Lenalidomide demonstrates clinical activity in anaplastic lymphoma kinase-positive large B-cell lymphoma

Abstract

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is known to be a rare and aggressive form of lymphoma that relapses quickly after both conventional chemotherapy and more targeted therapy. Lenalidomide is an immunomodulator that has shown safety and efficacy in multiple myeloma and is also approved for use in several types of lymphoma. In the case described here, the patient had a significant partial response to lenalidomide, which has not previously been described in this type of lymphoma. Given how aggressive and difficult to treat ALK+ LBCL is, further research is warranted to more completely elucidate the mechanism of action of lenalidomide in ALK+ LBCL and its role in treatment.

Background

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of B-cell non-Hodgkin’s lymphoma consisting of <1% of all large cell lymphomas. The entity was first identified in 1997 and there have been 134 cases reported in the literature. It is often under-recognised and carries limited treatment options.¹ A recent review of 134 cases of ALK+ LBCL showed a 5-year overall survival (OS) of 34%, with a median OS of 1.83 years. For patients with stage III or IV disease, 5-year OS was 8%, which underscores the limited effective treatment options for these patients.² Here, we present a patient with primary refractory disease who had a marked response to lenalidomide.

ALK+ LBCL is pathologically characterised by large monomorphic immunoblastic or plasmablastic cells in a diffuse and/or sinusoidal growth pattern. By immunohistochemistry, cases are positive for CD38, CD138 and MUM1 and are negative for CD20, CD79a, PAX5, CD2 and CD3. Infrequent cases express CD30. Most cases carry t(2;17) leading to the pathological ALK fusion protein.^{2 3}

Clinical features of ALK+ LBCL include a male predominance in a ratio of 3.5:1. The age of patients whose cases have been reported in the literature ranges from 9 to 72 years old. All patients reported were HIV negative, approximately 50% had B symptoms (fevers, chills and night sweats) at time of presentation, and 57% presented at clinical stages III/IV with bone marrow involvement noted in 30%.³

Treatment paradigms have been borrowed from other aggressive lymphomas given the rare nature of the disease. However, in patients with ALK+ LBCL treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens, median survival was 1.8 years and 5-year OS ranged in reports from 25% to 34%.^{2 4} Treatment of ALK+ LBCL using the ALK-inhibitor crizotinib has been attempted but with limited success.

Lenalidomide is an immunomodulatory treatment that has been shown to be effective in B-cell malignancies, most notably serving as a key treatment for multiple myeloma. It has also been shown to be effective in relapsed/refractory B-cell lymphomas, diffuse large B-cell lymphoma and follicular lymphoma, with one phase II trial showing an overall response rate of 33% and a median response duration of 10.2 months.^{5 6} Additionally, lenalidomide was well tolerated and the most common side effects, including neutropenia, are often not severe.⁷ Here, we present the first case report of clinical efficacy of lenalidomide in ALK+ LBCL.

Case presentation

We present an 84-year-old woman with a history of Alzheimer’s dementia and hypertension who was diagnosed with Ann Arbor stage III, ALK+ LBCL.

She initially presented with cervical lymphadenopathy and ultimately underwent an excisional biopsy, which was consistent with ALK+ LBCL. Pathology showed a population of malignant lymphoid cells, which were medium to large in size and showed a high degree of nuclear atypia and increased mitotic rate. Immunohistochemistry showed strong expression of CD138, ALK-1, CD10 and CD4. A small subset of tumour cells was weakly positive for CD20, and tumour cells were non-reactive for CD30, BCL-2 and BCL-6. These results were confirmed to be consistent with an ALK+ LBCL that was negative for CD19 and CD20. Bone marrow biopsy showed no evidence of lymphoma, and a positron emission tomography CT (PET/CT) scan with F-18 fluorodeoxyglucose (FDG) showed hypermetabolic lymphadenopathy in the head, neck and left axilla with no intra-abdominal or pelvic disease. She completed six cycles of CHOP. An interim FDG-PET/CT after three cycles showed a complete metabolic response, but her end-of-treatment FDG-PET/CT showed recurrent hypermetabolic lymphadenopathy in the cervical, supraclavicular, subpectoral, axillary and mediastinal regions, with additional new osseous lesions and new hypermetabolic subcutaneous soft tissue in the right supraclavicular region.

Investigations

She underwent a repeat excisional biopsy approximately 1 week later, which demonstrated ALK+ LBCL with similar features to her original diagnosis (figure 1). Commercially available targeted mutational profiling demonstrated the clathrin heavy polypeptide (CLTC)-ALK fusion as well as amplification of MYC. Given the plasmacytoid features of ALK+ LBCL and the efficacy of lenalidomide in diffuse large B-cell lymphoma (DLBCL), the decision was made to initiate lenalidomide at 20 mg daily.

Figure 1.

Section from left cervical lymph node (H&E staining) showing lymph node replaced by medium-to-large sized malignant lymphoid cells. Inset: tumour cells staining positive for anaplastic lymphoma kinase-1 (magnification 100×).

Treatment

After completing approximately 2 weeks of lenalidomide, the patient was admitted to the hospital with a vertebral fracture following a fall. Her course was complicated by pulmonary embolism, urinary tract infection and sepsis. Her dose was subsequently reduced to lenalidomide 15 mg daily. After 4 months of therapy, repeat imaging with a CT of the chest, abdomen and pelvis with contrast showed a substantial improvement in overall disease burden, though several sites of disease were unchanged, overall consistent with a marked partial response to therapy (figure 2).

Figure 2.

Transaxial CT images without contrast prior to lenalidomide (A, C) and transaxial CT images with intravenous contrast after 4 months of lenalidomide (B, D) are shown. A mediastinal lymph node at the level or the carina (arrows in A and B) substantially decreased in size. Similarly, soft tissue infiltration of the subcutaneous fat in the region of the right supraclavicular fossa (asterisks in C and D) almost entirely resolved.

Outcome and follow-up

The patient continued to suffer from progressive Alzheimer’s dementia and debilitation from her hospitalisations. After discussion with the patient’s family about further options, the decision was made to transition the patient to hospice care due to her dementia, and she expired approximately 1 month later.

Discussion

The aggressive nature of ALK+ LBCL has been described in many case reports, with median survival being particularly poor in older populations with a more significant burden of disease. Prior retrospective analyses have demonstrated that traditional chemotherapeutic regimens are often not effective for this particular type of lymphoma. Cases have been reported in which patients have progressed despite multiple lines of traditional therapy, and even with more aggressive treatments such as bone marrow transplantation.

Treatment with more targeted therapy has been attempted as well. Crizotinib, an ALK inhibitor, has been approved for use in non-small cell lung cancer and myofibroblastic tumours with ALK rearrangements. Additionally, preclinical testing has shown that crizotinib has in vitro activity against ALK+ LBCL. Case reports explore the use of crizotinib in patients with ALK+ LBCL who have developed recurrent disease despite standard regimens. These reports consistently show an initial response to crizotinib, followed by development of resistance to treatment and progression of disease.^8–11

In this case, we demonstrate an elderly patient with ALK+ LBCL who achieved a marked partial response to single-agent lenalidomide after being primary refractory to CHOP therapy. In this case, her lenalidomide was discontinued due to worsening performance status from her progressive dementia while in a marked partial remission from ALK+ LBCL. Lenalidomide has shown significant efficacy in other plasma cell and plasmacytic disorders, including newly diagnosed and relapsed/refractory multiple myeloma, refractory Waldenström macroglobulinaemia and systemic amyloidosis.^9–11

Lenalidomide has also been shown to have activity in a variety of lymphomas, including diffuse LBCL, follicular lymphoma and mantle cell lymphoma.¹² Specifically, overall response rates (ORR) in studies examining lenalidomide in diffuse LBCL range from 19% to 53% when used alone, with even higher response rates noted when used in combination with other chemotherapy. In relapsed/refractory mantle cell lymphoma and follicular lymphoma, ORR range from 27% to 53% with complete remission reported in 20% of patients.¹³ Case reports and a phase I clinical trial have provided initial evidence for the use of lenalidomide in T-cell lymphomas, and a retrospective review has demonstrated possible efficacy of lenalidomide in relapsed CNS lymphoma.^{14 15} Across a multitude of clinical trials, lenalidomide has demonstrated a favourable side effect profile. Grade 3–4 hematologic toxicites are seen, including neutropenia (39%–43%), thrombocytopenia (13%–28%) and anaemia (7%–11%). Rates of significant non-hematologic toxicities, including fatigue, rash, diarrhoea and dyspnoea, range from 7% to 23% and 5% of patients were noted to have thromboembolic events, which is similar to the rate of thromboembolic disease in patients with multiple myeloma receiving single-agent lenalidomide.¹³ Rates of grade 3–4 infection in trials studying single-agent lenalidomide range from 5% to 35%.^{6 12 16} These trials have led to Food and Drug Administration approval of lenalidomide for relapsed and refractory mantle cell lymphoma, as well as approval in combination with rituximab for pretreated follicular lymphoma and marginal zone lymphoma.^{16 17} In our patient who had multiple medical comorbidities, lenalidomide could have further contributed to her risk of complications, including pulmonary embolism and infection.

Conclusion

Given the plasmacytic features of ALK+ LBCL, lenalidomide is a reasonable treatment option with a favourable toxicity profile even in older patients. This case illustrates that lenalidomide has clinical activity in ALK+ LBCL. Given the limited treatment options in this rare and understudied disease, further studies of the mechanism and clinical efficacy of lenalidomide in ALK+ LBCL are warranted.

Learning points.

• Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare and aggressive form of lymphoma.

• Standard treatments, including chemotherapy, radiation and stem cell transplant, are often ineffective with poor response rates and high rates of relapse.

• Treatment with targeted therapy, such as the ALK inhibitor, crizotinib, has been attempted in case reports but has resulted in high rates of relapse and progressive disease.

• The use of lenalidomide, a well-tolerated oral immunomodulatory therapy, resulted in a very good partial response for this patient, despite her being refractory to other standard treatments.

• Further studies of the mechanism and efficacy of lenalidomide in the treatment of ALK+ LBCL are warranted.