RDC Development for Lymphoma

Lymphoma, as a heterogeneous entity, is one of the ten most prevalent cancers and includes Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), of which HL accounts for 10–15% and is characterized by the presence of Reed–Sternberg cells, while NHL accounts for 80–85% with a number of subtypes. Worldwide, lymphomas developed in 566 thousand people in 2012 and caused 305 thousand deaths, making up 3–4% of all cancers, as a group the seventh-most common form.

Non-Hodgkin Lymphoma

• B-cell Lymphomas

Small B-cell lymphocytic lymphoma and chronic lymphocytic leukemia, as a disease of elderly people, is believed to be different clinical manifestations of the same disease, which can be treated by fludarabine, cyclophosphamide, and rituximab, as well as three monoclonal antibody therapies.

Follicular lymphoma is the second most common lymphoma in the USA and Western Europe, accounting for about 20% of all non-Hodgkin lymphomas with a median age of 60 years at diagnosis, which can be treated by radiotherapy, such as 90Y-ibritumomab tiuxetan, as well as chemotherapy, such as rituximab.

Mantle-cell lymphoma with a median age of 58 years at diagnosis can be treated by standard treatment with a 3-year median overall survival, combining chemotherapy with or without rituximab.

Marginal-zone lymphoma, onset mostly in the stomach, is the third most common subtype of non-Hodgkin lymphoma, which can be treated by rituximab alone or chemotherapy regimens incorporating rituximab.

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma, counting for about a third of cases, which can be treated by rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) chemotherapy.

Burkitt's lymphoma occurs mostly in Africa, and sporadically around the world, which can be treated by chemotherapy with high dose intensity and the use of alternating non-cross-resistant regimens.

Precursor B-Cell Lymphoblastic Lymphoma (B-LBL), also known as B-lymphoblastic lymphoma with too many B-cell lymphoblasts in the blood and bone marrow which is one kind of immature white blood cells, counting for only 0.3% of NHL in adults, can be treated by VPDL chemotherapy with vincristine, methylprednisolone, daunorubicin, and L-asparaginase.

• T-cell Lymphomas

Peripheral T-cell lymphoma without otherwise specified is the most common of the peripheral T-cell lymphomas which can be treated by combination chemotherapy to achieve long-term survival in 12–45% of patients.

Angioimmunoblastic T-cell lymphoma is the second most common of peripheral T-cell lymphomas, which can be treated by combination chemotherapy with anthracycline-containing regimens to achieve long-term survival in about a third of patients.

Anaplastic large-cell lymphoma, accounting for 3–8% of all lymphomas, can be treated by approved antibody-drug conjugate brentuximab (anti-CD30 monoclonal antibody)-vedotin (Monomethyl Lauristatin E).

Precursor T-Cell Lymphoblastic Lymphoma (T-LBL), also known as T-lymphoblastic lymphoma with too many T-cell lymphoblasts in the lymph nodes and spleen which is one kind of immature white blood cells, can be treated by CHOP chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone.

Hodgkin Lymphoma

Hodgkin lymphoma contains two categories, such as classical Hodgkin lymphoma and the uncommon nodular lymphocyte-predominant Hodgkin lymphoma. Classical Hodgkin lymphoma can be further divided into nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte depletion Hodgkin lymphoma, and lymphocyte-rich Hodgkin lymphoma.

The management of early-stage Hodgkin lymphoma (stages I-IIA) with favorable or unfavorable prognostic factors includes chemotherapy for control of any distant areas in Hodgkin lymphoma, such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy, and chemotherapy combined with regional radiotherapy.

Advanced-Stage Hodgkin Lymphoma (stage IIB, III, and IV) is commonly managed with combination chemotherapy alone, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma, a subtype of Hodgkin lymphoma, can be treated by removal of the lymph node and the use of involved-field radiation therapy for patients with stage IA, as well as ABVD chemotherapy combined with rituximab, or rituximab treatment for patients with more advanced-stage.

Fig.1 Illustration of lymphoma.

Lymphoma Treatment with RDC

Even though chemotherapy represents an essential pillar for the treatment of various forms of hematological malignancies, a common theme emerges where these chemotherapy agents are usually associated with nonspecific toxicities and drug resistance, as a result of their high potency but low tumor selectivity.

• ²¹²Pb-ituximab for Lymphoma Treatment

CD20 is an overexpressed biomarker in a broad range of B-cell malignancies and is one of the most important developments in NHL treatment during the last 30 years. Rituximab, the first monoclonal antibody (mAb), is approved for the treatment of NHL in the therapeutic armamentarium. The novel RDC (Radionuclide Drug Conjugate) composed of alpha-emitter ²¹²Pb and Rituximab shows excellent efficacy in both in vitro and in vivo experiments, which may hint that ²¹²Pb-rituximab with promising efficacy is a potential radiotherapy agent in lymphoma treatment.

Fig.2 Efficacy of ²¹²Pb-rituximab treatment in the murine syngeneic lymphoma model. (Durand-Panteix, S., et al., 2021, British Journal of Cancer)

Reference

1. Durand-Panteix, S., Monteil, J., Sage, M., Garot, A., Clavel, M., Saidi, A., ... & Quelven, I. (2021). Preclinical study of ²¹²Pb alpha-radioimmunotherapy targeting CD20 in non-Hodgkin lymphoma. British Journal of Cancer, 125(12), 1657-1665.