Female long term survivors of allogeneic hematopoietic stem cell transplantation incur a significant burden of late effects. Genital GVHD, HPV reactivation, ovarian failure and infertility, sexual dysfunction and osteoporosis are concerns that can significantly impact quality of life. This review examines the risk, pathogenesis, clinical presentation and implications of these common complications. Recommendations are provided for evaluation and management of these late effects, and other obstetric and gynecologic issues that may arise in this patient population.

This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65-25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90-17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II-III/VIN II-III; OR=13.1, 95% CI=1.59-108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.

IMPORTANCE Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms.OBJECTIVE To determine the safety and immunogenicity of the quadrivalent HPV vaccine in clinically stable women post-allogeneic transplant compared with female healthy volunteers.INTERVENTIONS Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. DESIGN, SETTING, AND PARTICIPANTSThis prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. MAIN OUTCOMES AND MEASURESAnti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. RESULTS Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups.CONCLUSIONS AND RELEVANCE Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia.

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We studied the outcome significance of pre-HCT colonization with intrinsics by reviewing the medical records of all allo-HCT recipients with available pre-HCT rectal swab or stool culture results at our institution (2011)(2012)(2013)(2014)(2015)(2016)(2017). Cases with ≥1 positive pre-HCT result for E. gallinarum or E. casseliflavus and no positive test for VRE were defined as intrinsics. Patients with no positive pre-HCT test for intrinsics or VRE, and with at least 2 negative tests for these, were defined as controls. Due to the rare occurrence of colonization with intrinsics and the preponderance of pediatric patients with this condition, each intrinsic was matched to a control using the following hierarchical criteria: (i) Disease (malignant vs. nonmalignant), (ii) disease risk (standard vs. high vs. nonmalignant), (iii) donor (sibling vs. unrelated vs. cord), (iv) conditioning (ablative vs. reduced-intensity), and (v) age (±10 years). The groups were similar in all studied variables (Table 1). The intrinsic group had a higher 2-year overall survival (OS) of 86 [52-96]% vs. controls with OS of 35 [8-65]% (P < .01, Figure 1). This remarkable difference was due to a significantly lower non-relapse mortality (NRM) in the intrinsic group (0% vs. 36 [8-65]%, P = .01). Both deaths in the intrinsic group were due to relapse. In contrast, deaths in the control group were due to organ failure in 45%, relapse in 33%, infection in 11%, and GVHD in 11%. Other transplant outcomes (GVHD and relapse) were similar between the groups.

Background: High rates of cervical dysplasia in women after allogeneic stem cell transplantation (allo-HSCT) have been reported, but risk factors are not well defined.Objective: To determine rates and risk factors for genital tract dysplasia in post-transplant women. Methods: In a prospective long-term study after allo-HSCT, gynecologic and medical history, and cervical cytology (Pap) were ob-

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