Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies

Abstract

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.

Figure 1.

Relation between bleeding (measured using the World Health Organization bleeding scale) and the platelet count in patients with hypoproliferative thrombocytopenia. The percentage of days on which patients had bleeding of grade 2 or greater is shown, along with the associated 95% confidence intervals (dashed lines), according to the morning platelet count category. (From Slichter et al. and reproduced with the permission of the Massachusetts Medical Society.)

Figure 2.

The production of platelets from bone marrow stem cells. Stem cells differentiate into cells committed to megakaryocyte differentiation (megakaryocyte colony-forming cells, MK-CFC) which are mitotically active. MK-CFC then stop mitosis and start endomitosis producing immature megakaryocytes (MK) with polyploid nuclei. The immature MK then stop their endomitosis and mature into large, morphologically identifiable MK that then migrate to the bone marrow sinusoids and produce platelets.

Figure 3.

Log-linear correlation of thrombopoietin level with platelet counts. Patients undergoing double umbilical cord blood transplantation had serial platelet counts and thrombopoietin levels determined over their hospital course. As platelet counts declined, thrombopoietin levels rose. Figure created from data in the study by deFilipp et al.

Figure 4.

Recombinant human thrombopoietin and the thrombopoietin receptor agonists bind to and activate the thrombopoietin receptor in different ways. The thrombopoietin (TPO) receptor has been proposed to exist as an inactive preformed dimer (left side) with a proximal and distal hematopoietic receptor domain (HRD1 and HRD2, respectively). Upon binding of romiplostim or recombinant human TPO (not pictured) to the distal HRD2, the conformation of the receptor changes (right side) and a number of signal transduction pathways are activated which increase platelet production. The other TPO receptor agonists bind to the transmembrane region of the receptor and activate many of the same signal transduction pathways. TPO: thrombopoietin; HRD: hematopoietic receptor domain protein; STAT: signal transducer and activator of transcription; JAK: Janus kinase; GRP2: growth receptor bound protein 2; SOS: son of sevenless (a guanine nucleotide exchange factor); RAS: rat sarcoma virus (a small GTP-ase); RAF: rapidly accelerated fibrosarcoma (a serine/threonine kinase); MAPK: mitogen-activated protein kinase.

Figure 5.

Pegylated recombinant human megakaryocyte growth and development factor increases the platelet count in patients undergoing chemotherapy. Lung cancer patients being treated with carboplatin and paclitaxel were also given either placebo (purple circles) or pegylated recombinant human megakaryocyte growth and development factor (yellow circles) in a double-blind, randomized study. Platelet counts were measured daily. The inset shows the probability of recovery of the platelet count back to baseline in the two treatment groups. Figure adapted from published data. PEG-rhMGDF: pegylated recombinant human megakaryocyte growth and development factor.

Figure 6.

Recombinant human thrombopoietin reduces the need for platelet transfusions in patients undergoing carboplatin chemotherapy for gynecological malignancy. (A) Platelet count time course for patients in cycle 2 (treated with recombinant human thrombopoietin [rhTPO]) compared to that in patients in cycle 1 (treated without rhTPO). Figure provided by Pharmacia, Inc. (Peapack, NJ, USA). (B) Platelet counts and platelet transfusions in cycle 2 (treated with rhTPO) compared with cycle 1 (treated without rhTPO). Figure created from data in the study by Vadhan-Raj et al. d: days.

Figure 7.

Platelet counts of patients with chemotherapy-induced thrombocytopenia treated with romiplostim. Median weekly platelet counts for solid tumor patients (n=122, blue) with no predictors of non-response (no PNR); solid tumor patients (n=31, gray) with predictors of non-response (PNR: bone marrow invasion by tumor, prior pelvic irradiation, or prior temozolomide treatment); aggressive lymphoma patients (n=13, red); and myeloma patients (n=7, purple). Data reproduced with permission from Al-Samkari H et al.