Hematopoietic Cell Transplantation For Lymphoma Research Articles

Clonal Hematopoiesis Is Associated with Cardiovascular Disease Risk and Worse Survival after Autologous Hematopoietic Cell Transplantation for Lymphoma

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with relapsed or refractory lymphoma, and use of HCT has contributed to a growing number of survivors. Despite these improvements in outcomes, long-term survivors of lymphoma are at high risk of developing clinically significant cardiovascular disease (CVD) which, to date, has largely been attributed to pre-HCT cardiotoxic therapeutic exposures (e.g. anthracyclines, radiation) and modifiable risk factors (e.g. hypertension, diabetes, dyslipidemia) after HCT. In the general population, clonal hematopoiesis of indeterminate potential (CHIP), which refers to clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with aging-related health conditions including CVD. Accumulating data suggests CHIP is more prevalent in cancer patients compared to age-matched controls, due in part to clonal selection after genotoxic stressors. There is a paucity of information about the association between CHIP and CVD after HCT, including its interaction with modifiable risk factors and subsequent impact on survival after HCT. Methods: This was a retrospective cohort study of 861 consecutive patients who underwent autologous HCT for lymphoma between 2010 and 2016, with available pre-HCT DNA obtained from peripheral blood stem cells. We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP (variant allele frequency ≥2%). CVD outcomes of interest included de novo heart failure, coronary artery disease and stroke after HCT. Five-year cumulative incidence of CVD was calculated taking into consideration competing risk of death. Fine-Gray multivariable regression was used to evaluate the association between CHIP and CVD, adjusting for demographic, clinical and therapeutic factors. The Kaplan-Meier method was used to examine the effect of CHIP on overall survival after HCT. Results: Median age at HCT was 55.7 years (range 18.4-78.1 years); 63.3% were male; race/ethnicity: non-Hispanic White (56.9%), Hispanic (26.1%), Asian (10.8%), Black (5.1%); 78.0% had non-Hodgkin lymphoma; comorbidities at HCT: hypertension (32.1%), dyslipidemia (16.4%), diabetes (10.1%), high (≥3) HCT-comorbidity index (CI) score (46.1%). Nearly all patients (94.3%) had received anthracycline-based chemotherapy prior to HCT, and 63.3% were treated with cumulative dose ≥300mg/m 2; 6% had chest radiotherapy. Overall, 186 patients (21.7% of the cohort) had at least one CHIP variant and 57 (6.6%) had ≥2 variants. DNMT3A, PPM1D, TET2 and TP53 were the most frequently mutated genes. In total, 74 patients developed CVD within five years from HCT. The 5-year cumulative incidence of CVD was significantly higher in patients with CHIP (20.9% vs 9.1%, p<0.001), compared to those without CHIP, and there was a graded relationship between number of CHIP variants and incidence of CVD. In the adjusted (age, cancer diagnosis, HCT-CI, modifiable cardiovascular risk factors) multivariable model, CHIP was significantly and independently associated with a nearly two-fold (HR: 1.8, 95% CI=1.1-3.1; P=0.020) risk of CVD, as well as the individual outcome of heart failure (HR: 2.3, 95%CI=1.3-4.3; P=0.008). Patients who had both CHIP and hypertension had a 3-fold (HR: 3.0, 95%CI=1.4-6.5, p=0.006) risk of CVD (reference: no CHIP, no hypertension). Overall 5-year survival after HCT was significantly worse in patients with CHIP, compared to those without CHIP (47.2% vs 68.2%, p<0.001; adjusted HR: 1.9, 95%CI=1.4-2.6), attributed to the higher burden of non-relapse mortality in patients with CHIP. Conclusions: In this well-characterized and demographically diverse cohort of lymphoma patients undergoing HCT, CHIP was highly prevalent and associated with a significantly higher risk of CVD after HCT, with the highest risk among those with CHIP and hypertension. We confirmed the poor overall survival rate in patients with CHIP, independent of patient and disease-related risk factors. These findings highlight the potential role of CHIP as a novel biomarker to better define CVD risk in patients with lymphoma prior to HCT, setting the stage for better screening and implementation of interventions (e.g., aggressive management of modifiable risk factors) to reduce the risk of CVD and to ultimately improve long-term health outcomes after HCT.

Geriatric assessment in adults age 50 years and older undergoing autologous hematopoietic cell transplantation for lymphoma

Geriatric assessment (GA) is a comprehensive measure of multiple health domains relevant to older adults and can be used to define fitness and identify deficits in patients with hematologic malignancies. Prior to allogeneic hematopoietic cell transplantation (alloHCT), use of GA has been increasingly reported in both older and middle-aged adults, and GA components are prognostic for post-transplant outcomes [ 1 Lin R.J. Elko T.A. Devlin S.M. et al. Impact of geriatric vulnerabilities on allogeneic hematopoietic cell transplantation outcomes in older patients with hematologic malignancies. Bone Marrow Transplant. 2020; 55: 157-164 Crossref PubMed Scopus (24) Google Scholar , 2 Muffly L.S. Kocherginsky M. Stock W. et al. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. Haematologica. 2014; 99: 1373-1379 Crossref PubMed Scopus (148) Google Scholar , 3 Kennedy V.E. Olin R.L. Haematopoietic stem-cell transplantation in older adults: geriatric assessment, donor considerations, and optimisation of care. Lancet Haematol. 2021; 8 (e853-e61) Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar ]. While fewer studies have focused on GA prior to autologous HCT (autoHCT), GA has demonstrated a high frequency of functional deficits in older adult autoHCT candidates, even in patients with few comorbidities and preserved performance status [ 4 Lin R.J. Shahrokni A. Dahi P.B. et al. Pretransplant comprehensive geriatric assessment in hematopoietic cell transplantation: a single center experience. Bone Marrow Transplant. 2018; 53: 1184-1187 Crossref PubMed Scopus (16) Google Scholar , 5 Nawas M.T. Andreadis C. Martin T.G. et al. Limitation in patient-reported function is associated with inferior survival in older adults undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019; 25: 1218-1224 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar , 6 Rosko A.E. Huang Y. Benson D.M. et al. Use of a comprehensive frailty assessment to predict morbidity in patients with multiple myeloma undergoing transplant. J Geriatr Oncol. 2019; 10: 479-485 Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar ]. GA components are also predictive of post-autoHCT outcomes, even after adjustment for patient age and comorbidities [ [5] Nawas M.T. Andreadis C. Martin T.G. et al. Limitation in patient-reported function is associated with inferior survival in older adults undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019; 25: 1218-1224 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar , [6] Rosko A.E. Huang Y. Benson D.M. et al. Use of a comprehensive frailty assessment to predict morbidity in patients with multiple myeloma undergoing transplant. J Geriatr Oncol. 2019; 10: 479-485 Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar ].

Effect of Keratinocyte Growth Factor on Hospital Readmission and Regimen-Related Toxicities after Autologous Hematopoietic Cell Transplantation for Lymphoma

Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization.

Racial Differences in Utilization of Hematopoietic Cell Transplantation for Lymphoma in the United States

<h3>Introduction</h3> Racial disparities have been documented in hematopoietic cell transplantation (HCT), a complex and expensive therapeutic modality for hematologic malignancies. Prior work suggests that racial minorities in the US have lower rates of utilization of HCT compared to White patients. However, the available literature on racial disparities in HCT is limited, particularly with regard to lymphoma patients. <h3>Objectives</h3> The objective of this study was to determine if racial differences exist in utilization of HCT for lymphoma by comparing transplant activity to disease incidence rates between 2013-2016. <h3>Methods</h3> This was a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research; Surveillance, Epidemiology, End Results program; and US Census Bureau. All patients in the US who underwent HCT for Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) between 2013-2016 were included. Patients with unknown race or multiple races were excluded. We assessed transplant utilization by calculating the transplant utilization rate (TUR) for each disease, separately. Rates were operationalized as the number of transplants performed per 100 new cases of the disease diagnosed in the US during the same time period. <h3>Results</h3> There were a total of 18,569 transplants for HL and NHL included. Table 1 shows patient characteristics by transplant type. During the same time period, age-adjusted incidence rates [95% confidence interval (CI)] for HL for Whites, Blacks, Asians/Pacific Islanders (API), and American Indians/Alaska Natives (AI) were 2.65 (2.59-2.71), 2.61 (2.46-2.77), 1.24 (1.14-1.36), and 1.00 (0.73-1.34) cases/100,000 persons at risk, respectively. Incidence rates were higher for NHL for the same racial groups at 20.22 (20.05-20.38), 14.44 (14.06-14.82), 13.53 (13.16-13.90), and 8.75 (7.82-9.75), respectively. Transplant and incidence data were consistent from 2013-2016. There were no significant differences in TURs for HL between racial groups. However, Whites with NHL had a higher TUR than Blacks [7.02 (95% CI 6.90-7.13) vs 4.75 (95% CI 4.49-5.02), p < 0.001], which was due to differences in utilization of autologous rather than allogeneic HCT [5.77 (95% CI 5.67-5.88) vs. 3.56 (95% CI 3.33-3.79), p < 0.001 for autologous HCT and 1.24 (95% CI 1.20-1.29) vs. 1.19 (95% CI 1.06-1.33), p = 0.488 for allogeneic HCT]. Figure 1 shows the utilization data for both HL and NHL. The impact of this difference in utilization of autologous HCT was an estimated loss of 143 transplants per year for Black patients. <h3>Conclusion</h3> Autologous HCT for NHL is underutilized for Black patients compared to White patients in the US. Additional research is needed to understand the reasons for this difference.

Survivorship after Autologous Hematopoietic Cell Transplantation for Lymphoma and Multiple Myeloma: Late Effects and Quality of Life.

Although autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with lymphoma and multiple myeloma (MM), few studies have addressed late effects and quality of life (QoL) in long-term survivors after AHCT. Using long-term follow-up (LTFU) annual questionnaires with self-reported outcomes, we surveyed 665 patients who were at ≥5 years after AHCT for the diagnosis of lymphoma or MM. Three-hundred and eighty-nine patients completed the questionnaire (58% response rate) at a median of 11 years (range, 5-30 years) after AHCT. The median patient age was 63 years (range, 22-88 years) in the 268 patients with lymphoma and 69 years (range, 34-84 years) in the 121 patients with multiple myeloma. The most commonly reported medical conditions (>10% incidence) were sexual dysfunction, history of shingles, cataracts, osteoporosis or osteopenia, joint replacement, and skin cancer. Current medication use was more frequent in the patients with MM for infection prevention/treatment (19% for MM versus 5% lymphoma; P < .001), hypertension (41% versus 26%; P = .004), osteoporosis (23% versus 10%; P < .001), and pain (32% versus 11%, P < .001). Treated hypothyroidism was more common in lymphoma patients. In multivariate analysis combining lymphoma and MM, worse physical functioning was associated with older age, shorter interval since AHCT, comorbidities, relapse, and treatment for depression and/or pain. Worse mental functioning was associated with younger age and treatment for anxiety, depression, or pain. In conclusion, AHCT survivors report generally good QoL but many late effects and symptoms that are potentially amenable to intervention.

Hematopoietic-cell transplantation for lymphoma in the era of genetically engineered cellular therapy: it's not quite time to scrap the old vehicle for the new car.

Second-line platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic-cell transplantation (AHCT) has remained the standard of care (SOC) for relapsed and primary refractory (r/r) diffuse large B-cell lymphoma (DLBCL) for greater than 2 decades. In the postrituximab era, this strategy has yielded disappointing outcomes for r/r patients with curability in less one-quarter of the patients by intention-to-treat. Given the Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) modified T cells directed against CD19 (CD19 CAR T) for DLBCL following two lines of therapy and/or failed AHCT, encouragement with this therapy in the second line for r/r patients has naturally prompted randomized phase III studies against the aforementioned SOC. The predominant hurdle to procession to AHCT is chemotherapy sensitivity after platinum-based salvage therapy. In this review, we will discuss recent investigations to improve response rates in r/r DLBCL with the intent of proceeding to potentially curative AHCT, as well as investigations to decrease progression post-AHCT. In addition, data regarding currently FDA approved CD19 CAR T cells will be reviewed. Within 2-3 years, we will know if the multicenter/multinational studies of CD19 CAR T will replace SOC salvage therapy and AHCT in the second-line. The role of allogeneic HCT will also be briefly reviewed in the context of these therapies.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

287 - Influence of Pretransplant Platinum-Based Chemotherapy on Renal Function and Outcomes after Allogeneic Hematopoietic Cell Transplantation for Lymphoma

Background: Platinum derivatives play important roles in salvage chemotherapy of malignant lymphoma, but may cause renal dysfunction. We examined the influence of pretransplant platinum-based chemotherapy on renal function and outcomes after allogeneic hematopoietic cell transplantation (HCT) for lymphoma. Methods: This retrospective study cohort included 229 adult patients with malignant lymphoma who had a first allogeneic HCT between 2000 and 2014 at our center. We collected cumulative doses of cisplatin (CDDP) and carboplatin (CBDCA) before allogeneic HCT, and daily renal function (eGFR) during the first 100 days after HCT. Risk factors for renal injury (eGFR <75 ml/min/1.73 m2) are examined using logistic models. Changes in renal function between the groups were conducted by the repeated measures ANOVA. Non-relapse mortality rates were compared with the Gray test. Results: 145 patients were males and 84 females. The median patient age was 49 years (range, 19-67). Patients were divided into three groups according to the cumulative dose of each platinum agent: no CDDP (n = 129), CDDP ≤275 mg/m2 (n = 50) and >275 mg/m2 (n = 50); and no CBDCA (n = 111), CBDCA ≤1200 mg/m2 (n = 77) and CBDCA >1200 mg/m2 (n = 41). Proportions of patients with pretransplant renal injury were 32% in no CDDP group, 36% in CDDP ≤275 mg/m2 group, and 70% in CDDP >275 mg/m2 group (P < .01). Proportions did not differ statistically according to cumulative CBDCA doses. Multivariate analysis showed that cumulative CDDP doses >275 mg/m2, aggressive and highly aggressive B cell lymphoma, and patient age ≥50 years were associated with pretransplant renal injury. Changes in eGFR across time after HCT are shown in Figure 1. Repeated measures ANOVA showed significant differences in between–subject factor and within-subject factor between no CDDP group and CDDP >275 mg/m2 group. Between no CDDP group and CDDP ≤275 mg/m2 group, there was a significant difference in within-subject factor and interaction. Pretransplant renal injury was associated with a trend for higher 2-year nonrelapse mortality rates (17% versus 10%, P = .12). Proportions of renal-related causes of death were higher among patients with pretransplant renal injury than those with normal renal function (34% versus 13%, P = .02). Conclusion: We should pay attention to pretransplant cumulative CDDP doses in patients with malignant lymphoma who are eligible for allogeneic HCT. Our results may support avoidance of CDDP use for these patients. CBDCA could have less influence on renal injury than CDDP.

Comorbidities, Alcohol Use Disorder, and Age Predict Outcomes after Autologous Hematopoietic Cell Transplantation for Lymphoma

Autologous hematopoietic cell transplantation (HCT) is a treatment option for many patients diagnosed with lymphoma. The effects of patient-specific factors on outcomes after autologous HCT are not well characterized. Here, we studied a sequential cohort of 754 patients with lymphoma treated with autologous HCT between 2000 and 2010. In multivariate analysis, patient-specific factors that were statistically significantly associated with nonrelapse mortality (NRM) included HCT-specific comorbidity index (HCT-CI) scores ≥ 3 (HR, 1.94; P = .05), a history of alcohol use disorder (AUD) (HR, 2.17; P = .004), and older age stratified by decade (HR, 1.29; P = .02). HCT-CI ≥ 3, a history of AUD, and age > 50 were combined into a composite risk model: NRM and overall mortality rates at 5 years increased from 6% to 30% and 32% to 58%, respectively, in patients with 0 versus all 3 risk factors. The HCT-CI is a valid tool in predicting mortality risks after autologous HCT for lymphoma. AUD and older age exert independent prognostic impact on outcomes. Whether AUD indicates additional organ dysfunction or sociobehavioral abnormality warrants further investigation. The composite model may improve risk stratification before autologous HCT.

Prediction of infectious events by the high‐sensitivity C‐reactive protein level before autologous hematopoietic cell transplantation for lymphoma and multiple myeloma

Prediction of infectious events by the high‐sensitivity C‐reactive protein level before autologous hematopoietic cell transplantation for lymphoma and multiple myeloma

Longitudinal Assessment of Hematopoietic Abnormalities After Autologous Hematopoietic Cell Transplantation for Lymphoma

Autologous hematopoietic cell transplantation (HCT) is being increasingly used as an effective treatment strategy for patients with relapsed or refractory Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL) but is associated with therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) as a major cause of nonrelapse mortality. The phenomenon of hematopoietic reconstitution after autologous HCT and the role of proliferative stress in the pathogenesis of t-MDS/AML are poorly understood. Using a prospective longitudinal study design, we evaluated the nature and timing of alterations in hematopoietic progenitors and telomere length after HCT in patients undergoing autologous HCT at City of Hope Cancer Center (Duarte, CA). A significant reduction in primitive and committed progenitors was observed before HCT compared with healthy controls. Further profound and persistent reduction in primitive progenitors but only transient reduction in committed progenitors were seen after HCT. Primitive progenitor frequency in pre-HCT marrow and peripheral-blood stem cells predicted for primitive progenitor recovery after HCT. Shortening of telomere length was observed in marrow cells early after HCT, with subsequent restoration to pre-HCT levels. Patients within this cohort who developed t-MDS/AML had reduced recovery of committed progenitors and poorer telomere recovery, possibly indicating a functional defect in primitive hematopoietic cells. Our studies suggest that hematopoietic regeneration after HCT is associated with increased proliferation and differentiation of primitive progenitors. Increased proliferative stress on stem cells bearing genotoxic damage could contribute to the pathogenesis of t-MDS/AML. Extended follow-up of a larger number of patients is required to confirm whether alterations in progenitor and telomere recovery predict for increased risk of t-MDS/AML.

P-44 Longitudinal assessment ofhematopoietic abnormalities following autologous hematopoietic cell transplantation for lymphoma and association with risk of therapy-related myelodysplasia

P-44 Longitudinal assessment ofhematopoietic abnormalities following autologous hematopoietic cell transplantation for lymphoma and association with risk of therapy-related myelodysplasia