T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy

Nature Medicine · 2024 · 250 citations

• Medicine
• Oncology
• Internal medicine

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study

Blood Advances · 2023 · 32 citations

• Medicine
• Internal medicine
• Oncology

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Characteristics, Treatment, and Outcomes from 17 Academic US Centers

Blood · 2021 · 4 citations

• Medicine
• Internal medicine
• Pediatrics

Abstract Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: 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; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma

Blood Advances · 2020 · 428 citations

• Medicine
• Internal medicine
• Oncology

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.