Investigation and Management of Bone Mineral Density Following Hematopoietic Cell Transplantation : A Survey of Current Practice by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation

Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders. (c) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.Peer reviewe

Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients:an EBMT Transplant Complications Working Party study

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (&gt;day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p &lt; 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome. [Figure not available: see fulltext.]</p

Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients.

Importance Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited. Objective To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis. Design, Setting, and Participants This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018. Main Outcomes and Measures Median and 5-year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC. Results In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5-year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant-associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers. Conclusions and Relevance The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report

A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT

2009

ABSTRACT HSCT, to identify the risk factors related to potential infertility after HSCT and to provide data on longitudinal sperm recovery after HSCT. Design and Methods For this retrospective multicenter study of the Late Effects Working Party of the EBMT all centers were asked if they had performed seminal analysis (SFA) in male patients before and after allogeneic HSCT, and if they would agree to provide information on all patients who had. Five hundred and forty-three centers were contacted of which 93 responded. Twenty-three Transplant Centers reported having data on SFA, and 19 of them finally contributed reports on a total of 259 patients; 224 of 259 were treated with allogeneic HSCT. Overall, 224 patients were included in this study. The EBMT is a voluntary group of transplant centers each of which is required to provide transplant-related information on each patient using a specific anonymous data collection form. Patients provide written informed consent to have their data on disease, treatment and outcome, including late complications, reported to the registry. Clinical surveillance of HSCT recipients was approved by the local institutional review boards. Patients&apos; characteristics, HSCT conditioning regimens and clinical outcome data were collected prospectively and stored in the EBMT database. Details requested on seminal fluid parameters included the number and date of collections performed per patient, the sperm concentration, the motility and the morphology of the spermatozoa. Gonodotropic hormone and testosterone levels (if performed) were requested. Results of SFA were assessed according to the World Health Organization (WHO) guidelines. 15 Patients were considered to be normozoospermic when the sperm concentration exceeded 20x10 6 /mL, oligozoospermic when the sperm count was between 5 and 20x10 6 /mL, severely oligozoospermic with a sperm count below 5x10 6 /mL, and cryptospermic when spermatozoa were detected only after careful analysis of the concentrated sample. When no spermatozoa were detected patients were considered azoospermic. Statistical analysis Variables significantly associated with the risk of infertility after allogeneic HSCT were assessed by univariate and multivariate analysis. Any presence of spermatozoa in SFA was considered as existence of spermatogenesis. Patients with sperm detectable in the SFA were compared to patients with no evidence of spermatogenesis, using the c 2 test for categorical data and the MannWhitney U test for continuous variables. Variables considered for infertility risk analysis were age at HSCT, disease, type of conditioning regimen (TBI≥7.5 Gray vs. busulfan containing regimen vs. regimen without TBI and without busulfan), occurrence of acute and chronic GVHD, persistence of chronic GVHD at time of SFA, continuous treatment with immunosuppression, and time interval between HSCT and SFA. For multivariate analysis, logistical regression with 2-sided significance levels was used to assess the impact of risk factors with infertility. A backward stepwise procedure was used to eliminate non-significant variables. Since conditioning with TBI presented the strongest impact on the risk of infertility after HSCT, a multivariate analysis including and notincluding TBI as a variable was performed. Furthermore, a separate subgroup analysis was performed on patients with and without TBI. To predict infertility risk after allogeneic HSCT a score system was set up and applied to all patients. Significant variables in univariate analysis were included into the score calculation and weighted according to their impact. As a result, TBI counted for 2 points, age over 25 years at HSCT and ongoing chronic GVHD at time of SFA for 1 point each, and time interval between HSCT and SFA under eight years for 0.5 point. Patients with a score of 0 to 1.0 point were considered as low-risk, those with a score of 1.5 to 3 points as intermediate-risk, and those with a score of 3.5 points or more as high-risk for presenting infertility after allogeneic HSCT. We included in this calculation only patients where all 4 variables were available. Finally, subgroup analysis was performed on male patients for whom results on SFA before and after HSCT were available to assess the role of pre-existing spermatogenesis defects, and in those patients in which more than one SFA after allogeneic HSCT was collected, the longitudinal recovery spermatogenesis capacity was evaluated. In all statistical procedures, P&lt;0.05 was considered as the level of significance. Statistical analysis was performed using SPSS statistical software (IBM SPSS Statistics, version 19, IBM Co.). Patients&apos; characteristics From the 224 patients included in the present study, 166 (74%) had data on one SFA and 58 (26%) on two or more SFA after allogeneic HSCT. Data on SFA collected before and after HSCT were available from 17 (8%) patients. For the longitudinal subgroup analysis on 58 patients who had more than one SFA post-transplant, data of the first and last SFA collected after HSCT were compared. Characteristics of these 224 patients are presented in Results Results of seminal fluid analysis In the last SFA, presence of any degree of spermatozoa was reported in 70 (31%), and complete azoospermia in 154 (69%) patients. Among those with spermatogenesis, 22 (10%) patients had normozoospermia, 13 (6%) oligozoospermia, 28 (13%) severe oligozoospermia and 7 (3%) cryptospermia. Details on SFA, including data on sperm concentration, motility and morphology are shown in Risk factors analysis associated with azoospermia In the univariate analysis, having undergone conditioning with TBI of 7.5 Gy or over (P&lt;0.0001), ongoing chronic GVHD at time of last SFA (P=0.004), and age over 25 years at HSCT (P=0.01) were significant factors associated with azoospermia. When comparing the impact of the three main conditioning regimens on spermatogenesis, there was a clear statistical difference (P&lt;0.0001; In multivariate backward stepwise logistical regression analysis, being conditioned with TBI (RR 7.1; 95% CI: 3.4-14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09-5.2) were significantly associated with higher risk for azoospermia, whereas the presence of ongoing chronic GVHD at SFA showed a trend to remain azoospermic Risk score for azoospermia Out of 224 patients, 188 were included in the risk score analysis. The risk score for azoospermia was highly predictive: 36% (10 of 28) of the long-term survivors with a low risk score (0-1), 67% (67 of 100) of the long-term survivors with an intermediate score (1.5-3), and 92% (55 of 60) of the long-term survivors with a high risk score (3.5-4.5) had azoospermia after allogeneic HSCT (P=0.0001) Longitudinal sperm recovery analysis Data from 58 patients were available for a longitudinal analysis of the sperm recovery. The median time interval between HSCT and first or last SFA was 49 months (range 1-269), and 87 months (range 28-275), respectively. The median time interval between first and last SFA was 24 months (range 1.5-140 months). At first SFA, 7 patients (12%) were normozoospermic, one (2%) was oligozoospermic, 4 (7%) severely oligozoospermic, 3 (5%) cryptospermic, and 43 (74%) azoospermic. At last SFA, 9 (15%) were normozoospermic, 3 (5%) oligozoospermic, 6 (10%) severely oligozoospermic, 4 (7%) cryptospermic, and 36 (62%) azoospermic (P&gt;0.0001). In 12 (21%) out of 58 patients, there was an increase in sperm counts. We compared Ongoing GVHD is a risk factor for azoospermia after HSCT haematologica | 2013; 98 Analysis of patients with sperm analysis before and after HSCT In 28 patients, seminal fluid had been collected before HSCT and was available for the analysis. Sperm could be detected in 27 (96%): 20 (71%) of them presented normozoospermia, 4 (14%) oligozoospermia, 3 (11%) severe oligozoospermia, and one (4%) azoospermia. All patients with decreased sperm counts in the pre-transplant SFA had malignant disease (AML n=3; CML n=2; lymphoma n=2; MDS/MPN n=1), and most of them were heavily pretreated. Data from 17 of these 28 patients were also available post-transplant. After HSCT, 14 of 17 patients (82%) had azoospermia (10 of them conditioned with TBI), one oligozoospermia and 2 severe oligozoospermia. Paternity After HSCT, 29 of 211 (14%) patients with a median age at HSCT of 21 (2-55) years, became fathers (total number of children 44). The time interval between HSCT and the birth of the first child was a median of 7.2 (1-21.6) years. Among the patients who fathered a child after HSCT, 11 fathered naturally, and 11 were assisted conceptions (cryopreserved sperms); there is no information on conception for 7 patients. Among the 11 patients who fathered a child naturally, none was in the group of high-risk score. A. Rovó et al. 342 haematologica | 2013; 98(3) Discussion To our knowledge, this is the largest cohort of male patients in which spermatogenesis has been evaluated following allogeneic HSCT. In this study, one-third of all patients had some degree of spermatogenesis post-transplant, and 10% of patients had a normal sperm count. As previously reported, Patients transplanted with a busulfan containing conditioning regimen have some degree of spermatogenesis post-transplant, as well as a real chance to become father of a child. To accurately interpret the impact of treatment on posttransplant infertility, we need to know the degree of gonadal dysfunction before HSCT. Decreased sperm concentration before HSCT can be due to the underlying disease itself. Indeed, oligozoospermia has been reported in 25% of patients with Hodgkin&apos;s lymphoma and in 57% of patients with leukemia before starting any treatment. 20 Decreased sperm concentration can also be the consequence of treatment-induced gonadal dysfunction before HSCT. This high proportion of normozoospermic patients observed here before transplantation could be an overestimation. Indeed, sperm concentration does not decrease immediately after cytotoxic treatment. During the first 1-2 months sperm counts may remain normal and then diminish later during treatment. After radiation with a dose between 0.35 and 0.5 Gy, the nadir of sperm count occurs after 4-6 months only. Spermatogenic stem cells are more sensitive to chemotherapy and radiation, while later stage germ cells continue to mature after chemotherapy and radiation therapy. Therefore, recovery of spermatogenesis depends on the degree of destruction of the early sperm stem cells. 26 There are few data on longitudinal recovery of fertility Ongoing GVHD is a risk factor for azoospermia after HSCT 28 This is not surprising, since patients with aplastic anemia do not require chemotherapy before HSCT, and are usually conditioned with a reduced intensity regimen. In a subgroup analysis, we show that sperm recovery is possible, and is more likely the longer the time interval between HSCT and SFA. With a new scoring system, based on the four predictors for decreased sperm production, which are TBI, age over 25 years old at HSCT, ongoing chronic GVHD, and time interval between HSCT and SFA under eight years, we were able to detect long-term survivors with a probability of more than 90% of being azoospermic. This risk score does not replace the SFA for fertility assessment after HSCT, but can be used as a tool for patient counseling. The findings of this study have direct repercussions on long-term male survivors and their respective partners. These results may also support health care providers in counseling patients before and after HSCT. Because of the high probability of infertility after HSCT, fertility preservation by cryopreservation of spermatozoa early during the course of the disease before HSCT has to be advised. Our study has some limitations. First, this is a retrospective analysis with SFA performed at different centers, at different time points after HSCT, and for various reasons. The centers reported only on patients for whom an SFA had been performed. We have data on hormonal status such as FSH 10,31,32 LH and testosterone levels, but not on inhibin B, a parameter that seems to be more closely related to sperm activity. Acknowledgments Appendix of EBMT participating centers (CIC, country, city, investigator/s, number of patients) 169, Turkey, Ankara, Gülsan Sucak, 15; 202, Switzerland, Basel, Alicia Rovó, 39; 205, United Kingdom, London (Imperial College), Nina Salooja, Authorship and Disclosure

Role of Physical Therapy before and after Hematopoietic Stem Cell Transplantation: White Paper Report.

Hematopoietic stem cell transplantation (HSCT) patients can suffer from various musculoskeletal problems resulting in long-term functional incapacity. Physical therapy (PT), as a part of the healthcare team, has been historically advocated for regaining functional capacity and improving quality of life post-HSCT. Because of the nature of this condition and the burden of post-transplant complications, this patient group requires a unique approach toward their rehabilitation that takes into account their complex musculoskeletal presentation ranging from fascia, muscle, tendons, bones, and ligaments. However, to our knowledge there is no universal standardized PT protocol or pathway to help guide rehab specialists to achieve optimal gains for this patient group, and anecdotal evidence suggests that these patients do not always receive the PT care they require. Hence, in collaboration with the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation, the Survivorship Special Interest Group of the American Society of Blood and Marrow Transplantation, and the Quality of Life Committee of the Eastern Mediterranean Blood and Marrow Transplantation, herein the Physical Therapy Association for Graft Versus Host Disease provides a brief review on role of PT in mitigating musculoskeletal complications in HSCT patients and makes evidence-based recommendations for incorporation of PT into routine HSCT care.status: publishe