While reading my pile of mail on Friday, I realised that an interesting paper on Hodgkins Lymphoma (HL) appeared in the current edition of the New England Journal of Medicine (full reference below).

The basics of the paper are that despite advances in HL, including curative radiation in the early stages if the disease, one third of patients with advanced disease and about 15% of those with early disease have a relapse after treatment. 20% of people still die from the disease.  

The question is why?  

Well, unfortunately, current prognostic models have not been shown to be very accurate and so far, no biomarker has been found to be particularly useful.

The authors set out to use gene-expression profiling obtained from people with HL during diagnostic lymph node biopsy to determine which signatures were correlated with treatment.  They confirmed their findings with an independent cohort of 166 patients using standard immunohistochemical analysis.

What they found was fascinating:

  • A gene signature of of tumour associated macrophages was associated with primary treatment failure.
  • An increased number of CD68 macrophages correlated with likelihood of relapse after autologous stem cell transplantation.
  • The adverse prognostic factor (macrophages) outperformed the current International Prognostic Score for disease-specific survival.
  • The absence of an elevated number of CD68+ cells in patients with limited stage disease defined a sub-group of patients with long-term disease specific survival of 100% with the current therapies.

When I was at school, we learned that macrophages were associated with an immune response to invasion.  According to the NEJM Editorial, by DeVita and Costa, this may not be the case:

"Most of the evidence, however, now links the presence of tumor-associated macrophages with a poor prognosis."

In short, the data shows that increased number of tumour associated macrophages was strongly associated with shortened survival in HL and provides a biomarker for prognosis and risk stratification.  What does this all mean though, for clinical practice?

DeVita and Costa noted that:

"If at the time of diagnosis we could identify patients who are destined to have a poor response to treatment, most patients could be spared a combination of therapies or radiotherapy with its attendant long-term toxic effects."

This is an important observation alone.

For the future, though, the data suggests some new directions that clinical research could go in, such as an anti-CD68 monoclonal antibody perhaps.  There are some that have been identified for rheumatoid arthritis (RA) as the Kunisch paper shows below, but I don't think any are currently in commercial development at the moment.

For the moment, though, I'm left wondering more than there are answers.  

Why do people with macrophages do worse, what is the mechanism for this?  How can we best target the macrophages or the CD68 cells?  If people are screened and are found to have a poorer prognosis and are spared the exposure to chemotherapy or radiation as DeVita and Costa suggest, how should they be treated instead?

Perhaps more research will be galvanised by Steidl et al's findings.  Time will tell.

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, & Gascoyne RD (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. The New England journal of medicine, 362 (10), 875-85 PMID: 20220182

DeVita, V., & Costa, J. (2010). Toward a Personalized Treatment of Hodgkin's Disease New England Journal of Medicine, 362 (10), 942-943 DOI: 10.1056/NEJMe0912481

Kunisch, E. (2004). Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry Annals of the Rheumatic Diseases, 63 (7), 774-784 DOI: 10.1136/ard.2003.013029