Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses.

Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes.

A phase 2 study of pembrolizumab after autologous stem cell transplantation in patients with T-cell non-Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission.

The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) vs chimeric antigen receptor T-cell (CAR-T) therapy in patients with diffuse large B-cell lymphoma (DLBCL) who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult patients with DLBCL who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by computed tomography or positron emission tomography scan. We compared the clinical outcomes between the 2 cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs 42%; P = .1) and the rate of 100-day nonrelapse mortality (4% vs 2%; P = .3) were not different between the 2 cohorts, but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs 53%; P = .05) and a superior overall survival (OS) (69% vs 47%; P = .004) at 2 years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (hazard ratio = 1.49; P = .01) and a superior OS (hazard ratio = 1.63; P = .008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard of care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.

Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

Impact of COVID-19 monoclonal antibodies on outcomes of COVID-19 infection in hematopoietic stem cell transplant and chimeric antigen receptor therapy recipients.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell therapy (CAR-T) recipients are at higher risk of serious complications of COVID-19 infection than the general population. Though there is evidence that monoclonal antibodies (MCA) against COVID-19 reduce the risk of death and hospitalization in the general population, data regarding their efficacy in HSCT and CAR-T recipients remains scarce. METHODS: We conducted a retrospective review of HSCT and CAR-T recipients to compare 30-day outcomes between patients who did and did not receive MCA after their first episode of COVID-19 between May 1, 2020 and December 31, 2022. Outcomes were defined as the most severe complication experienced out of the following: 30-day emergency department visit, hospitalization, intensive care unit admission, and death after COVID-19 infection. RESULTS: We identified 166 patients comprised of 53.6% allogeneic HSCT, 35.5% autologous HSCT, and 10.8% CAR-T recipients; 107 had received a COVID-19 vaccine >2 weeks prior to testing positive, and 40 were treated with MCA. After adjusting for age, presence of symptoms at the initial positive test, and COVID-19 vaccination status, patients who did not receive MCA were five times more likely to develop complications after COVID-19 infection (adjusted odds ratio 5.0 [95% CI, 1.9-12.8], p = .001). CONCLUSION: HSCT and CAR-T recipients who received MCA following COVID-19 infection were far less likely to develop COVID-related complications than those who did not receive MCA, regardless of vaccination status. This underscores the potential benefit of developing novel MCA with efficacy against circulating COVID-19 strains.

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study.

We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant.

There have been no large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (allo-HCT). A total of 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (age 18-65 years), undergoing allo-HCT between 2008-2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation-specific comorbidity index (HCT-CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79-1.29; p = 0.95). Similarly, non-relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61-1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98-1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92-1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 acute graft-versus-host disease (HR = 0.67; 95% CI = 0.46-0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo-HCT for T-cell NHL.

Current Treatment of Peripheral T-cell Lymphoma.

The peripheral T-cell lymphomas (PTCLs) are a notoriously diverse family of non-Hodgkin lymphomas with generally aggressive biology. Clinical management is challenging given a largely inadequate literature base comprised of few randomized trials and heterogeneous observational reports. Herein, we provide an account of our practice in the treatment of the 3 most common nodal PTCLs: PTCL, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma (ALCL). In the up-front setting, we employ anthracycline-based induction, with the incorporation of brentuximab vedotin for all those with ALCL and consideration in those with other CD30-expressing PTCLs based on improved progression-free and overall survival in the absence of additional toxicity in the ECHELON-2 trial. We strongly consider high-dose therapy with autologous stem cell rescue in first complete remission. In the relapsed or refractory (R/R) setting, we often look to clinical trials or choose from 4 FDA-approved single agents-belinostat, brentuximab vedotin, romidepsin, and pralatrexate-based on tumor phenotype and side-effect profiles. Our goal in the R/R setting is achievement of complete remission followed by allogeneic transplant with curative intent in appropriate candidates or long-term disease control in others. Numerous investigational agents are advancing through trials and have potential to alter standards of care in the near future.

Effect of time to relapse on overall survival in patients with mantle cell lymphoma following autologous haematopoietic cell transplantation.

In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma.

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell-induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

Pilot Study of Telehealth Evaluations in Patients Undergoing Hematopoietic Cell Transplantation.

Telehealth involves the use of telecommunication and information technology for the delivery of clinical care and may be a mechanism to alleviate the burden of visits faced by patients undergoing hematopoietic cell transplantation (HCT). Few studies have evaluated the feasibility and acceptability of telehealth visits in the care of HCT patients. We conducted 27 telehealth visits with 25 patients undergoing HCT using a videoconferencing system that allows for real-time, 2-way interactions and administered satisfaction surveys to patients and providers. Of the 25 patients included in the study, 20 (80%) and 5 (20%) were undergoing autologous and allogeneic HCT, respectively. The telehealth visits were distributed as follows: 3 inpatient visits upon admission for HCT; 11 inpatient visits between 2 and 14 days post-HCT; 4 inpatient visits prior to discharge after HCT; 8 outpatient, post-HCT follow-up visits; and 1 handoff to a community oncologist. Out of a total of 54 provider assessments, 7 providers (13%) were unable to complete some part of the physical examination, but no provider reported being unable to manage patients' symptoms through telehealth. Eighty-one percent of patients were either satisfied or very satisfied with the telemedicine session. Overall satisfaction was higher among patients than providers (mean scores 4.12 versus 2.64; scale 1 to 5, with 1 = very poor to 5 = excellent). Technological barriers resulting in delays and suboptimal physical examination were largely responsible for provider dissatisfaction. The use of telehealth to deliver comprehensive follow-up care to HCT patients is feasible across different HCT types but is dependent upon quality of data streaming and videoconferencing technologies.

A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL.

In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.

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.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

ASBMT Statement on Routine Prophylaxis for Central Nervous System Recurrence of Acute Lymphoblastic Leukemia following Allogeneic Hematopoietic Cell Transplantation.

Hematologic malignancies treated with allogeneic hematopoietic cell transplantation (allo-HCT) have a variable incidence of post-transplantation central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. Although data supporting post-transplantation CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy era established this as standard practice, controversy exists regarding the role of post-transplantation CNS prophylaxis in the contemporary era. Here we review the most relevant (albeit exclusively retrospective) literature to date on the role of post-transplantation CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of post-transplantation CNS prophylaxis for ALL in the contemporary era, this position statement is anticipated to further stoke controversy and discussion within the transplantation community. Ultimately, only well-designed prospective clinical studies will elucidate the role of routine post-transplantation CNS prophylaxis.

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations.

TP53 alterations portend extremely poor prognosis in patients with mantle cell lymphoma treated with standard treatment modalities. We reviewed outcomes of 42 patients with available TP53 status who had received a reduced-intensity or non-myeloablative allogeneic haematopoietic cell transplant at our institution. We demonstrated a 2-year overall survival and progression-free survival of 78% [95% confidence interval (CI) 60-88] and 61% (95% CI 43-75), respectively. The 2-year cumulative incidences of relapse and non-relapse mortality were 19% and 20%, respectively. Importantly, there is no significant difference among patients with and without TP53 alterations, suggesting for the first time a beneficial treatment modality for these high-risk patients.

Longitudinal cognitive assessment in patients with primary CNS lymphoma treated with induction chemotherapy followed by reduced-dose whole-brain radiotherapy or autologous stem cell transplantation.

INTRODUCTION: The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT. METHODS: PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals. RESULTS: Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL. CONCLUSIONS: Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

Outcomes of Relapsed and Refractory Primary Mediastinal (Thymic) Large B Cell Lymphoma Treated with Second-Line Therapy and Intent to Transplant.

Primary mediastinal (thymic) large B cell lymphoma is a subtype of diffuse large B cell lymphoma with distinct clinical, molecular, and genetic features, many of which overlap with Hodgkin lymphoma. Increasingly, initial therapy for these patients has used dose-dense chemotherapy with or without radiation with excellent results. In patients with relapsed and primary refractory disease, outcomes of second-line therapy followed by consolidation with high-dose therapy and autologous stem cell transplantation remains largely undefined. We reviewed the outcomes of 60 transplant-eligible patients with relapsed or refractory primary mediastinal (thymic) large B cell lymphoma enrolled on sequential protocols with uniform second-line therapy with intent to consolidate with autologous stem cell transplant. The estimated 3-year overall and event-free survivals for all patients were 61% and 57%, respectively, and 68% and 65%, respectively, for patients proceeding to stem cell transplant. Multivariable analysis of risk factors before transplant revealed that an incomplete response to initial therapy, advanced Ann Arbor stage at disease progression, and failure to achieve a partial remission or better to second-line therapy to be independently associated with inferior event-free and overall survival. A risk score based on these variables was able to identify patients who are unlikely to respond to conventional second-line strategies. These results suggest that salvage chemoradiotherapy with intent of subsequent high-dose therapy and autologous stem cell transplant is successful in most patients with relapsed and refractory primary mediastinal (thymic) large B cell lymphoma. Alternative strategies are warranted for a significant subset of patients with high-risk disease who are unlikely to be cured with this strategy.

Distinctive Infectious Complications in Patients with Central Nervous System Lymphoma Undergoing Thiotepa, Busulfan, and Cyclophosphamide-conditioned Autologous Stem Cell Transplantation.

We investigated the incidence of viral, fungal, bacterial, and parasitic infections observed in 57 patients with central nervous system lymphoma after thiotepa, busulfan, and cyclophosphamide-conditioned autologous stem cell transplantation (TBC-ASCT) and 79 patients with systemic non-Hodgkin lymphoma after traditional carmustine, etoposide, cytarabine, and melphalan-conditioned ASCT (BEAM-ASCT). Twenty of 57 (35%) TBC-ASCT patients had detectable viremia with human herpesvirus 6, cytomegalovirus, adenovirus, or BK virus, versus 9 of 79 (11%) BEAM-ASCT patients. Eight TBC-ASCT patients had clinically relevant viral infections (4 human herpesvirus 6, 2 cytomegalovirus, 1 adenovirus, 2 BK virus), versus 0 in the BEAM-ASCT group. Four TBC-ASCT patients suffered infections from either a fungal or parasitic pathogen versus 1 BEAM-ASCT patient. TBC was associated with greater risk of viral reactivation compared with BEAM, independent of other factors (hazard ratio, 4.42; 95% confidence interval, 1.9 to 11.3; P < .001). Prolonged lymphopenia and steroid use in the peri- and post-ASCT period did not explain these observed differences. The pathogenesis of these unusual infections in TBC-ASCT patients remains incompletely understood, and may involve more potent immune suppression with TBC conditioning. Clinicians should be aware of these differences in infection risk in TBC-ASCT patients, which more closely parallel those seen in allogenic hematopoietic cell transplantation recipients. New prophylactic approaches to help minimize these infections should be considered in this population.