Bone Marrow Transplantation (2015) 50, 3–9 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt REVIEW Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD B Frey Tirri1, P Häusermann2, H Bertz3, H Greinix4, A Lawitschka5, C-P Schwarze6, D Wolff7, JP Halter8, D Dörfler9 and R Moffat10,11 Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients’ health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT. Bone Marrow Transplantation (2015) 50, 3–9; doi:10.1038/bmt.2014.242; published online 27 October 2014 INTRODUCTION practical guidelines for the use of supportive treatment 4,5 Complications after allogeneic hematopoietic SCT (HSCT) are modalities (summarized in Table 1). mainly due to adverse effects of cytotoxic treatment, acute and The evaluation of evidence and the subsequent recommenda- fi chronic GVHD (cGVHD), drug adverse effects or long-lasting tions were classi ed according to the rating system for ancillary immunodeficiency leading to prolonged susceptibility for therapy and supportive care published by Couriel in 2008 (ref. 27; opportunistic infections.1 To prevent permanent dysfunctions Table 2). On the basis of the National Institutes of Health (NIH) long-term follow-up programs for post-transplant patients have Consensus recommendations for clinical research in cGVHD, the focus of this report was to provide updated and more detailed been developed which address age- and gender-specific guidelines for the prevention and treatment of gender-specific characteristics.2 Despite many similarities, there are differences problems associated with cGVHD in female patients in daily in clinical symptoms, prophylaxis and treatment of post-transplant clinical routine. Strength of recommendation and evidence levels complications between female and male patients. For example, (Table 3) were based on a PubMed-based literature search with hypogonadism due to premature gonadal failure is highly subsequent rating by an expert panel approval of the recom- prevalent after intensive chemotherapy and TBI for conditioning mendations by all participants of the consensus process. Only in men and women. However, in women gonadal dysfunction is English literature was considered. Abstracts from the Bone Marrow more pronounced and occurs more often and earlier after HSCT, Transplantation Tandem meetings, the European Bone Marrow 3 and the recovery of gonadal function is less likely. This report Transplantation meetings and the American Society of Hematol- focuses on some post-transplant issues, which are important ogy meetings were cited but not included in the evidence rating. to consider in female patients after allogeneic HSCT Reference lists from the articles retrieved were also evaluated for including cGVHD. relevant information. Data on this consensus process have been presented at the German, Austrian and Swiss Consensus Conference on clinical practice in cGVHD held in Regensburg in 2009 and have been INCIDENCE AND RISK FACTORS FOR FEMALE GENITAL CGVHD updated in a workshop held in Wiesbaden 2013. Updates were The first report on female genital involvement of cGVHD discussed during the cGvHD consortia meetings in 2011 and 2013. was published in 1982.28 It took another 20 years until The consensus summarizes the currently available evidence for this problem became more widely recognized and discussed in first-line, second-line and topical therapies in cGVHD and provides the literature.29,30 Women rarely report genital symptoms to 1Women’s Hospital, Cantonal Hospital Baselland, Bruderholz, Switzerland; 2Department of Dermatology, University Hospital Basel, Basel, Switzerland; 3Department of Hematology and Oncology, Albert Ludwigs-University Medical Center, Freiburg, Germany; 4Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; 5St Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria; 6University Children’s Hospital Tuebingen, Tuebingen, Germany; 7Department of Medicine III, University of Regensburg, Regensburg, Germany; 8Department of Hematology, University Hospital Basel, Basel, Switzerland; 9Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria; 10Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, Basel, Switzerland and 11Fertisuisse, Center for Reproductive Medicine, Olten, Switzerland. Correspondence: Dr B Frey Tirri, Women’s Hospital, Cantonal Hospital Baselland, CH-4101 Bruderholz, Switzerland or Dr R Moffat, Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, CH-4031 Basel, Switzerland. E-mail: [email protected] or [email protected] Received 30 December 2013; revised 5 September 2014; accepted 17 September 2014; published online 27 October 2014 Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al 4 Table 1. Summary of recommendations Recommendation Strength Clinical assessment Asymptomatic women should be offered a gynecological examination once a year6 BIIa Symptomatic women should be referred to a gynecologist with experience in GVHD6 BIIIa Pediatric patients: clinical assessment should be performed by an experienced pediatric gynecologist and includes Tanner staging, AIIIb inspection of external genitalia and reevaluation every 3–6 months7 Treatment Use of water only for genital hygiene is recommended. Perfumed lotions and soaps and tight underwear and clothes should be AIIIb avoided8 In case of genital atrophy, use topical estrogen in the form of creams, capsules or estrogen-releasing rings even if the patient is using BIb HT9 In case of genital cGVHD, achieve rapid control of inflammation with topical class IV corticosteroids10–12 BIb Topical calcineurin inhibitors may be suitable for long-term treatment to reduce and replace topical corticosteroids. However, recent CIb meta-analyses did not detect efficacy in patients with lichen planus13 and lichen sclerosus12 Regular intercourse, use of dilatators and surgery can improve vaginal narrowing14 CIIIa Secondary malignancies of the female genital tract Regular gynecological examination including cervical cytology should be performed once a year15,16 BIIa If treatment of suspected genital cGVHD is not successful in a timely manner (6–8 weeks), biopsy of the lesion should be performed to AIIa avoid incorrect diagnosis, erroneous treatment and exclude malignancies15,17 Biopsy is recommended for all genital lesions suspicious for dysplasia or malignancy15 BIIa HPV vaccination may be offered to young women (12–26 years) after transplantation18 BIIIa Premature ovarian failure Women with POF under the age of 40 years should be offered systemic HT irrespective of symptoms if risk factors are inexistent19–21 BIIb until the median age of natural menopause at 51 years The risk for breast cancer after allogeneic HSCT is substantially increased after TBI or local chest radiotherapy.22,23 Early mammographic AIa screening starting at the age of 25 years or 8 years after radiation of the chest or TBI24–26 is therefore recommended Abbreviations: cGVHD = chronic GVHD; HT = hormone therapy; POF = premature ovarian failure. Table 2. Strength of recommendation Category Definition A Should always be offered B Should generally be offered C Evidence for efficacy is insufficient to support for or against, or evidence might not outweigh adverse consequences or cost of the approach. Optional D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered Table 3. Quality of evidence supporting the recommendation Quality of evidence Definition of evidence level I Evidence from one or more properly randomized, controlled trial(s) II Evidence from one or more well-designed clinical trial(s) without randomization, from cohort or case-controlled analytic studies (preferable from 41 center), or from multiple time series or dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies or reports from expert committees Qualifier for categories I–III a Evidence derived directly from study(s) in GVHD b Evidence derived indirectly from study(s) in analogous or other pertinent disease their health care providers and rather neglect genital Currently, the actual incidence of female genital cGVHD is symptoms