T-cell prolymphocytic leukaemia associated with immune checkpoint inhibitor (pembrolizumab)

Background

Pembrolizumab is a member of the class of immunotherapies known as immune checkpoint inhibitors (CPIs) and has been widely used to treat a variety of cancers, including lung cancer. This treatment has been associated with a spectrum of immunotherapy-related adverse events (irAEs), including dermatitis, secondary hypothyroidism, pneumonitis, colitis, as well as infusion reactions. We describe a possible association between the use of pembrolizumab and the progression of secondary haematological malignancy, in this case T-cell prolymphocytic leukaemia (T-PLL). CPIs have been shown to improve survival in their target population, but the suspected potential to induce rapid progression of haematological malignancies can be fatal. This potential association warrants further evaluation to determine whether there is a true relationship between CPIs and development of T-cell lymphoproliferative disorders. If indeed there is an association, then further investigations are warranted to understand the mechanisms behind it to establish a causality hypothesis.

Case presentation

A man in his 60s we are describing here has a medical history of depression, chronic bronchitis, hypertension, atrial flutter, diabetes mellitus type 2, 80 pack-year history of tobacco use, squamous cell carcinoma of the lung with brain metastasis currently on CPI treatment and a recent new diagnosis of T-PLL. He was admitted to an outside hospital two times in the span of 2 weeks with complaints of dyspnoea. First presentation included acute worsening of shortness of breath and narrow complex tachycardia requiring cardioversion by emergency medical services. After discharge he presented a few days later to the emergency department with complaints of worsening dyspnoea and palpitations. He was noted to be in atrial flutter with rapid ventricular response. He was placed on bilevel positive airway pressure and started on rate-control medications. He subsequently was transferred to our hospital for higher level of care and haematological evaluation due to findings of rapidly worsening leucocytosis with lymphocyte predominance.

His home medications included allopurinol 300 mg daily, lurasidone 40 mg daily, vitamin B₁₂ with folic acid (1000–400 µg) lozenges sublingual once daily, prednisone 50 mg two times per day (started on recent previous admission for chronic obstructive pulmonary disease exacerbation), Colace 100 mg two times per day, albuterol 90 µg HFA 2 puffs by inhalation every 4 hours as needed, sotalol 80 mg two times per day, metformin 1000 mg tablet daily.

His oncological history is notable for a stage IIIB left upper lobe squamous cell carcinoma of the lung. He received two cycles of neoadjuvant chemotherapy with cisplatin and etoposide concurrent with radiation followed by left extrapleural pneumonectomy including partial pericardiectomy. A year later he developed recurrence of his lung cancer with a left medial frontal brain metastasis for which he received stereotactic radiosurgery. Molecular phenotyping of his resected malignancy demonstrated programmed death-ligand 1 (PD-L1) expression of greater than 90%. Therefore, he was started on palliative intent treatment with pembrolizumab as supported by the KEYNOTE-024 trial.1 He had received maintenance therapy with pembrolizumab for 19 months and the last dose was administered 2 weeks prior to presentation to our hospital.

A little over a year after starting pembrolizumab the patient developed persistent leucocytosis and hepatosplenomegaly. He underwent a bone marrow biopsy, which was consistent with a T-cell prolymphocytic polymorphic leukaemia diagnosis. The patient was scheduled to stop pembrolizumab and start alemtuzumab for treatment of this newly diagnosed leukaemia prior to this admission but the treatment had not yet been initiated.

Investigations

At the time of initial diagnosis with T-PLL the patient was noted to have persistent leucocytosis of about 20.4×10³/µL (4–9×10³/µL) on complete blood count (CBC) with an absolute neutrophil count of 12.0×10³/µL (1.5–5.2×10³/µL) and absolute lymphocyte count of 7.3×10³/µL (1.1–3.9×10³/µL). CBC also revealed a haemoglobin of 12.8 g/dL (13.6–16.7 g/dL), haematocrit 40.50% (40.0%–49.0%), platelet count of 315×10³/µL (130–350×10³/µL). The diagnosis of T-PLL was achieved by the assertion of two major criteria, known as T-PLL defining characteristics (T-cell clonality by flow cytometry and T-PLL phenotypical cells on blood and bone marrow) and one minor criterion (abnormality of chromosome 11q involving the ATM gene).2 Flow cytometry in October of 2020 revealed increased CD4/CD8 ratio with expansion of the CD4 positive T cells. Molecular genetics testing for T-cell receptor gamma gene rearrangement was suggestive of monoclonality. Bone marrow biopsy showed atypical CD4 positive T cells comprising 20% of the marrow cellularity with increase in the prolymphocytic forms consistent with T-cell lymphoproliferative disorder (figure 1). Cytogenetics analysis and fluorescence in situ hybridisation (FISH) of the peripheral blood revealed a complex, unstable karyotype with multiple structural and numerical abnormalities that included deletion of 8p and 11q involving the ATM gene. There was no rearrangement of the TCL1 gene on FISH analysis or presence of T-cell receptor rearrangement.

On presentation to our hospital initial CBC showed a white cell count of 475.5×10³/µL (4–9×10³/µL) with an absolute neutrophil count of 71.3×10³/µL (1.5–5.2×10³/µL) and absolute lymphocyte count of 9.5×10³/µL (1.1–3.9×10³/µL) with 361.4×10³/µL atypical immature T-PLL cells. Haemoglobin of 10 g/dL (13.6–16.7 g/dL), haematocrit 32.4% (40.0%–49.0%), platelet count of 115×10³/µL (130–350×10³/µL). His metabolic panel showed hyperkalaemia with potassium of 7.1 mEq/L (3.4–5.2 mEq/L), lactate dehydrogenase of 3211 IU/L (90–255 IU/L), phosphorus 4 mg/dL (2.4–4.7 mg/dL) and lactic acid 2.97 mmol/L (0.5–2.2 mmol/L).

CT angiogram was negative for pulmonary embolism. He was tested for SARS-CoV-2, which was negative, influenza and respiratory syncytial virus were also negative. Blood cultures were subsequently negative.

Differential diagnosis

Differential diagnoses were contemplated but due to rapid rise in white blood cell count and a known underlying haematological malignancy there were not many alternative hypotheses other than rapid progression of T-PLL. Additional differential diagnoses would include a possible infection, which can worsen leucocytosis in many haematological malignancies. However, complete infectious workup returned negative. Moreover, the degree of leucocytosis would make this differential very unlikely. Progression to active T-PLL was our main diagnosis, supported by the acute presentation, degree of haematological abnormality and lack of other conceivable differential diagnoses.

Outcome and follow-up

On transfer to our hospital, he was noted to be in respiratory failure requiring intubation. He was admitted to the critical care unit with haemodynamic instability requiring intravenous vasopressor support. He had severe leucocytosis causing tumour lysis and hyperviscosity syndromes. He was started on leucapheresis and continuous renal replacement therapy for worsening acute renal failure and hyperkalaemia. We started the process to emergently acquire alemtuzumab to administer in the hospital to treat active T-PLL. Unfortunately, the patient continued to deteriorate with no promise of improvement. Ultimately, the patient was made comfort care measures only by healthcare proxy and passed away shortly after in the presence of his family.