Development of Adult T-Cell Leukemia/Lymphoma During Treatment with PD-L1 Inhibitor for Lung Cancer

Abstract

Advancements in immunotherapy, the phenomenon of hyperprogression in cancer patients, have garnered increasing attention. We herein report a case of acute adult T-cell leukemia/lymphoma (ATL) that developed after administration of the programmed death-ligand1 inhibitor durvalumab in a patient with lung cancer. Although the patient was a carrier of human T-cell leukemia virus type 1 (HTLV-1), this was unknown prior to durvalumab treatment. HTLV-1 bZIP factor was detected in formalin-fixed lymph node tissue, confirming the diagnosis of ATL. Our findings suggest a potential association between immune checkpoint inhibition and ATL development in HTLV-1 carriers.

Introduction

Cancer treatment has advanced significantly in recent years, with immune checkpoint inhibitors (ICIs) gaining attention for their efficacy in a broad spectrum of malignancies (1). However, adverse effects related to excessive immune activation have been reported (2), which may influence treatment outcomes. Therefore, careful monitoring of the patients during treatment is essential. The programmed death-ligand 1 (PD-L1) inhibitor durvalumab is an effective treatment option for inoperable, advanced, or recurrent non-small cell lung cancer (NSCLC) (3).

This report describes a case of acute adult T-cell leukemia/lymphoma (ATL) that developed in a patient with NSCLC following durvalumab therapy, in which the human T-cell leukemia virus type 1 (HTLV-1) carrier status was unknown prior to the initiation of lung cancer treatment. Furthermore, our findings raise the question of whether or not anti-HTLV-1 antibody screening should be performed prior to ICI administration in cancer patients. This report further emphasizes the utility of a method that can detect monoclonal expansion of HTLV-1-infected cells, even in formalin-fixed, paraffin-embedded tissue sections.

Case Report

A 75-year-old man with a history of lung cancer presented with swelling of cervical lymph nodes during ongoing treatment. In November 20xx-1, he was diagnosed with right lower lobe squamous cell carcinoma of the lung (cT4N3M0, Stage IIIc). He underwent concurrent chemoradiotherapy consisting of cisplatin (40 mg/m²) and docetaxel (40 mg/m²) on days 1, 8, 29, and 36 and simultaneous chest radiation (60 Gy in 30 fractions). From January 20xx, consolidation therapy with durvalumab (10 mg/kg every 2 weeks), a PD-L1 inhibitor, was administered. He was born in Tokyo, and his social and family histories were unremarkable.

In August 20xx, during the 14th cycle of durvalumab, the patient presented with swelling near the left submandibular gland and was admitted for a further evaluation. Upon completion of chemoradiotherapy, a partial response was achieved for the lung cancer. This response was maintained after nine cycles of durvalumab treatment.

Laboratory findings showed a normal white blood cell count (4,300 /μL), lactate dehydrogenase (LD, 176 U/L), and mild elevation of C-reactive protein (0.53 mg/dL). No abnormal or atypical cells were detected in the peripheral blood and hypercalcemia was not observed. During this time, anti-HTLV-1 antibodies were not tested. Cytokeratin-19 fragment levels were within normal limits. No abnormalities were noted in thyroid-stimulating hormone, free triiodothyronine, or free thyroxine levels. Neck and chest contrast-enhanced computed tomography (CT) revealed lymphadenopathy measuring 2.5 cm in the left submandibular lymph node (Fig. 1) and 1 cm in the left deep cervical lymph node. No lymph node enlargement was observed in the abdominal or pelvic region. A comparison of chest contrast-enhanced CT revealed a significant reduction in the right lower lobe primary lung tumor compared to the pre-treatment images.

Figure 1.

Neck contrast-enhanced computed tomography (CT). Enlargement of the left submandibular lymph node was not observed on CT following 5 cycles of durvalumab (A). Upon reviewing the CT findings after 9 cycles, lymph node enlargement to 1 cm was noted (B). After 14 cycles, the lymph node had increased in size to 2.5 cm (C).

After hospitalization, a biopsy of the left submandibular lymph node was performed. A histopathological examination revealed a loss of follicular structures and diffuse distribution of small lymphocytes. Flow cytometry showed positivity for cluster of differentiation (CD) 2, CD3, CD4, CD25, CD45 and programmed cell death 1 (PD-1), and negativity for CD5, CD7, and CD8. Immunohistochemical staining was positive for CC chemokine receptor 4 (CCR4) (4,5). Simultaneous blood tests revealed the presence of HTLV-1 antibodies. Although frozen tissue was not preserved, and Southern blotting was not performed, ultrasensitive RNA in situ hybridization using RNAscope for HTLV-1 bZIP factor (HBZ-RNAscope) (6,7) was conducted on formalin-fixed paraffin-embedded tissues. Numerous cells were positive for HBZ (Fig. 2). Based on these findings, the patient was diagnosed with ATL.

Figure 2.

Identification of human T-cell leukemia virus type 1 (HTLV-1)-infected tumor cells. HTLV-1 was achieved using ultrasensitive RNA in situ hybridization using RNAscope for HTLV-1 bZIP factor (HBZ-RNAscope) in the cervical lymph node of the patient. Numerous cells showed positive signals of HBZ. Original magnification, ×400.

As the prognosis and disease course of ATL are worse than those of lung cancer, the treatment for lung cancer was discontinued, and the patient began CHOP therapy consisting of cyclophosphamide 750 mg/m², hydroxydaunorubicin 50 mg/m², and vincristine 1.4 mg/m² on day 1 and prednisolone 100 mg/day from days 1 to 5 for ATL. At the time of initiation of CHOP therapy, the serum LD level was 429 U/L and the soluble interleukin-2 receptor (sIL-2R) level was 8,961 U/mL. Starting from the second cycle, the treatment was further augmented with mogamulizumab, an anti-CCR4 antibody. The therapy is currently ongoing. After initiating CHOP therapy, lymphadenopathy reduced, and both LD and sIL-2R levels decreased. Furthermore, during the period between the discontinuation of the PD-L1 inhibitor and the start of CHOP, there was no change in lymphadenopathy, and no progression of lung cancer was observed.

The clinical course of the patient is summarized in Fig. 3.

Figure 3.

Clinical course of our patient who developed adult T-cell leukemia/lymphoma following durvalumab therapy. LD: lactate dehydrogenase, CYFRA: cytokeratin-19 fragment, sIL-2R: soluble interleukin-2 receptor, CHOP: cyclophosphamide, hydroxydaunorubicin, vincristine (oncovin), prednisolone

Discussion

The number of HTLV-1 carriers is approximately 1.08 million. The lifetime risk of developing ATL among HTLV-1 carriers is reported to be 2-5%, with nearly 1,000 new cases annually (8). The modes of transmission include mother-to-child transmission via breast milk, blood-borne transmission through transfusion, and sexual transmission. The clinical types of ATL include acute, lymphomatous, chronic, and smoldering forms (9). Among these, acute, lymphomatous, and chronic ATL have poor prognostic factors (such as abnormal levels of LD, albumin, or blood urea nitrogen) and are classified as aggressive ATL. Aggressive ATL tends to progress rapidly and has a median survival of only 13 months, making it one of the most aggressive hematological malignancies.

In the present case, no abnormal or atypical cells were detected in the peripheral blood, and there were no skin lesions, suggesting that ATL was unlikely to have developed from an asymptomatic carrier prior to durvalumab administration. Enlargement of the left submandibular lymph node was not observed on CT following 5 cycles of durvalumab. However, upon reviewing the CT findings after 9 cycles, lymph node enlargement to 1 cm was noted, and on CT findings after 14 cycles, the lymph node had increased in size to 2.5 cm.

Wartewig et al. (10) reported that PD-1 functions as a tumor-suppressive molecule in T-cell tumors, and administration of PD-1 or PD-L1 inhibitors inhibits this function, potentially promoting tumorigenesis. A previous report described three cases of ATL that rapidly deteriorated after a single cycle of the PD-1 inhibitor nivolumab (11). These cases included one with the indolent chronic type, one with the smoldering type characterized by a very slow progression, and one with the acute type, which had been stable prior to treatment. In contrast, a separate report of eight cases of aggressive ATL, all of which received at least one cycle of nivolumab, found no cases of disease progression (12). However, given the small sample sizes in these reports, the safety of PD-1 inhibitors in ATL remains unclear.

In a study of lung cancer patients receiving ICIs, 3 of 67 patients were anti-HTLV-1 antibody-positive asymptomatic carriers (13). Among these, 2 patients received nivolumab (at 1 or 4 months), and 1 patient received pembrolizumab for more than 16 months without developing ATL. The authors suggest that the use of PD-1 inhibitors in the treatment of cancers with a poor prognosis, such as advanced NSCLC, should not be restricted to such patients. However, a more recent report described a lung cancer patient who developed acute ATL after receiving two cycles of nivolumab (14). In this case, ATL was not diagnosed before nivolumab administration, and anti-HTLV-1 antibody was found to be positive only after the onset of acute ATL.

Our patient also lacked a family history of HTLV-1-related diseases, and there were no clinical findings suggestive of ATL, which is why anti-HTLV-1 antibody testing was not performed before durvalumab administration. Although ICIs have demonstrated considerable efficacy in cancer treatment, some patients may develop progressive disease. It should be considered that asymptomatic HTLV-1 carriers might be at risk for developing symptomatic ATL. Therefore, measuring HTLV-1 antibodies prior to ICI therapy could be valuable in identifying patients at risk of ATL. Patients with positive results should be informed of the potential risk of ATL before proceeding with cancer treatment. Furthermore, with the accumulation of such case reports, it is essential to assess whether or not HTLV-1 antibody testing should be routinely conducted prior to initiating ICI therapy.

To exclude the possibility that HTLV-1-infected individuals may develop T-cell tumors other than ATL, it is essential to demonstrate that the tumor is caused by monoclonal expansion of HTLV-1-infected cells. Methods such as Southern blotting (15) and next-generation sequencing (16) are commonly employed to demonstrate clonality; however, these tests are limited by insurance restrictions. Furthermore, their complex procedural requirements render them impractical for routine use in general hospital laboratories. In addition, Southern blotting necessitates the use of frozen or fresh tissue samples as well as relatively large quantities of material. Given that there have been numerous cases clinically diagnosed as ATL in which these tests could not be performed (14), there remains a strong need for the development of novel diagnostic methods.

HBZ is the only gene that is consistently expressed in both HTLV-1-infected and ATL cells, making it a valuable marker for identifying infected cells. HBZ-RNAscope, a sensitive RNA in situ hybridization technique, can detect HBZ RNA, which is persistently expressed in both HTLV-1-infected and ATL cells from formalin-fixed tissues. This method enables clear visualization of the localization of HTLV-1-infected tumor cells (6), positioning it as a potentially valuable tool for routine clinical practice. In addition, it facilitates both the accurate and rapid pathological diagnosis of ATL and is expected to contribute significantly to the understanding of the pathophysiology of the disease.

The authors state that they have no Conflict of Interest (COI).