Autologous Blood Or Marrow Transplantation Research Articles

Late morbidity and mortality after autologous blood or marrow transplantation for lymphoma in children, adolescents and young adults—a BMTSS report

We determined the risk of late morbidity and mortality after autologous blood or marrow transplantation (BMT) for lymphoma performed before age 40. The cohort included autologous BMT recipients who had survived ≥2 years after transplantation (N = 583 [HL = 59.9%; NHL = 40.1%]) and a comparison cohort (N = 1070). Participants self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Logistic regression estimated the odds of grade 3–4 conditions in survivors vs. comparison subjects. Proportional subdistribution hazards models identified predictors of grade 3–5 conditions among BMT recipients. Median age at BMT was 30.0 years (range: 2.0–40.0) and median follow-up was 9.8 years (2.0–32.1). Survivors were at a 3-fold higher adjusted odds for grade 3–4 conditions (95% CI = 2.3–4.1) vs. comparison subjects. Factors associated with grade 3–5 conditions among BMT recipients included age at BMT (>30 years: adjusted hazard ratio [aHR] = 2.31; 95% CI = 1.27–4.19; reference: ≤21 years), pre-BMT radiation (aHR = 1.52; 95% CI = 1.13–2.03; reference: non-irradiated), and year of BMT (≥2000: aHR = 0.54; 95% CI = 0.34–0.85; reference: <1990). The 25 years cumulative incidence of relapse-related and non-relapse-related mortality was 18.2% and 25.9%, respectively. The high risk for late morbidity and mortality after autologous BMT for lymphoma performed at age <40 calls for long-term anticipatory risk-based follow-up.

Health care utilization by long-term survivors of blood or marrow transplantation-A Bone Marrow Transplant Survivor Study report.

Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long-term BMT survivors were evaluated. Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT-related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%-53% had undergone routine checkups, 37%-38% reported BMT-related visits, and 28%-29% reported transplant/cancer center visits. The presence of severe/life-threatening conditions and chronic graft-vs-host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. This study identified vulnerable populations of long-term BMT survivors who would benefit from specialized risk-based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations.

Late Morbidity and Mortality after Autologous Blood or Marrow Transplantation (BMT) for Lymphoma in Children, Adolescents and Young Adults - a Report from the BMT Survivor Study (BMTSS)

Introduction: Autologous BMT is an integral part of consolidation and/or salvage therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, there is paucity of information regarding the long-term outcome after autologous BMT for lymphoma performed in this age group. We address this gap by leveraging the BMTSS to determine the magnitude of risk of chronic health conditions as well as cause-specific late mortality in patients undergoing autologous BMT for lymphoma between 1980 and 2014 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, patients had to have received a single or tandem autologous BMT before age 40y and survived ≥2y after transplantation. BMT recipients (n=583 [HL: 59.7%; NHL: 40.3%]) and a sibling comparison group (n=330) completed a 255-item survey, and self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Vital status and cause of death information was ascertained using the National Death Index (NDI), medical records and Accurint databases. Logistic regression estimated the odds of grade 3-4 conditions in BMT recipients alive at study participation compared to siblings. Fine-Gray regression estimated the hazard of grades 3-5 chronic health conditions among BMT recipients (alive and deceased), treating death as a competing risk. Results: Median age at BMT was 30.0y (range: 2.0-39.0); median length of follow-up was 9.6y (2.0-32.1) and median age at study participation was 41.1y (13.7-67.1). Severe/life-threatening chronic health conditions in BMT survivors compared with siblings: By age 45y, the cumulative incidence of a grade 3-4 chronic health condition was 31.2% (95%CI; 25.5-37.0) among the BMT survivors and 12.9% (95%CI; 8.8-17.7) among the siblings (p<0.0001) (Figure 1). BMT survivors were at a 3.2-fold greater odds of a grade 3-4 condition (aOR=3.2, 95%CI=2.2-4.8) compared to siblings. Greater odds were observed among BMT survivors vs. siblings for the following conditions: joint replacement (OR=4.9, 95%CI=1.7-13.7), cataract (OR=4.2; 95%CI=1.4-13.0), cardiovascular disease (OR=2.2, 95%CI=1.2-4.0), and multiple conditions (OR=4.9; 95%CI=2.6-9.5). Severe/life-threatening/fatal chronic health conditions among BMT recipients: The 20y cumulative incidence of grade 3-5 conditions for the entire cohort was 46.8% (95%CI=41.6-51.7%). The 20y cumulative incidence was 42.1% (95%CI=34.2-49.7%) for patients with NHL and 49.6% (95%CI=42.9-56.0%) for patients with HL, placing HL patients at a 1.4-fold higher adjusted hazard of grade 3-5 conditions (95%CI=1.0-1.8, p=0.0232). Late mortality in BMT survivors: Conditional on surviving the first 2y after BMT, the all-cause mortality rate was 54.3% (95%CI=48.8-59.4%) at 25y from BMT (HL: 62.6%; NHL: 42.3%). The adjusted hazards of all-cause mortality were higher in HL patients (HR=1.8, 95%CI, 1.3-2.4; reference: NHL), and among Black patients (HR=3.0, 95%CI, 1.9-4.6; reference: non-Hispanic white). Causes of death were available for 84% of the cohort, and included primary disease (35%), subsequent neoplasm (16%), infection (13%), cardiac disease (8%), pulmonary disease (3%), and homicide/suicide/accident (3%). As shown in Figure 2, relapse-related mortality (RRM) plateaued after 20y from BMT, whereas the non-relapse-related mortality (NRM) continued to climb, crossing RRM at 20y from BMT. The 25y cumulative incidence of RRM was 28% (95%CI=22-34%), while that for NRM was 37% (95%CI=31-44%). Patients with HL were at increased risk for RRM (HR=2.3, 95%CI=1.3-3.8, p=0.0029; reference: NHL). The hazard of NRM was greater among HL patients (HR=1.7, 95%CI=1.1-2.7), and Black patients (HR=3.1, 1.5-6.4; reference: non-Hispanic white). Conclusions: The burden of severe/life-threatening chronic health conditions was 3-fold higher in autologous BMT recipients for lymphoma when compared with a non-BMT sibling comparison group. Patients with HL were at increased risk of a severe/life-threatening/fatal conditions as well as late mortality, when compared to patients with NHL. Finally, Black patients were at a higher risk for non-relapse-related mortality. These findings suggest a need for long-term surveillance among the vulnerable sub-populations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trends in Late Mortality and Life Expectancy After Autologous Blood or Marrow Transplantation Over Three Decades: A BMTSS Report.

We determined trends in life expectancy and cause-specific late mortality after autologous blood or marrow transplantation (BMT) performed over a 30-year period, using the BMT Survivor Study. We constructed a cohort of 4,702 individuals with hematologic neoplasms who lived ≥ 2 years after autologous BMT performed between 1981 and 2014 at three transplant centers. The end of follow-up was April 19, 2021. The primary exposure variable was autologous BMT performed in four eras: 1981-1999; 2000-2005; 2006-2010; and 2011-2014. Vital status and cause of death were obtained from National Death Index Plus program and Accurinct databases. The median age at BMT was 53 years (range, 0-78 years), 58.7% were male, 67.8% were non-Hispanic White, and 28.3% had undergone transplantation between 2011 and 2014. Autologous BMT recipients experienced a 7-year reduction in life expectancy. The adjusted hazard of 5-year all-cause mortality declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005 = 0.77; 95% CI, 0.62 to 0.94; HR2006-2010 = 0.64; 95% CI, 0.51 to 0.79; HR2011-2014 = 0.56; 95% CI, 0.45 to 0.71; Ptrend < .001), as did years of life lost (5.0 years to 1.6 years). The reduction in all-cause mortality was most pronounced among those transplanted for Hodgkin lymphoma or plasma cell dyscrasias, but was not observed among those transplanted for non-Hodgkin lymphoma or those conditioned with total-body irradiation. We also observed a decline in late deaths because of infection (Ptrend < .0001; primarily for BMTs before 2006) and subsequent neoplasms (Ptrend = .03; confined to decline in therapy-related myeloid neoplasm-related mortality) but not because of cardiovascular or renal disease. Late mortality among autologous BMT recipients has declined over a 30-year period. However, ongoing efforts are needed to mitigate development of infections, subsequent neoplasms, and cardiovascular and renal disease to further reduce late mortality.

Conditioning intensity and probability of live birth after blood or marrow transplantation, a BMTSS report

AbstractWe examine the impact of conditioning intensity (low intensity: nonmyeloablative/reduced intensity vs high intensity: myeloablative) and total body irradiation (TBI) on the probability of live birth after blood or marrow transplantation (BMT). Study participants were drawn from the BMT Survivor Study (BMTSS) and included 1607 transplant survivors between 1974 and 2014 at age ≤45 years, with survival ≥2 years post-BMT and age at study ≥18 years. Closest-age, same-sex biologic siblings (n = 172) were 1:1 matched with 172 survivors. Survivors and siblings self-reported information on sociodemographic, chronic health conditions, and pregnancies. Within survivor analysis: the association between the primary exposure variable (no TBI/low-intensity conditioning; 200 to 800 cGy TBI/low-intensity conditioning; no TBI/high-intensity conditioning; >800 cGy TBI/high-intensity conditioning) and the odds of no post-BMT live birth were examined using multivariable logistic regression, adjusting for clinical and demographic variables. Median age at BMT was 31 years (IQR, 0 to 45), and median length of follow-up was 14.3 years (IQR, 2.4 to 41.4); 39.3% were autologous BMT recipients, and 46.6% were female. Overall, 120 (8.7%) survivors reported post-BMT live births. Receipt of >800 cGy TBI/high-intensity conditioning (odds ratio [OR], 3.7; 95% CI, 1.9-7.0; ref: no TBI/low-intensity conditioning) was associated with higher odds of reporting no live birth post-BMT. In contrast, 200 to 800 cGy TBI/low-intensity conditioning (OR, 1.3; 95% CI, 0.5-3.3), and no TBI/high-intensity conditioning (OR, 0.9; 95% CI, 0.5-1.7) were at similar risk of reporting post-BMT live birth as no TBI/low-intensity conditioning. Comparison with biologic siblings: Using conditional logistic regression, we found that BMT survivors were more likely to report no live birth (OR, 2.0; 95% CI, 1.2-3.3) compared with siblings. These findings could inform conditioning intensity options for patients wishing to preserve fertility post-BMT.

Conditioning Intensity and Probability of Live Birth after Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: The observed inter-individual variability in the probability of live birth after BMT is due to exposure to gonadotoxic agents (including total body irradiation [TBI]), age at exposure to gonadotoxic agents, sex of the BMT recipient, and post-BMT morbidity. The last decade has seen an increase in use of non-myeloablative (NMA) conditioning to reduce the risk of early post-treatment mortality. However, the impact of TBI in the context of conditioning intensity (NMA vs. myeloablative conditioning [MAC]) on the probability of post-BMT live birth remains unknown. We addressed this gap by utilizing the BMTSS - a multi-institutional collaborative designed to understand the burden of morbidity after BMT.Methods: This study included 1,607 BMT survivors who underwent BMT between 1974 and 2014 at age ≤45, had survived ≥2y, and were ≥18y of age at study. This study also included pair-matched nearest-age, same-sex biologic siblings (≥18y of age at study) to control for genetic or environmental factors that could affect fertility. Survivors and their siblings completed the BMTSS survey. Sociodemographic characteristics (race/ethnicity, annual household income, availability of health insurance, level of education), chronic health conditions, medical assistance for fertility assistance and details about all pregnancies and their outcomes were retrieved from the BMTSS survey. Clinical characteristics were obtained from the institutional BMT databases and/or participants' medical record. Within survivor analysis: Potential risk factors for not reporting a live birth after BMT were analyzed using multivariable logistic regression. Exposure to TBI and conditioning intensity were consolidated to create four distinct exposure groups: no_TBI/NMA (least intense), TBI/NMA, no_TBI/MAC, TBI/MAC (most intense). Matched-pair comparison with biologic siblings: We matched 172 survivors with their closest-age, same-sex, biological siblings and used conditional logistic regression to determine the failure to report live birth in BMT survivors when compared with their siblings.Results: In this cohort of 1,607 survivors, 599 (37.3%) were autologous BMT recipients, and 765 (47.6%) were female. Median age at BMT was 30y, and at study participation was 45y (IQR: 18-73); median length of follow-up from BMT to study was 14.4y (IQR: 2.4-41.4). The primary indications for BMT included HL/NHL (30.6%), AML/MDS (24.3%), CML (13.4%), ALL (12.2%), and other diagnoses (13.5%). Of the 1,607 survivors, 120 (7.5%) reported one or more live births after BMT. Within survivor comparison: Multivariable analysis (Figure) revealed that receipt of TBI/MAC (OR=2.9, 95%CI: 1.5-5.8; ref: no_TBI/ NMA) was associated with an increased risk of not reporting a post-BMT live birth. Of note, TBI/NMA (OR=1.5, 95%CI, 0.5-5.0), and no_TBI/ MAC (OR=0.9, 95%CI, 0.4-2.0) were at a similar risk of reporting a post-BMT live birth as no_TBI/NMA. Other factors associated with increased risk of not reporting a post-BMT live birth included older age at BMT (>35y: OR=3.5, 95%CI, 1.4-7.9; reference: <12y), lower income ($50k-100k: OR=2.0, 95%CI, 1.1-3.6; <$50k: OR=3.2, 95%CI, 1.6-6.4; reference: >$100k), no medical interventions to facilitate pregnancy (OR=2.7, 95%CI, 1.6-4.6), and history of pre-BMT live birth (OR=2.7, 95%CI, 1.6-4.6). Matched-pair comparison with biologic siblings: Multivariable conditional logistic regression revealed that BMT survivors were less likely to report live birth (OR=0.5, 95%CI: 0.3-0.8) compared to their siblings. However, once pregnant, they were also less likely to report a miscarriage (OR=0.4. 95%CI: 0.2-0.8).Conclusion: While full dose TBI in the setting of myeloablative conditioning is associated with a lower probability of live birth after BMT, lower doses of TBI in the setting of myeloablative or reduced intensity conditioning yield a similar probability of live birth as no TBI. These findings provide evidence for alternative conditioning regimens for patients who wish to have children after BMT. [Display omitted] DisclosuresWeisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

Subsequent Malignant Neoplasms of the Gastrointestinal Tract after Blood or Marrow Transplantation - a BMTSS Report

Background and Purpose: Subsequent malignant neoplasms (SMNs) are a leading cause of non-relapse mortality after blood or marrow transplantation (BMT). Cancers of the gastrointestinal (GI) tract are of special interest since their clinical behavior is often aggressive, but early detection through screening is possible for specific GI malignancies. There is limited information regarding the risk of GI SMNs following BMT. The purpose of this study was to report the risk of GI SMNs after BMT and to identify specific exposures associated with increased risk.Materials and Methods: The BMT Survivor Study (BMTSS) is a multi-institutional retrospective cohort study of patients transplanted between 1974 and 2014, with survival ≥2y. Disease and treatment characteristics were obtained from institutional databases and medical records. GI SMNs were identified by review of the BMTSS survey or death records and confirmed by pathology report and/or medical record review. Standardized incidence ratios (SIRs) were calculated to determine excess risk of GI SMNs compared with the general population. Fine-Gray competing risks models examined the association between treatment exposures and GI SMNs.Results: Clinical/demographic characteristics of the cohort are provided in Table 1. The 6,710 BMT recipients in this cohort contributed 62,479 person-years of follow-up, yielding 148 patients with GI SMNs occurring a median of 8.9y (range, 0.3-36.6y) from BMT. The GI SMNs in the cohort included colorectal (n=45), liver (n=36), pancreatic (n=27), esophageal (n=22), gastric (n=11), and other GI (n=7) cancers. By age 70, the cumulative incidence of a GI SMN was 4.8% for allogeneic BMT recipients vs. 1.9% for autologous BMT recipients (p<0.0001, Fig 1). The SIR for a GI SMN after BMT was 1.95 for allogeneic BMT recipients vs. 1.03 for autologous BMT recipients (p=0.8). The risk of esophageal (SIR=3.19, p<0.01), liver (SIR=3.06, p<0.01) and pancreatic cancer (SIR=1.79, p<0.01) was increased when compared to the general population whereas the risk for gastric (SIR=1.15, p=0.6) and colorectal cancers (SIR=0.86, p=0.3) was not. Radiation exposure: Exposure to TBI at age <30y was associated with significantly higher risk for colorectal (SIR=2.67, p=0.003), stomach (SIR=5.16, p=0.005), and liver (SIR=11.61, p<0.001) cancers; the risks were not elevated when TBI exposure occurred at age >60 (Fig 2). The cumulative incidence of GI SMNs by age 70 was significantly higher (p<0.0001) among patients who received high-dose TBI (≥8Gy: 4.8%) vs. those who received low-dose TBI (<8Gy: 2.5%) or no TBI (2.1%) (Fig 3). High-dose TBI (and not low-dose) was associated with a 2.5-fold higher risk of colorectal cancer (95%CI=1.3-4.7). Pre-BMT abdominal radiation was associated with 9.55-fold increased risk of GI SMN (95%CI=2.5-36.5) among allogeneic BMT recipients; the association was primarily driven by pancreatic and esophageal cancer. Chemotherapeutic agents: Pre-BMT anthracyclines (HR=4.84, 95%CI=1.2-20.4) and etoposide conditioning (HR=2.87, 95%CI=1.6-5.3) were associated with an increased risk of liver cancer. Cytarabine conditioning was associated with increased risk of colorectal cancer (HR=3.08, 95%CI=1.4-6.9). Chronic GvHD: Risk of esophageal cancer was 9.6-fold higher among allogeneic BMT recipients with chronic GvHD (95%CI=3.3-28.4), when compared with those who received an autologous BMT.Conclusions: This study provides evidence that allogeneic BMT survivors are at increased risk for developing GI SMNs in the setting of specific pre-BMT and BMT-related therapeutic exposures and chronic GvHD. In particular, exposure to myeloablative doses of TBI at age <30y and conditioning with cytarabine and etoposide were associated with increased risk. In addition, pre-BMT exposure to abdominal radiation and anthracyclines were associated with specific types of GI SMNs. These findings and the very high risk of esophageal cancer among those with chronic GvHD provide a framework for developing personalized screening recommendations for those at highest risk. [Display omitted] DisclosuresMcDonald: Varian Medical Systems: Consultancy, Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Arora: Syndax: Research Funding; Pharmacyclics: Research Funding; Kadmom: Research Funding.

Association between learning and memory problems and health outcomes after blood or marrow transplantation (BMT): A BMT survivor study (BMTSS) report.

12014 Background: Cognitive impairment after BMT for hematologic malignancies typically involves processing speed, attention and working memory. Survivors perceive these deficits as learning and/or memory problems. However, limited information exists regarding learning/memory problems experienced by survivors several years after BMT. We addressed this gap using the BMTSS. Methods: BMTSS is a retrospective cohort study examining long-term outcomes of individuals who survived ≥2y after BMT performed between 1974 and 2014 at three transplant centers. Study participants completed a 255-item questionnaire covering diagnosis by a healthcare provider of health conditions (including learning/memory problems), sociodemographic characteristics, and functional status. We used a nested matched case-control study design. Cases consisted of individuals with learning/memory problems developing after BMT (n = 543). Each case was matched to a BMTSS participant without memory problems (controls: n = 543) using the following criteria: cancer diagnosis, race/ethnicity, type of BMT (allogeneic or autologous), and time from BMT. Multivariable conditional logistic regression analysis was used to identify clinical factors (age at BMT, stem cell source, chronic graft vs. host disease [cGvHD], total body irradiation [TBI], fatigue, pain) and demographic factors (household income, education, sex) associated with learning/memory problems. We also examined the association between learning/memory problems and instrumental activities of daily living (IADL). Analyses were stratified by type of BMT. Results: For all survivors (n = 1,086), mean age at BMT was 40.7y and at study participation was 53.3y (18-85); 47% of the study population was females; 78% were non-Hispanic whites; 31% reported an annual household income &lt; $50k. Primary diagnoses included leukemia (50%), lymphoma (36%), and other (14%); 55% received an allogeneic BMT (36% developed cGvHD); 54% received TBI; and 68% received peripheral blood stem cells. Allogeneic BMT survivors with fatigue (odds ratio [OR] = 2.2, 95% CI, 1.4-3.3; p = 0.001), significant pain (OR = 1.8, 95% CI, 1.1-2.9; p = 0.02) and &lt; college education (OR = 1.6, 95% CI, 1.1-2.5; p = 0.02) had higher odds of reporting learning/memory problems. Autologous BMT survivors exposed to TBI (OR = 2.8, 95% CI, 1.4-5.4; p = 0.003) and reporting significant pain (OR = 1.7, 95% CI, 1.0-2.9; p = 0.05) had higher odds of reporting learning/memory problems. Learning/memory problems were associated with increased odds of impairments in IADL in both autologous (OR = 2.1, 95% CI, 1.1-4.0; p = 0.03) and allogeneic (OR = 2.0, 95% CI, 1.2-3.3; p = 0.01) BMT survivors. Conclusions: Modifiable risk factors, such as fatigue and pain, can be targeted to mitigate the learning/memory problems and improve the functional outcomes of BMT survivors.

Incidence and Outcome of Hepatic Veno-Occlusive Disease After Blood or Marrow Transplantation: A Prospective Cohort Study of the European Group for Blood and Marrow Transplantation

AbstractTo determine the incidence and outcome of hepatic veno-occlusive disease (VOD) after blood or marrow transplantation (BMT), we prospectively evaluated all consecutive patients receiving a BMT during a 6-month period in participating EBMT centers. All of them were evaluated for occurrence of VOD according to previously defined clinical criteria. The clinical course, outcome, value of prophylactic and therapeutic interventions, and the influence of previously described risk factors were analyzed. During the study period, 1,652 BMT were performed in 73 centers. VOD was diagnosed in 87 patients (5.3%; 95% confidence interval [CI], 4.2% to 6.4%). Fifty-six of 631 allogeneic BMT (8.9%) and 31 of 1,010 autologous BMT (3.1%) developed this complication (P < .0001). VOD was classified as mild in 7 (8%), moderate in 56 (64.4%), and severe in 24 (27.6%) cases. Sixteen patients died of VOD (corresponding to 1% of the whole series, 18.4% of VOD patients, and 66.7% of severe VOD). The use of unfractionated heparin did not significantly decrease the incidence of VOD. Independent variables associated with an increased risk of VOD were allogeneic BMT (relative risk [RR], 2.8; P< .001), pre-BMT elevation of serum aspartate aminotransferase (RR, 2.4; P = .001), high-dose cytoreductive therapy (RR, 2.3;P = .003), Karnofsky performance score less than 90% (RR, 2.7; P = .006), and prior abdominal radiation (RR, 2.9;P = .03). In conclusion, this prospective study shows that (1) the incidence of VOD is lower than that reported in smaller studies from single centers, (2) about one fourth of cases of VOD progress to severe disease, (3) main risk factors have a major impact on incidence of VOD, and (4) the use of prophylactic unfractionated heparin does not seem to reduce the incidence of VOD.

Total Body Irradiation and Risk of Breast Cancer After Blood or Marrow Transplantation: A Blood or Marrow Transplantation Survivor Study Report.

To examine the association between total body irradiation (TBI) and subsequent breast cancer in women treated with blood or marrow transplantation (BMT) for hematologic malignancies. Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived for ≥ 2 years after BMT. Patients with pre-BMT chest radiation or a history of breast cancer were excluded. Participants completed the BMTSS survey, which included details regarding breast cancer diagnosis. Subsequent breast cancer was confirmed by pathology report review or physician notes. Cox proportional hazards models assessed the association between TBI and subsequent breast cancer. Standardized incidence ratios were calculated to determine the excess risk of subsequent breast cancer compared with that in the general population. A total of 1,464 female BMT survivors (allogeneic: n = 788; autologous: n = 676) participated, with a median follow-up of 9.3 years from BMT. TBI was used in 660 patients (46%). Thirty-seven women developed subsequent breast cancer (allogeneic: n = 19; autologous: n = 18). Multivariable analysis revealed that exposure to TBI was associated with an increased risk of subsequent breast cancer among allogeneic BMT survivors (hazard ratio [HR], 3.7 [95% CI, 1.2 to 11.8]; P = .03) and autologous BMT survivors (HR, 2.6 [95% CI, 1.0 to 6.8]; P = .048). Pre-BMT exposure to alkylating agents was associated with an increased risk of subsequent breast cancer among autologous BMT survivors (HR, 3.3 [95% CI, 1.0 to 9.0]; P = .05). Compared with that in the general population, exposure to TBI at age < 30 years was associated with a 4.4-fold higher risk of subsequent breast cancer in allogeneic BMT survivors and a 4.6-fold higher risk in autologous BMT survivors. The association between TBI and subsequent breast cancer, especially among those exposed at a young age, as well as pre-BMT exposure to alkylating agents, should inform breast cancer screening for early detection.

Burden of Long-Term Morbidity Borne By Survivors of Acute Myeloid Leukemia (AML) Treated with Blood or Marrow Transplantation (BMT) - a Report from the BMT Survivor Study (BMTSS)

Background: BMT is now an integral part of consolidation and/or salvage for patients with AML. With the growing population survivors, there is a need to understand the quality of survival. This would allow for appropriate resource allocation and implementation of risk-based screening for early detection of chronic health conditions over time. Yet, a comprehensive evaluation of the long-term burden of morbidity borne by AML patients treated with BMT remains unknown. We addressed this gap by evaluating long-term severe/life-threatening/fatal chronic health conditions (CHCs) in AML patients treated with BMT using the BMTSS. Methods: Patients were eligible if they had undergone an allogeneic or autologous BMT for AML between 1974 and 2014 at one of 3 BMT centers in the US, had survived for ≥2y after BMT, and were ≥21y of age at BMT. Of the 1,113 eligible subjects, 711 (64%) participated. BMT survivors identified a nearest-age sibling to constitute an unaffected comparison group (N=1,136). Survivors and siblings completed a 231-item BMTSS survey that included questions regarding CHC diagnosis by their healthcare provider, including age at onset of CHC. Scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0) to determine the severity of CHCs. Using multivariable logistic regression, we determined the risk of any severe (CTCAE grade 3) or life-threatening (CTCAE grade 4) CHC in survivors compared with siblings, adjusting for age at study, sex, race/ethnicity, education, annual household income and insurance status. Information regarding therapeutic exposures (pre-BMT and transplant-related) was abstracted from medical records. Cumulative incidence of CHCs (including fatal [CTCAE grade 5] CHCs) were calculated for BMT survivors, treating relapse-related death as a competing risk. Results: Mean age at BMT was 48.6±13.8y and at survey was 58.2±11.5y. Mean interval between BMT and study participation was 9.7±6.8y; 53% were females, and 78% were non-Hispanic white; 86% received allogeneic BMT (48% from an unrelated donor). Conditioning was Fludarabine/Melphalan-based in 53% and TBI-based in 35%; stem cell source was peripheral blood (70.3%), bone marrow (19.3%), and cord (10.4%). For the siblings, the mean age at survey was 56.9+13.4y; 61% were females, and 88% were non-Hispanic white. BMT survivors vs. sibs: 53.3% of the BMT survivors and 30.4% of the sibs reported grades 3-4 CHCs, placing the survivors at a 3.0-fold higher odds of grades 3-4 CHC (95%CI, 2.4-3.7, p&amp;lt;0.0001). The odds of developing the following CHCs were significantly higher in BMT survivors when compared with siblings: subsequent malignant neoplasms (SMNs: odds ratio [OR]=10.0, 95% CI, 5.5-17.9, p&amp;lt;0.0001), diabetes (OR=5.3, 95% CI, 3.0-9.3, p&amp;lt;0.0001), venous thromboembolism (OR=3.8, 95%CI, 2.5-5.8 p&amp;lt;0.0001), cataracts (OR=3.7; 95%CI, 2.7-5.0, p&amp;lt;0.0001), and major joint replacement (OR=1.5, 95% CI, 1.1-2.1, p=0.02). Among BMT survivors: The 10- and 20y cumulative incidence of a grade 3-5 CHC was 52.0%±1.4% and 66.2%±1.6%, respectively (Figure 1). 75 survivors had developed SMNs: skin (melanoma/ squamous cell [56%]), breast (13%), colon (7%), prostate (7%), and other cancers (24%). The 10- and 20y-cumulative incidence of the most common CHCs were as follows (Figure 2): SMN (10y: 17.9%±1.7%, 20y: 32.1%±2.9%), cataract (10y: 21.5%±1.9%, 20y: 31.5%±3.0%), major joint replacement (10y: 12.5%±0.9%, 20y: 17.5%±3.4%), venous thromboembolism (10y: 8.6%±1.1%, 20y: 13.2%±2.1%), and diabetes (10y: 6.0%±1.9%, 20y: 8.0%±1.5%). Conclusion: The burden of severe/life-threatening CHCs is substantially higher in BMT survivors when compared with an unaffected comparison group. The incidence of severe/ life-threatening/ fatal chronic health condition following BMT for AML exceeds 50% at 10y, and continues to increase with time, approaching 70% at 20y post-BMT. Subsequent malignant neoplasms, diabetes, thrombo-embolic events, cataracts, and major joint replacement constitute the largest burden of morbidity. These findings suggest the need for increased awareness of the long-term burden of morbidity, to ensure close monitoring of these survivors to anticipate and manage morbidity. Disclosures Weisdorf: Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy.

Risk of venous thromboembolism in patients with non-Hodgkin lymphoma surviving blood or marrow transplantation.

Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE), particularly when they are receiving treatment. Blood or marrow transplantation (BMT) is recommended for relapsed/refractory NHL, and the risk of VTE after these patients undergo BMT is uncertain. Patients with NHL who survived 2years or longer after BMT were surveyed for long-term health outcomes, including VTE. The median follow-up was 8.1years (interquartile range, 5.6-12.9years). The risk of VTE in 734 patients with NHL versus 897 siblings without a history of cancer and the risk factors associated with VTE were analyzed. BMT survivors of NHL were at increased risk for VTE in comparison with siblings (odds ratio for allogeneic BMT survivors, 4.61; P<.0001; odds ratio for autologous BMT survivors, 1.75; P=.035). The cumulative incidence of VTE was 6.3%±0.9% at 5years after BMT and 8.1%±1.1% at 10years after BMT. In allogeneic BMT recipients, an increased body mass index (BMI; hazard ratio [HR] for BMI of 25-30kg/m2 , 3.52; 95% confidence interval [CI], 1.43-8.64; P=.006; HR for BMI>30kg/m2 , 3.44; 95% CI, 1.15-10.23; P=.027) and a history of chronic graft-versus-host disease (HR, 3.33; 95% CI, 1.59-6.97; P=.001) were associated with an increased risk of VTE. Among autologous BMT recipients, a diagnosis of coronary artery disease (HR, 5.94; 95% CI, 1.7-20.71; P=.005) and prior treatment with carmustine (HR, 4.91; 95% CI, 1.66-14.51; P=.004) were associated with increased VTE risk. Patients with NHL who survive BMT are at risk for developing late occurring VTE, and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high-risk patients with NHL are needed.

Total body irradiation (TBI) and risk of breast subsequent malignant neoplasm (SMN) after blood or marrow transplantation (BMT): A report from the BMT survivor study (BMTSS).

11572 Background: The association between TBI and breast SMN in BMT recipients is not clearly defined. We address this limitation to develop evidence for screening guidelines for those at risk. Methods: Study participants were drawn from BMTSS – a multi-site retrospective cohort of patients who had received BMT between 1974 and 2014 and survived ≥2y post-BMT. Participants completed the BMTSS survey that included sociodemographics and health conditions. Breast SMN was confirmed by pathology report review. Clinical characteristics, pre-BMT and BMT exposures were abstracted from medical records. Using multivariable Cox proportional hazards models, freedom from breast SMN was measured from birth and TBI was treated as a time-varying covariate in analyses stratified by type of BMT (allogeneic; autologous). Results: 1546 female participants (allogeneic 808; autologous 738) received BMT at a mean age of 43.1±17.6y and were followed for 9.4±7.7y; primary diagnoses: HL/NHL (28%), AML/MDS (27%), PCD (19%), other (28%). TBI was used in 671 patients (allogeneic 57%; autologous 30%). Patients with pre-BMT chest radiation (n = 45) were excluded from the analysis. A total of 38 cases of breast SMN were identified (allogeneic 19; autologous 19). Allogeneic BMT: exposure to TBI (HR = 3.4; 95%CI 1.1-10.9, p = 0.04) and age at BMT &lt; 40y (HR = 4.0; 95%CI 1.3-12.8, p = 0.02) were associated with increased risk of breast SMN. Risk of breast SMN was higher and breast SMN developed earlier among those exposed to TBI before age 40y vs. those exposed after 40y (8.7% vs. 0% by attained age 50; 10.6% vs. 5.8% by attained age 60, p = 0.003). Autologous BMT: Age &lt; 40y was associated with a 4.8-fold higher risk (95%CI 1.1-20.1, p = 0.03) of breast SMN. TBI was associated with a 2-fold higher risk (p = 0.2). The cumulative incidence of breast SMN among those exposed to TBI at age &lt; 40y vs. age ≥40y was 5.1% vs. 2.4% by attained age 60 (p = 0.07). Conclusions: TBI is associated with breast SMN among allogeneic BMT recipients. The risk is especially high and occurs at a younger age, among those exposed at age &lt; 40y. These findings provide evidence for initiating screening at a young age after exposure to TBI.

DNA Repair Genes May Influence Cognitive Outcomes in Adult Patients with Hematologic Malignancies (HM) Treated with Blood or Marrow Transplantation (BMT)

Introduction: We recently demonstrated that cognitive impairment (CI) is prevalent and persistent in HM patients treated with BMT (Sharafeldin et al., J Clin Oncol, 2018). While the impact of genetic factors on cognition in the non-oncology realm is well-recognized, limited information exists in HM patients treated with BMT. We tested the hypothesis that genetic variants in blood-brain barrier (BBB), drug transporter, telomere homeostasis, neurotransmission, neural repair and DNA repair are associated with CI in HM patients treated with BMT. We previously presented preliminary results of the Discovery cohort (Sharafeldin et al., Blood, 2016); here we present additional analyses (at the gene level) on the Discovery cohort, and replication of salient findings in an independent Validation cohort.Methods: The Discovery cohort consisted of prospective, longitudinally-assessed patients undergoing autologous or allogeneic BMT for HM at a single center. Cognitive function was assessed objectively using a battery of standardized tests prior to BMT, and at 6mo, 1y, 2y, and 3y post-BMT; germline DNA was collected pre-BMT. Global Deficit Score (GDS) was used as an indicator of CI (GDS ≥0.5 indicated CI). We employed a candidate gene approach, relying on biologically-plausible hypotheses for gene selection. Standard quality control procedures yielded 985 SNPs in 68 genes with a total genotyping call rate of 99% in 277 BMT recipients. Generalized estimating equation models were fitted to examine association of individual SNPs with CI. Linkage disequilibrium-based pruning yielded 326 independent tests, with an overall p-value threshold of 1.53x10-4 using Bonferroni correction for multiple testing. We also conducted gene-level analysis considering each gene as a SNP-set using the machine learning approach of logic regression, with cross-validation, to identify SNP-SNP interactions at the gene-level (Bonferroni p ≤ 7.94x10-4). An independent Validation case-control set from the BMT Survivor Study was used to replicate significant findings from the Discovery cohort, using conditional logistic regression models. Cases (n=141) were BMT survivors who reported: i) presence of memory/learning problems; and ii) severity of memory/learning problems. Controls (n=258) were BMT survivors without cognitive problems, matched (1-2/case) on race/ethnicity, HM, and time from BMT.Results:Discovery: Among the 277 patients in the Discovery cohort, mean age at BMT was 50y, 59% were males, 69% were non-Hispanic whites and 47% received an allogeneic BMT. Male sex (OR=3.2, 95%CI, 1.5-6.7, p=0.002) and lower pre-BMT cognitive reserve (OR=4.6, 95%CI, 2.2-9.6, p <0.0001) were associated with CI. Risk of CI was increased in the younger patients (<50y) if they received TBI (age*TBI interaction OR=3.86, 95%CI, 1.0-15.1, p=0.05). Final genetic models were adjusted for relevant variables with significant independent main effects including BMT type, age at BMT, sex, race/ethnicity, and cognitive reserve. We identified significant associations between CI and BBB, telomere homeostasis and DNA repair SNPs using the single-SNP (Fig 1) and gene-level analyses. Replication: The mean age at BMT was 44y, 54% were males, 88% were non-Hispanic whites and 5% received an allogeneic BMT. Replication models were adjusted for age at BMT, sex, race, and education and income levels. Of the 69 SNPs identified for replication, DNA repair SNPs from the single-SNP analysis rs13006837 on XRCC5 (OR=5.8, 95%CI, 2.7-12.3, p=2.0 x 10-5) and rs293796 on OGG1 gene (OR=11.4, 95%CI, 4.6-28.5, p-value=1.08 x 10-6) were successfully replicated. Five SNPs on DNA repair genes from the gene-level analysis showed individual statistically-significant associations in the Validation cohort: rs238417 on ERCC2 (OR=0.48, 95%CI, 0.25-0.91, p=0.03); rs2526698 on EXO1 (OR=0.57, 95%CI: 0.33-0.98, p=0·04); rs3793906 on MGMT (OR=1.96, 95%CI: 1.2-3.3, p=0.01); rs4725016 on RPA3 (OR=0.20, 95%CI, 0.05-0.92, p=0.04); and rs1479569 on XRCC4 (OR=2.3, 95%CI, 1.3-4.1, p=0.005).Conclusion: Our study provides genetic characterization of adult HM patients at increased risk of cognitive impairment following BMT; associations with DNA repair variants were independently replicated. These findings could have implications towards the personalized management of patients undergoing BMT. DisclosuresForman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Chronic Severe Pain and Use of Prescription Pain Medications in Older Survivors of Hematologic Malignancies (HM) Several Years after Treatment with Blood or Marrow Transplantation (BMT): A Report from BMTSS

Background: BMT is increasingly offered to older patients with HM. The high burden of comorbidity in older BMT survivors places them at a higher risk for chronic severe pain - an issue that has not been comprehensively evaluated. We used BMTSS to investigate the prevalence and predictors of chronic severe pain several years after BMT. We examined the impact of pain on physical performance and frailty and also examined the relation between chronic severe pain and use of prescription pain medications and opioids in this population.Methods: The cohort included 601 HM patients who had received a BMT at age ≥60y at one of 3 transplant centers between 1974 and 2014 and had survived ≥2y after BMT; 183 unaffected siblings also participated. Self-reported domains included sociodemographics, chronic GvHD, physical performance, frailty, and medication use. Clinical information obtained from institutional databases included primary HM diagnosis, donor source, and conditioning regimen. Study participants completed a detailed questionnaire that examined pain in the following 3 domains: moderate-to-severe bodily pain, prolonged pain, and moderate-to-extreme pain interference; these 3 domains were used to create a composite variable, wherein presence of ≥1 domain was indicative of “chronic severe pain”. An adjusted multivariable logistic regression model for chronic severe pain was used to compare BMT survivors to siblings. Analyses restricted to BMT survivors were stratified by donor type.Results: Survey participation rates were 62.7% and 60%, for the BMT survivors and siblings, respectively. Median age at study participation was 69.8y (61-89) for BMT survivors and 68.9y (65-80) for siblings. Median time from BMT was 5.0y (2-17) for BMT survivors. Chronic severe pain: Overall, 39.4% of the BMT survivors reported chronic severe pain; multivariable analysis revealed a 2.5-fold greater odds of BMT survivors reporting chronic severe pain (95%CI, 1.7-3.8, p <0.0001) when compared with siblings. Domain-specific prevalence and magnitude of risk of pain are shown in Fig 1. Among allogeneic BMT recipients, survivors with lower education (<high school: OR=5.2, 95%CI: 1.5-18.3, p=0.01; ref grp: >college) and lower income (<$50k: OR=6.0, 95%CI, 1.7-20.8, p=0.005; $50k-<$100k: OR=3.8, 95%CI, 1.3-11.4, p=0.02; ref group: ≥$100k) had higher odds of reporting chronic severe pain; presence of active chronic GvHD was associated with 2.3-fold higher odds, but did not reach statistical significance (p=0.1). Among autologous BMT recipients, lower income (<$50k: OR=2.2, 95%CI, 1.1-4.4, p=0.02) was associated with higher odds of reporting chronic severe pain. Pain and physical performance/frailty: Allogeneic and autologous BMT recipients with chronic severe pain were at a 2.7-fold (95%CI, 1.2-6.0, p=0.02) and 3.0-fold (95%CI, 1.9-4.9, p<0.0001) higher odds of reporting impaired physical performance, respectively, when compared to those without pain. Allogeneic and autologous BMT recipients with chronic severe pain were at 8.2-fold (95%CI, 2.4-27.6, p=0.0007) and 7.5-fold (95%CI, 3.3-16.8, p<0.0001) higher odds, respectively of having frailty when compared to those without pain. Use of prescription pain medications and opioids: Overall, 17.8% of BMT survivors reported using prescription pain medications, and 6.5% reported using opioids; those with chronic severe pain were at a 2.5-fold higher odds of using prescription pain meds (95%CI, 1.6-3.8, p<0.0001) and at a 6.0-fold higher odds of using opioids (95%CI, 2.8-12.9, p <0.0001), when compared with those without pain.Conclusions: Nearly 40% of older BMT survivors followed for a median of 5y after BMT, report chronic severe pain. BMT survivors are at a 2.5-fold higher odds of reporting chronic severe, life-interfering pain as compared with siblings. Chronic severe pain is associated with impaired physical performance and frailty. Finally, nearly 18% of long-term BMT survivors report use of prescription medications and 6.5% are using opioids. This study draws attention to the vulnerability of older BMT survivors and provides evidence for the need to develop effective strategies to address the underlying causes of pain. DisclosuresNo relevant conflicts of interest to declare.

Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report

AbstractAutologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P = .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades.

Optimizing the Timing of Allogeneic Blood or Marrow Transplantation (BMT) in a Prospective Cohort of Relapsed or Refractory Acute Myeloid Leukemia (AML)

Abstract 3096Relapsed or refractory AML is difficult to treat even with allogeneic BMT. In an attempt to reduce leukemia burden and limit toxicities from multiple re-induction attempts, we initiated a treatment strategy to offer allogeneic BMT prior to count recovery, within 3 to 4 weeks after re-induction. Among 156 consecutive AML patients referred to our BMT program between 01/2003 and 03/2008, 84 (54%) patients did not receive an allogeneic BMT due to: death (n=25, 30%), patient refusal (n=13, 16%), disease progression (n=13, 16%), autologous BMT (n=11, 13%) and other (n= 22, 26%). Seventy-two (46%) patients received an allogeneic BMT: 21 (29%) patients were prospectively identified with very high risk features (primary induction failure (PIF) or refractory relapse (RR)) and received re-induction with the intent-to-induce hypoplasia and transplant prior to count recovery. The remaining 51 patients received re-induction with the goal of inducing complete remission (CR) prior to BMT (the intent-to-induce remission group). Patient and BMT-related characteristics, as well as BMT outcomes are summarized in Table 1. Patients were prospectively accrued to myeloablative or reduced intensity BMT protocols depending on their age, KPS, co-morbidities, disease risk and the degree of HLA match. The intent-to-induce hypoplasia group had a lower 2-year PFS and OS (reflecting their very high risk disease characteristics). In subgroup analysis in patients with PIF or RR, there was no difference in 2-year PFS (15% vs. 22%, p=0.39) or 2-year OS (20% vs. 33%, p=0.32) between the intent-to-induce hypoplasia and the intent-to-induce remission groups. The overall and day 100 TRM was similar in both groups of patients with PIF or RR. Using this prospective strategy of identifying patients with very high risk disease with the intent to transplant them during hypoplasia after re-induction therapy, 46% of all the referred AML patients were able to undergo allogeneic BMT. This is higher than other published series where < 30% of patients proceeded to transplant where the goal of re-induction was to induce and achieve CR prior to transplant. Our data show that it is safe to transplant advanced AML patients early (within 3 to 4 weeks) after re-induction with acceptable mortality in patients with very high risk AML who otherwise might not be transplant candidates.TablePatient Characteristics and OutcomesFactorIntent-to-induce remission (N=51)Intent-to-induce hypoplasia (N=21)PN(%)N(%)Patient and Disease CharacteristicsAge at BMT18-4016 (31)4 (19)NS41-6028 (55)13 (62)61+7 (14)4 (19)KPS at BMT≥9023 (45)1 (5)<0.01≤8028 (55)20 (95)WBC at diagnosis≥30 x 109/L12 (24)9 (43)NS<30 x 109/L39 (76)12 (57)Cytogenetics at diagnosisFavorable2 (4)1 (5)NSIntermediate25 (49)14 (67)Adverse24 (47)6 (29)De novo vs. Secondary AMLDe novo39 (76)17 (81)NSSecondary12 (24)4 (19)Disease status at BMTFirst CR38 (75)0 (0)<0.01Second or greater CR4 (8)1 (5)PIF/RR9 (18)20 (95)BMT-Related CharacteristicsDonor sourceRelated24 (47)8 (38)NSUnrelated27 (53)13 (62)Stem cell typeBM±PB10 (20)1 (5)NSPB41 (80)20 (95)HLA 10/10 matchMatched46 (90)16 (76)NSMismatched5 (10)5 (24)Gender matchMatched30 (59)13 (62)NSMismatched21 (41)8 (38)Myeloablative conditioningCT±V15 (29)0 (0)<0.01BuCy5 (10)1 (5)Reduced intensity conditioningFluMel27 (53)15 (71)<0.01FluCy4 (8)5 (24)Prior BMTPrior auto BMT2 (4)3 (14)NSNo prior auto BMT49 (96)18 (86)BMT-Related Outcomes2-yr PFS53%18%<0.0012-yr OS56%23%<0.001Day 100 TRM10%33%0.03NS: not significant, P>0.1 Disclosures:Hahn:Novartis: stock.

Extended Follow-up of Autologous Bone Marrow Transplantation with 4-Hydroperoxycyclophosphamide (4-HC) Purging for Indolent or Transformed Non-Hodgkin Lymphomas

Autologous blood or marrow transplantation (ABMT) for low-grade lymphomas can prolong event-free survival (EFS) but requires long-term follow-up. We report one of the longest follow-ups to a prospective transplantation study in such diseases. On a phase II study, 80 patients with low-grade, transformed, or mantle cell lymphoma received ABMT with 4-hydroperoxycyclophosphamide (4-HC) purging as part of initial or salvage therapy. Diagnoses included nontransformed follicular lymphoma in 63% and transformed lymphoma in 15%. With 16.6-year median follow-up for survival, actuarial 10-year EFS and overall survival (OS) were 34% (95% confidence interval [CI], 25%-46%) and 45% (35%-57%). Median EFS and OS were 3.0 and 8.0 years. Early nonrelapse mortality incidence was 8%; myelodysplastic syndrome or leukemia incidence was 4%. Most relapses occurred within 3 years, with a median time to diagnosis of relapse of 1.8 years (range: 0.1-15.6 years). On multivariate analysis, age >50 years, ≥3 prior chemotherapy regimens, and ABMT after relapse were associated with significantly inferior survival. Fifteen patients (19%) were event-free >15 years after transplantation, raising the possibility of a plateau in the progression-free survival curve. Thus, 4-HC-purged ABMT can produce extended remissions in a subgroup of patients with indolent lymphomas.

Clinical Outcome following Autologous and Allogeneic Blood and Marrow Transplantation for Relapsed Diffuse Large-Cell Non-Hodgkin’s Lymphoma

High-dose chemotherapy followed by blood or marrow transplantation (BMT) is generally considered the best salvage option for patients with relapsed diffuse large–B-cell non-Hodgkin’s lymphoma (DLCL). The relative roles for allogeneic and autologous BMT remain controversial. We reviewed the clinical outcome of 183 patients with relapsed DLCL who underwent BMT at Johns Hopkins University in 1985-2001. A total of 45 patients received T-cell–depleted HLA-matched allogeneic bone marrow (allo-BMT), and 138 patients received autologous marrow or peripheral blood stem cells (auto-BMT). The allo-BMT recipients had a higher proportion of patients with chemoresistant disease ( P = .004) and had received more chemotherapy before BMT ( P = .02). The auto-BMT recipients were older ( P < .001) and were of more advanced-stage disease ( P = .01). The 3-year overall survival (OS) was 23.7% (median survival, 129 days) after allo-BMT and 33.1% (median survival, 263 days), after auto-BMT (log-rank, P = .17). The 3-year OS for patients with sensitive disease was 51.9% after allo-BMT and 46.2% after auto-BMT (log-rank, P = .38). For patients with resistant disease, the 3-year OS was 12.1% after allo-BMT and 19.1% after auto-BMT (log rank, P = .08). In multivariate analysis, significant predictors of death were disease sensitivity (hazard rate [HR], 0.3; 95% confidence interval [CI] 0.2-04; P < .001), age >40 years (HR, 2.42; 95% CI, 1.7-3.4; P < .001), and stage at diagnosis (HR, 1.2; 95% CI, 1.0-1.4; P = .04). The 3-year event-free survival (EFS) for patients with sensitive disease was 52.7% after allo-BMT and 42.0% after auto-BMT (log-rank, P = .29). For patients with resistant disease, the 3-year EFS was 6.2% after allo-BMT and 19.4% after auto-BMT (log-rank, P = .1). The 3-year probability of relapse for chemosensitive patients was 30% after allo-BMT and 46.1% after auto-BMT (log-rank, P = .25). The 3-year relapse rate in patients with resistant disease was 75.0% after allo-BMT and 69.9% after auto-BMT (log-rank, P = .58). In multivariate analysis, only disease sensitivity status (HR, 0.4; 95% CI, 0.2-2.1; P < .001) and age >40 years (HR, 1.7; 95% CI, 1.1-2.9; P = .03) appear to have a significant impact on relapse. Transplant-related mortality (TRM) was the cause of death for 51.1% of allo-BMT recipients and 23.9% of auto-BMT recipients ( P < .001). Mortality from lymphoma was 26.6% in allo-BMT recipients and 43.5% in auto-BMT recipients ( P = .02). Auto-BMT and allo-BMT produced similar survival for patients with relapsed DLCL. For patients with sensitive disease, allo-BMT seemed to provide longer survival with less relapse; however, this was achieved at the cost of greater TRM.

Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma

To evaluate high-dose therapy and autologous or allogeneic blood or marrow transplantation (BMT) for mantle cell lymphoma, patients receiving BMT for newly diagnosed or relapsed mantle cell lymphoma were identified through the registry at Johns Hopkins. The pathologic diagnostic criteria were reviewed, and details of the presentation, transplant procedure, and survival outcomes were determined. Fifty-eight patients were identified, of whom 64% underwent transplantation in first remission and 12% had primary induction failure. Nineteen patients (one third) received an allograft. Preparative regimens consisted of cyclophosphamide in combination with either busulfan or total body irradiation. On multiple regression analysis, transplantation after 1 or more relapses (hazard ratio, 2.98; P = .02), primary induction failure (hazard ratio, 5.39; P = .002), and allogeneic transplantation (hazard ratio, 3.03; P = .007) were associated with an inferior event-free survival (EFS). However, EFS curves were not statistically different for autologous and allogeneic BMT performed in first remission, with an estimated 3-year EFS approaching or equaling 70%. Primary induction failure and residual bone marrow involvement were the only statistically significant predictors of relapse on multiple regression analysis. At 3 years, the estimated EFS for the entire cohort after BMT was 51%, the probability of relapse was 31%, and the overall survival was 59%. The benefit of autologous or allogeneic BMT for mantle cell lymphoma is thus most apparent when transplantation is performed in first remission. Whether allogeneic BMT ultimately confers an advantage because of a graft-versus-lymphoma effect remains to be determined.