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Allogeneic stem cell transplant recipients surviving at least 2 years without relapse: outcome and risk factors
Grønvold, B. L., Ali, M. M., Myklebust, TÅ, Lenartova, A., Remberger, M., Abrahamsen, I. W., Tjønnfjord, G. E., Myhre, A. E., Fløisand, Y., Gedde-Dahl, T.
EJHaem. 2024;5(1):117-124
Abstract
Outcomes of 2-year survivours undergoing allo-haematopoietic stem cell transplantation at Oslo University Hospital were retrospectively assessed with the objectives of identification of risk factors for late death as possible means for precautionary measures and interventions to improve long-term survival. 421 patients with haematological malignancy, transplanted between 2005 and 2019, alive and free of disease after 2 years were included with data reported from The OUS-HSCT registry. Median follow-up was 6.2 years (2.016.1), and 232 patients (55%) were observed for minimum 5 years. The probability of being alive 5 and 10 years after HSCT was 86% and 76%. Primary risk factors for late death included initial diagnosis of age ≥ 60 years, chronic lymphocytic leukaemia (CLL), previous blood stream- or invasive fungal infection (BSI, IFI), and chronic graft-versus-host disease (cGVHD). Transplant-related mortality (TRM) and relapse at 5 years were 9.0% and 7.7%, respectively. Two factors were associated with the latter: cytomegalovirus (CMV) seronegative donor and CLL. Compared with the age- and gender-matched Norwegian general population, life expectancy was lower for each disease, except for CML. The prospect for the long-term survival is good for 2-year survivors of the allogeneic hematopoietic stem cell transplantation. However, life expectancy remains inferior to the age- and gender-matched general population. Optimising prophylaxis and treatment for chronic GVHD, BSI and IFI are needed along with the improved adherence to guidelines for early detection of secondary malignancies. Measures to improve immune reconstitution, possibly the microbiota, and the use of CMV seropositive donors regardless of recipient sero-status may be warranted and should be addressed in further studies.
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2.
Cardiovascular Risk Stratification of Patients Undergoing Hematopoietic Stem Cell Transplantation: The CARE-BMT Risk Score
Vasbinder, A., Catalan, T., Anderson, E., Chu, C., Kotzin, M., Murphy, D., Cheplowitz, H., Diaz, K. M., Bitterman, B., Pizzo, I., et al
Journal of the American Heart Association. 2024;13(1):e033599
Abstract
BACKGROUND Evidence guiding the pre-hematopoietic stem cell transplantation (HSCT) cardiovascular evaluation is limited. We sought to derive and validate a pre-HSCT score for the cardiovascular risk stratification of HSCT candidates. METHODS AND RESULTS We leveraged the CARE-BMT (Cardiovascular Registry in Bone Marrow Transplantation) study, a contemporary multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019 (N=2435; mean age at transplant of 55 years; 4.9% Black). We identified the subset of variables most predictive of post-HSCT cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, heart failure, stroke, atrial fibrillation or flutter, and sustained ventricular tachycardia. We then developed a point-based risk score using the hazard ratios obtained from Cox proportional hazards modeling. The score was externally validated in a separate cohort of 919 HSCT recipients (mean age at transplant 54 years; 20.4% Black). The risk score included age, transplant type, race, coronary artery disease, heart failure, peripheral artery disease, creatinine, triglycerides, and prior anthracycline dose. Risk scores were grouped as low-, intermediate-, and high-risk, with the 5-year cumulative incidence of cardiovascular events being 4.0%, 10.3%, and 22.4%, respectively. The area under the receiver operating curves for predicting cardiovascular events at 100 days, 5 and 10 years post-HSCT were 0.65 (95% CI, 0.59-0.70), 0.73 (95% CI, 0.69-0.76), and 0.76 (95% CI, 0.69-0.81), respectively. The model performed equally well in autologous and allogeneic recipients, as well as in the validation cohort. CONCLUSIONS The CARE-BMT risk score is easy to calculate and could help guide referrals of high-risk HSCT recipients to cardiovascular specialists before transplant and guide long-term monitoring.
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Impact of Second Primary Malignancy Post-Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis
Ragon, B. K., Shah, M. V., D'Souza, A., Estrada-Merly, N., Gowda, L., George, G., DeLima, M., Hashmi, S., Kharfan-Dabaja, M. A., Majhail, N. S., et al
Blood advances. 2023
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Editor's Choice
Abstract
The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials employing auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in MM patients following auto-HSCT using CIBMTR registry data. Adult MM patients who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n=3,948). At a median follow up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (HR 2.62, P<.001 and HR 5.01, P<.001, respectively) and OS (HR 3.85, P<.001 and HR 8.13, P<.001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% versus 30% and 53% versus 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in MM patients and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.
PICO Summary
Population
Drawn from the CIBMTR registry, adults with multiple myeloma (MM) who underwent first auto-HSCT with melphalan conditioning regimen and received maintenance therapy (n=3,948)
Intervention
Identification of second primary malignancies (SPM) or second haematological malignancies (SHM) following HSCT.
Comparison
None
Outcome
At a median follow up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (HR 2.62 and HR 5.01 respectively) and OS (HR 3.85, and HR 8.13, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% versus 30% and 53% versus 18%, respectively).
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Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC
Kaphan, E., Bettega, F., Forcade, E., Labussière-Wallet, H., Fegueux, N., Robin, M., De Latour, R. P., Huynh, A., Lapierre, L., Berceanu, A., et al
Transplantation and cellular therapy. 2023
Abstract
Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010 and December 31, 2016, considering data from the French national retrospective register ProMISe (SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy)). We included patients presenting LR, defined as a relapse occurring at least two years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, 7,582 AHSCT were performed in 29 centers and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered as LR, representing an incidence of 4.2% from the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia, and 40 (13.8%) with acute lymphoid leukemia. Median delay from AHSCT to LR was 38.2 months (29.2-49.7) and 27.2% of patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (5.6-46.4). The most common salvage therapy was induction regimen (55.5%), with complete remission being obtained for 50.7%. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (7.1-49.1). Non-relapse mortality after second AHSCT was 18.2%. We identified in the Cox model some of the associated factors with delay of LR: the disease status not in first complete remission at first HSCT (odds ratio (OR) 1.31, 1.04-1.64, p=0.02) and the use of post-transplant cyclophosphamide (OR 2.23, 1.21-4.14, p=0.01). Chronic GVHD appeared to be a protective factor (OR 0.64, 0.42-0.96, p=0.04). Prognosis of LR is better than early relapses, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity.
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A pilot study of donor-engrafted clonal hematopoiesis evolution and clinical outcomes in allogeneic hematopoietic cell transplant recipients using a national registry
Gillis, N., Padron, E., Wang, T., Chen, K., DeVos, J. D., Spellman, S. R., Lee, S. J., Kitko, C. L., MacMillan, M. L., West, J., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Improved treatment options, such as reduced-intensity conditioning, enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. OBJECTIVE We aimed to determine the prevalence of CH in older HLA-matched sibling donors pre-transplant and to assess the clinical impact of donor-engrafted CH on HCT outcomes. STUDY DESIGN This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (#1202) were included. Older donors and patients (both ≥ 55 yrs) receiving first reduced-intensity HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute GVHD (aGVHD), chronic graft-versus-host disease (cGVHD), overall survival, relapse, non-relapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. RESULTS A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency ≥ 2%, there were 44 CH mutations in 13.7% (41/299) of HLA-matched sibling donors. CH mostly involved DNMT3A (27, 61.4%) and TET2 (9, 20.5%). Post-HCT samples from 13 recipients were also sequenced, of which 7 had CH+ donors. All of the donor CH mutations (7/7, 100%) were detected in recipients at day 56 or 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change 0.005, range -0.008 - 0.024). Doubling time analysis of recipient day 56 and 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in recipients with CH+ donors (37.5% vs. 25.1%); however, risk for aGVHD by donor CH status did not reach statistical significance (HR 1.35, 95% CI 0.61-3.01, p=0.47). There were no statistically significant differences in cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, incidence of cGVHD was lower in recipients with DNMT3A-CH+ donors versus donors without DNMT3A-CH (34.4% vs 57%, p=0.035). Donor cell leukemia was not reported in any donor-recipient pairs. CONCLUSION CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, reduced-intensity conditioning, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential of differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.
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Risk of Secondary Malignancies in Hematopoietic Stem Cell Transplantation recipients: A nationwide population-Based Study in Taiwan
Liu, H. L., Chen, Y. H., Chung, C. H., Wu, G. J., Tsao, C. H., Sun, C. A., Chien, W. C., Hung, C. T.
Balkan medical journal. 2023
Abstract
BACKGROUND The improvement of survival after hematopoietic stem cell transplantation has brought about a need to evaluate long-term complications, for instance, secondary malignancies. The risk of subsequent malignancies after hematopoietic stem cell transplantation must be clarified in a large population. AIMS To estimate the risk of secondary malignancies in hematopoietic stem cell transplantation survivors and compare it with the risk in patients without hematopoietic stem cell transplantation history. STUDY DESIGN We conducted a population-based retrospective cohort study of 3,059 hematopoietic stem cell transplantation recipients from the National Health Insurance Research Database of Taiwan, containing 1,378 autologous, 1,641 allogeneic, and 40 cord blood stem cell transplantation recipients between 2000 and 2013. A control group of 12,236 patients without an hematopoietic stem cell transplantation history was identified. METHODS The covariates included age, sex, comorbidities, stem cell source, facility level of care, and history of total body irradiation. Comorbidities were estimated by the revised Charlson comorbidity index, and a higher score suggested more severe comorbidity. Adjusted hazard ratios were determined by adjusting for age, sex, comorbidity, and facility level of care. RESULTS Overall, hematopoietic stem cell transplantation recipients had a higher risk of secondary malignancies with an adjusted hazard ratios of 1.348 (p = 0.017). Being male and female (adjusted hazard ratios 1.395, p = 0.009 and adjusted hazard ratios 1.291, p = 0.042, respectively) and pre-hematopoietic stem cell transplantation total body irradiation (adjusted hazard ratios 1.591, p < 0.001) were correlated with a high risk of secondary malignancies. Among the subsequent neoplasms, bone cancer showed the highest risk (adjusted hazard ratios 27.899, p < 0.001), followed by laryngeal (adjusted hazard ratios 6.643, p < 0.001), kidney (adjusted hazard ratios 5.580, p < 0.001), esophageal, pancreatic, thyroid (adjusted hazard ratios 1.993, p < 0.001), and skin (adjusted hazard ratios 1.992, p < 0.001) cancers. The median follow-up duration was 2.16 years in the hematopoietic stem cell transplantation group and 2.57 years in the control group, and the overall median follow-up duration was 2.21 years. CONCLUSION Medical practitioners should be aware of the high risk of secondary malignancies in hematopoietic stem cell transplantation recipients later in life. These recipients should be informed about the importance of regular follow-up and photoprotective measures. Lifelong surveillance is recommended.
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Clinical characteristics of late-onset interstitial pneumonia after allogeneic hematopoietic stem cell transplantation
Fujii, N., Onizuka, M., Fukuda, T., Ikegame, K., Kawakita, T., Nakamae, H., Kobayashi, T., Kataoka, K., Tanaka, M., Kondo, T., et al
International journal of hematology. 2023
Abstract
Non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT) remain fatal. In particular, information regarding late-onset interstitial lung disease predominantly including organizing pneumonia and interstitial pneumonia (IP) is limited. A retrospective nationwide survey was conducted using data collected from the Japanese transplant outcome registry database from 2005 to 2010. This study focused on patients (n = 73) with IP diagnosed after day 90 post-HSCT. A total of 69 (94.5%) patients were treated with systemic steroids, and 34 (46.6%) experienced improvement. The presence of chronic graft-versus-host disease at the onset of IP was significantly associated with non-improvement of symptoms (odds ratio [OR] 0.35). At the time of last follow-up (median, 1471 days), 26 patients were alive. Of the 47 deaths, 32 (68%) were due to IP. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates were 38.8% and 51.8%, respectively. In the multivariate analysis, the predictive factors for OS were comorbidities at IP onset (hazard ratio [HR]: 2.19) and performance status (PS) score of 2-4 (HR 2.77). Furthermore, cytomegalovirus reactivation requiring early intervention (HR 2.04), PS score of 2-4 (HR 2.63), and comorbidities at IP onset (HR 2.90) were also significantly associated with increased risk of NRM.
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Second primary malignancies in patients with lymphoma in Denmark after high-dose chemotherapy and autologous haematopoietic stem-cell transplantation: a population-based, retrospective cohort study
Trab, T., Baech, J., Jakobsen, L. H., Husby, S., Severinsen, M. T., Eloranta, S., Gørløv, J. S., Jørgensen, J. M., Gudbrandsdottir, S., Larsen, T. S., et al
The Lancet. Haematology. 2023
Abstract
BACKGROUND Second primary malignancies (SPMs) are known complications after chemotherapy, but the risk is not well characterised for patients with lymphoma treated with high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the rate of SPMs in this population relative to matched control individuals from the general population. METHODS In this retrospective, population-based cohort study, patients aged 18 years or older with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT in Denmark between Jan 1, 2001, and Dec 31, 2017, were included from the Danish Lymphoma Registry and matched (1:5) to control individuals from the general population on birth year and sex via the Danish Civil Registration System. Patients were eligible if they had a registered date of autologous HSCT and patients with primary CNS lymphoma were excluded. Exclusion criteria for both patients and matched control individuals were HIV infection, organ transplantation, or other malignancies before inclusion. The key endpoint was the incidence of SPMs assessed in all study participants. The effect of treatment on SPMs was also investigated in patients who were followed up from first lymphoma diagnosis, with high-dose chemotherapy and autologous HSCT as a time-dependent exposure. FINDINGS Of 910 patients with lymphoma assessed, 803 were included (537 [67%] were male and 266 [33%] were female); 4015 matched control individuals were included (2685 [67%] were male and 1330 [33%] were female). Ethnicity data were not available. Median follow-up was 7·76 years (IQR 4·77-11·73). The SPM rate was higher among patients receiving high-dose chemotherapy and autologous HSCT than matched control individuals (adjusted hazard ratio [HR] 2·35, 95% CI 1·93-2·87, p<0·0001). Patients receiving high-dose chemotherapy and autologous HSCT had a higher rate of non-melanoma skin cancer (2·94, 2·10-4·11, p<0·0001) and of myelodysplastic syndrome or acute myeloid leukaemia (AML; 41·13, 15·77-107·30, p<0·0001) than matched control individuals, but there was no significant difference in the rate of solid tumours (1·21, 0·89-1·64, p=0·24). The cumulative risk of SPMs at 10 years was 20% (95% CI 17-23) in patients compared with 14% (13-15) in matched control individuals. High-dose chemotherapy and autologous HSCT was associated with an increased risk of SPMs when analysed as a time-dependent exposure from first lymphoma diagnosis (adjusted HR 1·58, 95% CI 1·14-2·17, p=0·0054). INTERPRETATION High-dose chemotherapy and autologous HSCT was associated with an increased risk of non-melanoma skin cancer and myelodysplastic syndrome or AML but not with increased risk of solid tumours in patients treated for lymphoma. These findings are relevant for future individualised risk-benefit assessments when choosing between high-dose chemotherapy and autologous HSCT and chimeric antigen receptor T-cell therapy in this setting. FUNDING Danish Cancer Society.
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9.
Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis
Blue, B. J., Brazauskas, R., Chen, K., Patel, J., Hashmi, S., Lehmann, L., Bhatt, N., Wood, W., Saber, W., Majhail, N.
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Racial/ethnic minorities have demonstrated a worse survival after allogeneic hematopoietic cell transplantation (HCT) compared to Whites. Whether the racial disparity in HCT outcomes persists in long-term survivors, and possibly may even be exacerbated in this population that frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study we compared long-term outcomes among one-year allogeneic HCT survivors by race/ethnicity and socioeconomic status (SES). METHODS The Center for International Blood and Marrow Transplant (CIBMTR) database was used to identify 5,473 patients with acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or myelodysplastic syndromes who received first allogeneic HCT between 2007-2017 and were alive and in remission for at least 1 year after transplantation. Study was restricted to patients transplanted in the United States. SES was defined using patient neighborhood poverty level estimated from the recipient's ZIP code of residence; a ZIP code with ≥20% of persons below the federal poverty level was considered a high poverty area. The primary outcome was to evaluate the association of race/ethnicity and neighborhood poverty level with overall survival (OS), relapse, and non-relapse mortality (NRM). Cox regression models were used to determine associations of ethnicity/race and SES with (OS), relapse, and (NRM). Standardized mortality ratios (SMR) were calculated to compare mortality rates of the study patients to their general population peers matched on race/ethnicity, age and sex. RESULTS Patients were reported to be Non-Hispanic White (n=4,385), Non-Hispanic Black (n=338), Hispanic (n=516), and Asian (n=234). Overall, 729 (13%) patients resided in areas with high poverty level. We found that a significantly larger proportion of non-Hispanic Black (37%) and Hispanic (26%) patients lived in areas with higher poverty levels compared to Non-Hispanic Whites (10%) and Asians (10%) (p<0.01). In multivariable analysis, we observed no significant association between OS, PFS, relapse, or NRM and race/ethnicity or poverty level when adjusted for patient-, disease- and transplant-related covariates. CONCLUSIONS Our retrospective cohort registry study highlights that among adult allogeneic HCT recipients who survived at least 1-year in remission, there was no observed association between race/ethnicity, neighborhood poverty level, and long-term outcomes.
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10.
Primary Cancer Matters in Therapy-related Myeloid Neoplasm Patients Receiving Allogeneic Hematopoietic Cell Transplantation: A Study From the Chronic Malignancies Working Party of the EBMT
Robin, M., de Wreede, L. C., Schroeder, T., Stölzel, F., Kröger, N., Koster, L., Platzbecker, U., Finke, J., Ganser, A., Blaise, D., et al
HemaSphere. 2023;7(4):e851