Efficacy and safety of outpatient fludarabine, cyclophosphamide, and rituximab based allogeneic hematopoietic cell transplantation in adults with severe aplastic anemia.

The age effect in severe aplastic anemia (SAA) following allogeneic hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning (RIC) regimens in older adults. We implemented a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) to improve HCT outcomes in SAA. Patients who underwent first HCT for SAA utilizing an FCR regimen between January 2016 and May 2022 were included. Outcomes analyzed included time to engraftment, incidence of graft failure, GVHD, viral reactivation, disease recurrence, and GVHD-free, relapse-free survival (GRFS). Among 24 patients included, median age was 43.5 years (22-62) and a variety of donor types and stem cell sources were represented. At median follow-up of 26.9 months (2.4-72.7), no cases of grade III-IV acute (aGVHD) or severe chronic GVHD (cGVHD) were recorded. Viral reactivation was minimal, and there were no cases of graft failure or PTLD, with 100% disease-free and overall survival at last follow up. The estimate of 1-year GRFS was 86.3% (95% CI: 72.8-100%), with moderate cGVHD accounting for all events. The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates. These encouraging findings should be validated in larger prospective trials.

How old is too old? Frailty and geriatric assessments of older patients undergoing allogeneic HCT.

Allogeneic hematopoietic cell transplantation (HCT) is a curative-intent treatment for many hematologic malignancies but carries a significant risk of morbidity and mortality. An increasing number of older adults are receiving HCT, but current pretransplant evaluations overlook the unique vulnerabilities that older adults face. Oncology-specific geriatric and frailty assessments provide a comprehensive evaluation of older adults, help better weigh the risks of HCT with patients, and guide personalized optimization strategies to minimize vulnerabilities. Geriatric assessments evaluate seven domains: comorbidities, physical function, mental health, cognition, nutrition, medications, and social support. Frailty indices provide unique evaluations into a patient's overall status. Various standardized measures have been used to evaluate these areas in older adults prior to HCT. Different care models exist for the integration of geriatrics and geriatric principles into HCT evaluation: a multidisciplinary consultative clinic, a geriatrician alongside the HCT clinic, or a primary geriatric hematologist/transplant physician. Future studies are needed to investigate the use of geriatric assessments in selecting the conditioning regimen and intensity and measuring the impact of geriatric assessment-driven interventions on quality of life and toxicities post transplant.

TP53 Mutations Are Associated with Increased Infections and Reduced Hematopoietic Cell Transplantation Rates in Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.

Relapsed or refractory large B-cell lymphoma after chimeric antigen receptor T-cell therapy: Current challenges and therapeutic options.

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy can provide durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after failure of chemoimmunotherapy. However, patients who are refractory or relapsing after CAR-T therapy have poor outcomes. Multiple mechanisms of CAR-T therapy failure have been proposed but management of these patients remains a challenge. As CAR-T therapy moves earlier in the treatment of DLBCL, we urgently need trials focused on patients with relapse after CAR-T therapy. Recent advances in novel immunotherapies such as bispecific antibodies, antibody-drug conjugates and next-generation CAR-T therapies may provide avenues for treatment. Here we review the available data on using these drugs after failure of CAR-T therapy and provide a framework for the ideal sequencing of these novel agents.

Change in Patients' Perceived Cognition Following Chimeric Antigen Receptor T-Cell Therapy for Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy can lead to durable responses in patients with relapsed/refractory hematologic malignancies. Immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) are common and may place patients at risk for longer-term cognitive impairment. This study examined changes in cognition in the first year after CD19-directed CAR T-cell therapy for lymphoma, as well as CAR T-cell therapy-specific risk-factors (e.g., ICANS, CRS) and nonspecific risk factors (e.g., baseline quality of life, frailty) for worsening cognition. Patients' perceived cognition was assessed at baseline and at days 90 and 360. Clinical variables were abstracted from medical records. Piecewise mixed models were used to examine acute change (i.e., within 90 days) and longer-term change (i.e., from 90 days to 360 days) in cognition, as well as to explore risk factors for worsening cognition. Among 118 participants (mean age 61, 59% male), mean levels of perceived cognition did not change from baseline to day 90 (P> .05) but worsened from day 90 to day 360 in global cognition and in the domains of memory, language, organization, and divided attention (P< .05). Although statistically significant, changes were small (d values 0.15-0.28). Greater baseline fatigue, anxiety, and depression were associated with worse global cognition at day 90 (P< .01). Patients with more severe ICANS post-CART reported worse global cognition at day 360 (P< .05), although there were no differences in perceived cognition by severity of CRS (P> .05). Other putative risk factors were not associated with acute or longer-term changes in perceived cognition (P> .05). CAR T-cell therapy recipients reported delayed deterioration in several cognitive domains, although changes were small. These findings may be useful when educating future patients on what to expect when receiving CAR T-cell therapy.

Change in Neurocognitive Performance Among Patients with Non-Hodgkin Lymphoma in the First Year after Chimeric Antigen Receptor T Cell Therapy.

The success of chimeric antigen receptor (CAR) T cell therapy in treating patients with relapsed/refractory hematologic malignancies is leading to a growing number of survivors treated with this regimen. To our knowledge, no previous studies have examined neurocognitive performance in adult CAR T cell therapy recipients, despite high rates of neurotoxicity and cytokine release syndrome (CRS) in the acute treatment period. This study examined changes in neurocognitive performance in the first year after CAR T cell therapy for non-Hodgkin lymphoma (NHL). Putative risk factors for worsening neurocognitive performance (eg, neurotoxicity, CRS) were explored as well. Neurocognition was assessed before initiation of CAR T cell therapy and at 30, 90, and 360 days post-treatment. Clinical variables were abstracted from medical records. Mixed models were used to examine change in total neurocognitive performance (TNP) and cognitive domains (ie, attention, executive function, verbal ability, immediate and delayed memory, and visuospatial abilities). Among 117 participants (mean age, 61 years; 62% male), TNP and executive function declined slightly on average from baseline to day 90 and then improved from day 90 to day 360 (P < .04). Small but significant linear declines in visuospatial ability on average were also observed over time (P = .03). Patients who had 4 or more lines of previous therapy and those with worse neurotoxicity (but not CRS) demonstrated worse TNP. CAR T cell therapy recipients reported transient or persistent deterioration in several cognitive domains, although changes were slight. These findings may be useful when educating future patients on what to expect when receiving CAR T cell therapy.

Association of Patient-Reported Physical Activity on Allogeneic Hematopoietic Cell Transplant Outcomes.

BACKGROUND: Physical function prior to allogeneic hematopoietic cell transplant (HCT) is associated with survival and may be associated with patient physical activity (PA). Tools to evaluate PA prior to HCT are scarce. We aimed to evaluate the impact of easily obtained patient-report of PA prior to HCT on survival. METHODS: HCT recipients between January 1, 2011 and July 5, 2018 and who completed an International Physical Activity Questionnaire Short Form were included. This patient survey captures self-reported activities over the preceding week to determine PA level. RESULTS: We report a retrospective study of 587 adult (age ≥18) HCT recipients. The median age for the cohort was 57.9 years (range 19.9-76.1) with 149 patients (25.4%) age ≥65. Younger patients reported higher PA (low, median age 59.7 years; moderate, 56.1; high, 55.7; p < 0.001). High activity level was reported by males (66.7%; p < 0.001). Patients with low PA had HCT-comorbidity index (HCT-CI) ≥ 3 (68.1%, p = 0.002). When controlling for HCT-CI and disease risk index, higher PA was associated with improved overall survival (HR 0.954, 95% CI 0.921-0.988, p = 0.009). After adjusting for HCT-CI, higher PA was associated with reduced non-relapse mortality (NRM) (HR 0.931, 95% CI 0.891-0.972, p = 0.0013). Subgroup analysis in adults age ≥65 years also found that PA was lower in this population and associated with NRM mortality (HR 0.95, 95% CI 0.90-0.99, p = 0.041). CONCLUSION: Patient-reported PA is a predictor of post-HCT survival. Future studies to validate incorporation of self-report tools to better predict patient-related adverse risk are warranted.

Quality of life in caregivers of patients receiving chimeric antigen receptor T-cell therapy.

OBJECTIVE: Informal family caregivers provide critical support for patients receiving chimeric antigen receptor (CAR) T-cell therapy. However, caregivers' experiences are largely unstudied. This study examined quality of life (QOL; physical functioning, pain, fatigue, anxiety, and depression), caregiving burden, and treatment-related distress in caregivers in the first 6 months after CAR T-cell therapy, when caregivers were expected to be most involved in providing care. Relationships between patients' clinical course and caregiver outcomes were also explored. METHODS: Caregivers completed measures examining QOL and burden before patients' CAR T-cell therapy and at days 90 and 180. Treatment-related distress was assessed at days 90 and 180. Patients' clinical variables were extracted from medical charts. Change in outcomes was assessed using means and 99% confidence intervals. Association of change in outcomes with patient clinical variables was assessed with backward elimination analysis. RESULTS: A total of 99 caregivers (mean age 59, 73% female) provided data. Regarding QOL, pain was significantly higher than population norms at baseline but improved by day 180 (p < .01). Conversely, anxiety worsened over time (p < .01). Caregiver burden and treatment-related distress did not change over time. Worsening caregiver depression by day 180 was associated with lower patient baseline performance status (p < .01). Worse caregiver treatment-related distress at day 180 was associated with lower performance status, intensive care unit admission, and lack of disease response at day 90 (ps < 0.01). CONCLUSIONS: Some CAR T-cell therapy caregivers experience pain, anxiety, and burden, which may be associated patients' health status. Further research is warranted regarding the experience of CAR T-cell therapy caregivers.

Acute patient-reported outcomes in B-cell malignancies treated with axicabtagene ciloleucel.

Chimeric antigen receptor T-cell therapy with axicabtagene ciloleucel (axi-cel) has considerably improved survival in adults with relapsed/refractory large B-cell lymphoma. This study reports patient-reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi-cel (N = 103, mean age = 61, 39% female) completed SF-36 or PROMIS-29 QOL questionnaires prior to treatment and 90 days after. PRO-Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient-reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient-reported toxicities.

Association between a cognitive screening test and severe chemotherapy toxicity in older adults with cancer.

INTRODUCTION: Cognitive impairment (CI) increases chemotherapy toxicity risk with need to understand this association utilizing publicly available short screening tools. We evaluated this utilizing a lower threshold on a short screening tool in older adults with cancer. MATERIALS AND METHODS: We analyzed data from the Cancer and Aging Research Group (CARG) Chemotherapy Toxicity Risk tool (CARG score) development and validation cohorts (n = 703), which recruited adults age ≥ 65 with cancer from academic centers. Cognition was evaluated with the Blessed Orientation-Memory-Concentration test (BOMC). Patients with BOMC score ≥ 11 were excluded. Utilizing cut-points for older adults, we considered moderate BOMC scores (5-10) as potential CI. Logistic regression was used for analysis. RESULTS: Patient baseline characteristics included: mean age 73; 85% white; 63% college or higher education; 250 (36%) potential CI; 385 (55%) severe toxicity. Patients with potential CI were more likely non-white (p ≤ 0.01) and to have high school or lower education (p ≤ 0.01) and high CARG score (p = 0.04). Potential CI was associated with increased severe toxicity risk (OR = 1.54, p ≤ 0.01). After adjusting for CARG score, this association became nonsignificant (OR = 1.35; p = 0.08). Among patients with lower education (n = 258; 36.7%), potential CI remained associated with severe toxicity, even after adjusting for CARG score (OR = 1.87, p = 0.03). CONCLUSIONS: Our findings suggest potential cognitive impairment, defined by BOMC score 5-10, in older adults with cancer and lower education is associated with increased severe toxicity risk. Future studies are needed to validate these findings. Healthcare providers should consider cognitive testing before treatment for these vulnerable patients.