In-hospital management of patients with thrombocytopenia due to hematological diseases (5) - Thrombocytopenia due to chemotherapy in acute leukemia

Author: Liu Jiajun, Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen
University
Acute leukemia (AL) is a rapidly progressive hematological malignancy with a short natural course
.

Radiotherapy, chemotherapy, hematopoietic stem cell transplantation and immunotherapy are currently the main treatment methods for AL, while chemotherapy is the basic treatment method for acute leukemia.
A sufficient amount of chemotherapy is used to remove leukemia cells and minimal residual disease in the bone marrow to achieve disease remission
.

During chemotherapy of acute leukemia, because the bone marrow is severely invaded by leukemia cells, it directly destroys hematopoietic stem/progenitor cells and the hematopoietic microenvironment, and inhibits normal bone marrow hematopoietic function.
Patients often suffer from pancytopenia, causing clinical symptoms of anemia, infection and bleeding
.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of peripheral blood thrombocytopenia due to the inhibitory effect of chemotherapy drugs on the bone marrow, especially megakaryocytes in the bone marrow.
It is a common clinical dose-limiting adverse reaction of chemotherapy drugs.

.

The occurrence of CIT increases the bleeding risk of patients.
At the same time, it may reduce the dose of chemotherapy drugs or delay the chemotherapy time, or even terminate the chemotherapy, so that the chemotherapy cannot be carried out as planned in a sufficient amount and a full course of treatment, thereby affecting the clinical efficacy and patient survival, and increasing medical expenses
.

The myelosuppression in patients with acute leukemia is usually more severe than that in solid tumors.
Therefore, the management of such thrombocytopenia is different from that of solid tumors, with more emphasis on timely and critical management
.

Evaluation and process of acute leukemia CIT The normal lifespan of platelets is 8 to 10 days
.

After leukemia chemotherapy, the platelet count generally begins to decrease on the 5th day after chemotherapy, reaches the lowest value on the 14th day, and gradually returns to the basic value from the 28th day to the 35th day
.

The recovery of platelet count in leukemia patients is also related to the effect of chemotherapy
.

CIT was associated with the dose of the initial cycle of chemotherapy and the additive effect of multiple cycles of chemotherapy, usually appearing on days 6 to 14 after treatment
.

When a leukemia patient develops CIT after chemotherapy, the patient's bleeding risk should be assessed first, especially if the patient is receiving anticoagulants and other treatments that may increase bleeding
.

CIT patients with the following characteristics are more prone to bleeding: (1) a history of bleeding; (2) platelet count <75×109/L before chemotherapy; (3) receiving platinum, gemcitabine, cytarabine, anthracycline (4) Bone marrow infiltration of tumor cells; (5) Poor physical fitness score (≥2 points); (6) Previously received or currently receiving radiotherapy, especially for long bones and flat bones (pelvis, sternum, etc.
)
.

Then, according to the National Cancer Institute Common Toxicity Criteria (CTCAE) 5.
0, the severity of CIT was assessed and graded according to the degree of thrombocytopenia, grade 1: platelet count ≥75×109/L and <100×109/L; grade 2 : Platelet count ≥50×109/L and <75×109/L; Grade 3: Platelet count ≥25×109/L and <50×109/L; Grade 4: Platelet count <25×109/L; Grade 5 : death
.

The treatment strategy of acute leukemia CIT in the treatment of leukemia emphasizes a combination chemotherapy regimen of sufficient dose and course of treatment, so that the tumor can be relieved in a short period of time.
Insufficient or delayed chemotherapy dose will affect the treatment effect and patient survival
.

Therefore, improving platelet levels and reducing bleeding risk in leukemia patients after chemotherapy is the first choice for clinical treatment of CIT
.

General interventions for CIT include: treatment of the cause of thrombocytopenia, such as discontinuation of chemotherapeutic drugs or radiotherapy that cause thrombocytopenia; treatment of coagulation disorders; increase in platelet counts; postponing the next cycle of chemotherapy, reducing the number of chemotherapy cycles, reducing dose, or change the chemotherapy regimen
.

Platelet transfusion Platelet transfusion is an important means to rapidly increase the platelet count of patients and avoid serious bleeding events.
It is still the first choice for the prevention and treatment of TCP after chemotherapy
.

Guidelines issued by the British Committee for Standards of Hematology (BCSH) in 2017 also recommended that patients with thrombocytopenia due to reversible myelopoiesis should be counted by prophylactic platelet transfusion when high-dose chemotherapy is required.
10×109/L or more
.

The platelet transfusion guidelines issued by the American Association of Blood Banks (AABB) in 2014 suggested that the threshold of prophylactic platelet transfusion should be less than 10×109/L of peripheral blood platelets in patients; while therapeutic platelet transfusion is only recommended for patients with significant bleeding.
symptoms, or when a traumatic procedure is expected
.

Some studies have shown that a lower transfusion threshold does not increase the bleeding rate of patients, nor does it reduce the efficiency of platelet transfusion, but can achieve some favorable outcomes such as reduced platelet requirements and reduced total hospitalization costs
.

At present, the widely used indication for platelet transfusion in domestic clinical work is 20 × 109/L.
Prophylactic platelet transfusion is required when there is obvious bleeding tendency or fever
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There are adverse reactions of platelet transfusion, mainly including infection, allergy, alloimmune reaction, and platelet transfusion ineffective
.

It should be noted that 18% of patients develop HLA allogeneic immunity even after transfusion of leukocyte apheresis platelets, and approximately 3% of patients develop ineffective immune-mediated platelet transfusions
.

Thrombopoietic drugs currently approved by the China Food and Drug Administration (CFDA) for the treatment of tumor CIT are only rhTPO and rhIL-11
.

rhTPO: TPO is an endogenous cytokine that can act on all stages of megakaryocyte generation and stimulate the growth and differentiation of megakaryocytes
.

The current clinical use is the full-length glycosylated rhTPO expressed by Chinese hamster ovary cells.
Its pharmacological effect is similar to that of endogenous TPO.
It activates the downstream JAK2-STAT5, Ras-Raf-MAPK and PI3K-Akt signals by binding to the TPO receptor.
pathway, induces the proliferation, maturation and differentiation of megakaryocytes and increases platelet count
.

A number of clinical studies have shown that rhTPO can reduce the degree of thrombocytopenia in patients with leukemia after chemotherapy, shorten the duration of thrombocytopenia, reduce the number and volume of platelet transfusions, and ensure that chemotherapy can be carried out smoothly as planned, and most adverse reactions are mild.
Well tolerated
.

Consensus on the treatment of acute leukemia CIT: It generally takes more than 3 to 7 days for platelet-raising drugs to take effect.
Since leukemia patients are expected to rapidly develop severe bone marrow suppression, it is generally recommended to start using platelet-raising drugs when platelets are less than 75×109/L.
, or start application 24h after chemotherapy
.

Medication method: The dose of rhTPO is 300U/kg per day, 1 time/d, subcutaneous injection, continuous application for 14 days
.

During the medication, the blood routine should be closely monitored.
When the platelets are ≥100×109/L or 50×109/L higher than before the medication, the medication should be discontinued in time
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rhTPO prophylaxis is recommended for patients with grade 3 or 4 CIT in the previous chemotherapy cycle, or for patients at high risk of bleeding
.

The adverse reactions of rhTPO are mainly injection-related adverse events, among which systemic symptoms and musculoskeletal system damage are the most common, manifested as fever, fatigue, joint musculoskeletal pain, etc.

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Platelet level and blood routine should be regularly monitored for rhTPO before administration, during administration and during follow-up after administration
.

Blood routine should be checked regularly during use, generally 2 times a week, or once every other day for special patients according to the situation, and pay close attention to the changes in peripheral blood platelets
.

In addition, when severe leukopenia or anemia occurs during chemotherapy, rhTPO can be used in combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) or recombinant human erythropoietin (rhEPO), respectively
.

rhIL-11: rhIL-11 plays an effect on a variety of hematopoietic cells.
When it acts on early and late hematopoietic progenitor cells, it can stimulate the differentiation and maturation of megakaryocytes, increase platelet levels, and promote hematopoiesis, anti-inflammatory, and self-inhibition.
Immunity and protection of mucosal epithelium
.

A number of studies at home and abroad have confirmed that rhIL-11 can reduce the severity of chemotherapy-induced thrombocytopenia, accelerate the recovery of platelets, shorten the duration of thrombocytopenia, and reduce platelet transfusion
.

The effect of rhIL-11 on promoting platelet increase was dose-dependent, and peaked at 14-21 days after starting the drug
.

Recommended medication method: It can be used 24-48 hours after chemotherapy, the recommended dose is 25-50 μg/kg, subcutaneous injection, once a day, for 7-14 days, until platelets ≥ 100×109/L, or absolute platelet count.
The drug was discontinued when the value increased by 50×109/L compared with the baseline
.

It should not be used 2 days before the start of chemotherapy in the next cycle and during chemotherapy
.

The adverse reactions of rhIL-11 include dyspnea, atrial arrhythmia, muscle and joint pain, water and sodium retention, fever, syncope and fatigue.
It should be used with caution in elderly patients and strictly followed the instructions
.

Other drugs With the in-depth research of basic and clinical trials at home and abroad, new TPO receptor agonists such as romiprostim, eltrombopag and avatrombopag have been launched
.

Eltrombopag has the effect of inhibiting the proliferation of leukemia cells, which makes the preventive treatment of thrombocytopenia after AL chemotherapy possible, but more basic and clinical trials are needed to guide clinical application
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Avatrombopag is a potential drug candidate for thrombocytopenia of multiple etiologies
.

A randomized, double-blind, placebo-controlled phase III clinical trial (NCT03471078) was designed to observe the efficacy and safety of avatrombopag in the treatment of tumor chemotherapy-related thrombocytopenia
.

The study is ongoing and is expected to enroll 120 patients with non-hematological malignancies undergoing chemotherapy, including ovarian cancer, non-small cell lung cancer, and bladder cancer
.

Patients received avatrombopag (60 mg d-1) or placebo for 5 days before and after chemotherapy.
The primary endpoint was that avatrombopag increased platelet counts in patients with chemotherapy-induced thrombocytopenia, thereby avoiding platelet transfusions.
Note, the proportion of patients who reduced the dose of chemotherapy drugs (reduced <15%) or delayed the administration (delayed <4d)
.

The main component of caffeic acid tablets is caffeic acid
.

Caffeic acid, also known as 3-(3,4-dihydroxyphenyl)-2-acrylic acid, is a phenolic acid compound.
Caffeic acid tablets can stimulate the maturation of megakaryocytes and increase the number of megakaryocytes, and can effectively prevent and treat drug-induced Thrombocytopenia has antioxidant and anti-apoptotic effects, thereby increasing platelet levels
.

Caffeic acid tablets can effectively prevent and reduce myelosuppression during chemotherapy, and help the white blood cell count and platelet count return to normal
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Application method of caffeic acid tablets: 3 tablets/time, 3 times/d, orally
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Special circumstances management For leukemia patients receiving chemotherapy regimens with high bleeding risk, attention should be paid to secondary prevention of CIT
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The purpose of secondary prevention is to ensure that the chemotherapy regimen for leukemia patients can be completed in full as planned
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If grade 3 or 4 CIT has occurred after previous chemotherapy, and the platelet count has decreased after the end of this cycle of chemotherapy, as long as the platelet count is lower than normal, it is recommended to start using rhTPO or rhIL-11 within 24 hours after chemotherapy
.

For patients with a history of fluid retention, congestive heart failure, and atrial arrhythmia, especially elderly patients, rhTPO is preferentially recommended
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For patients with high risk of venous thromboembolism and pulmonary thromboembolism, platelet levels should be closely monitored when using thrombopoietic drugs.
Refer to the Chinese expert guidelines for the prevention and treatment of tumor-related venous thromboembolism (2015 edition)
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For long-term chemotherapy and/or early platelet nadir, rhTPO needs to be administered early before and after chemotherapy, which may affect platelet transfusion and platelet nadir, thereby improving efficacy
.

Reference consensus: Chinese expert consensus on the diagnosis and treatment of thrombocytopenia caused by chemotherapy in acute leukemia (2019) RECOMMEND recommended reading 1.
In-hospital management of patients with thrombocytopenia caused by hematological diseases (1) - immune thrombocytopenia 2.
Hematological diseases In-hospital management of patients with thrombocytopenia caused by blood system diseases (2) - aplastic anemia 3.
In-hospital management of patients with thrombocytopenia caused by blood system diseases (3) - hematopoietic stem cell transplantation 4.
Thrombocytopenia caused by blood system diseases In-hospital management of patients with myelodysplastic syndrome (4) - Myelodysplastic syndrome, click "read the original text", we will make progress together