Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and MethodsA total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. ResultsHematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P , .001) and chronic (HR, 0.35; P , .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). ConclusionPB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.

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Background: Patients with advanced-stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies. Axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy is approved for the treatment of R/R large B cell lymphoma after ≥ 2 lines of systemic therapy. Here, we present the primary analysis of ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL. Methods: Adults with FL (Grades 1-3a) or MZL (nodal or extranodal) had R/R disease after ≥ 2 lines of therapy (must include an anti-CD20 mAb plus an alkylating agent), and ECOG 0 - 1. Patients underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (per Lugano classification; Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary efficacy analysis occurred when ≥ 80 treated patients with FL had ≥ 12-months follow-up. Results: As of 3/12/2020, 146 patients with iNHL (124 FL; 22 MZL) received axi-cel; 84 patients with FL had ≥ 12-months follow-up. The median age was 61 years (range, 34 - 79); 57% of patients were male. Thirty-eight percent of patients had ECOG 1, 86% had stage III/IV disease, 47% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Patients had a median 3 prior lines of therapy (range, 1 - 10); 64% had ≥ 3 prior lines. Progression < 2 years after initial chemoimmunotherapy (POD24) occurred in 55% of patients, and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients. With a median follow-up of 17.5 months (range, 1.4 - 31.6), the ORR was 92% among efficacy-evaluable patients with iNHL (n = 104), with a 76% CR rate. In patients with FL (n = 84), the ORR was 94% (80% CR rate); in those with MZL (n = 20), the ORR was 85% (60% CR rate). ORR was comparable across key risk groups analyzed by FLIPI, POD24, GELF, refractory status, and prior lines of therapy. As of the data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for DOR, PFS, and OS were not reached; 12-month estimated rates were 72% (95% CI, 61 - 80), 74% (95% CI, 63 - 82), and 93% (95% CI, 86 - 97), respectively. AEs of any grade occurred in 99% of all treated patients. Grade ≥ 3 AEs occurred in 86% of patients with iNHL (85% in FL; 95% in MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee, et al, Blood. 2014) occurred in 7% of patients with iNHL (6% in FL; 9% in MZL). Grade ≥ 3 neurologic events (NEs; per CTCAE v4.03) occurred in 19% of patients with iNHL (15% in FL; 41% in MZL). Most CRS (118/119) and NEs (81/87) of any grade resolved by data cutoff. Grade 5 AEs occurred in 3 patients: multisystem organ failure in the context of CRS (Day 7; related to axi-cel; n = 1 FL), aortic dissection (Day 399; unrelated to axi-cel; n = 1 FL), and coccidioidomycosis infection (Day 327; unrelated to axi-cel; n = 1 MZL). The median peak CAR T cell level was 38 cells/µL (range, 0 - 1415) in all treated patients with iNHL, with 36 cells/µL (range, 0 - 1415) in those with FL and 53 cells/µL (range, 2 - 453) in those with MZL. The AUC0 - 28 was 448 cells/µL × days (range, 6 - 19,900) in all treated patients with iNHL, with 422 cells/µL × days (range, 6 - 19,900) and 552 cells/µL × days (range, 13 - 6468) in those with FL and MZL, respectively. The median time to peak was 9 days (range, 8 - 371) in all patients, 8 days (range, 8 - 371) in patients with FL, and 15 days (range, 8 - 29) in patients with MZL. In efficacy-evaluable patients with FL, median peak CAR T cell levels were numerically greater in those with ongoing response at 12 months than in those who relapsed (P = .057). In all treated patients with FL, CAR T cell peak was associated with Grade ≥ 3 CRS (P = .031) and NEs (P = .005). Conclusions: Axi-cel had considerable and durable clinical benefit in patients with iNHL, with high ORR and CR rates. Axi-cel had a manageable safety profile, with lower rates of Grade ≥ 3 NEs observed in patients with FL vs those in patients with MZL and those previously reported in aggressive NHL (Locke, et al. Lancet Oncol. 2019). Disclosures Chavez: Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy. Sehgal:Juno Therapeutics: Research Funding; TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. William:Celgene: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding; Guidepoint Global: Consultancy; Kyowa Kirin: Consultancy, Honoraria. Munoz:Incyte: Research Funding; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Millenium: Research Funding. Salles:BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Munshi:Kite, a Gilead Company: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Maloney:Celgene: Consultancy, Honoraria, Research Funding; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties, Research Funding; Gilead Science: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Genentech: Consultancy, Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy. Reshef:Kiadis: Research Funding; Monsanto: Consultancy; Novartis: Honoraria; Magenta: Consultancy; Atara: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Immatics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Leslie:Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Fung:AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Takeda: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Rosenblatt:Merck: Other: consultancy or advisory role ; Biograph55: Other: consultancy or advisory role, Research Funding; Synergy: Patents & Royalties; University of Miami: Other: Leadership. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Plaks:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Lee:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Godfrey:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Vezan:Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support; Abbvie: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Avanzi:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership ; MSKCC: Patents & Royalties. Neelapu:N/A: Other; Calibr: Other; Poseida: Research Funding; Cellectis: Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties.

Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6