Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Anaplastic large cell lymphoma.
Treatment: Chemotherapy regimen that includes Brentuximab, Daratumumab and Lenalinomide.
The insurer denied chemotherapy regimen that includes Brentuximab, Daratumumab and Lenalinomide.
The determination is overturned.


The patient has relapsed/refractory anaplastic lymphoma kinase positive (ALK+) large B cell lymphoma (LBCL). The patient was originally diagnosed with ALK+ Large B cell Lymphoma (LBCL). He was treated as per the Children's Oncology Group (COG) ANHL 1131 protocol C1 arm with cytotoxic chemotherapy (Cyclophosphamide, Oncovine, Prednisone, Adriamycin, and Methotrexate (COPADM), cytarabine and etoposide  (CyVE), and maintenance combination chemotherapy) with the addition of the ALK inhibitor, Crizotinib. He achieved a complete remission and completed therapy. However, on his 3 month surveillance positron emission tomography (PET) scan, he was found to have relapsed disease, confirmed by biopsy. He was then treated with several salvage chemotherapy/immunotherapy regimens including ICE [ifosfamide, carboplatin, etoposide] + crizotinib and nivolumab + alectinib but his disease remained refractory to therapy. He was recommended a therapy regimen including gemcitabine + oxaliplatin +daratumomab + brentuximab +lenalidomide based on data showing efficacy of these agents in relapsed/refractory LBCL, with the goal of achieving a remission and proceeding to a stem cell transplant. At issue is whether the proposed health service or treatment chemotherapy regimen that includes Brentuximab, Daratumumab and Lenalidomide is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

ALK+ Large B cell Lymphoma (LBCL) is a rare aggressive cluster of differentiation (CD) 20-negative Non-Hodgkin lymphoma (NHL), which is even more rare in children. In a large review of 184 cases of ALK+ LBCL, the median age at diagnosis was 38 years (range 9-90 years) and only 10% of patients were less than (<) 18 years of age. The standard of care for upfront therapy is to treat with chemotherapy regimens that would be used for Diffuse Large B cell Lymphoma (with omission of Rituximab) with strong consideration for the addition of an ALK inhibitor. However, due to the rarity of this disease, there is limited data for effective salvage regimens for relapsed/refractory patients and, therefore, no established standard of care. Furthermore, clinical trial development and Food and Drug Administration (FDA) approval of targeted drugs for rare diseases in children lag far behind that of adults, due, in part, to mandated preceding safety data in adults and the rarity of childhood cancers, leading to lower priority by pharmaceuticals and slower trial enrollment, among other factors.
There have been, however, a number of clinical trials in adults establishing single agent and multi-agent activity of Brentuximab, Daratumumab, and Lenalidomide in the treatment of relapsed/refractory NHL, including ALK+ LBCL.
Brentuximab vedotin is a CD30 targeted antibody conjugated to monomethyl auristatin E (MMAE), which binds to CD30, becomes internalized, and then releases MMAE causing apoptosis as an antitubulin agent. Brentuximab has shown great efficacy in the treatment of CD30+ lymphomas and is now considered the standard of care for upfront treatment of Hodgkin Lymphoma in combination with chemotherapy. It has also been shown to have significant efficacy in the treatment of ALK+ anaplastic large cell lymphoma (ALCL) in COG studies in children in both the relapsed and upfront setting.
Daratumumab is a human immunoglobulin (Ig)1 monoclonal antibody that targets CD38 surface antigen which is over-expressed in certain hematologic malignancies, including large B cell lymphomas. Early phase clinical trials have shown tolerability and efficacy, albeit limited as a single agent in relapsed/refractory NHL patients.
Finally, Lenalidomide is an oral immunomodulator with direct antineoplastic activity and immunologic effects, blocking tumor cell proliferation and angiogenesis, and stimulating T-cell and natural killer (NK) -cell-mediated cytotoxicity in malignant cells. Based on landmark clinical trial data, Lenalidomide has been FDA-approved for treatment of multiple myeloma, 5q-myelodysplasia, and relapsed/refractory mantle cell lymphoma. A 2011 study (Witzig, et al.) showed a 35% overall response rate in patients with relapsed/refractory aggressive NHL treated with single agent Lenalidomide. Furthermore, multiple clinical trials have demonstrated an impressive synergistic effect of lenalidomide in combination with monoclonal antibodies, particularly rituximab, for relapsed/refractory NHL, setting a precedent for the use of 'non-chemotherapeutic,' lenalidomide-containing options for patients with lymphoma. In terms of use in children, an early phase pediatric clinical trial established safety and tolerability of Lenalidomide treatment for children with relapsed/refractory brain tumors.
In the case, the patient has failed a number of treatment regimens and the treating oncology team has developed a salvage treatment regimen based on available clinical trial data for this rare condition and based on the biology of the patient's disease, utilizing a targeted precision medicine approach.
In the current landscape of cancer care, with improved access to biologic classification of malignancies (based on immunohistochemistry, flow cytometry, and molecular sequencing) and the emergence of more targeted therapies, it is becoming widespread practice and the gold standard of care to treat patients with targeted therapy if available, especially when limited alternative options exist. In this case, the best chance for cure for this child would be to undergo a stem cell transplant which can only be pursued if he achieves a complete remission with chemo-immunotherapy. Given the limited options that his treating team is faced with, the treatment regimen that was proposed, including Brentuximab, Daratumumab, and Lenalidomide in combination with Gemcitabine and Oxaliplatin is appropriate and likely to be more beneficial than any alternative treatment. This multimodal approach combines standard cytotoxic chemotherapy proven to be effective for lymphoma in the relapse setting with targeted agents of diverse mechanisms tailored to the specific biology of the patient's disease, each of which have clinical trial data to support their efficacy for this rare disease.