Resolution of massive pleural effusion due to lymphoma with intrapleural interleukin‐2
Authors: Dahlia Elkadi, Peter H. Wiernik, Tommy R. Tong
Journal: American Journal of Hematology (2009)

Interleukin-2 has therapeutic activity against mouse lymphomas [1], human lymphoma xenograft mouse models [2], and human B- and T-cell lymphomas clinically [3-6]. Furthermore, some data suggest that the agent is synergistic with rituximab against human B-cell lymphoma [7]. Intrapleural interleukin-2 has been reported to resolve malignant pleural effusions in patients with mesothelioma [8] and lymphoma [9]. We recently successfully treated a woman with a massive malignant pleural effusion secondary to B-cell lymphoma with intrapleural interleukin-2 and report the details of her case here. The patient, a 56-year-old African-American woman presented to the emergency room with progressively worsening shortness of breath for 1 month and a 20 pound weight loss over 4 months. She had no significant past or family medical history. Anasarca, ascites, a right large pleural effusion and generalized lymphadenopthay were noted on physical examination. A CT scan demonstrated hepatosplenomegaly, para-aortic lymphadenopathy, a large right pleural effusion, and a small pleural effusion on the left (see Image 1). She was severely anemic, with a hemoglobin concentration of 4.8 gm/dl and a hematocrit of 13.7%, normal WBC and differential WBC, as well as a normal platelet count. After admission to the hospital, an axillary lymph node biopsy as well as bone marrow biopsy and aspiration was performed. Both biopsies yielded a diagnosis of low-grade B-cell lymphoma. CT chest scan revealing bilateral pleural effusion, right greater than left. The patient received a regimen of rituximab, cyclophosphamide, vincristine, and prednisione and within minutes became hypoxic and was thought to have had an allergic reaction to rituximab. She was treated with solumedrol and diphenhydramine and responded well. However, on the following day, she developed acute respiratory distress which required intubation and she was transferred to the intensive care unit. Appropriate investigations excluded pulmonary embolus or cardiac dysfunction but her pleural effusions had increased. A right chest tube was placed and 1 liter of sterile pleural fluid devoid of tumor cells was withdrawn. The patient improved and she was discharged home on the seventh hospital day. She returned 3 weeks later for her second cycle of chemotherapy and was found again to be severely anemic with a hemoglobin of 5.6 gm/dl and a hematocrit of 19% and was admitted for blood transfusion. Several hours later, she developed severe respiratory distress and arterial blood gas studies revealed respiratory acidosis. She was started on Bipap but her condition continued to deteriorate. A right thoracentesis was performed and 1.5 liters of pleural fluid was removed, but the patient did not improve. She was intubated and readmitted to the intensive care unit. A CT of the chest revealed bilateral pleural effusions and alveolar infiltrates. Bilateral thoracenteses were performed and pleural fluid contained lymphoma cells. Her pleural effusions continued to worsen, and a pleural biopsy was diagnostic of B-cell lymphoma ( Image 2-Image 5). Parietal pleura infiltrated by monotonus small lymphoid cells with scanty cytoplasm and slightly irregular, round oval nuclei, and dense chromatin. Occasional nuclei are enlarged but show similar nuclear morphology (arrow head). Parietal pleura lymphoma cells infiltrate extrapleural adipose tissue. Lymphoma aggregates are present in the lung parenchyma subjacent to the visceral pleura. Arrowhead shows environmental pigments in subpleural lymphatic system. CD20 diffuse strong membranous staining of lymphoma cells. Intrapleural interleukin-2, 21 million units was instilled through her chest tube daily for 5 days. The patient tolerated the instillation with no side effects observed. She also had left pleurodesis with talc. By the fourth day of intrapleural treatment, the patient began to improve. On day 10, a CT scan (see Image 6) demonstrated the absence of pleural effusions and, to date, she has remained free of effusions for more than 2 years. She completed five cycles of R-CVP with partial response, followed by rituximab and IL2 of which she completed two cycles with only stable disease as a result. Subsequently, therapy was changed to bendamustine for 10 cycles that resulted in a complete remission, which continues. CT of the chest showing complete resolution of pleural effusions on day 10 after intrapleural IL2 instillation on the right and talc on the left. Recombinant interleukin-2 has been used for more than 20 years primarily for the treatment of metastatic renal cell carcinoma and metastatic melanoma [10]. Although its presumed mechanism of action is immunologic, its therapeutic activity may in part be mediated through induction of capillary leaks within responsive tumors [1], and capillary leak syndrome is the primary source of clinical toxicity of the agent when administered systemically [11, 12]. Interleukin-2 therapy has not been fully explored in hematologic malignancies, although there is ample evidence of activity against acute myeloid leukemia [13] and lymphoma [1-5], and evidence that it may be synergistic with rituximab and other agents against lymphoma in mouse [2, 7] and man [14-16]. Interleukin-2 has been previously reported to resolve pleural effusions in a number of patients with mesothelioma [8] and in at least one patient with lymphoma [9]. Little or no toxicity has been reported after intrapleural injection of the agent. Our patient had a dramatic and durable response to intrapleural interleukin-2 and experienced no toxicity from it. Intrapleural administration of interleukin-2 for pleural effusion associated with lymphoma and other neoplasms deserves formal study.