MSK ASH 2023 Insights: Managing and Reducing Treatment-Related Toxicities

Dr. Cy Wilkins, Dr. Jae Park, Dr. Karthik Nath, Dr. Alina Markova, and Dr. Roni Shouval presented research related to managing and reducing treatment-related toxicities at the 2023 ASH meeting.

(Clockwise from upper left) Dr. Cy Wilkins, Dr. Jae Park, Dr. Karthik Nath, Dr. Alina Markova, and Dr. Roni Shouval presented research related to managing and reducing treatment-related toxicities at the 2023 ASH meeting.

Memorial Sloan Kettering Cancer Center (MSK) experts shared the results of their latest research at the 65th American Society of Hematology (ASH) Annual Meeting, held in San Diego, December 9 to 12, 2023.

Highlights included essential insights into managing and reducing treatment-related toxicities, including factors that predict adverse outcomes with CAR T cell therapy, a promising prophylactic therapy for reducing CAR T cell therapy-related neurotoxicity, a novel treatment for reducing cutaneous graft-versus-host disease (GVHD), and a lack of survival benefit for a platelet-boosting drug in patients with solid tumors who experienced chemotherapy-induced thrombocytopenia (CIT).

CAR T cell therapy is an effective treatment for relapsed/refractory large B cell lymphoma (LBCL). However, morbidity and mortality related to toxicity from CAR T therapy are significant concerns.

Hematologist-oncologist Roni Shouval, MD, PhD, an Assistant Attending physician on the BMT and Cellular Therapy Service at MSK, presented results from the largest analysis to date of toxicities due to CD19-directed CAR T cell therapy on behalf of an international research team. They retrospectively investigated patterns, risk factors, and the implications of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19-targeted CAR T therapy in patients with LBCL.

The analysis included outcomes for 1,916 patients treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel between 2018 and 2020, as reported to the Center for International Blood and Marrow Transplant Research. 75% of patients received axi-cel, and 25% received tisagenlecleucel. The investigators analyzed the incidence, severity, and onset timing of CRS and ICANS, the factors associated with these outcomes, and their impact on overall survival (OS).

The median age of patients was 64 years, and 67% did not receive bridging therapy. CRS occurred in 75% of patients, with 9% experiencing severe CRS grades 3 or higher. The median time to toxicity was four days for CRS and less than seven days for ICANS. Nearly all patients (98%) who developed ICANS also experienced CRS.

The use of axi-cel was associated with a significantly higher risk of developing CRS (odds ratio (OR) = 4.6) and ICANS (OR = 5.85) compared with tisagenlecleucel. Other factors associated with CRS incidence were female gender (OR = 1.39) and high lactate dehydrogenase at the time of infusion (OR = 1.56). Additional factors associated with the development of ICANS included age over 65 (OR = 1.83), Karnofsky Performance Status below 80% (OR = 2.48), treatment-resistant disease at infusion (OR = 1.98), and untreated disease relapse (OR = 2.62).

After a median follow-up of 14 months, the estimated 12-month OS was 62%, progression-free survival was 42%, and treatment-related mortality was 4.3%. Overall, grade 3 or higher CRS or ICANS and early onset ICANS were significantly associated with higher mortality.

These results underscore the need to develop novel strategies to mitigate the incidence of higher-grade CRS and ICANS to improve patient outcomes.

Read ASH 2023 Abstract 355. Explore MSK clinical trials for CAR T cell therapies. Access disclosures for Dr. Shouval.

Tocilizumab is effective for managing CRS after CAR T cell therapy, but there are no targeted therapies for ICANS. Rates of severe ICANS are approximately 30% in patients who receive the commercial CAR T cell therapies axi-cel and brexucabtagene autoleucel (brexu-cel).

Anakinra is an interleukin-1 receptor antagonist shown to reduce CAR T-related immune toxicities without affecting efficacy in preclinical models. Hematologist-oncologist Jae Park, MD, Chief of the Cellular Therapy Service at MSK, has been leading a phase 2 trial of prophylactic anakinra to prevent severe ICANS in patients receiving commercial CAR T cell therapies for relapsed/refractory B-cell lymphoma (NCT04148430).

Dr. Park and colleagues reported results from cohort 1 in Nature Medicine in July 2023. The rate of severe ICANS was 9.7% in 31 patients with relapsed/refractory large B cell lymphoma or mantle cell lymphoma who received subcutaneous anakinra from day 2 to at least day 10 post-CAR T infusion.

At ASH 2023, hematologist-oncologist Karthik Nath, MBBS, PhD, a member of the Cellular Therapy Service at MSK, presented results from cohort 2 of the trial. A complete prophylactic strategy was utilized in cohort 2 with patients receiving anakinra from day 0 to at least day 7 post-CAR T infusion. Similar to cohort 1, the study design utilized a dose-escalation strategy where anakinra could be increased up to 100 mg every six hours and extended beyond 7 days for patients with persistent or progressive CRS or ICANS. Thirty patients with relapsed/refractory diffuse large B cell, high-grade B cell, follicular, or mantle cell lymphoma received anakinra.

Among the total group, 19 patients received axi-cel (63%), 5 received brexu-cel (17%), 4 received lisocabtagene maraleucel (13%), and 2 received tisagenlecleucel (7%). The rate of severe ICANS in cohort 2 was 10%, and all events were grade 3 only, with no grade 4 or 5 events. The findings from cohort 2 replicated and validated those seen in cohort 1.

The authors concluded that the early administration of anakinra and risk-adapted dosing strategy likely contributed to the low rates of severe ICANS. Together, the results from both cohorts demonstrate that prophylactic anakinra is safe, feasible, and reduces the rate of severe ICANS without affecting CAR T cell therapy efficacy in patients with B cell lymphoma.

Read ASH 2023 Abstract 357. Explore MSK clinical trials for lymphoma. Access disclosures for Dr. Park and disclosures for Dr. Nath.

Chronic Cutaneous Graft Versus Host Disease: Topical Ruxolitinib Safe and Effective

Topical steroids are standard therapy for patients who develop cutaneous chronic graft-versus-host disease (GVHD) after bone marrow transplantation. However, steroids are associated with significant side effects and may not fully treat the condition, prompting the use of systemic therapies. Oral ruxolitinib, a JAK1/2 inhibitor, is FDA-approved for the treatment of acute and chronic GVHD.

MSK dermatologist Alina Markova, MD, presented the results of the first study to characterize the effect of a topical JAK1/2 blockade on cutaneous chronic GVHD. The single-center, phase 2 trial (NCT03954236) evaluated the safety and efficacy of ruxolitinib 1.5% topical cream in patients 12 years and older with nonsclerotic or superficially sclerotic cutaneous GVHD affecting 2% or more of their body surface area. The research team included experts from the Adult Bone Marrow Transplantation Service and the Pediatric Stem Cell Transplantation and Cellular Therapies Service at MSK.

A total of 24 patients were randomly assigned to receive ruxolitinib cream to the left or right side of the face or body and a placebo cream to the contralateral side twice daily for 28 days. The median time from transplant to enrollment in the study was 455 days, and 132 days from the onset of cutaneous chronic GVHD to enrollment. Most patients had nonsclerotic cutaneous GVHD with lichen planus-like, papulosquamous, or maculopapular rash/erythema features. Patients were heavily pretreated with a median of two prior systemic treatments, and most had not responded to two or more topical therapies, including steroids, calcineurin inhibitors, and phototherapy. 

The ruxolitinib cream significantly reduced body surface area affected by cutaneous GVHD compared to the placebo cream from day 1 (14% BSA) to day 14 (7.7% with ruxolitinib versus 10.4% with placebo) and to day 28 (6.2% with ruxolitinib versus 10.4% with placebo). Scores for Physician’s Global Assessment and Composite Assessment of Index Lesion Severity were significantly improved with ruxolitinib starting on day 14 and continuing into day 28.

RNA sequencing of skin samples collected using noninvasive adhesive patches from ruxolitinib- and control-treated pairs at day 28 found 324 differentially expressed genes. The investigators also identified genomic signature differences in interleukin-12 signaling between responders and nonresponders.

These encouraging results support a larger clinical trial to further evaluate the efficacy and safety of topical ruxolitinib in patients with cutaneous chronic GVHD.

Read ASH 2023 Abstract 777. Explore MSK clinical trials for GVHD. Access disclosures for Dr. Markova.

Solid Tumor Chemotherapy Induced Thrombocytopenia: Lack of Survival Benefit with Romiplostim Administration

The thrombopoietin receptor agonist romiplostim is commonly used off-label to increase platelet count and facilitate the administration of chemotherapy in patients with solid tumors who experience chemotherapy-induced thrombocytopenia (CIT). In a phase 2 trial led by MSK (NCT02052882), romiplostim effectively corrected CIT and allowed for resumption of chemotherapy without recurrence of thrombocytopenia or dose reduction of chemotherapy in most patients. However, whether the platelet booster improves clinical outcomes has yet to be established.

MSK hematologist-oncologist Cy R. Wilkins, MD, presented the results of a retrospective cohort analysis that assessed the impact of romiplostim on OS in patients with solid tumors with CIT compared to a matched control population receiving granulocyte-colony stimulating factor (G-CSF).

Patients were matched using a logistic regression model based on primary cancer site, presence or absence of metastatic disease, age, time from cancer diagnosis to treatment with romiplostim or G-CSF, number of prior lines of therapy, comorbidities, and platelet counts. There were 162 patients in the romiplostim and 609 in the G-CSF analysis cohorts.

The analysis revealed no difference in OS between the romiplostim and G-CSF cohorts. The median OS was 12.6 months for patients who received G-CSF versus 14.5 months for romiplostim (log-rank P = 0.81). Lack of survival benefit was seen across different platelet count intervals.

These results highlight an urgent need to conduct additional studies evaluating clinically meaningful endpoints, such as survival, when assessing the use of thrombopoietin receptor agonists for the management of CIT.

Read ASH Abstract 801. Explore MSK clinical trials. Access disclosures for Dr. Wilkins.

The researchers above receive essential philanthropic support from the MSK Giving community, including the Lymphoma Research Foundation, the Steven A. Greenberg Charitable Trust, and Swim Across America, Inc. for Dr. Shouval,  Comedy vs Cancer, Cycle for Survival, and Douglas and Lisa Harris for Dr. Park, and The Society of MSK for Dr. Markova.

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