Recent evidence has shown that an increased number of tumor-associated macrophages is associated with decreased survival in patients with classic Hodgkin lymphoma.
Eighty-one patients treated for relapsed and refractory classical Hodgkin lymphoma at Memorial Sloan-Kettering Cancer Center from 1995 to 2003 were identified. Patients received either standard ICE based chemotherapy or a risk stratified salvage therapy approach based on the number of pre-salvage therapy risk factors present (B symptoms, extranodal disease, and/or remission duration less than 1 year). Patients were also evaluated by functional imaging with gallium or fluorodeoxy glucose positron emission tomography (FDG-PET), as well as computed tomography (CT) prior to both salvage therapy and autologous stem cell transplant (ASCT). Patients with at least minimal response to salvage therapy proceeded to ASCT. Paraffin embedded tissue blocks were obtained from each patient. A tissue microarray (TMA) of tumor samples was constructed with triplicate 0.6mm tissue cores. A 4um section of the TMA was stained by immunohistochemistry with the anti-CD68 antibody (Ventana, CONFIRM anti-CD68 [KP-1]) on the Ventana Discovery XT instrument following manufacturerÕs protocol. Staining was scored based on the percentage of CD68 positive cells compared to the total number of cells in selected representative areas. The final percent of CD68 positivity for each case was based on the average of the cores available for examination. Scoring was performed independently by two individuals (CC and MA).
Scores for CD68 positive tumor associated macrophages ranged from 0–74%. Patients were grouped into two categories based on scores of 0–29%, and >30%. Forty three percent of patients (35/81) had scores of 29% or less. Fifty six percent (46/81) had scores of 30% or greater. In the intent to treat population, patients with relapsed and refractory Hodgkin lymphoma and CD68 scores > 30% had shortened overall survival (OS) compared with scores < 30%; 4.5 years versus 12.2 years, respectively (p=.048). Patients proceeding to salvage ASCT with CD68 scores > 30% also had inferior OS compared with patients who had scores < 30%; 4.69 years versus 12.7 years (p=.015). Increased levels of CD68 tumor-associated macrophages also impacted progression free survival (PFS) in patients undergoing salvage therapy and ASCT. CD68 levels > 30% were associated with an inferior PFS. Patients with CD68 scores < 30% had a median PFS that was not reached, compared with 1.1 years for patients with scores > 30% (p=.03).
Pre-salvage therapy tumor biopsy specimens with elevated levels of CD68 positive tumor-associated macrophage were associated with poor outcomes. Scores > 30% conferred an inferior OS and PFS for patients with relapsed and refractory Hodgkin lymphoma undergoing salvage therapy and ASCT. We believe this score can be used to risk stratify salvage therapy in transplant eligible patients with relapsed and refractory Hodgkin lymphoma. In future studies we will correlate the scores of the initial tumor specimen with that of the relapsed tumor specimen.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.