Sequential treatment with valemetostat and conventional anti‐cancer drugs for refractory aggressive adult T‐cell leukemia/lymphoma: A case report

Abstract A 79‐year‐old man presented with respiratory distress associated with a mediastinal mass and pleural effusion, and was diagnosed as having adult T‐cell leukemia/lymphoma. The patient was highly refractory to anticancer drugs and radiotherapy from the time of onset and had progressive respiratory deterioration. However, his condition became stable with the administration of valemetostat for 11 days, and subsequent low‐dose‐anticancer agents led to a rapid improvement accompanied by high fever and a surge in C‐reactive protein. In this case, the in vivo priming effect of valemetostat on tumor cells may have increased the sensitivity of these cells to conventional anti‐cancer drugs.

Pathological examination of a blocked specimen of pleural effusion cells confirmed peripheral T-cell lymphoma (positive for CD3, CD4, CD25, and CD164), clinically diagnosed as ATL.Initially, the patient underwent mogamulizumab and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), resulting in a reduction of enlarged mediastinal lymph nodes and pleural effusion.However, this effect was short-lived, and the disease progressed rapidly, leading to a worsened respiratory status.Subsequently, the patient underwent another course of CHOP followed by two courses of combined therapy involving carboplatin, etoposide, and irinotecan.Despite these treatments, the patient only experienced a temporary response, prompting the administration of irradiation for the mediastinal mass.Unfortunately, the response to radiation therapy was also temporary, necessitating an additional course of similar chemotherapy.However, the disease continued to progress rapidly, further deteriorating the patient's respiratory status.The subsequent treatment course is shown in   as confirmed by a stable disease based on laboratory findings, there was no improvement in respiratory function.After the administration of valemetostat for 11 days, a reduced-dose GCD regimen was administered, resulting in rapid improvement of the respiratory status.
However, 4 days after low-dose GCD, the patient presented with high fever, respiratory deterioration, and a rapid increase in C-reactive protein (CRP).There was no evidence of disease progression or infection, the administration of a low dose of prednisolone rapidly improved these findings, and sIL2R also showed a rapid decrease.Considering the sequence of events outlined above, the fever and elevated CRP were deemed to be linked to tumor lysis.Despite the reduction in GCD dosage, platelet levels fell to 22 × 10 9 /L, prompting the resumption of valemetostat following confirmation of an upward trend in the platelet count.Subsequently, the patient remained on valemetostat administration for the next 5 months, maintaining a partial remission characterized by decreased mediastinal lymph node enlargement, notable improvement in pleural effusion, and marked improvement in laboratory parameters.Throughout the treatment period, aside from a mild taste disturbance, no significant adverse effects were observed.

DISCUSSION
Valemetostat has been demonstrated to show anti-cancer activity by inducing the expression of various genes, including tumor suppressor genes, through the inhibition of histone protein methylation [3].
However, its variable mechanism of action remains unclear, and there may be marked variations among individuals.A limited-scale clinical trial reported a 48% efficacy rate with valemetostat used alone [2].While individual detailed information was not available, given the average 60-day interval from the last treatment, it can be inferred that the registered cases were likely characterized by a relatively slow progression.Therefore, the efficacy of valemetostat monotherapy in aggressive, treatment-resistant cases encountered in clinical practice is considered to be limited.In this case, it is plausible that the in vivo priming effect of valemetostat on tumor cells increased the sensitivity of these cells to conventional anti-cancer drugs.Thus, how to select more appropriate concomitant anti-cancer agents and administration schedules needs to be clarified in the future.However, several issues may arise with the combination of valemetostat and other drugs: 1, The effectiveness of valemetostat may be limited to a subset of cases, and combining it with other drugs may only increase adverse effects, such as thrombocytopenia, without improving efficacy.
2, Concerns over increased adverse effects may lead to a reduction in the intensity of conventional anticancer agents, ultimately decreasing treatment efficacy.An initial trial of valemetostat as a single agent for a brief period to assess the efficacy, as conducted in this case, is one of the desirable management strategies.Given the difficulty in improving the prognosis of ATL patients with conventional chemother-apy, the development of innovative therapies using novel agents is warranted.
ray indicated a large amount of pleural effusion.(B) Computed tomography revealed enlarged lymph nodes in the mediastinum and pleural effusion.(C) Positron emission tomography showed a high concentration in the mediastinal mass.

Figure 2 .
Figure 2.For the 7th course of chemotherapy, GCD therapy (comprising carboplatin, gemcitabine, and dexamethasone) was chosen.However, its effect was short-lived, with disease exacerbation noted

TA B L E 1
Laboratory findings at diagnosis.