Incidence and Causes of Prolonged Hematologic Toxicity after Chimeric Antigen Receptor T Cell Therapy: A City of Hope (COH) Experience
Authors: Shouse Geoffrey , Cao Thai , Zhang Jianying , Mei Matthew , Herrera Alex F. , Nikolaenko Liana , Zain Jasmine , Siddiqi Tanya , Popplewell Leslie L. , Forman Stephen J. , Budde Lihua E 
Published: February 2021

Introduction
The most common toxicities after chimeric antigen receptor (CAR) T cell therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and hematologic toxicity. The reported grade 3 and higher neutropenia, anemia and thrombocytopenia lasting longer than 30 days occurred in 15%, 3% and 18% of patients treated with Axicabtagene ciloleucel (Axi-Cel) (Yescarta package insert). Early hematologic toxicity after lymphodepleting chemotherapy (LDP) prior to infusion of CAR T cells is expected. However, prolonged cytopenias lasting longer than 28 days cannot be explained by the toxicity of LDP alone. Here, we described the incidence and potential causes for prolonged cytopenias in patients (pts) treated with Axi-cel for r/r aggressive B cell lymphoma.
Methods
We retrospectively analyzed 78 consecutive pts receiving Axi-cel at our institution between November 1, 2017 and April 1, 2020. This study was conducted with approval from the COH Institutional Review Board.
All patients received standard LDP regimen with cyclophosphamide and fludarabine followed by infusion of Axi-cel at day 0. Clinical response was determined between day 28-35.
Neutropenia, anemia and thrombocytopenia were defined as meeting the NCI CTCAE v5.0 criteria and were considered prolonged if lasting &gt;28 days. CRS and ICANS severity were graded using the ASTCT criteria.
Results
A total of 78 pts were included with the median age of 61 years (range, 22-77), 33% &gt; 65 years old, 68% male. Seventeen (22%) pts had transformed follicular lymphoma (tFL), 55 had diffuse large (DLBCL), and 6 (8%) had primary mediastinal (PMBCL). Median lines of prior treatment were 3 (range 2-6) with 18 (23%) having prior autologous stem cell transplant (ASCT). Responses were seen in 71 pts (91%), with 25 (32%) partial responses (PR) and 46 (59%) complete responses (CR) at the first assessment. Forty-eight pts (62%) remained progression free with a median follow up of 252 days (range, 56-785). CRS was noted in 67 pts (86%), with 6 (8%) grade 3 (G3), while 35 (45%) developed ICANS, with 8 (10%) G3. No grade 4 or higher CRS or ICANS were seen.
All pts developed ≥ G3 neutropenia and lymphopenia that lasted a median of 51 days (range 7-456), and 39 days (range 6-737) respectively. G3 and higher anemia and/or thrombocytopenia were seen in 49% of pts. Prolonged ≥ G3 cytopenias were seen in 72% of pts with 47%, 23%, and 29% showing prolonged neutropenia, anemia and thrombocytopenia respectively. Importantly, CRS was associated with a statistically significant increase (79% vs 27%) in risk of developing prolonged cytopenias (p=0.001). In addition, a biphasic pattern of hematologic toxicity in which late cytopenias recurred after a period of recovery, was noted in 8% of pts. These delayed cytopenias were associated with lymphocyte recovery after CAR T cell administration. Finally, 7% of pts with prolonged ≥ G3 cytopenias developed therapy related MDS: the median age in this group was 60 (range 50-74), with a median of 3 prior lines of therapy (range 2-4), and 75% having prior ASCT. Overall, infections were seen in 14 pts (18%) and 9 were after day 28. In pts with prolonged ≥ G3 neutropenia, rates of infection beyond day 28 (9%) were similar to those without prolonged neutropenia (8%). Use of GCSF did not correlate with increased CRS, ICANS or prolonged cytopenias.
Conclusion
Our real-world experience reported high response rates and favorable incidences of CRS, and ICANS with no grade 4 noted in comparison to that described in clinical trials and by others. We identified CRS as a significant risk factor associated with development of prolonged hematologic toxicity and this may indicate an underlying bone marrow suppressive effect of the inflammation associated with CRS. Like others, we also observed a biphasic hematologic toxicity associated with recovery from B cell aplasia. Due to significant rates of therapy related MDS, bone marrow evaluation before and after CAR T therapy should be considered, especially in patients with prior transplant. Last, despite the high rates of prolonged hematologic toxicity, infection rates were not higher in patients with prolonged neutropenia, underscoring the importance of supportive medical management.

Disclosures
Shouse: Kite Pharma: Honoraria, Speakers Bureau. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Herrera:AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Karyopharm: Consultancy. Zain:Seattle Genetics: Research Funding; Mundi Pharma: Research Funding; Kyowa Kirin: Research Funding. Siddiqi:BeiGene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Speakers Bureau; TG Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Oncternal: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Budde:Amgen: Research Funding; Merck: Research Funding; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Roche: Consultancy; Gilead Sciences: Consultancy; Kite, a Gilead Company: Consultancy.