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Pretransplantation mogamulizumab increases risk for GVHD–related mortality
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Receipt of mogamulizumab prior to allogeneic hematopoietic stem cell transplantation significantly increased risk for graft-versus-host disease–related mortality in adults with T-cell leukemia/lymphoma, according to a retrospective analysis of a large database study.
Thus, mogamulizumab (Poteligeo, Kyowa Hakko Kirin) should be “cautiously used” in patients with T-cell leukemia/lymphoma (ATLL) who are eligible for allogeneic HSCT, according to the researchers.
Regulatory T cells play a significant role in the maintenance of immune tolerance after adults with ATLL undergo allogeneic HSCT (allo-HSCT), which is an important treatment option for these patients.
Mogamulizumab— an anti-CCR4 monoclonal antibody — was recently approved for the treatment of ATLL in Japan. However, because regulatory T cells express CCR4, they are depleted in vivo for several months after mogamulizumab is administered.
“Therefore, major concerns exist about the use of mogamulizumab before allo-HSCT because pretransplantation administration of mogamulizumab could theoretically exacerbate acute graft-versus-host disease (GVHD) in patients with ATLL; depletion of regulatory T cells abrogates the maintenance of immune tolerance after allo-HSCT, as suggested in animal models,” Shigeo Fuji, MD, from the department of hematopoietic stem cell transplantation at the National Cancer Center Hospital, and colleagues wrote. “However, no direct evidence has demonstrated regulatory T-cells depletion in humans.”
The researchers conducted nationwide survey in Japan of 996 allo-HSCT recipients (median age, 55 years; range, 20-69) with aggressive ATLL to construct a new large database. All patients received intensive chemotherapy with multiple chemotherapeutic drugs as first-line therapy; 82 patients had received mogamulizumab.
Patients who received mogamulizumab tended to be older (median age, 61 years vs. 55 years) and were more likely to have acute-type ATLL (84.1% vs. 70.1%; P < .01 for both) compared with patients who did not receive mogamulizumab.
Median interval from the last administration of mogamulizumab to allo-HSCT was 45 days (range, 9-1,077). The number of administered doses totaled five or more in 37 patients, fewer than five in 40 patients, and was unknown for five patients.
Grade 2 to grade 4 acute GVHD occurred in 58% of patients in the mogamulizumab group compared with 43.6% of patients in the non-mogamulizumab group (RR = 1.33; 95% CI, 1.09-1.62); grade 3 to 4 acute GVHD occurred in 30.9% of patients in the mogamulizumab group and 17.2% of patients in the non-mogamulizumab group (RR = 1.8; 95% CI, 1.26-2.57).
A greater proportion of patients in the mogamulizumab group received systemic corticosteroids for acute GVHD (73.4% vs. 23.5%; RR = 1.23; 95% CI, 1.04-1.44); of these patients, those who had received mogamulizumab also were more likely to become refractory to systemic corticosteroids (48.9% vs. 23.5%; RR = 2.09; 95% CI, 1.47-2.96).
Patients treated with mogamulizumab demonstrated a higher 1-year cumulative incidence of nonrelapse mortality (43.7% vs. 25.1%; HR = 1.93; 95% CI, 1.29-2.88), as well as inferior 1-year OS (32.3% vs. 49.4%; HR = 1.67; 95% CI, 1.23-2.26)
Researchers then divided the mogamulizumab arm into two groups — those who had received mogamulizumab at least 50 days prior to undergoing allo-HSCT (n = 38) and those who underwent allo-HSCT fewer than 50 days after receiving mogamulizumab (n = 42).
A greater proportion of patients who received mogamulizumab fewer than 50 days before allo-HSCT experienced nonrelapse mortality by 1 year (55.1% vs. 34.4%) and fewer achieved 1-year OS (20.2% vs. 44.1%; P < .01 for both).
“The results provoke the discussion of how mogamulizumab can be incorporated in patients with ATLL who are eligible for allo-HSCT,” the researchers wrote.
Fuji and colleagues recommended that clinicians consider the risks and benefits of mogamulizumab before its use in transplant-eligible patients.
“At present, it seems reasonable to pay careful attention to the use of mogamulizumab for patients with ATLL or other diseases who are eligible for allo-HSCT,” they added. “The clinical safety and efficacy to intensify GVHD prophylaxis should be explored in patients who receive mogamulizumab before allo-HSCT.” – by Kristie L. Kahl
Disclosure: Fuji receives honoraria from Kyowa Hakko Kirin. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Peter Riedell, MD, and Sonali M. Smith, MD
The paper by Fuji and colleagues from Japan is a provocative and cautionary note in the development of new agents targeting the immune milieu of malignancies. Adult T-cell leukemia/lymphoma (ATLL) is a rare and highly aggressive subtype of peripheral T-cell lymphoma associated with the human T-cell leukemia virus type I and with essentially no long-term survivors following standard therapy.
An important advance is the development of mogamulizumab (Poteligeo, Kyowa Hakko Kirin), a monoclonal antibody targeting CCR4, which is expressed on over 90% of malignant ATLL cells. Mogamulizumab monotherapy has conferred an overall response rate of 50%, and an international prospective randomized trial from non-Asian countries presented at this year’s ASCO Annual Meeting showed a significant benefit compared with investigator’s choice in relapsed disease. Mogamulizumab is approved in Japan for treatment of ATLL and is undergoing active testing in other T-cell malignancies.
However, CCR4 also is expressed in nonmalignant T-cell subsets, specifically T-regulatory cells (Treg), which are thought to play a pivotal role in antitumor immunity and immune tolerance following allogeneic hematopoietic stem cell transplant. Treg depletion following mogamulizumab exposure is well established and theoretically could contribute to post-allogeneic HSCT toxicity.
With this hypothesis in mind, Fuji and colleagues compared outcomes in 82 patients receiving mogamulizumab at any time prior to allogeneic HSCT with outcomes from 914 patients not receiving the agent. The key findings are that pretransplant mogamulizumab was associated with increased risk for grade 3 to grade 4 acute graft-versus host disease (RR = 1.8; P < .01), higher 1-year cumulative incidence of nonrelapse mortality (43.7% vs. 25.1%; P < .01), higher incidence of corticosteroid resistance (48.9% vs. 23.5%; P < .01) and inferior OS (49.4% vs. 32.3%; P < .01).
Patients receiving mogamulizumab were older, had more-aggressive acute-type ATLL, and had a higher likelihood of receiving reduced-intensity condition. Notably, the timing of mogamulizumab exposure appears critical, as most of the toxicity occurred in patients receiving the agent within 50 days of allogeneic HSCT. Whether this observation is a function of mogamulizumab half-life or the timing of Treg repletion is unclear.
This study has important broader implications for mogamulizumab and other T-cell modifying agents, such as checkpoint inhibitors. Although there are no large published series, emerging anecdotal reports of increased GVHD and veno-occlusive disease have prompted a label modification of the PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb), and it is possible that this is a class effect, although the precise mechanisms of increased toxicity may differ.
The current analysis, thus, serves as an important consideration in further development of these otherwise exciting and active agents. In particular, the timing of agents targeting malignant and nonmalignant T cells prior to cellular therapies, such as allogeneic HSCT or CAR-T cell treatment, will need to be carefully studied to maximize benefit and minimize toxicity in a new era of therapeutic options.
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Phillips AA, et al. Abstract 7501. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Riedell and Smith report no relevant financial disclosures.
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