Factors Affecting Hemopoietic Recovery in Patients Following CAR T-Cell Therapy

Craig Sauter, MD

Craig Sauter, MD

Following CAR T-cell therapy, patients with hematologic malignancies often develop cytopenia, but to date, there are limited data around the occurrence of cytopenia and the pathobiology that contributes to their onset, said Craig Sauter, MD.

In an effort to shed light on this issue, investigators at Memorial Sloan Kettering Cancer Center (MSKCC) carried out a retrospective review of real-world patients, providing the largest body of proof for hemopoietic recovery following CAR T-cell therapy and the factors that contribute to recovery.

The analysis included 115 adult patients who were given CAR T-cell therapy at MSKCC. The results of the analysis show that in 83 of those patients, that by 1 month, there was 61% hemoglobin recovery, 51% platelet improvement, 33% absolute neutrophil count (ANC) recovery, and 28% white blood cell count recovery. By 3 months, these percentages increased to 93%, 90%, 81%, and 59%, respectively.

Upon further examination, the investigators found that in cases where recovery of hemoglobin, platelets, ANC, and complete count values did not occur at 1 month in some patients, there was a statistically significant association with the type of CAR construct. Specifically, patients with higher-grade cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and higher peak C-reactive protein and ferritin were less likely to recover.

The lack of hemoglobin recovery at 1 month was also found to be associated with lymphodepletion using high dose cyclophosphamide. The analysis showed that 58% of these patients recovered, whereas 42% do not (P=.01). Acute lymphocytic leukemia diagnoses were also associated with no recovery of hemoglobin, as recoveries and non-recoveries were observed in 65% and 35% of patients, respectively (P≤.0001).

Patients who received prior homologous stem cell transplantation (HCT) were less likely to have ANC recovery. The investigation showed that 87% did recover and 13% did not (P= .004). Subjects who had received more than 3 prior lines of HCT were even less likely to have had ANC recovery (78% vs. 22%, P=.04)

In an interview withTargeted Oncology at the2020 Transplantation & Cellular Therapy Meetings, Sauter, a hematologic oncologist and clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, discussed the retrospective real-world review of patients with hematologic malignancies who developed cytopenia post-CAR T-cell therapy. He also made predictions about the role of CAR T cells in the future.

TARGETED ONCOLOGY: What was the rationale for your retrospective review?

Sauter: This is an anecdotal observation in real-world patients. The FDA approval experience of CAR-modified T cells is that patients often are left with moderate to severe cytopenia for a prolonged period. This includes lymphopenia and occasional transfusion requirements going out weeks to months, for both platelets and red blood cells. If the patient failed their CAR T-cell therapy, this becomes a critical issue if patients need further therapy because if they progress, they will require further cytotoxic therapy with an adequate amount of hematopoietic reserve to be able to tolerate the CAR T-cell therapy. This is a key issue, and the pathophysiology of this is being investigated. Going forward, we hope to have more insight to circumnavigate this complication.

TARGETED ONCOLOGY: What is important for community oncologists to know about this analysis?

Sauter: Be vigilant of cytopenia following CAR T-cell therapy, particularly around anti-microbial prophylaxis for viruses as well as other organisms such as fungi orPneumocystis jirovecipneumonia. Physicians should be more vigilant in patients who are profoundly lymphopenic.

TARGETED ONCOLOGY: How do you see the role of CAR T-cell therapy evolving in 10 years?

Sauter: In diffuse large B-cell lymphoma, the randomized phase III studies like ZUMA-7 (NCT03391466), BELINDA (NCT03570892), and TRANSFORM (NCT03575351) are going to be key to answering the question of whether CAR T-cell therapy should be moved up to patients that fail rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)-like chemotherapy and initial induction as opposed to requiring 2 lines of therapy, salvage therapy, or autologous transplant.

TARGETED ONCOLOGY: What issues still need to be addressed in this space?

Sauter: We understand that the majority of patients are going to progress with their lymphoma following the administration of CAR-modified T cells. Enhancing efficacy, especially in patients with large tumor volume and tumor bulk [will be important]. With some of the products, toxicity mitigation is important. Being able to prospectively investigate strategies to mitigate toxicities as well as enhancing efficacy are going to be key to [improving treatment with CAR-modified T cells in the future].

TARGETED ONCOLOGY: What is the key takeaway from your presentation?

Sauter: While this proof-of-concept and this therapy are exciting, the majority of patients are progressing after treatment with the presumed intent of cure. We have to improve upon efficacy.

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Reference:

Jain T, Knezevic A, Pennisi, M et al. Hematopoietic recovery following chimeric antigen receptor t cell (car t) therapy in hematological malignancies. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020. Orlando, FL. Abstract 84. https://bit.ly/2V57Qg1.