Use of hematologic biomarkers during chemotherapy predicts survival in ovarian cancer patients

Objective: The optimal strategy for combining chemotherapy with immunotherapy in ovarian cancer patients is currently under investigation. Increasing evidence indicates that the lymphopenia induced by chemotherapy may promote homeostatic proliferation and thereby enhance antitumor immunity. Furthermore, there has been much discussion and even discord over the effects of anemia and blood transfusion in the perichemotherapy period. The goals of this retrospective study were to determine the timing of chemotherapy induced lymphopenia and to observe perichemotherapy hemoglobin levels, and the impact of the timing and depth of lymphopenia and anemia on clinical outcomes of ovarian cancer patients. Materials and Methods: A chart review was performed on 115 patients identified in the electronic medical record from May 2005 until May 2011. Identified patients were only those who received at least six cycles of carboplatin and paclitaxel under the present authors’ care for primary peritoneal, ovarian, or fallopian tube carcinoma. Specifically, the authors focused on lymphocyte and hemoglobin nadir and the reconstitution kinetics for this population. For each patient’s lymphocyte count, nadir values were abstracted from weekly complete blood counts. They then split the population into two groups based on whether the nadir occurred at or after the nine-week mark (third cycle) for the lymphopenia data; this point was chosen because it was good for prognosis and it corresponds to patients whose trajectories bottom out. The intrachemotherapy hemoglobin levels were observed and an exploratory analysis was performed to attempt to identify a range that significantly effected patient outcomes. Results: Lymphocytes: The nadir of absolute lymphocyte concentrations is associated with platinum status and clinical response (Figure 1A). 94/115 patients had a lymphocyte count nadir after the third cycle of chemotherapy. 71/94 (75.5%) were platinum sensitive, 21/94 (22.3%) were resistant, and 2/94 (2.1%) were refractory. Of those that experienced a nadir before three cycles, ten (47.6%) were sensitive, ten (47.6%) were resistant, and one (4.7%) was refractory (p = 0.04). Considering nadir values continuously, both overall survival (OS, p = 0.0068) and progression free survival (PFS, p = 0.0321) were strongly associated with late nadir points. Twenty-one of the 115 patients had a nadir value earlier than the third draw and this was associated with progressive disease, platinum resistance, poor overall survival, and poor progression free survival. The effect sizes were great [median OS 33 vs. 66 months median PFS, 14 vs. 38 months, early vs. late nadir respectively (Figure 1B)]. Hemoglobin: A mean Hb less than 12.5 is associated with both overall survival (OS) (HR = 2.11, 95% CI: 1.03-4.33; p = 0.042) and progression free survival (PFS) (HR = 1.91, 95% CI: 1.02-3.56; p = 0.041), as were low Hb level at outset of chemotherapy and a decreasing Hb trend over the course of treatment. Furthermore, for each cycle of chemotherapy in which the hemoglobin was recorded at a value less than 11, hazard increased, with OS (HR = 3.51, 95% CI: 1.63-7.54, p = 0.0013), and PFS (HR = 2.20, 95% CI:1.12-4.33; p = 0.0223). Deeper analysis revealed that outcomes were significantly affected when a patient had three or more cycles with Hb less than 11 with both OS (HR = 2.34, 95% CI: 1.37-4.01; Wald-Test p = 0.0020, Log Rank p = 0.00145) and PFS (HR = 1.88, 95% CI: 1.17-3.02; Wald-Test p = 0.009, Log Rank p = 0.00743). Conclusion: The nadir of absolute lymphocyte concentrations is an independent predictor of overall survival and progression free survival. This is an easily measurable biomarker which can be utilized for identifying patients that will be likely to respond to immunomodulation. Furthermore, this evidence showing significant improvement in OS and PFS with two or less cycles with hemoglobin < 11 sheds new light on the need for further studies on growth stimulating factors and blood transfusion during this treatment period.

Hematologic biomarkers; Chemotherapy induced lymphopenia; Homeostatic proliferation;

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