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 a history of relapsed and refractory anaplastic lymphoma kinase positive (ALK+) anaplastic large B cell lymphoma. He was treated with Children's Oncology Group (COG) mature B cell therapy per ANHL1131 Group C1 (cerebrospinal fluid (CSF) negative) of cyclophosphamide and Oncovin and prednisone (COP), Cyclophosphamide, Oncovine, Prednisone, Adriamycin, and Methotrexate (COPADM)1,and cytarabine and etoposide (CyVE1) chemotherapy. He also received crizotinib which selectively targets ALK. He completed therapy having achieved a complete response. A positron emission tomography (PET) scan 3 months after completing therapy showed recurrent disease. A bone marrow exam was negative and a biopsy of right femur confirmed ALK+ lymphoma. He was then treated per COG ANHL0121 with 3 cycles of ICE [ifosfamide, carboplatin, etoposide]  + crizotinib per ANHL12P1. A repeat PET/ computed tomography (CT) scan showed a mixed to minimal response. He was started on Nivolumbit and alectinib. A repeat PET/CT scan showed tumor progression with many new fluorodeoxyglucose (FDG)-avid bone lesions, hepatic lesions and pulmonary nodules.  A PET scan showed progression of disease with innumerable hypermetabolic lesions including a new liver lesion and increased retroperitoneal lymphadenopathy. He was started on treatment with gemcitabine and oxaliplatin per Mounier et al., Haemotolgica, 2013), daratumumab (as per Lokhorst, NEJM, 2015) and brentuximab. The treating physician is requesting the use of lenalidomide to his treatment regimen.
Human leucocyte antigen (HLA) typing of his family identified two matches. The treatment plan is to induce a remission and proceed with a matched sibling allogenic transplant. This patient is high risk with refractory lymphoma poorly and non-responsive to intensive chemotherapy. Lenalidomide acts by directly inducing tyrosine phosphorylation of cluster of differentiation (CD) 28 on thymus (T) cells leading to activation of downstream targets such as  Phosphatidylinositol-3-Kinase (PI3K), growth factor receptor-bound protein 2 (GRB-2-OS), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-b), thus partially overcoming cytotoxic T-lymphocyte associated protein 4 (CTLA4) immunoglobululin (Ig) blockade and leading to T cell clonal proliferation. Lenalidomide downregulates expression of checkpoint inhibitors, including programmed death-ligand 1 (PD-L1, CD274) on the surface of lymphoma cells. Lenalidomide upregulates expression of several genes involved in immune responses in mantle cell lymphoma (MCL) cells, including cluster of differentiation (CD) 86, CD40, CD58, and CD1c.
At issue is whether the 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.

Yes. Lenalidomide acts by directly inducing tyrosine phosphorylation of CD28 on T cells leading to activation of downstream targets such as PI3K, GRB-2-OS, and NF-b, thus partially overcoming CTLA4 Ig blockade and leading to T cell clonal proliferation. Lenalidomide downregulates expression of checkpoint inhibitors, including programmed death-ligand 1 (PD-L1, CD274) on the surface of lymphoma cells. Lenalidomide upregulates expression of several genes involved in immune responses in MCL cells, including CD86, CD40, CD58, and CD1c.
The National Comprehensive Cancer Network (NCCN) guidelines list and recommend oxaliplatin and gemcitabine for relapsed large cell lymphoma in addition to brentuximab for CD30 positive (+) disease, daratumumab as well as lenalidomide for non-germinal center B-cell-like (non-GCB) large cell lymphoma. Lenalidomide has been shown in clinical trials to be active against large cell lymphoma as a single agent as well as in combination therapy with other agents. It has been used in clinical trials in pediatrics and is safe and effective with doses up to 116 milligrams per square meter (mg/m2).
There is compelling evidence in this very high risk patient with relapsed/refractory large cell lymphoma that the addition of lenalidomide to the regimen of gemcitabine and oxaliplatin, daratumumab, and brentuximab will be beneficial and is the best standard of care for this patient. The NCCN guidelines list and recommend oxaliplatin and gemcitabine for relapsed large cell lymphoma in addition to brentuximab for CD30+ disease, daratumumab as well as lenalidomide for non-GCB large cell lymphoma. Lenalidomide has been shown in clinical trials to be active against large cell lymphoma as a single agent as well as in combination therapy with other agents. It has been used in clinical trials in pediatrics and is safe and effective with doses up to 116 mg/m2.