Recombinant human interleukin-11 (rhIL-11, also known as oprelvekin(Drug information on oprelvekin) [Neumega]), is the only platelet growth factor currently available in the United States for the prevention of chemotherapy-associated severe thrombocytopenia in patients with nonmyeloid malignancies who are at high risk for the development of this condition. The recommended treatment regimen in adults is 50 µg/kg administered subcutaneously, once daily, beginning 6 to 24 hours after completion of the chemotherapy cycle and continuing until the platelet count is ³ 50,000/µL. Individual treatment courses longer than 21 days are not recommended, and the drug should be discontinued at least 2 days before the start of the next chemotherapy cycle.
The results of several clinical trials have established the role of rhIL-11 as a thrombopoietic growth factor. Dose-ranging and placebo-controlled[2,3] clinical trials of rhIL-11 in adults and open clinical trials of rhIL-11 in children[4,5] undergoing chemotherapy for solid tumors or lymphoma have provided clinical evidence of attenuation of platelet nadir and stimulation of platelet production. These trials have shown that rhIL-11 accelerates the recovery of platelet counts, facilitating the administration of the planned chemotherapy without dose modification. This article presents background pharmacologic information and a discussion of data from clinical trials supporting the efficacy of rhIL-11, through its thrombopoietic effects, for the prevention of chemotherapy-induced severe thrombocytopenia in high-risk patients with nonmyeloid malignancies.
rhIL-11 is well absorbed subcutaneously with a bioavailability of more than 80%; repeated doses do not accumulate in plasma. The pharmacodynamic properties of rhIL-11 were determined in a phase I dose-ranging study in nonmyelosuppressed patients (age range: 26 to 67 years) with locally advanced (stage IIIB, n = 3) or metastatic (stage IV, n = 13) breast cancer. rhIL-11 was administered both before (cycle 0) and after up to four monthly cycles of dose-intensive chemotherapy.
After a 14-day washout period following the prechemotherapy dosing of rhIL-11, patients received two to four cycles of chemotherapy with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) at a dose of 1,500 mg/m² and doxorubicin(Drug information on doxorubicin) at 60 mg/m² administered on the first day of each cycle. Chemotherapy was repeated every 28 days. Cohorts of at least three patients received rhIL-11 alone at doses of 10, 25, 50, 75, or 100 µg/kg/d subcutaneously for 12 days (days 3 through 14 of each treatment cycle). The use of granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) (5 µg/kg/d) was permitted during the third and fourth chemotherapy cycles if patients experienced a febrile neutropenic event or an absolute neutrophil count (ANC) of £ 500/µL for more than 5 days during the first two cycles.
In nonmyelosuppressed patients (ie, cycle 0, prior to chemotherapy), daily dosing with rhIL-11 over the dose range of 10 to 75 µg/kg produced a dose-dependent rise in platelet count that was apparent between 5 and 9 days after the start of dosing (Figure 1). Platelet counts reached peak levels after a median of 14 to 19 days. Figure 1 shows the platelet-response profile at doses of 10, 25, and 50 mg/kg per day.[1,7] These doses produced increases in platelet counts of 76%, 93%, and 108%, respectively, from baseline values. At the 50-µg/kg/d dose, peak platelet counts occurred at a median of 16 days after the initiation of therapy. As seen in Figure 1, increases in platelet counts were sustained for approximately 1 week after rhIL-11 was discontinued. At the 75-µg/kg/d dose, an increase of 185% over the baseline value was observed.
Across two chemotherapy cycles (myelosuppressed state), rhIL-11 doses ³ 25 µg/kg/d produced higher median nadir platelet counts (> 100,000/µL) than the 10-mg/kg/d dose (< 70,000/µL). Only doses that were ³ 25 µg/kg/d prevented severe thrombocytopenia (defined as a platelet count < 20,000/µL, the level often used as a threshold for platelet transfusion).
Effects on Platelet Function and Coagulation Factors
Treatment with rhIL-11 had no apparent effect on platelet function. There were no changes in either adenosine(Drug information on adenosine) diphosphate (ADP)induced platelet activation or platelet aggregation induced by various agents (ADP, epinephrine(Drug information on epinephrine), collagen(Drug information on collagen), ristocetin, or arachidonic acid), indicating a lack of effect of rhIL-11 on platelet reactivity or platelet aggregating behavior, respectively. At all doses studied, treatment with rhIL-11 was not associated with significant changes in prothrombin time or partial thromboplastin time.
At the 50-µg/kg/d dose, a statistically significant increase from baseline in mean fibrinogen level was seen by day 12 of treatment. These findings are in accordance with those of an earlier study in healthy adult volunteers in which treatment with rhIL-11 (25 µg/kg/d subcutaneously for 7 days), resulted in statistically significant increases in mean plasma fibrinogen concentration and mean von Willebrand factor, compared with both baseline and placebo (fibrinogen: P < .001 vs baseline, P < .01 vs placebo; von Willebrand: P < .001 vs baseline, P = .02 vs placebo).
In this study, rhIL-11 alone (without G-CSF) did not ameliorate chemotherapy-associated leukopenia or neutropenia, suggesting that the predominant biological activity of rhIL-11 is on the megakaryocytic cell lineage, contrasting with the stimulation of other hematopoietic lineages observed in vitro. There was no evidence of interference by rhIL-11 on the efficacy of G-CSF in ameliorating neutropenia when these cytokines were administered concurrently. This is an important finding because the simultaneous use of these two cytokines addresses the two major dose-limiting toxicities of myelotoxic chemotherapy.
Treatment with rhIL-1l was associated with dose-related increases in acute-phase proteins during both pre- and postchemotherapy cycles. At all doses studied, maximal increases in C-reactive protein occurred within the first week of therapy and remained at statistically significantly (P < .05) elevated levels from day 5 through day 15, compared with baseline pretreatment levels. Levels of C-reactive protein rapidly returned to baseline levels following discontinuation of rhIL-11.
Treatment with rhIL-11 was associated with an expansion in plasma volume of approximately 20%, which is believed to occur secondary to rhIL-11 stimulation of renal sodium reabsorption. The reversible expansion in plasma volume led to the development of dependent peripheral edema and dilutional anemia as two of the most commonly reported side effects. Edema and constitutional symptoms (myalgia, arthralgia, headache, and fatigue) were primarily considered to be mild or moderate in severity at rhIL-11 doses of £ 50 µg/kg/d.
Edema was also a common occurrence during subsequent controlled clinical evaluations of rhIL-11 at 50 µg/kg, but it was usually mild to moderate, easily managed, and either resolved spontaneously or relieved by temporary use of a diuretic.[2,3] In these studies, plasma volume expansion was also the most likely underlying cause of other observed side effects, such as palpitations, dyspnea, headache, and transient atrial arrhythmias. Increased plasma volume may have contributed to the development of atrial arrhythmias in a subset of patients by causing atrial distention (which has been demonstrated in dogs treated with rhIL-11) and a subsequent decrease in the atrial refractory period.
In patients with cancer, transtelephonic monitor data showed no evidence of any effects of rhIL-11 treatment on cardiac conduction intervals, specifically PR, QRS, QT, or QTc intervals, indicating that rhIL-11 has no direct effect on cardiac function.
rhIL-11 did not cause clinically significant fevers or capillary leak syndrome. The 75-µg/kg/d dose was not associated with true dose-limiting toxicity but was subjectively less well tolerated than lower doses. Thus, evaluation of this dose was not pursued in subsequent studies.