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Women undergoing stem cell transplantation (SCT) are mostly young and have more than 90% probability of ovarian failure, which is often permanent. A woman's age, use of radiotherapy and alkylating chemotherapy, and the allogeneic type of transplant are associated with a higher rate of premature ovarian failure and worse residual ovarian function. Premature ovarian failure has serious systemic and psychological effects that may need treatment and should be managed by practitioners trained to treat this particular population of women. Ultrasonographic evidence of ovarian follicles is often associated with a future resumption of cycles, but there are no serum markers to predict the return of ovarian function in these patients. In our center, the rate of ovarian function recovery was 7% after allogeneic SCT and 25% after autologous SCT (P<0.05). There are no guidelines on how to manage premature ovarian failure induced by myeloablative treatments followed by SCT. Because of the likelihood of the need for long-lasting estrogen plus progestin therapy (EPT) and the increased risk of secondary neoplasia after SCT, the EPT should be as physiological as possible. In our experience, the cyclical sequential combination of estradiol (2 mg daily) plus dydrogesterone (10 mg for 14 d/mo) was associated with excellent compliance because of its simple administration and few adverse effects. Such a treatment led to a dramatic improvement in vasomotor, urogenital, and psychological symptoms related to estrogen deficiency. However, in the allogeneic transplantation setting, up to 25% of women may suffer from gynecological chronic graft-versus-host disease, which may become apparent as hematocolpometra after introduction of EPT. Thus, accurate pretreatment evaluation and frequent monitoring during treatment are required. Moreover, EPT absorption may be reduced in patients who received allotransplants and have gastrointestinal or skin chronic graft-versus-host disease.

Background: Frequent endocrine disorders have been reported after allogeneic stem-cell transplant, but data on adult survivors of autologous transplants are still scarce., Methods: In this prospective study we investigated early (at 3 months) and late (at 12 months) endocrine dysfunctions in 95 consecutive autologous stem-cell transplant recipients (47 men and 48 women) aged 16 to 55 years. The functions of the hypothalamic-pituitary-gonadal/thyroid/adrenal/somatotroph axis were evaluated., Results: Three months after the transplant, insulin-like growth factor-1 values were below the normal range in 53 patients (56%); 37 of 40 women (93%) of reproductive age experienced precocious ovarian failure; 39 of 46 men (85%) showed high follicular stimulating hormone, and 17 men (37%) showed low testosterone levels. Adrenal insufficiency occurred in 28 patients (30%) during the peritransplant period after corticosteroid withdrawal. Transient subclinical hyperthyroidism was found in 15 patients (16%). Transient "low T(3)" syndrome was revealed in 29 patients (31%). Twelve months after the transplant, insulin-like growth factor-1 values were still low in 36 patients (38%). Menstrual cycles resumed in four women; follicular stimulating hormone, luteinizing hormone, and estradiol levels improved in 10 patients. Testosterone was low in only two men (4%). Seminal analysis revealed azoospermia in 32 (91%) of 35 men examined. Subclinical hypothyroidism was found in 11 patients (12%); eight of them had previously received radiotherapy for the upper half of the body., Conclusion: This study documents frequent endocrine disorders during the first year after autologous stem-cell transplant. Despite a tendency to improve, in more than half of the cases, the complications persisted for more than 1 year. Therefore, to diagnose and correct early and late endocrine dysfunctions, endocrine screening is required during the first year in all patients undergoing autografting.

Objectives: Gynecological manifestation of chronic graft-versus-host disease (cGVHD) has been invariably described in association with its extensive form. We have also observed it in a patient with the limited cGVHD form., Design: We here describe our experience of gynecological complications in a population of 30 women who were followed up in a single center 12-120 months after allogeneic stem cell transplant (allo-SCT) due to hematological malignancies. All of them manifested premature ovarian failure because of the received treatments., Results: Three out of 14 women who were affected by cGVHD developed hematocolpometra after estrogen + progestogen therapy (EPT) introduction, due to uterine and vaginal dystrophy and synecchiae. Extensive cGVHD, including dermal and mucosal localization, was present in two women while the third had only liver involvement. None of our patients had received radiation therapy or had a posttransplant history of infection. Local application of estrogens consistently improved the gynecological complication. However, vaginal synecchiae tended to relapse when local treatment was interrupted, despite no other apparent evidence of active cGVHD., Conclusions: All women with cGVHD should undergo gynecological examination before introducing EPT, to avoid unpleasant complication as hematocolpometra. Vaginal and cervical synecchiae should be treated with prolonged local treatments, and temporary use of continuous EPT regimens may be preferable in these women. Moreover, close monitoring by pelvic exam and ultrasonography is advisable during the initial cycles to detect any complication caused by possible intrauterine adhesions undetected during the previous gynecological examination.

In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)-10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course. Subsequently, those patients younger than 46 years with an HLA-identical sibling donor were assigned to undergo allogeneic (allo) stem cell transplantation (SCT), and patients without such a donor were planned for autologous (auto) SCT. Between November 1993 and December 1999, of 1198 patients aged younger than 46 years, 822 achieved CR. The study group constituted 734 patients who received IC: 293 had a sibling donor and 441 did not. Allo-SCT and auto-SCT were performed in 68.9% and 55.8%, respectively. Cytogenetic determination was successfully performed in 446 patients. Risk groups were good (t(8;21), inv16), intermediate (NN or -Y only), and bad/very bad (all others). Median follow-up was 4 years; 289 patients relapsed, 66 died in CR1, and 293 died. Intention-to-treat analysis revealed that the 4-year disease-free survival (DFS) rate of patients with a donor versus those without a donor was 52.2% versus 42.2%, P =.044; hazard ratio = 0.80, 95% confidence interval (0.64, 0.995), the relapse incidence was 30.4% versus 52.5%, death in CR1 was 17.4% versus 5.3%, and the survival rate was 58.3% versus 50.8% (P =.18). The DFS rates in patients with and without a sibling donor were similar in patients with good/intermediate risk but were 43.4% and 18.4%, respectively, in patients with bad/very bad risk cytogenetics. In younger patients (15-35 years), the difference was more pronounced. The strategy to perform early allo-SCT led to better overall results than auto-SCT, especially for younger patients or those with bad/very bad risk cytogenetics.

Background: The most debilitating skeletal complication of stem cell transplantation (SCT) is avascular necrosis (AVN)., Methods: Two hundred seven consecutive patients were evaluated prospectively for AVN. They survived disease free for more than 180 days after autologous or allogeneic SCT for hematologic malignancies. The diagnosis of AVN in suspicious cases was confirmed by magnetic resonance imaging. Possible correlations with treatments, bone mineral density (BMD), graft versus host disease (GVHD), and in vitro growth of fibroblast progenitors were investigated. Bone mineral density was evaluated by dual-energy X-ray absorptiometry in 100 transplanted patients, and the in vitro growth of fibroblast progenitors was monitored by a fibroblast colony-forming unit (CFU-F) assay in 30 patients after allogeneic SCT., Results: Twelve patients developed AVN 3-114 months (median, 26 months) following SCT: 10 (10%) after allogeneic SCT and 2 (1.9%) after autologous SCT (P = 0.04). Twenty-five joints were affected by AVN. All patients had femoral head involvement, which was managed with hip replacement in six of them. All but one patient who developed AVN after allogeneic SCT suffered from chronic GVHD (cGVHD). Avascular necrosis occurred 1-4 months after exacerbation or progression of cGVHD. Cumulative dose of steroids was similar in both SCT groups (including steroids given pretransplant for the basic disease), whereas treatment duration was significantly longer in the allogeneic SCT group. Avascular necrosis was related to the decreased number of bone marrow CFU-F colonies in vitro, but not to BMD values., Conclusions: Avascular necrosis is a skeletal complication that occurs more often after allogeneic than after autologous SCT. Occurrence of AVN symptoms after clinical follow-up of cGVHD suggests that cGVHD requiring long-term steroid therapy is one of the main risk factors for AVN. Avascular necrosis may be facilitated by a severe deficit in the repopulating capacity of bone marrow stromal stem cells after SCT., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11373)

Bone complications after allogeneic stem cell transplant (allo-SCT) include osteoporosis, fractures, and osteonecrosis. We investigated bone abnormalities in long-term survivors after busulfan cyclophosphamide-conditioning regimen, followed by human leukocyte antigen-identical sibling SCT. Bone density was measured by dual-energy x-ray absorptiometry at lumbar spine (LS) and femoral neck (FN) and phalangeal osteosonogrammetry (OSG) in 41 patients 1-10 yr after allo-SCT. Using colony-forming units-fibroblast (CFU-F) assay, we analyzed the repopulating capacity of clonogenic fibroblast progenitors belonging to the osteogenic stromal lineage. LS and FN bone mineral density (BMD) and phalangeal densitometric values were significantly reduced, compared with 188 healthy controls (P < 0.001). Decrease in T-score less than 1 SD was documented in 29% and 52% of patients at the LS and FN, respectively. OSG detected densitometric values with a T-score less than 1 SD in 68% of transplanted patients. The patients examined within the first 3 yr after transplant showed low BMD, which remained stable at FN and improved at LS. Phalangeal densitometry was low up to 10 yr after transplant. CFU-F was found permanently depressed and unable to give rise to a confluent stroma. Low serum osteocalcin levels were present throughout the whole follow-up period. A significant correlation was found between densitometric values detected by both techniques and CFU-F growth in vitro. Osteonecrosis was associated with lower FN BMD, and phalangeal densitometry correlated inversely with duration of amenorrhea and chronic graft vs. host disease requiring long-lasting steroid therapy. In conclusion, dual-energy x-ray absorptiometry and phalangeal OSG may provide complementary information on bone density after allo-SCT. Prolonged severe impairment of femoral BMD and phalangeal densitometry suggest that bone loss may persist for many years after transplant. Inability to regenerate a normal number of osteoblastic precursors in the stromal stem cell compartment may in part account for severe long-lasting posttransplant decrease in bone mass.

Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the longestablished ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting. [ABSTRACT FROM AUTHOR]