Sunday, September 24, 2023
The incidence and severity of thrombocytopenia in patients with leukemia vary according to the type and stage of the disease. Patients with chronic myelogenous leukemia (CML) tend to have an elevated platelet count during the chronic phase of the disease. Thrombocytopenia can develop as a result of cytotoxic therapy or when the disease progresses to the accelerated and blastic phases. Similarly, patients with chronic lymphocytic leukemia (CLL) tend to develop thrombocytopenia only in the advanced stages of the disease.
On the other hand, thrombocytopenia is very common at presentation in patients with acute leukemia (myelogenous and lymphocytic). Easy bruisability and other bleeding symptoms are very typical presentations in these patients and could be the first symptoms that lead to the diagnosis of acute leukemia. In addition, patients with acute leukemia are usually treated with combination chemotherapy to induce remission. As a result, thrombocytopenia is essentially universal in these patients and can persist for several weeks until the healthy bone marrow recovers.
In addition to bone marrow infiltration by leukemia cells leading to decreased production of platelets, other factors might contribute to thrombocytopenia in these patients (Table). Such factors are increased platelet destruction from hypersplenism, sepsis, and disseminated intravascular coagulation. Also, cytotoxic drugs are common contributors to thrombocytopenia in patients with leukemia. Immune destruction of platelets may occur in some patients with CLL.
| • Increased platelet destruction from hypersplenism • Sepsis • Disseminated intravascular coagulation • Chemotherapy and radiotherapy • Immune destruction of platelets • Immune response to medications (heparin is most common) |
Bleeding complications occur more frequently as the severity of thrombocytopenia increases, but only after the platelet count crosses a threshold of about 10 to 30 x 103. A normal platelet count is not required to support normal hemostasis. Traditionally, although supported by few data, a platelet count of 50 x 103 is often considered sufficient to provide hemostasis for invasive procedures. Clinically important spontaneous bleeding does not occur until the platelet count is very low or unless other disorders are present. Of course, other disorders, such as infections, are common in patients with leukemia. When bleeding occurs, it could be minor, such as skin and gingival bleeding, or more serious, such as gastrointestinal, intracranial, retinal, or pulmonary bleeding.
Two studies have attempted to better determine the platelet count below which the bleeding complications increase. The first study involved 92 patients treated for acute leukemia at the National Cancer Institute between 1956 and 1959.[1] These patients were observed for bleeding complications without any platelet transfusion support, in the era before current methods of platelet collection and storage were developed and before platelet transfusions were routinely available. In patients with a platelet count <1 x 103/mcL, gross bleeding occurred on 33% of the study days. At platelet counts between 5 x 103/mcL and 20 x 103/mcL, gross bleeding occurred only on 3% of the study days. When this study was conducted, the antiplatelet properties of aspirin were not known, and it is possible that many of these patients received aspirin when they developed fever.
The second study was conducted in a group of 20 patients with aplastic anemia who received no platelet transfusions and no medications.[2] Patients were injected with radiolabeled chromium, and stool samples were collected to estimate the amount of blood loss in the gastrointestinal tract. When platelet counts exceeded 10 x 103/mcL, the amount of blood loss in the stools was similar to that of healthy persons: It was slightly higher at levels between 5 and 10 x 103/mcL and markedly elevated in patients with platelet counts < 5 x 103/mcL. This study remains the best evidence that only very few platelets are required to support normal hemostasis in patients without other overt illness and who are not taking medications. This observation is consistent with what is seen in patients with other bleeding disorders, such as congenital hemophilia: Patients with absent factor VIII have a severe bleeding disorder, but bleeding in patients with only 1% to 2% of normal factor levels is substantially less.
The leukemic process itself could also contribute to platelet function abnormalities. In a study of 14 patients with active acute leukemia,[3] all patients had platelet function abnormalities. In 2 patients whose leukemia went into complete remission, the platelets regained normal function.
Platelet transfusion remains the most common intervention in the management of thrombocytopenia in patients with leukemia.
Autopsy studies have shown that bleeding complications leading to death became much less frequent with the introduction of
platelet transfusion.[4-7] In a study conducted at the National Cancer Institute to assess the risk for bleeding with thrombocytopenia, the investigators
were not able to determine a threshold below which platelets needed to be transfused prophylactically.[1] However, following this study, it became common practice to transfuse platelets prophylactically when the count falls below
20x103/mcL. Several subsequent randomized studies showed that using a platelet
count< 10x103/mcL as the trigger for prophylactic platelet transfusion did not increase the risk for bleeding.[8-11] The optimal dose of platelets to be transfused remains highly controversial.[12] A current National Institutes of Health-sponsored randomized clinical trial carried out by the Transfusion Medicine/Hemostasis
Clinical Trials Network has just completed enrollment of 1350 patients in a platelet dose study to better define the optimal
dose of platelets to be administered with each transfusion.
Platelet transfusion has its limitations, including the risk for alloimmunization[13] and transmission of viral and bacterial infections.[14,15] Alloimmunization is particularly common in patients with leukemia because they tend to receive multiple platelet transfusions.[16] In addition, platelets have a short shelf-life and are commonly in short supply. Several pharmacologic agents have been introduced to help maintain a patient's platelet count without transfusion.
Oprelvekin (recombinant human interleukin [IL]-11) is approved by the US Food and Drug Administration for the prevention of severe thrombocytopenia from chemotherapy in patients with nonmyeloid malignancies.[17] Clinical studies on the effectiveness of this agent in patients with acute leukemia are lacking. Cell line studies have suggested that IL-11 may have a stimulatory effect on IL-3-dependent growth of leukemia cells.[18] IL-11 has also been proposed to have an autocrine effect in acute megakaryoblastic leukemia.[19] It is unlikely that oprelvekin will have any significant clinical usefulness in the management of thrombocytopenia in patients with acute leukemia.
IL-3 acts on early progenitor cells and therefore promotes the differentiation of all myeloid cells.[20] Administration of recombinant IL-3 to patients with AML has not been shown to shorten the duration of neutropenia or thrombocytopenia.[21] At the same time, IL-3 administration has been associated with significant toxicity, including fluid retention, rash, bone pain, and headache.
IL-6 is a multifunctional cytokine that exerts various effects in the body. The physiologic effects of IL-6 include the induction of immunoglobulin synthesis, activation of T lymphocytes and natural killer cells, induction of fever, stimulation of megakaryopoiesis, induction of acute-phase protein synthesis by the liver, and corticotropin release by the pituitary gland.[22] In human bone marrow cultures, IL-6 has been shown to induce granulocytic and monocytic differentiation in the presence of additional colony- stimulating factors.[23] Thrombopoiesis is by far the most pronounced hematopoietic function of IL-6, as shown in studies in mice.[24,25] Administration of human recombinant IL-6 to monkeys resulted in megakaryocyte maturation and increased the platelet count consistent with a thrombopoietic effect.[26] On the other hand, several studies have raised concern about the safety of IL-6 administration in patients with leukemia. It has been suggested that IL-6 co-stimulates proliferation of clonogenic leukemia cells together with various colony-stimulating factors and IL-1.[27,28]
Thrombopoietin (Mpl ligand) is a hematopoietic growth factor that stimulates megakaryocyte and platelet proliferation and differentiation.[29,30] Two recombinant forms of Mpl ligand, pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and recombinant human thrombopoietin (rHuTPO), have been tested in clinical trials. Initial phase 1 studies of PEG-rHuMGDF were promising.[31-33] Randomized, double-blind, phase 3 studies on PEG-rHuMGDF in patients with acute leukemia failed to show an improvement in the severity or duration of thrombocytopenia following induction chemotherapy.[34,35] In addition, PEG-rHuMGDF administration to healthy volunteers and patients receiving chemotherapy was associated with episodes of prolonged thrombocytopenia related to the development of antibodies to PEG-rHuMGDF that cross-reacted with the endogenous thrombopoietin.[36,37] Both PEG-rHuMGDF and rHuTPO are no longer in clinical development.
Recombinant activated factor VII (rFVIIa) was originally developed for the management of bleeding in patients with hemophilia A or B with factor VIII or IX inhibitors, respectively. This agent has been used in various other bleeding settings, including trauma, obstetric complications, and platelet disorders.[38-41] A recent audit of its use to control bleeding in patients with thrombocytopenia associated with hematologic malignancies has shown promising activity.[42] Among 24 patients, rFVIIa was reported to stop bleeding in 11 (46%) and markedly decrease it in 8 (33%). Hemostasis was achieved within 2.5 hours of administration in most patients. rFVIIa is a therapeutic option in patients with thrombocytopenia and bleeding that is not responding to platelet transfusions.
Multiple new agents are in development for management of thrombocytopenia that may have important benefits for patients with leukemia. The first 2 agents to enter clinical trials, romiplostim (formerly known as AMG 531) and eltrombopag, will likely be approved for use in patients with idiopathic thrombocytopenic purpura (ITP) in 2008. Romiplostim is described as a "peptibody"; the molecule is composed of 4 peptides with no sequence homology to endogenous thrombopoietin joined to IgG1 Fc components. The peptides bind to the thrombopoietin receptor and the Fc fragments provide stability for prolonged circulation so that romiplostim can be administered subcutaneously once weekly. In a phase 1 study in 48 healthy volunteers, romiplostim caused a consistent increase in the platelet count without inducing any neutralizing or cross-reacting antibodies against thrombopoietin.[43] This agent has been tested in patients with chronic ITP and has shown very effective activity.[44,45] It is well tolerated with no significant side effects. Eltrombopag is a small, nonpeptide molecule that also binds to the thrombopoietin receptor and stimulates intracellular signaling pathways identical to endogenous thrombopoietin. It is administered orally once daily and has demonstrated effectiveness in patients with ITP[46] and thrombocytopenia associated with hepatitis C.[47] These agents, and others in preliminary stages of development, hold promise for the management of thrombocytopenia in patients with acute leukemia. No clinical trials have reported on their activity in this patient population.
Thrombocytopenia in patients with leukemia is a significant and common problem. Mortality and morbidity from bleeding complications in these patients remain frequent. Currently, platelet transfusions remain the mainstay of therapy for these patients. To date, no single pharmacologic agent has shown consistent improvement in the platelet count in patients with leukemia without causing significant side effects. rFVIIa has promising activity in controlling bleeding in patients not responding to platelet transfusions. Romiplostim, eltrombopag, and other thrombopoietin mimetic molecules have yet to be tested in this patient population.
This activity is supported by an educational donation provided by Amgen.
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