Epidemiology, Diagnosis, and Treatment of HIV-Associated Non-Hodgkin Lymphoma in Resource-Limited Settings

Lymphoma was a common complication of HIV infection in the pre-antiretroviral era, and the incidence of HIV-associated lymphoma has dropped dramatically since the introduction of combination antiretroviral therapy (cART) in resource-rich regions. Conversely, lymphoma is an increasingly common complication of HIV infection in resource-limited settings where the prevalence of HIV infection is high. Relatively little is known, however, about the true incidence and optimal treatment regimens for HIV-associated lymphoma in resource-poor regions. We review the epidemiology, diagnosis, and treatment of HIV-associated non-Hodgkin lymphoma in developing nations and highlight areas for further research that may benefit care in both settings. Examples include risk modification and dose modification of chemotherapy based on HIV risk factors, improving our understanding of the current burden of disease through national cancer registries, and developing cost-effective hematopathological diagnostic strategies to optimize care delivery and maximize use of available chemotherapy

Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma

Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients >= 65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed = 65 years were random-ized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P = 3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P = 65 and = 65 years with R/R LBCL

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A CIBMTR Analysis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes

Three-Year Follow-Up Analysis of Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5)

•Axi-cel demonstrated durable responses in patients with FL and MZL after 3 years of follow-up.•Elevated baseline total metabolic tumor volume and recent prior bendamustine use may impact durable remissions in patients with FL. Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel in patients with R/R indolent non-Hodgkin lymphoma (iNHL; N=104), including FL and marginal zone lymphoma (MZL). In the primary analysis (17.5 months median follow-up), overall response rate (ORR) was 92% (74% complete response rate). Here we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2×106 CAR T cells/kg). The primary endpoint was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n=127) and 31.8 months in MZL (n=31), ORR was comparable to the primary analysis (94% in FL; 77% in MZL). Median progression-free survival was 40.2 months in FL and not yet reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest occurring since the prior analysis were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study is registered at ClinicalTrials.gov (NCT NCT03105336

Long-Term Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B); 1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1)); other malignancies included squamous cell carcinoma of skin (n=3); sarcoma (n=1); endometrial (n=1); lung (n=1); mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. J.Y.S and M.D.J contributed equally; S.D and M.L contributed equally. Figure 1 Figure 1. Disclosures Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy. Nastoupil: Pfizer: Honoraria, Research Funding; MorphoSys: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Bayer: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Lin: Gamida Cell: Consultancy; Juno: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Oluwole: Curio Science: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. McGuirk: EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Goy: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; Xcenda: Consultancy; Acerta: Consultancy, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Genentech/Hoffman la Roche: Research Funding; MorphoSys: Honoraria, Other; Karyopharm: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Incyte: Honoraria; Medscape: Consultancy; Novartis: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Infinity/Verastem: Research Funding; Rosewell Park: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Hill: Pfizer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equit