine patients (46%) underwent HSCT for acute leukemia and 16 (25%) underwent HSCT for aplastic anemia (AA). The conditioning regimen was myeloablative conditioning (MAC) in 37 patients (59%) and reduced-intensity conditioning (RIC) in 26 (41%). Fifty-eight patients completed the survey, and 34 were evaluated for ovarian function. Symptoms of hypoestrogenism were reported by 86% of the patients and changes in sexual life were reported by 76%, due mainly to low sex drive, negative impact of infertility problems, physical sequelae, and loss of self-confidence. Premature ovarian failure (POF) occurred in 74% of patients and was significantly associated with conditioning regimen (MAC versus RIC; P = .001) and baseline disease (bone marrow failure versus acute leukemia versus others; P < .001). However, one-half of the patients developed a POF despite the use of a RIC regimen. For 27 patients (47%), disease and treatments modified their desire for pregnancy, due mainly to fear of relapse and of disease transmission to offspring. Thirteen pregnancies were reported (21%), of which 8 were spontaneous and 5 were obtained through assisted reproductive technologies, mainly oocyte donation. With a median post-transplantation follow-up of 12.2 years, the 10-year cumulative incidence of first pregnancy was 16.6% (95% CI, 8.8-30.0). Among 20 patients (32%) who engaged in a family planning initiative, 13 (65%) succeeded in having children: 11 got pregnant and 2 adopted. Sixteen patients benefited from fertility preservation techniques consisting of ovarian tissue cryopreservation, and a single autologous ovarian tissue transplantation had been performed at the time of this report. This study shows a strong impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of HSCT. It demonstrates the need to improve clinicians' awareness of sexual health- and fertility-related issues after HSCT. The difficulty of predicting ovarian function and fertility issues after RIC supports wide indications of pretransplantation fertility preservation. Evaluation of the use of cryopreserved ovarian tissues is warranted.