Drug Discov Today. 2008 Jul 15. [Epub ahead of print]

Emerging treatments for thrombocytopenia: Increasing platelet production

Peeters K, Stassen JM, Collen D, Van Geet C, Freson K.
Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.


Thrombocytopenia is a common medical problem. The first generation thrombopoietic agents, recombinant THPO and 'megakaryocyte growth and development factor' (PEG-rHuMGDF) entered clinical trials, but their development was discontinued owing to neutralizing auto-antibodies cross-reacting with endogenous THPO, causing thrombocytopenia in healthy volunteers. Although an approved drug for prevention of severe thrombocytopenia following myelosuppressive chemotherapy (human Interleukin-11) exists, the search for new thrombopoietic agents continued because its use is limited by side effects. Several second generation thrombopoietic factors have entered clinical trials and some new negative regulators of megakaryopoiesis have been found, such as platelet factor 4 (PF4) and the pituitary adenylate cyclase activating polypeptide (PACAP). Their inhibition may be useful in the treatment of thrombocytopenia. This article reviews second generation thrombopoietic factors and those recently discovered regulators of megakaryopoiesis.


PMID: 18602017 [PubMed - as supplied by publisher]

Lancet. 2008 Feb 2;371(9610):395-403

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial

Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL.
Massachusetts General Hospital, Boston, MA 02114, USA. kuter.david@MGH.harvard.edu


BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.


PMID: 18242413 [PubMed - indexed for MEDLINE]

Cancer. 2008 Jul 15. [Epub ahead of print]

The effect of interleukin 11 on thrombocytopenia associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

Aribi A, Kantarjian H, Koller C, Thomas D, Faderl S, Garcia-Manero G, Cortes J.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

BACKGROUND.: During therapy with tyrosine kinase inhibitors (TKIs), approximately 20% to 50% of patients with chronic myeloid leukemia (CML) develop grade >/=3 thrombocytopenia leading to treatment interruptions and dose reductions. Interleukin 11 (IL-11) reduces the incidence and the severity of thrombocytopenia in solid tumors. METHODS.: The authors investigated the efficacy and safety of low-dose IL-11 for improving thrombocytopenia associated with TKI therapy in 14 patients with CML. The starting dose of IL-11 was 10 mug/kg 3 times weekly, and the dose was escalated by 1 dose level every 2 weeks if the patients had no sustained platelet increase. RESULTS.: The median patient age was 52 years. The median platelet count at the time IL-11 was started was 37 x 10(9)/L. All patients had prior TKI dose reductions. After the initiation of IL-11, 8 of 14 patients (57%) had an increase in platelet count with a median peak platelet count of 110 x 10(9)/L. One additional patient had no platelet increase but was able to tolerate an imatinib dose increase. Eleven patients had a decrease in the number of days of TKI therapy interruption secondary to thrombocytopenia after the initiation of IL-11 (6% of total treatment time vs 34% of total treatment time before IL-11). Therapy was well tolerated. CONCLUSIONS.: The current results indicated that IL-11 may correct thrombocytopenia associated with TKI therapy for patients with CML and that it has a favorable toxicity profile. Cancer 2008. (c) 2008 American Cancer Society.


PMID: 18629842 [PubMed - as supplied by publisher]