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Reduced Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplant: Gonadal Toxicity and Fertility Following Pediatric HSCT
Bender, J. D., Toro, H. O., Benoit, J., Howell, J. C., Badia, P., Davies, S. M., Grimley, M. S., Jodele, S., Phillips, C., Burns, K., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Hematopoietic stem cell transplant (HSCT) is a curative therapy for many pediatric malignancies and non-malignant conditions. Gonadal insufficiency or infertility is present in almost all survivors of myeloablative conditioning (MAC). Reduced intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with non-malignant diagnoses to limit the toxicities associated with HSCT, however the short and long-term gonadal toxicity of RIC remains unknown in pediatric and young adult survivors. OBJECTIVES To compare the prevalence of gonadal insufficiency and infertility among pubertal and post-pubertal pediatric and young adult survivors of HSCT who underwent RIC versus MAC. STUDY DESIGN Twenty-three females (RIC=8, MAC=15) and 35 males (RIC=19, MAC=16) were included in this single center, retrospective, cross-sectional study. Eligible patients were defined as being ≥ 1 year post-HSCT and aged <40 years, having reached puberty, and having available laboratory results. FSH, LH, estradiol, and anti-Müllerian hormone (AMH) levels were measured in females and FSH, LH, total testosterone, and inhibin B in males. Twenty-one males (RIC=11, MAC=10) underwent semen analysis through a separate consent. Parametric and non-parametric analyses were undertaken to compare RIC versus MAC groups. RESULTS Female patients who underwent RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (p=0.02) and low estradiol (p=0.01) or elevated LH (p=0.09). Most RIC (75%) and MAC (93%) females demonstrated low AMH indicating low or absent ovarian reserve, with no significant difference between cohorts (p=0.53). In males, there were no significant differences seen in prevalence of abnormal FSH, LH, testosterone, or inhibin B between the 2 cohorts. Ten of 11 (91%) RIC males and 10/10 (100%) MAC males had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range: 1.3-12.2 years). CONCLUSIONS RIC may pose less risk for primary ovarian insufficiency than MAC among female survivors of HSCT. However, female and male patients undergoing either RIC or MAC are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling to outline the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.
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Health-related quality of life in reduced intensity hematopoietic cell transplantation based on donor availability in patients aged 50-75 with advanced myelodysplastic syndrome: BMT CTN 1102
Cusatis, R., Martens, M. J., Nakamura, R., Cutler, C. S., Saber, W., Lee, S. J., Logan, B. R., Shaw, B. E., Gregory, A., D'Souza, A., et al
American journal of hematology. 2022
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Abstract
INTRODUCTION For myelodysplastic syndrome (MDS), allogeneic hematopoietic cell transplantation (alloHCT) is the only available curative therapy. The Blood and Marrow Transplant Clinical Trials Network study 1102 (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial based on matched donor availability in adults aged 50-75 with higher risk de novo MDS who were candidates for reduced-intensity conditioning (RIC) alloHCT. The primary analysis showed that those who received alloHCT had a survival benefit, but whether this is at the cost of worse quality of life (QOL) has not been described in detail. METHODS English and Spanish-speaking trial participants completed the Functional Assessment of Cancer Therapy - General (FACT-G), the SF-36, and the EQ-5D, at enrollment, every 6 months until 24 months, and 36 months. We compared patient-reported outcome (PRO) scores between study arms using an inverse probability weighted - independent estimating equation (IPW-IEE) model. RESULTS Between January 2014 and November 2018, 384 subjects (median age 66.7 years, range: 50.1-75.3) enrolled at 34 centers. PRO completion rates were generally high at 65-78%. The PRO trajectories for both arms were similar, with most decreasing or stable from baseline to 6 months and improving thereafter. Baseline PRO scores were the most consistent independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient-level factors. DISCUSSION For older adults with MDS, the survival advantage associated with Donor availability and alloHCT did not come at the cost of worse QOL. These results should reassure older patients and clinicians who prefer a curative approach to treating MDS. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Adults aged 50-75 with higher risk de novo myelodysplastic syndrome,, who were candidates for reduced-intensity conditioning and allogeneic transplant, identified in 34 centres in the USA (n=384)
Intervention
Patients with an available donor and were transplanted (n=261)
Comparison
Patients with no available donor who did not receive transplantation (n=123)
Outcome
The patient recorded outcome (PRO) trajectories for both arms were similar, with most decreasing or stable from baseline to 6 months and improving thereafter. Baseline PRO scores were the most consistent independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient-level factors.
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Impact of lung function on bronchiolitis obliterans syndrome and outcome after allogeneic hematopoietic cell transplantation with reduced intensity conditioning
Duque-Afonso, J., Ihorst, G., Waterhouse, M., Zeiser, R., Wasch, R., Bertz, H., Muller-Quernheim, J., Finke, J., Marks, R., Prasse, A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Lung function deterioration contributes to treatment-related morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Better understanding of impaired lung function including bronchiolitis obliterans syndrome (BOS) as chronic manifestation of Graft-versus-Host-Disease (GvHD) might improve outcomes of patients after allo-HCT. In order to detect early pulmonary function tests abnormalities associated with BOS incidence and outcome after allo-HCT, we performed a retrospective analysis of homogenous-treated 445 patients (median age 61.9 years, range 19-76) with a reduced intensity/toxicity conditioning protocol. The cumulative incidence of BOS was 4.1% (95% CI 2.6-6.4) at 1 year and 8.6% (95% CI 6.3-11.6) at 5 year after allo-HCT with a median follow-up of 43.2 months (range 3.3-209). In multivariate analysis, pre-existence of moderate small airway disease reflected by decreased mid-expiratory flows prior allo-HCT was associated with increased risk for BOS development. In addition, severe small airway disease prior allo-HCT and combined restrictive/obstructive lung disease at day +100 after allo-HCT were associated with higher risk for non-relapse mortality due mainly to pulmonary cause of death. In summary, we identified novel pulmonary function tests abnormalities prior and after allo-HCT associated with BOS development and non-relapse mortality. These findings might help to identify a risk population and result in personalized GvHD prophylaxis and preventive or early therapeutic interventions.
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Ovarian insufficiency following allogeneic hematopoietic stem cell transplantation
Kawano, M., Komura, H., Kawaguchi, H., Shimizu, S., Yada-Hashimoto, N., Shimizu, M., Sato, M., Inoue, M., Ida, S., Etani, Y., et al
Gynecological Endocrinology. 2017;33(2):156-159
Abstract
Ovarian insufficiency is a serious complication for young women who undergo hematopoietic stem cell transplantation (HSCT). Reduced-intensity conditioning (RIC) has been utilized more widely due to its reduced toxicity; however, there is a lack of data concerning ovarian function after HSCT with RIC. We investigated the ovarian function in patients who received HSCT with RIC, compared to those who received myeloablative conditioning (MAC). The records of 69 female patients who received allogeneic HSCT at the institution under 40 years of age at transplantation from 1991 to 2012 were retrospectively analyzed. Prevalence of ovarian insufficiency was significantly lower in patients conditioned with RIC than in those conditioned with MAC (4/27=14.8% for RIC and 36/42=85.7% for MAC, p<0.0001). A younger age at HSCT was associated with a lower risk of ovarian insufficiency. Among the 40 patients with ovarian insufficiency, four patients recovered ovarian function, and two conceived following hormone-replacement therapy (HRT). A higher serum E2 level prior to HRT was a significant predictor for the restoration of ovarian function (p=0.0028). In conclusion, RIC was significantly less toxic to ovarian function compared with MAC. HSCT-associated ovarian insufficiency is not irreversible, and a higher E2 level may predict the restoration of ovarian function.
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Late Complications and Quality of Life after Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation
Clavert, A., Peric, Z., Brissot, E., Malard, F., Guillaume, T., Delaunay, J., Dubruille, V., Le Gouill, S., Mahe, B., Gastinne, T., et al
Biology of Blood & Marrow Transplantation. 2017;23(1):140-146
Abstract
Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Cardiovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant questionnaires, most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Long-Term Follow-Up after Reduced-Intensity Conditioning and Stem Cell Transplantation for Childhood Nonmalignant Disorders
Madden, L. M., Hayashi, R. J., Chan, K. W., Pulsipher, M. A., Douglas, D., Hale, G. A., Chaudhury, S., Haut, P., Kasow, K. A., Gilman, A. L., et al
Biology of Blood & Marrow Transplantation. 2016;22(8):1467-72
Abstract
Reduced-intensity conditioning (RIC) before hematopoietic stem cell transplantation (HCT) in children could result in fewer complications during follow-up compared with myeloablative regimens. Hence, many RIC regimens are under investigation, but long-term follow-up is essential. We describe late follow-up beyond 2 years post-HCT in 43 children with nonmalignant disorders who underwent related or unrelated donor (56%) HCT on a multicenter study using a RIC regimen (alemtuzumab, fludarabine, and melphalan) followed by bone marrow (n = 30), peripheral blood (n = 3), or umbilical cord blood (n = 10) HCT for immune dysfunction, bone marrow failure, metabolic disorders, or hemoglobinopathy. Recipients (median age, 7.5 years; range, 3 to 26) underwent HCT 2 to 8 years (median, 3.1 years) before this report. Full donor (67%) or stable mixed chimerism (33%) was noted without late graft rejection. Five patients (12%) required systemic immunosuppression therapy (IST) beyond 2 years post-HCT for graft-versus-host disease (GVHD); 2 patients died 38 and 79 months later, whereas the others improved, enabling an IST wean. Overall, 17 complications were documented in 10 patients (23%). Complications not related to GVHD included hypothyroidism (n = 2), low grade neoplasms (n = 2), and delayed puberty (n = 1). One patient with GVHD had ovarian failure; all other postpubertal females resumed normal ovarian function. Twenty-seven of 28 school-age recipients were functioning at grade level. RIC HCT recipients thus had few regimen-related toxicities during long-term follow-up. However, objective long-term follow-up is still necessary to identify complications so timely intervention may be planned. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Health-Related Quality of Life in leukemia Survivors of Allogeneic Hematopoietic Stem Cell Transplantation Employing the Mexican Reduced-Intensity Conditioning
Gonzalez-Ramirez, M. P., Miravete-Lagunes, K., Gomez-de-Leon, A., Ponce-de-Leon, S., Tenorio-Rojo, A. P., Martagon-Herrera, N. A., Hernandez-Reyes, J. A., Garcia-Villasenor, A., Burguette, E., Vallejo-Villalobos, M. F., et al
Revista de Investigacion Clinica. 2015;67(2):109-16
Abstract
BACKGROUND Quality of life (QOL) is an important consideration in the counseling, implementation, and post-treatment management of arduous treatments for life-threatening conditions such as allogeneic hematopoietic cell transplantation (allo-HCT). OBJECTIVE To analyze the QOL of leukemia patients allografted with the Mexican reduced-intensity conditioning regimen in two Mexican academic medical centers. MATERIAL AND METHODS By means of the quality metric short form 36 version 2 to measure generic health concepts, relevant QOL was analyzed in leukemia patients who underwent allo-HCT using reduced-intensity conditioning on an outpatient basis at either the Centro de Hematologia y Medicina Interna de Puebla of the Clinica Ruiz or the Hematology Service of the Internal Medicine Department of the Hospital "Dr. Jose Eleuterio Gonzalez" of the Universidad Autonoma de Nuevo Leon, and who had survived more than 12 months after the allograft, who could be approached, who were in a continued complete remission (with or without graft-versus-host disease), and who were willing to respond to the questionnaire. Thirty-five patients fulfilling these requirements were included, and a sex- and age-matched group of 35 reference subjects was also studied. RESULTS Allografted patients were found to have a slightly better mental component summary than the reference subjects (53.23 vs. 48.66 points; p = 0.01), whereas the physical component summary did not show a difference (54.53 vs. 52.05 points; p = 0.59). Most of the differences between allografted individuals and reference subject controls were not significant. CONCLUSIONS Despite several sources of bias, these data suggest that allografted individuals employing the Mexican reduced-intensity conditioning regimen enjoy a health-related QOL life similar to that of reference subjects, adding another advantage of this method of conducting stem cell allografts. However, more work needs to be done to elucidate the impact of reduced-intensity conditioning on post allo-HCT QOL.