Survival benefit associated with human anti-mouse antibody (HAMA) in patients with B-cell malignancies

Abstract

Background: About one-third of patients with relapsed B-cell malignancies develop human anti-mouse antibody (HAMA) following mouse antibody treatment. The purpose of this study was to assess the relationship between HAMA and survival in patients given a mouse anti-lymphoma monoclonal antibody (mAb), Lym-1, directed against a unique epitope of HLA-DR antigen that is up-regulated on malignant B-cells.

Methods: ELISA was used to quantify HAMA in 51 patients with B-cell malignancies treated with iodine-131 (131I) labeled Lym-1. Sera were collected prior to and following radioimmunotherapy (RIT) with 131I-Lym-1 until documented to be HAMA negative or throughout lifetime. Univariate, then multivariate analyses including other risk factors, were used to analyze the relationship of HAMA to survival. The relationships of HAMA to prior chemotherapies and to absolute lymphocyte counts prior to RIT were also assessed.

Results: Eighteen of 51 patients (35%) developed HAMA following RIT (range of ultimate maximum titers, 6.6-1,802 microg/ml). Using the time dependent Cox proportional hazards model, maximum HAMA titers were associated with survival (P=0.02). HAMA continued to be significant for survival in multivariate analyses that included known risk factors. In Landmark analysis of 39 patients that survived at least 16 weeks, median survival of patients with HAMA less than 5 microg/ml was 61 versus 103 weeks for patients with HAMA equal or greater than 5 microg/ml at 16 weeks (P=0.02). The median survival of the five patients with highest maximum HAMA titers was 244 weeks. At 16 weeks, there was an inverse correlation between the maximum HAMA titer and the number of previous chemotherapies (P<0.003). Absolute lymphocyte counts prior to 131I-Lym-1 treatment for patients that seroconverted were higher than those for patients that did not seroconvert (P=0.01).

Conclusions: Patients with B-cell malignancies that developed high HAMA titers had longer survival that was not explained by risk factors or histologic grade, suggesting the importance of the immune system.

Fig. 1

Kaplan–Meier survival curves for 39 patients who survived at least 16 weeks from initial ¹³¹I-Lym-1 treatment and categorized according to HAMA titer (μg/ml) by 16 weeks. Comparison of the two patient populations by the log-rank test demonstrated a significant survival advantage for patients whose HAMA titers were positive (Table 4). Survival time for the one patient in the HAMA positive group surviving to the date of the analysis (932 weeks) is not shown on the graph

Fig. 2

A graphic depiction of the negative Spearman correlation between the log of maximum HAMA titers and the number of prior chemotherapies for the 39 patients who were alive at 16 weeks. All patients that failed to develop HAMA were assigned the value of 0. As there were several HAMA negative patients with the same number of prior treatments, the number of seronegative patients with the number of prior treatments is given below each symbol with a value of 0. The Spearman correlate, rho, was −0.47 with P<0.003