Pegylated Recombinant Human Granulocyte Colony Stimulating Factor (pegfilgrastim) Reduces Hematological Toxicity in Dose-Adjusted (DA) R-EPOCH in the treatment of Diffuse Large B Cell Lymphoma.

Hematological toxicity is a significant dose limiting side effect in the aggressive treatment of Diffuse Large B Cell Lymphoma (DLBCL). In the current study, pegfilgrastim was given to patients following each cycle of DA R-EPOCH. ANC and platelet nadirs were then compared to a previous report utilizing filgrastim. Pegfilgrastim is a covalent conjugate form of filgrastim, whereby a molecule is covalently bonded to the N terminal of filgastrim, allowing the molecule to be cleared slower than filgastrim. The prolonged effect on the promotion of granulocyte proliferation allows for pegfilgrastim to be given once every 2 weeks in comparison to filgrastim which is injected daily. In this study, records of 5 patients treated with DA R-EPOCH for DLBCL were examined. There were a total of 20 cycles with 15 cycles qualifying for analysis in regards to hematological toxicity. To qualify each cycle met the following criteria: i) treatment with R-EPOCH at starting dose or dose-escalation; ii) pegfilgrastim was administered 24 to 48 hours after completion of chemotherapy at the standard dose of 6mg sc; iii) follow-up of at least two weeks following each cycle; iv) CBC monitored at least once weekly. Of the cycles excluded, 3 cycle did not have at least 2 weeks of follow-up, 1 cycle was followed by filgrastim and 1 cycle was treated with R-CHO. Nadir was defined as lowest value obtained from initiation of one cycle to initiation of next cycle or to two weeks from last day of all chemotherapy. Hematological toxicities were graded according to WHO criteria. Grade 4 neutropenia (ANC less than 0.5 x 10⁹/L) occurred in 13% (2/15) of cycles. There was no Grade 3 neutropenia (ANC 0.5 – 1.0 x 10⁹/L). Range of ANC nadir was 0.02 – 4.4 x 10⁹/L with mean of 2.4 x 10⁹/L. There was no Grade 3 thrombocytopenia (Platelet 25 – 50 25 x 10⁹/L) nor Grade 4 thrombocytopenia (Platelet < 25 x 10⁹/L). Range of platelet nadir was 53 – 230 x 10⁹/L with mean of 130. Examining treatment records, 13 cycles of 20 were candidates for dose escalation. Each cycle was included if it followed a cycle of R-EPOCH and the patient had received pegfilgrastim for neutropenic support. Excluded cycles included 5 cycles at starting doses, 1 cycle in which filgrastim was administered prior, and 1 cycle in which the R-CHO was given prior. Following the criteria for allowable DA EPOCH according to the paradigm published in Blood Apr 15, 2002, Vo 99, No 8 pp 2685– 2693, dose escalation was allowed for ANC of at least 0.5 x 10⁹/L and platelets of at least 25 x 10⁹/L. 11 of 13 (85%) cycles in this study were eligible for dose escalation based on the above mentioned paradigm. In the previous mentioned publication filgrastim was given after completion of each cycle of EPOCH with 49% of cycles complicated by Grade 4 neutropenia and 7% complicated by Grade 4 thrombocytopenia. 58% of the cycles were dose escalated in the previous study. In conclusion this study indicates that pegfilgrastim results in less hematological toxcity in DA R-EPOCH. This allows for DA in a higher percentage of treatment cycles. In addition, examination of the cost reveals the average whole sale price of a single 6 mg dose of pegfilgrastim is $3127, while the average whole sale price of a daily dose of 480 mcg of filgrastim for 10 days is $3500.