Page 2525 - Hematology_ Basic Principles and Practice ( PDFDrive )

2248 Part XIII Consultative Hematology

progression. This relationship between ESA use and thrombosis may hematologic malignancy, thrombocytopenia is even more common,
be related to the target hemoglobin concentration as higher hemo- particularly with induction or conditioning chemotherapy regimens.
globin targets are associated with increased rates of thrombotic events The typical mechanism by which chemotherapy causes thrombocy-
in cancer patients. topenia is through marrow suppression; however, some agents are
In addition to thrombotic events, a number of concerns have been also associated with immune-mediated thrombocytopenia. Immune
raised about ESA use and potential worsening of overall survival or thrombocytopenia is typically characterized by a sudden and isolated
time to disease progression. Data regarding ESAs and progression of drop in platelet count. For example, trastuzumab and oxaliplatin have
disease are conflicting; some studies in patients with breast cancer both been associated with immune-mediated thrombocytopenia.
and patients with head and neck cancer suggested worsening Thrombocytopenia may also be a result of bone marrow infiltration
progression-free survival or local control of disease with ESA use. The by tumor cells, thrombotic microangiopathy, consumptive coagu-
mechanism behind tumor progression is unknown but may relate to lopathy, or as an autoimmune manifestation of the malignancy itself.
decreased chemosensitivity in the setting of ESA use or relate to Bone marrow involvement, often occult, is more common in prostate,
tumor vascularity and oxygen supply. One study isolated breast lung, and breast cancer; such patients typically have multiple cell
cancer stem-like cells, which are thought to promote tumor progres- lines involved, and display a leukoerythroblastic appearance on the
sion and relapse, and identified expression of the EPO receptor on peripheral smear. The laboratory features of disseminated intravascu-
the cell surface of these chemoresistant cells. Moreover, the concur- lar coagulation (DIC), elevated D-dimer, and fibrinogen degradation
rent administration of ESAs during chemotherapy had a chemopro- products, can be seen in cancer patients, and are more common
tective effect. Other mechanisms that may underlie the association with advanced disease, where they may be present in up to 90% of
of EPO administration with tumor progression include augmenta- patients.
tion of red cell mass and effects on tumor oxygenation. Treatment of thrombocytopenia in cancer patients is generally
Because of concerns about thrombotic events, as well as the supportive. For patients with active bleeding, platelet transfusion and
potential for worsened overall survival and time to disease progres- correction of other coagulopathies are the mainstays of therapy. The
sion, ESA use is generally restricted to certain indications in patients use of agents such as tranexamic acid in these patients may be con-
with cancer. In general, transfusion of blood products and, if indi- sidered as well. In the absence of active bleeding, a threshold of <10
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cated, iron therapy, remain the standard of care for anemia associated × 10 /L for prophylactic platelet transfusion is generally recom-
with malignancy. Future studies considering the safety of ESAs for mended. This is based on a study which randomized 600 patients
lower target hemoglobin levels, as well as alternative preparations of with hematologic malignancies to prophylaxis or no prophylactic
iron therapy may provide viable treatment options for cancer patients transfusions; both were treated for bleeding events. Rates of World
with anemia. There are some instances where ESAs may be useful Health Organization grade 2, 3, or 4 bleeding were high in both
adjuncts, specifically among patients with moderate or severe chronic groups, but higher (50%) in the no-prophylaxis group (50%),
kidney disease, or in palliative settings. In such situations, reversible compared with the prophylaxis group (43%). Prophylactic platelet
causes of anemia should be ruled out before ESA use, and the minimal transfusion has been used in patients with solid tumors, but without
amount of EPO be used to avoid RBC transfusion. as much evidence-based support.
Other agents, with or without platelet transfusion, may also have
a role in chemotherapy-related thrombocytopenia. Thrombopoietin
Erythrocytosis (TPO) receptor agonists are an area of increasing interest in the
management of thrombocytopenia during chemotherapy, particularly
Outside of patients with myeloproliferative neoplasms, and specifically as a means to maintain treatment schedules which may be delayed
polycythemia vera, erythrocytosis is an uncommon manifestation of by thrombocytopenia. A 2015 phase I trial compared placebo to
cancer. Polycythemia vera, and other myeloproliferative neoplasms, eltrombopag in patients receiving gemcitabine-based chemotherapy
are typified by acquisition of somatic mutations that upregulate the and found that fewer patients receiving eltrombopag required dose
Janus kinase (JAK)/signal transducer and activator of transcription delays and/or reductions in chemotherapy compared with those
(STAT) signaling pathway, typically the JAK2 V617F mutation, and receiving placebo. This evidence is promising and further clinical
phenotypically present as an expansion of myeloid-origin cells, with trials may reveal a role for romiplostim and/or eltrombopag in the
an elevated hemoglobin and suppressed EPO levels. In these cancers, management of thrombocytopenia resulting from malignancy.
erythrocytosis is caused by primary expansion of the malignant clone.
In contrast, when erythrocytosis is seen in association with solid
tumors, it typically is the result of a paraneoplastic phenomenon. Thrombocytosis
This can be seen in the setting of increased erythropoietin levels
related to malignancy, for instance with clear cell renal cell car- While thrombocytopenia may be more clinically apparent because of
cinoma. Other rare causes of cancer-associated erythrocytosis may bleeding or delays in the administration of chemotherapy, reactive
include aromatase inhibition in breast cancer. There may be an thrombocytosis is actually more common than thrombocytopenia in
association with a common predisposing condition; for instance, patients with solid tumors. The clinical impact of thrombocytosis is
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patients with von Hippel-Lindau disease are at risk for renal and less clear; however, having a platelet count greater than 350 × 10 /L
central nervous system tumors, and the mechanism of erythrocytosis before initiating chemotherapy is associated with a greater risk for
is typically through paraneoplastic EPO expression. Nonetheless, venous thromboembolism (VTE). Cancer-related thrombocytosis is
elevated RBC counts are rare in patients with malignancy, par- thought to be mediated by inflammatory cytokines, and elevated
ticularly those receiving chemotherapy, and usually do not require levels of interleukin (IL)-6, IL-11, and TPO have been documented
intervention. in cancer patients. Rarely, thrombocytosis may be the result of a
paraneoplastic phenomenon, which has been described in breast and
ovarian malignancies. In many tumor types including breast, renal
PLATELETS cell, gastric, and advanced stage non–small cell lung cancer, elevated
platelet counts seem to confer an adverse prognosis. The mechanism
Thrombocytopenia for this association is unclear.

Chemotherapy and immunosuppressive agents are the most
common causes of thrombocytopenia in the cancer patient. For Platelet Dysfunction Secondary to Malignancy
instance, patients receiving cisplatin/gemcitabine for bladder cancer
or carboplatin/gemcitabine for lung cancer have rates of clinically In addition to abnormalities in absolute platelet number, cancer
significant thrombocytopenia of 30% to 60%. Among patients with patients may have alterations in platelet function, which can