Recombinant Human Thrombopoietin in Myelosuppressive Chemotherapy

ABSTRACT: Recombinant human thrombopoietin (rhTPO) is a full-lengthglycosylated molecule that has been under evaluation in the setting ofchemotherapy-induced myelosuppression. It has been shown to be a potentstimulator of platelet production in cancer patients when administered prior tochemotherapy. The peak platelet response to a single dose of rhTPO is observedaround day 12, and is accompanied by a significant increase in the number ofmature megakaryocytes in bone marrow. Consistent with this biologic effect,rhTPO administered postchemotherapy has been shown to be effective inattenuating severe thrombocytopenia induced by carboplatin, which produces alate platelet nadir. Early clinical experience with a regimen that produces anearly nadir, however, such as AI (doxorubicin [Adriamycin] and ifosfamide[Ifex]), suggests that administration of rhTPO both prior to and followingchemotherapy might be important to reduce thrombocytopenia severity. Treatmentwith rhTPO in these clinical trials has been well tolerated with a favorablesafety profile. Randomized clinical trials have been initiated to determinefurther the importance of schedule in the prevention and treatment of severethrombocytopenia in cancer patients. [ONCOLOGY 15(Suppl 8):35-38, 2001]

Introduction

Myelosuppression is a majorclinical problem in the management of cancer patients receiving cytotoxic therapy. The availability ofrecombinant myeloid growth factors, granulocyte colony-stimulating factor (G-CSF[Neupogen]), and granulocyte-macrophage colony-stimulating factor (GM-CSF[Leukine, Prokine]) has reduced the duration of severe neutropenia.[1] Morerecently, focus has been directed to potential agents that may attenuatethrombocytopenia. The relationship between the severity of thrombocytopenia andthe risk of bleeding complications is established[2].

Platelet transfusions, which may decrease the risk of severebleeding complications, also carry potential risks, including transfusionreactions, transmission of infectious agents, graft-vs-host disease, and mostimportantly, alloimmunization. In the past decade, several cytokines withthrombopoietic potential, such as the interleukins (ILs) (IL-1, IL-3, IL-6,IL-11 [Interleukin 11, Neumega]), hybrid cytokine PIXY 321 (a GM-CSF/IL-3 fusionprotein), and engineered chimeric growth factor receptor agonists (myelopoietin[Leridistim], promegapoietin [SC71858]) have been evaluated in clinicaltrials.[3-7] Some of these agents have shown thrombopoietic activity in vivo;however, their clinical utility has often been limited by toxicities.

Thrombopoietin, the ligand for the c-mpl receptors, is a primaryregulator of platelet production in vivo. Since thrombopoietin was cloned,[7-11]two recombinant forms have been evaluated in clinical trials. The full-lengthglycosylated molecule is referred to as recombinant human thrombopoietin(rhTPO), and the truncated, pegylated version of the molecule is known aspegylated recombinant human megakaryocyte growth and development factor (MGDF).Both of these molecules have shown potent biologic effects in vivo in phase I/IIclinical trials.[12-19]

Clinical trials of MGDF have been discontinued, however, becauseof the development of neutralizing antibodies and clinically significantthrombocytopenia in some cancer patients and normal donors receiving this agent.In early clinical trials, rhTPO, the full-length molecule, was found to have anexcellent tolerability and a favorable safety profile, and is currently underclinical development. This article briefly reviews the clinical experience withrhTPO in cancer patients receiving myelosuppressive chemotherapy.

Clinical Studies With rhTPO

We assessed the safety and in vivo biologic effects of rhTPO incancer patients receiving myelosuppressive chemotherapy in three clinicaltrials. The initial study investigated effects of rhTPO administeredintravenously (IV) in a dose-escalated manner to sarcoma patients receiving AI(doxorubicin [Adriamycin] and ifosfamide [Ifex]) chemotherapy.[12-17]Recombinant human thrombopoietin (0.3-2.4 mg/kg) was administered 3 weeksprior to chemotherapy (as a single dose or two doses given 2 days apart) toexamine its clinical tolerability and hematopoietic effects. Three weeks later,patients received high-dose AI (doxorubicin, 90 mg/m²; ifosfamide, 10g/m²)without rhTPO (cycle 1). The second cycle of AI was followed by rhTPO (cycle 2)at the same doses. Because AI causes cumulative myelosuppression, cycle 1 servedas an internal control for cycle 2, during which patients were expected toexperience more thrombocytopenia than in the previous course.

Prechemotherapy Phase of Study

In the prechemotherapy phase of the study, rhTPO elicited anincrease in circulating platelet count (1.3 to 3.6-fold) in a dose-dependentmanner.[12] Although the increase in platelet count was evident beginning on day4, the peak effect was observed on approximately day 12. The platelet responsewas sustained, with a gradual decrease to near baseline level around day 21,prior to chemotherapy administration. This sustained response may be related, inpart, to the prolonged serum half-life (20 to 30 hours) of this glycosylatedmolecule. The platelets appeared normal in morphology and exhibited normalaggregation in response to various agonist stimuli. Bone marrow examinationperformed 1 week after rhTPO administration revealed a marked increase in thenumber of megakaryocytes. These cells appeared normal in morphology; some werevery large and appeared mature with abundant cytoplasm (Figure1). There wasalso a significant increase in the number of hematopoietic progenitor cells ofmultiple lineages in the marrow, and mobilization of these cells in theperipheral blood.[20] However, no major changes in peripheral white blood cellcounts or hematocrit values were noted.

Postchemotherapy Phase of Study

In the postchemotherapy treatment phase, rhTPO was administeredin different schedules[16]. Results showed that the schedule of rhTPOadministration (ie, one, two, or seven doses) postchemotherapy did not have aconsistent effect on reducing the depth of the platelet nadir; in some patients,however, thrombocytopenia was less severe in cycle 2 (with rhTPO) than in cycle1 (without rhTPO). Several factors implied that earlier administration of rhTPOmight ameliorate myelosuppression associated with chemotherapy, including thelength of the AI regimen (4 days) and its association with an early plateletnadir (around day 12), the late peak effect of rhTPO on platelets, and thebiologic effects of rhTPO on progenitor cells and on marrow megakaryocytes. Wetherefore examined the effects of rhTPO administered both prior to and afterchemotherapy (starting from day -1) as one predose and two postdoses. Thefindings supported the importance of earlier administration of rhTPO in order toreduce severe thrombocytopenia.

Our next trial in this setting aims to optimize the rhTPOschedule to reduce AI-induced cumulative thrombocytopenia.[21] Recombinant humanthrombopoietin 1.2 mg/kg × 4 is administered as all predoses (ie,prechemotherapy), all postdoses (ie, postchemotherapy), or as pre/post doses(3/1 [ie, three predoses, one postdose], 2/2, or 1/3). So far, most of thepatients who have received rhTPO starting from day -5 of chemotherapy (on days-5, -3, -1, and 4) have had higher platelet nadirs in cycle 2 (with rhTPO)than in cycle 1 (withoutrhTPO). The finding further supports the importance of timing of rhTPO inrelation to chemotherapy to attenuate thrombocytopenia. This trial will alsoassess the effect of scheduling both predosing and postdosing of rhTPOon reducing the need for platelet transfusions.

The third trial investigated the safety and biologic effect ofrhTPO administered subcutaneously (SC) to patients with gynecologic malignancieswho are receiving high-dose carboplatin.[17] Patients received a single rhTPOdose (0.6-3.6 mg/kg) SC prior to chemotherapy. Three weeks later, patientsreceived carboplatin at an area under the concentration-time curve[AUC] of 11)alone as a control cycle. The second carboplatin cycle was followed byrhTPO given every other day for four doses, since carboplatin causes a delayednadir (around day 16). Sixteen patients, most of whom were heavily pretreated,received rhTPO in the dose-escalation phase of the study. Results showed that asingle dose, administered SC, induced a dose-related increase in circulatingplatelet count, although the increase was not as high as that previouslyobserved in chemotherapy-naive patients.

In the postchemotherapy phase, for all doses combined (0.6-3.6mg/kg, n=16), the platelet nadir was higher in cycle 2 than in cycle 1 (meanplatelet nadir, 53,000/mL vs 35,000/mL,P = .005). The duration of grade 3 thrombocytopenia was reduced from 6 days to 3days (P = .002).[17]

In this trial, the optimal biologic dose was defined as thelowest active dose at which the platelet response reached a plateau. The 1.2 mg/kg dose was found to be the optimal biologic dose by this schedule and withthis regimen. To assess further the efficacy of rhTPO in attenuating severethrombocytopenia, 12 patients receivedrhTPO as secondary prophylaxis. Recombinant human thrombopoietin significantlyreduced the need for platelet transfusions, particularly in patients whoreceived rhTPO at the optimal biologic dose (75% of patients in cycle 1 withoutrhTPO required transfusion vs 25% in cycle 2 with rhTPO), P = .013 (Figure 2). The treatment has been well tolerated without seriousadverse events. No constitutional symptoms, fluid retention, major organtoxicities, or enhanced incidence of thrombosis have been observed in thesetrials.

Discussion

Results of these early clinical trials show that rhTPO isclinically safe and mediates potent biologic effects in vivo. Thepharmacokinetics and pharmacodynamics, kinetics of platelet response, and biologic effects at the precursorlevel of rhTPO all suggest that the best rhTPO administration schedule willdepend on the type of chemotherapy regimen being used and the kinetics ofplatelet nadir associated with that regimen. Our findings suggest that with alate-nadir regimen, such as single-agent carboplatin (Paraplatin), postdosing ofrhTPO may be sufficient in decreasing the severity of thrombocytopenia. However,with early-nadir regimens, especially with the long regimen,[16] earlieradministration (both pre- and postdosing) might be important for bestamelioration of thrombocytopenia. An ongoing trial[16] is examining theimportance of dose and schedule of rhTPO in achieving optimal biologic effect.

Conclusions

The potent biologic effects ofrhTPO suggest several potential clinical applications for this novel cytokine,including prevention and management of thrombocytopenia associated withmyelosuppressive cytotoxic treatment, stem/progenitor cell-supportedmyeloablative treatment, bone marrow failure conditions, congenital and acquiredthrombocytopenias, and mobilization of progenitor cells. Recombinant humanthrombopoietin may also be useful in facilitating harvesting of platelets forcryopreservation and subsequent transfusions in cancer patients as well as incertain non-oncology treatment settings. Future trials will further define thesafety profile and the optimal role of this agent in various clinicalconditions.

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