Chemo-Immunotherapy With Hyper-CVAD/MA and Rituximab For B-Cell Lymphomas Leads To Prolonged Immune Suppression Compared To Conventional Treatment With R-CHOP
Authors: Matsuki Eri , Kikuchi Taku , Hashimoto Norisato , Souma Shunsuke , Kohashi Sumiko , Toyama Takaaki , Sakurai Masatoshi , Karigane Daiki , Abe Daichi , Shimizu Takayuki , Yokoyama Kenji , Nakajima Hideaki , Okamoto Shinichiro 
Published: October 2019

Abstract

Background
Fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine (MA) therapy is a widely used combination chemotherapy for lymphoid malignancies. Its use in combination with Ribuximab (R) has been shown to be safe and effective for Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). Acute toxicities of the treatment are mostly hematologic, leading to cases with neutropenic fever and infection. However, long-term toxicities in terms of patients' immune function have not been fully elucidated.

Purpose
To evaluate the long-term immune function after R-hyper-CVAD/MA therapy, and to compared it with those after R-CHOP therapy.

Method
Patients who have received R-hyper-CVAD/MA therapy or R-CHOP therapy for more than 6 cycles for B-cell lymphomas (diffuse large B cell lymphoma (DLBCL), BL and MCL) between January 2007 and December 2012 were identified. The patients' immune functions were assessed in regards to white blood cell (WBC) count, lymphocyte count, lymphocyte surface marker analysis and immunoglobulin (Ig) measurement.

Result
Altogether, 21 patients underwent evaluation. 11 patients received R-CHOP therapy, and 10 patients received R-hyper-CVAD/MA therapy. The mean age of the patients was 57 and 53.3 years-old, respectively. All patients in the R-CHOP group had DLBCL, whereas patients who received R-hyper-CVAD/MA were either treated for BL in 4, MCL in 1 and DLBCL in 5 patients. The median time from the initiation of treatment to the assessment of immune function was 1060 (range 434 – 2475) and 947.5 (range 448 – 1966) days, respectively. In terms of immune function, IgG level, the proportion of CD4, CD8 positive (+) cells, CD4/8 ratio were significantly different between those who received R-CHOP therapy and R-hyper-CVAD/MA therapy. The median IgG level was 910 mg/dL in those who received R-CHOP therapy as opposed to 484 mg/dL in those who received R-hyper-CVAD/MA therapy. 4 patients in the R-CHOP group presented with IgG level below normal range, whereas 9 patients in the R-hyper-CVAD/MA group had an IgG level below normal range (p = 0.011). The median proportion of CD4 and CD8 (+) cells were 32.7%, 24.8% in the R-CHOP group and 23.35%, 41.35% in the R-hyper-CVAD/MA group, leading to the median CD4/8 ratio of 1.22 and 0.5, respectively. The total WBC count, lymphocyte count, proportion of CD19 (+) cells, IgM or IgA levels were within normal limit, and did not significantly differ between groups. Of the patients in the R-hyper-CVAD/MA group, 3 patients required regular immunoglobulin replacement, and 1 patient had 2 episodes of hospitalization within 2 years of last treatment, one due to viral meningitis and another due to pneumonia. None of the patients in the R-CHOP group presented with infection episodes that required hospitalization.

Conclusion
Our results suggest that patients with aggressive B-cell lymphoma treated with R-hyper-CVAD/MA therapy remain at higher risk of developing hypo-gammaglobulinemia, even after 5 years out of treatment. Despite the recovery of B-lymphocytes, the proportion of CD4 (+) cells remained low in those who received R-hyper-CVAD/MA therapy, leading to an increased proportion of CD8 (+) cells and decreased CD4/8 ratio. Patients who have received R-hyper-CVAD/MA therapy should be closely monitored for their immune function for a longer period due to prolonged hypogammaglobulinemia.

Disclosures:
Okamoto: Novartis, BMS, GSK, Kirin, Chugai, Alexion: Honoraria, Research Funding.