CD68+ cell count, early evaluation with PET and plasma TARC levels predict response in Hodgkin lymphoma

Abstract

Early response evaluation with [(18) F]fluordeoxyglucose (FDG) positron emission tomography after 2 cycles of chemotherapy (interim PET) has been indicated as the strongest predictor for outcome in classical Hodgkin lymphoma (HL). We studied the prognostic role of the number of tumor-infiltrating CD68+ cells and of the plasma levels of TARC (thymus and activation-regulated chemokine) in the context of interim PET in 102 patients with classical HL treated with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD). After 2 ABVD cycles, interim PET according to Deauville criteria was negative (score 0-3) in 85 patients and positive (score 4-5) in 15 patients (2 patients technically not evaluable). TARC levels were elevated in 89% of patients at diagnosis, and decreased after 2 cycles in 82% of patients. Persistently elevated TARC levels in 18% of patients were significantly associated with a positive PET result (P = 0.007). Strong predictors for progression-free survival (PFS) were a negative interim PET (85% vs. 28%, P < 0.0001) and CD68+ cell counts <5% (89% vs. 67%, P = 0.006), while TARC levels at diagnosis and at interim evaluation had no prognostic role. In multivariate analysis, interim PET, CD68+ cell counts and presence of B-symptoms were independently associated with PFS. We conclude that although TARC levels are a biomarker for early response evaluation, they cannot substitute for interim PET as outcome predictor in HL. The evaluation of CD68 counts and B-symptoms at diagnosis may help to identify low-risk patients regardless positive interim PET.

Keywords: CD68+ tumor-infiltrating macrophages; Hodgkin lymphoma; TARC; interim PET; prognosis.

Figure 1

Thymus and activation‐regulated chemokine (TARC) Plasma levels are increased in Hodgkin lymphoma (HL) patients at diagnosis than in controls. TARC levels were significantly higher in HL patients (n = 80, median 162 U/mL) when compared to controls (n = 63, median 64 U/mL) (P < 0.001). The upper border of the box indicates the 75th percentile, while the lower border indicates the 25th percentile, and the horizontal line in the box the median. The vertical lines are the whiskers indicating the maximum and minimum values. TARC levels in controls were used to define the upper normal value (dashed line, 162 U/mL).

Figure 2

Elevated Plasma levels of thymus and activation‐regulated chemokine (TARC) at diagnosis predicted interim positron emission tomography (PET) results. TARC levels were elevated at interim PET in only 6 of 51 (12%) patients with a negative interim PET (A), while they persisted elevated in 6 of 12 (50%) patients with a positive interim PET (B, P = 0.007). The dashed line indicates the upper normal value.

Figure 3

Progression‐free Survival according to interim [¹⁸F]fluordeoxyglucose (FDG)‐positron emission tomography (PET)/CT scan, CD68+ cell counts and thymus and activation‐regulated chemokine (TARC) levels at diagnosis and at interim PET. Patients with an interim PET score of 1–3 were considered PET‐negative (n = 85), and patients with a score of 4–5 were scored PET‐positive (n = 15). After a median observation time of 32 months, the probability of progression‐free survival (PFS) was 85% (95% CI: 75–91%) for PET‐negative patients, while it was only 28% (95% CI: 8–53%) for PET‐positive patients. The difference was highly statistically significant (P < 0.0001). (A) Patients with CD68+ cell counts <5% (n = 40) had a significantly higher probability of PFS at 32 months (89%, 95% CI: 72–96%), than patients with CD68+ cell count >5% (n = 39) (67%, 95% CI: 50–79%; P = 0.006). (B) The PFS probability was similar for patients with TARC levels below or over >1000 U/mL at initial diagnosis (n = 32 and n = 48, respectively) (C) Petients with increased TARC levels (>162 U/mL, n = 12) at interim PET had a PFS (PFS: 67%, 95% CI: 34–86%), similar to patients with TARC levels <162 U/mL (n = 53, PFS: 80%, 95% CI: 66–89%, P = 0.3). (D) Patients with B‐symptoms (n = 38) had a significant inferior probability of PFS (57%, 95% CI: 39–72%), when compared to patients without B‐symptoms (n = 64) (88%, 95% CI:77–94%) (P = 0.002).

Figure 4

Progression‐free survival according to interim positron emission tomography (PET) scan in patients according to CD68+ cell count and B‐symptoms. PFS curves are shown for patients with CD68+ <5% and no B‐Symptoms (A), CD68 > 5% or B‐symptoms (B), and CD68% >5 and B‐symptoms (C). The continuous line indicates patients with negative interim PET, the dashed line patients with a positive interim PET. The survival difference is significant in patients with both CD68 counts >5% and B‐symptoms (P = 0.003), while there is a trend for significance in the group with either CD68 count>5% or B‐symptoms (P = 0.06).