Chemotherapy-related Thrombocytopenia Research Articles

IVIg treatment increases thrombin activation of platelets and thrombin generation in paediatric patients with immune thrombocytopenia.

Clinical manifestations and laboratory parameters of haemostasis were investigated in 23 children with newly diagnosed immune thrombocytopenia (ITP) before and after intravenous immunoglobulin (IVIg) treatment. ITP patients with platelet counts of less than 20 × 109 /L and mild bleeding symptoms, graded by a standardized bleeding score (BS), were compared with healthy children with normal platelet counts and children with chemotherapy-related thrombocytopenia. Markers of platelet activation and platelet apoptosis in the absence and presence of platelet activators were analysed by flow cytometry; thrombin generation in plasma was determined. ITP patients at diagnosis presented with increased proportions of platelets expressing CD62P and CD63 and activated caspases, and with decreased thrombin generation. Thrombin-induced activation of platelets was reduced in ITP compared with controls, while increased proportions of platelets with activated caspases were observed. Children with a higher BS had lower proportions of CD62P-expressing platelets compared with those with a lower BS. IVIg treatment increased the number of reticulated platelets, the platelet count to more than 20 × 109 /L and improved bleeding in all patients. Decreased thrombin-induced platelet activation, as well as thrombin generation, were ameliorated. Our results indicate that IVIg treatment helps to counteract diminished platelet function and coagulation in children with newly diagnosed ITP.

Cell Death Markers in Children with Immune Thrombocytopenic Purpura: A Preliminary Study

Immune thrombocytopenic purpura (ITP) is an autoimmune disease with possible dysregulation of the apoptotic pathways. We aimed to evaluate the possible role of some apoptotic markers (caspase 3, caspase 8 and BCL2) in the pathogenesis and course of ITP. We investigated some apoptotic markers (caspase 3, caspase 8 and BCL2) using the flow cytometry in 60 children with newly diagnosed ITP, 20 children with chemotherapy-related thrombocytopenia (CRT) and 20 healthy children. We also assessed the effects of intravenous immunoglobulin (IVIG) and methyl prednisolone therapies on the platelet apoptosis in children with newly diagnosed ITP. We demonstrated significantly higher values of caspase 3 in the newly diagnosed ITP group than control and CRT groups, and non-significantly higher values of caspase 8 in the ITP group than the healthy group. After IVIG treatment, the platelet count increased in all patients, and there was a significant decrease in caspase 3 and caspase 8 levels while BCL2 level increased. Regarding methylprednisolone treatment, there was a significant decrease in BCL2 and caspase 8 levels while caspase 3 levels did not significantly decrease. There is a possible role of the caspase dependent cell death pathway of the platelets in the occurrence of newly diagnosed ITP. There is heterogeneity in the apoptotic changes of newly diagnosed ITP children who received IVIG versus those who received methylprednisolone.

The predictive model for risk of chemotherapy-induced thrombocytopenia based on antineoplastic drugs for solid tumors in eastern China

Chemotherapy-related thrombocytopenia (CIT) is a significant adverse event during chemotherapy, which can lead to reduced relative dose intensity, increased risk of serious bleeding and additional medical expenditure. Herein, we aimed to develop and validate a predictive nomogram model for prediction of CIT in patients with solid tumor. From Jun 1, 2018 to Sep 9, 2021, a total of 1541 patients who received 5750 cycles of chemotherapy were retrospectively enrolled. Cox regression analysis was performed to identify predictive factors to establish the nomogram model for CIT. The incidence of chemotherapy-induced thrombocytopenia was 21.03% for patient-based and 10.26% for cycles of chemotherapy. The top five solid tumors with CIT are cervix, gastric, bladder, biliary systemic, and ovarian. The incidence of chemotherapy dose delays in any cycle because of CIT was 5.39%. Multivariate analysis showed that tumor site, treatment line, AST, oxaliplatin, and capecitabine were significantly associated with CIT. Moreover, we established a nomogram model for CIT probability prediction, and the model was well calibrated (Hosme-Lemeshow P = 0.230) and the area under the receiver operating characteristic curve was 0.844 (Sensitivity was 0.625, Specificity was 0.901). We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical characteristics. The predictive model based on clinical and laboratory indices represents a promising tool in the prediction of CIT, which might complement the clinical management of thrombocytopenia.

Efficiency and Safety of Avatrombopag in the Management of Thrombocytopenia with TPO or Tpora Ineffective：a Prospective, Single Arm, Exploratory Clinical Study

Thrombocytopenia refers to the sum of a series of clinical diseases with a platelet count of less than 100×109/L in peripheral blood, including primary immune thrombocytopenia (ITP), tumor chemotherapy-related thrombocytopenia (CIT), infection, etc. The traditional treatments of thrombocytopenia are not always effective and often lead to serious side effects. Therefore, thrombopoietin (TPO) and TPO receptor agonist (TPORA) have been found to play a role as early recombinant thrombopoietin and gradually become a new alternative treatment. At present, there are few studies on the treatment of thrombocytopenia with Avatrombopag, as a second-generation TPORA, at home and abroad. We designed a prospective, single arm, exploratory clinical study to evaluate the efficacy and safety of Avatrombopag in the treatment of thrombocytopenia with TPO or TPORA ineffective. The patients with platelet counts less than 25×109/L who have failed to respond to TPO or other TPORA (including Eltrombopag，Herombopag) treatment in the Fourth Affiliated Hospital of Medical College of Zhejiang University were recruited. All the eligible patients were administered oral Avatrombopag at an initial dose of 20mg/d or 40 mg/d, monitored complete blood count at least once a week, and adjusted the drug dose according to the platelet level. The efficacy and safety of the drug were analyzed by monitoring the changes of platelet level and bleeding grade within 4 weeks after treatment, and the adverse reactions of Avatrombopag. This study was registered at chictr.org.cn (ChiCTR2200061853). 22 patients were enrolled in the clinical trial, aged from 18 to 83 years, with a median age of 74 years, including 16 patients with immune thrombocytopenia (ITP), 5 patients with chemotherapy-induced thrombocytopenia (CIT) and one patient with thrombocytopenia caused by MDS. Baseline characteristics of patients enrolled in the study are shown in Table 1. During 4-w Avatrombopag treatment period, the median platelet count in ITP group was higher than that in CIT group (Table 2 and Figure 1). 20 patients (90.9%) had bleeding symptoms at baseline, which decreased to 36.4% (8/22) in the end of follow-up (Figure 2). After 4 weeks of treatment, 17 patients showed response to the drug (platelet count between 30 and 100×109/L, at least doubling of the baseline count, and absence of bleeding), with a median response time of 14 (5-27) days. Among them, 13 patients were ITP, 3 patients were CIT, and 1 patient was MDS-induced-thrombocytopenia. The difference was not statistically significant (p=0.654). 9 patients achieved complete response (platelet count higher than 100×109/L and absence of bleeding), all of them were ITP. Compared with CIT patients, the difference was statistically significant (p=0.045) (Table 3 and Figure 3). 20 of 22 patients (90.9%) no longer required platelet transfusion at the study end point. During the administration period, one patient was found to have mild liver dysfunction that is difficult to explain by other diseases, and the other patients were not found to have drug-related adverse effects. In conclusion, Avatrombopag is an effective and safe drug for the treatment of patients with relapse and refractory thrombocytopenia. Compared with CIT patients, Avatrombopag have faster response to platelets and higher remission rate for ITP patients. he research was supported by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; the Key Project of Jinhua Science and Technology Plan, China, No. 2020-3-011; the 2019-2022 Key Medical Discipline (Hematology) Fund of Jinhua, China. Correspondence to : Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Downregulation of hypoxia-inducible factor-1α contributes to impaired megakaryopoiesis in immune thrombocytopenia.

Impaired megakaryocyte maturation and exaggerated platelet destruction play a pivotal role in the pathogenesis of immune thrombocytopenia (ITP). Previous studies have shown that HIF-1α promotes the homing and engraftment of haematopoietic stem cells (HSCs), thereby stimulating HSC differentiation. However, whether HIF-1α plays a role in megakaryocytic maturation and platelet destruction in ITP remains elusive. Using enzyme-linked immunosorbent assays (ELISAs), we demonstrated that there were lower HIF-1α levels in the bone marrow (BM) of ITP patients than in that of healthy donors and patients with chemotherapy-related thrombocytopenia. Subjects with lower megakaryocyte (<100/slide) and platelet (<30 × 109/L) counts exhibited significantly decreased BM HIF-1α levels, compared to those with higher megakaryocyte (≥100/slide) and platelet (≥30 × 109/L) counts. To test whether HIF-1α regulates megakaryopoiesis and platelet production, megakaryocytes derived from mouse BM cells were treated with an HIF-1α activator (IOX-2; 50 µM) or inhibitor (PX-478; 50 µM). PX-478 significantly decreased HIF-1α expression, cell size, and the populations of CD41-positive and high-ploidy cells. Importantly, to evaluate the role of HIF-1α as a potential therapeutic target in ITP, mouse BM cells were incubated with plasma from ITP patients in the presence or absence of IOX-2. IOX-2 significantly attenuated the ITP plasma-induced decrease in cell size as well as the proportions of CD41-positive and high-ploidy cells. In addition, IOX-2 increased the number of megakaryocytes from mouse BM cells treated with ITP plasma. Our findings indicate that decreased HIF-1α may contribute to impaired megakaryopoiesis in ITP, and HIF-1α may provide a potential therapy for ITP patients.

Thrombopoietin Levels May Predict Responsiveness to Therapy with Thrombopoietin Agonists Among Patients with Immune Thrombocytopenic Purpura,

Abstract 3288▪▪This icon denotes a clinically relevant abstract INTRODUCTION:Thrombopoietin (TPO) is the major regulator of platelet production. In prior clinical studies, thrombopoietin levels have been shown to vary inversely with circulating platelet mass and with the rate of platelet production. Thus, TPO levels may help distinguish between the various disorders of thrombocytopenia. In addition, the introduction of TPO agonists has created an interest in predicting the response of patients to these agents. Determining TPO levels may help predict such treatment responses. METHODS:Sera from 121 patients with a history of abnormal platelet counts were tested using a novel, commercially available ELISA assay that measures TPO levels. The TPO assay detected TPO levels as low as 7 pg/mL and was linear for levels up to 2000 pg/mL. The coefficient of variation ranged from 27% near the lower limit of detection to 9% at a TPO concentration of 669 pg/mL. The reference range for TPO was established in serum samples from 118 apparently healthy individuals (58 males and 60 females) and was 7–99 pg/mL. The Wilcoxon test was used to compare continuous variables and the Fisher’s exact test was used to compare categorical variables. RESULTS:The patient population included 40 patients with a consumptive thrombocytopenia (38 with primary or secondary immune thrombocytopenic purpura (ITP), 2 with thrombotic thrombocytopenic purpura), 34 patients with myeloproliferative disorders (23 with essential thrombocytosis, 9 with polycythemia vera, 2 with an ill-defined myeloproliferative disorder), and 47 patients with hypoproliferative thrombocytopenia (29 with chemotherapy-related thrombocytopenia, 19 with primary or secondary bone marrow failure syndromes). Among the 38 patients with ITP, 11 were taking TPO agonists (9 on romiplostim, 2 on eltrombopag), 19 were taking immunomodulatory agents (16 on steroids alone or in combination with other therapies, 2 on azathioprine, 1 on danazol), and 12 were off ITP-specific therapy when the TPO level was measured. 9 out of 38 (24%) patients with ITP had undergone splenectomy and/or been previously treated with rituximab. The median serum TPO level in patients with consumptive thrombocytopenia was 64.5 pg/mL (interquartile range, 48.5–97.5 pg/mL) and the corresponding median platelet count was 68,000/μL (interquartile range, 27,000–144,500) (Figure). While patients with myeloproliferative disorders had similar TPO levels [median 87.0 pg/mL (38.0–125.5)], their platelet counts were significantly higher than those of patients with consumptive thrombocytopenia [median 549,500/mL (431,250–693,000] (P <0.0001). Contrastingly, comparable platelet counts [median 61,000/μL (31,000–118,000)] were observed among patients with hypoproliferative thrombocytopenia, but serum TPO levels were significantly higher than those of patients with consumptive thrombocytopenia [844 pg/mL (409.5–1551.5), P <0.0001]. [Display omitted] Among 22 evaluable patients meeting diagnostic criteria for primary or secondary ITP who had taken a TPO agonist for at least 1 month, serum TPO levels appeared to predict responsiveness to the drug. A clinical response to a TPO agonist was defined as achieving a platelet count ≥50,000/μL after starting the drug and maintaining it at or above that count in ≥50% of subsequent complete blood counts from initiation until discontinuation of the drug, loss to follow-up, or 6 months had passed, whichever was longest, without the need for recurrent rescue therapy. Whereas 14 out of 16 (88%) ITP patients with a TPO level <99 pg/mL met our definition for a clinical response to treatment with a TPO agonist, only 1 out of 6 patients (17%) with a TPO level >99 pg/mL responded (P <0.005 for the difference in clinical response to TPO agents.) CONCLUSIONS:TPO levels may have diagnostic utility in discriminating between patients with hypoproliferative and consumptive thrombocytopenia. High TPO levels among patients with ITP may predict a poor clinical response to treatment with TPO agonists. Further studies are required to confirm these data. Disclosures:Zhukov:Quest Diagnostics: Employment. Sahud:Quest Diagnostics: Employment. Kuter:Quest Diagnostics: Consultancy, Research Funding.

Intracranial Hemorrhage (ICH) In Patients (Pts) Presenting with Myeloid Leukemia to a Tertiary Care Center

AbstractAbstract 2170 Background:ICH is a significant source of morbidity and mortality in pts with acute leukemias. Only relatively small retrospective series of pts with ICH have been reported previously. We evaluated the clinical characteristics of a large cohort of contemporary pts who developed ICH at MD Anderson Cancer Center (MDACC) to help better define the characteristics of pts at risk. Methods:We retrospectively searched the leukemia database at MDACC and identified 2421 pts who presented from 2005–2009 to MDACC with de novo acute myeloid leukemia (AML; n=1265), acute lymphoblastic leukemia (ALL; n=304), myelodysplastic syndrome (MDS; n=728), or blast-crisis CML (BC-CML; n=124). Clinical characteristics were obtained by chart review. Results:Among 2421 pts, a total of 119 pts developed ICH, as diagnosed by either CT or MRI brain (AML, n=72, 5.7%; ALL, n=19, 6.3%; MDS, n=13, 1.6%; CML-BC, n=15, 12.1%). Median age was 58years (range: 14–81), 58 (48.7%) were male, median WBC at the time of ICH was 2200/ul (0-186,000), platelet count 19,000/ul (0-318,000),hemoglobin 9.0 g/dl (4.5-14.7), peripheral blast count 0% (0-92%), INR 1.4 (0.4-12), PTT 29sec (17-66), creatinine 0.9mg/dl, and albumin 3.0g/dl (1.4-4.9). The localization of the bleed was intraparenchymal (IPH) in 58%, subdural (SDH) in 30%, subarachnoid (SAH) in 12%, and epidural (EDH) in 2.5%. Three pts had 2 different types of bleed. Median time from diagnosis to ICH was 210 days (0-1953). Only 18.5% of the patients bled within 30 days of diagnosis. Three patients had acute promyelocytic leukemia (APL), 2/3 bled within 2 days of diagnosis. Among 72 AML patients, the most common cytogenetic abnormality was del(5-, 7-) (26/72; 36.1%), and only 1/15 pts with diploid cytogenetics had a Flt3 point mutation. Surgical intervention for ICH was performed in 12 patients (10.1%). Median OS for all 119 patients was 40wks (0-257), and for those 12 undergoing surgery 42 wks (3-257). OS by type of bleed was as follows: IPH 33 wks (0-257), SDH 40 wks (1-174), SAH 41wks (1-86), EDH 8 wks(0-13). Conclusions:To our knowledge, we report here the largest cohort of contemporary pts with leukemia who develop ICH. While most previous studies highlight APL as the premier cause of ICH, in our cohort of over 2400 pts only 3 pts with APL developed ICH, likely due to heightened awareness for bleeding complications in these pts and aggressive transfusion. Pts in BC-CML have the highest relative proportion of ICH, suggesting a low threshold for head imaging in these pts. Most pts with ICH are profoundly thrombocytopenic at the time of the bleed, whereas the majority of them are not significantly coagulopathic. Less than 5% of all pts present with ICH at diagnosis or shortly thereafter, indicating that the major cause for developing ICH is chemotherapy-related thrombocytopenia or relapsed disease. Analyses to identify independent predictors of ICH in patients with leukemia are currently underway. The goal is to establish a novel predictive and/or prognostic model for ICH in patients with acute leukemias and MDS. Disclosures:Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Kantarjian: AstraZeneca: Research Funding.

Thromboembolic Complications in Pediatric Hematologic Malignancies

Thromboembolism (TE) is an uncommon entity in childhood. Overall 25% of children with thrombosis and more than 40% of children with central venous line (CVL) -related TE enrolled on the Canadian Pediatric Thrombophilia Registry had underlying diagnosis of cancer. However, so far there are very little data describing the epidemiology of TE in children with cancer. Most of the available information in this area originates mainly from retrospective and some prospective observational cohort studies conducted in children with acute lymphoblastic leukemia (ALL). Although ALL has been the most common cancer reported in association with thrombosis in children, available data from small studies indicate that TE is equally common in children with acute myeloid leukemia and lymphoma. TE in association with leukemia and lymphoma seems to be a multifactorial entity. Potential risk factors include increased thrombin generation related to leukemia, age of the patients, use of CVL, chemotherapy including asparaginase and corticosteroids, infections, and inherited prothrombotic state. Management of TE in a child with cancer presents a unique challenge in terms of balancing risk versus benefit. Conservative therapy could lead to clot extension and risks of additional morbidity or mortality; however, chemotherapy-related thrombocytopenia and coagulopathy increase the risk of bleeding complications. In summary, TE is a frequent and serious complication in children with hematologic malignancies. More prospective studies are required to define the epidemiology, pathogenesis, and management of TE in children with hematologic malignancies.

Chemotherapy-Associated Thrombocytopenia

Chemotherapy-related thrombocytopenia, although less frequent than granulocytopenia, may represent a life-threatening and less easily controlled event. It is usually the consequence of hypoplasia or aplasia of the megakaryocytic series in the bone marrow, although some cytotoxic and biologic agents are known to induce immune thrombocytopenias and thrombocytopenia associated with thrombopathic microangiopathy. The differential diagnoses should include the idiopathic thrombocytopenic purpura-like syndrome, progressive cancer involving bone marrow, and disseminated intravascular coagulation with thrombocytopenia caused by Gram-negative sepsis, tumor lysis syndrome and widespread metastatic cancer. Patients at risk of spontaneous bleeding are those with National Cancer Institute (NCI) grade 4 thrombocytopenia (i.e. those with a platelet count below 10×109/L); even patients with a higher platelet count may spontaneously bleed if there is an associated vascular disorder or coagulopathy. Chemotherapy-related thrombocytopenia is usually acute and requires urgent therapeutic decisions.

Timely Withdrawal of G-CSF Reduces the Occurrence of Thrombocytopenia During Dose-dense Chemotherapy

Post chemotherapy Granulocyte colony stimulating factor (G-CSF) reduces leucopenia, while G-CSF priming shortly before chemotherapy increases myelotoxicity. We performed a trial with a two-schedule crossover design to determine the optimal G-CSF schedule for densified 2-weekly chemotherapy. During 2-weekly chemotherapy days 1 and 2, G-CSF was given on days 3-10, with a G-CSF-free interval before the next chemotherapy cycle of 5 days, or on days 3-13, with a G-CSF-free interval of 2 days. In schedule A, cycle II was preceded by a 5 days, cycle III and IV by a 2 days and cycle V by a 5 days G-CSF free interval. In schedule B, this was 2, 5, 5, and 2 days, respectively. Intra-patient comparison for cycles II versus III and cycles IV versus V showed that platelet (PLT) nadir count was significantly lower for cycles preceded by a 2-days compared to a 5-days G-CSF free interval: mean difference 45.7 x 10(9)/l (95% CI 33.2-58.2, p = 0.0001). Neutrophil count did not differ significantly (p = 0.85). Timely withdrawal of G-CSF in dose-dense chemotherapy reduces chemotherapy-related thrombocytopenia. Leucopenia was not aggravated, reflecting a protective effect of post-chemotherapy G-CSF.

Cancer and thrombosis: mechanisms and treatment.

Standard venous thromboembolic event (VTE) treatment practices including the use of intravenous unfractionated heparin (UFH) for initial anticoagulation, oral warfarin for chronic anticoagulation, and the prescription of only 3 to 6 months total therapy may not be optimal in the setting of active cancer and ongoing anti-cancer therapy. Challenges of VTE management in cancer patients include heparin resistance due to excess circulating acute-phase proteins, increased recurrence rates during and following standard-intensity warfarin therapy, limited venous access to support therapeutic monitoring, and anticoagulation intensity-independent increased bleeding rates during anticoagulation. Bleeding during anticoagulation is of particular concern in the treatment of cancer patients with disease- or chemotherapy-related thrombocytopenia, central nervous system involvement, or recent invasive procedures. Low-molecular weight heparins (LMWH) have been shown to be at least as effective and safe for initial anticoagulation compared with UFH in persons with acute VTE and have gained popularity in the setting of VTE in cancer. LMWHs have the advantage of less non-specific protein binding, subcutaneous weight-based dosing without the need for monitoring in most cases, and probably less heparin-induced thrombocytopenia. Recent trials have demonstrated efficacy superiority of select LMWHs in place of oral warfarin for long-term anticoagulation in the cancer patient. The potential for anti-tumor effects and a survival advantage associated with select classes of anticoagulant agents is actively being investigated.

Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies.

Venous thromboembolic disease (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is an underdiagnosed and underappreciated clinical problem in cancer patients that results in significant patient morbidity and mortality. Standard treatment practices, including the use of intravenous unfractionated heparin (UFH) for initial anticoagulation, the use of oral warfarin for chronic anticoagulation, and the prescription of only 3 to 6 months total therapy, may not be optimal in the setting of active cancer and ongoing anticancer therapy. Challenges of VTE management in cancer patients include heparin resistance because of excess circulating acute phase proteins, increased recurrence rates during warfarin therapy (target international normalized ratio 2 to 3), limited venous access to support therapeutic monitoring, and increased bleeding rates during anticoagulation. Bleeding during anticoagulation is of particular concern in patients with disease- or chemotherapy-related thrombocytopenia, central nervous system involvement with cancer, and recent surgical intervention. Low-molecular-weight heparins (LMWHs) have been shown to be equally effective and safe for initial anticoagulation compared with UFH and have gained popularity, especially in the setting of VTE in cancer. LMWHs have the advantage of less nonspecific protein binding, subcutaneous weight-based dosing without the need for monitoring in most cases, and less heparin-induced thrombocytopenia. Recent clinical trials have shown LMWHs are at least as effective as oral warfarin for long-term anticoagulation in cancer patients. Interest in LMWHs and several new classes of parenteral and oral anticoagulants extends beyond the primary and secondary prevention of VTE and includes antiangiogenesis, metastasis prevention, and survival prolongation.