Thrombocytopenia In Cancer Patients Research Articles

Risk of Thrombocytopenia With Platelet-Derived Growth Factor Receptor Kinase Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis of Phase 2/3 Randomized, Controlled Trials.

We performed a systematic review and meta-analysis to fully investigate the thrombocytopenia of platelet-derived growth factor receptor kinase inhibitors (PDGFR-TKIs) in cancer patients. Databases were searched for randomized, controlled trials (RCTs) treated with PDGFR-TKIs until January 2021. The relevant RCTs in cancer patients treated with PDGFR-TKIs were retrieved, and the systematic evaluation was conducted. Nineteen RCTs and 3962 patients were included. Our study suggests that PDGFR-TKIs significantly increased the risks of all-grade (risk ratio [RR], 5.72; 95%CI, 4.32-7.59; P < .00001; I2 = 32%) and high-grade (RR, 5.65; 95%CI, 3.28-9.75; P < .00001; I2 = 0%) thrombocytopenia in cancer patients. Sunitinib is associated with the highest risk of thrombocytopenia among the included PDGFR-TKIs. The RR of high-grade thrombocytopenia varies significantly according to treatment line and median age. The available data suggested that the use of PDGFR-TKIs was associated with a significantly increased risk of thrombocytopenia.

Identification of novel TUBB1 variants in patients with macrothrombocytopenia.

Background/aim Macrothrombocytopenia is an autosomal-dominant disorder characterized by increased platelet size and a decreased number of circulating platelets. The membrane skeleton and the link between actin filaments of the skeleton and microtubules, which consist of alpha and beta tubulin [including the tubulin beta-1 chain (TUBB1)] heterodimers, are important for normal platelet morphology, and defects in these systems are associated with macrothrombocytopenia.Materials and methods In this study, we sequenced the exons of the TUBB1 gene using DNA isolated from the peripheral blood samples of healthy controls (n = 47) and patients with macrothrombocytopenia (n = 37) from Turkey. The TUBB1 expression levels in fractioned blood samples from patients and healthy controls were analyzed by RT-qPCR and Western blot. Microtubule organization of the platelets in the peripheral blood smears of patients, and in mutant TUBB1 -transfected HeLa cells, were analyzed by immunofluorescence staining.Results A new TUBB1 c.803G>T (p.T178T) variant was detected in all of the control and patient samples. Importantly, we found 3 new heterozygous TUBB1 variants predicting amino acid substitutions: G146R (in 1 patient), E123Q (in 1 patient), and T274M (in 4 patients); the latter variant was associated with milder thrombocytopenia in cancer patients treated with paclitaxel. Ectopic expression of TUBB1 T274M/R307H variant in HeLa cells resulted in irregular microtubule organization.Conclusion Further clinical and functional studies of the newly identified TUBB1 variants may offer important insights into their pathogenicity in macrothrombocytopenia.

Problems of hematological toxicity during the treatment of blood system malignancies

Background. Treatment of blood malignancies is often accompanied by the hematological toxicity. Thrombocytopenia is one of the most common phenomena, which can be caused by pseudothrombocytopenia, production deficiency or increased destruction of platelets, their pathological distribution or aggregation.&#x0D; Objective. To determine the features of hematological toxicity in the treatment of malignant blood diseases.&#x0D; Materials and methods. Analysis of literature data and recommendations on this topic.&#x0D; Results and discussion. Diagnosis of thrombocytopenia involves a detailed study of a peripheral blood smear to assess the morphology of all cells, as well as additional studies (determination of lactate dehydrogenase, D-dimer, fibrinogen, etc.; aspiration and bone marrow biopsy; virological and bacteriological studies; clinical examination). The main causes of thrombocytopenia in cancer patients are chemotherapy (ChT) and radiation therapy (RT), however, the diagnosis should take into account all possible nosological options. The assessment should be performed if the platelet count is &lt;100,000/μl. The normal lifespan of platelets is 8-10 days, so after many types of ChT thrombocytopenia develops about 7th days after treatment, reaches a maximum of 14th days and ends in 28-35th days. After RT thrombocytopenia usually starts in 7-10th days after its termination and is present during 30-60 days. Before treating thrombocytopenia, the need for ChT should be re-evaluated and the risk of bleeding assessed, and the ChT regimen should be changed if possible. If the risk of bleeding is high or the platelet count is critically low, platelet transfusion is prescribed, however, it has recently been found that absolute platelet count is not a predictor of bleeding risk in this patient population (PLADO study). In addition, platelet transfusion is limited in resources and costly, and is accompanied by the risk of side effects (acute lung damage due to transfusion, fever, bacterial sepsis, development of transfusion intolerance). This became the basis for the search for alternative treatment options. Recombinant interleukin-11 (oprelvekin) reduces the need for platelet transfusion from 96 to 70 % of patients on ChT. However, although this drug is FDA-approved, it is characterized by a large number of side effects. In turn, thrombopoietin receptor agonists (subcutaneous romiplostin, oral eltrombopag) bind to the corresponding receptors and increase the number of platelets in the blood. The effectiveness of treatment is within 70 %. Emaplag (“Yuria-Pharm”) is the first and only eltrombopag in Ukraine. Emaplag is indicated for the treatment of thrombocytopenia caused by ChT in patients with solid tumors, patients with platelet counts &lt;50×109/L, and in cases where the physician decides to increase platelet count. With regard to anemias, their main causes in cancer patients are the factors of the underlying disease (bone marrow infiltration, infectious processes), the impact of ChT or RT, other causes (malnutrition, bleeding, renal dysfunction). Examination of patients with anemia should include history taking, evaluation of blood smear and iron metabolism, exclusion of occult gastrointestinal bleeding and renal failure, Coombs’ test, determination of endogenous erythropoietin. Treatment options for ChT-induced anemia include blood transfusions and the use of erythropoietins (epoetins α and β, darbepoetin) with or without iron supplements (oral or intravenous). The advantages of using erythropoietin include reducing the need for transfusion of erythrocyte mass, a gradual increase in hemoglobin, increasing quality of life. However, erythropoietins are not recommended for use in cancer patients who do not receive ChT or receive RT, because in these cases, their use is associated with an increased mortality risk. Because in some patient groups erythropoietins accelerate tumor growth or reduce survival, the patient must give a written informed consent for their use. Given these data, it is advisable to prescribe intravenous iron, as it allows not only to quickly increase hemoglobin and improve quality of life, but also to reduce the dosage of erythropoietins. Iron carboxymaltose if the most modern parenteral iron preparation. It is characterized by low toxicity and high stability.&#x0D; Conclusions. 1. Thromboconcentrate transfusion is a fast and effective way to correct thrombocytopenia, which has a number of disadvantages. 2. Thrombopoietin receptor agonists (eltrombopag) make it possible to increase the effectiveness of treatment without interrupting the planned therapy. 3. In the presence of anemia, all possible causes should be corrected before prescribing erythropoietins. 4. If the anemia is caused by ChT, the patient needs to take erythropoietins. 5. Addition of intravenous iron preparations to erythropoietin therapy significantly increases the effectiveness of treatment.

Risk of bleeding and significant thrombocytopenia in cancer patients treated with immune checkpoint inhibitors.

e15000 Background: Immune checkpoints inhibitors (ICIs) are associated with multiple side effects. Complications can affect any organ system including; endocrine, gastrointestinal, pulmonary, and less frequently hematological system.We evaluated the risk of bleeding and significant thrombocytopenia in cancer patients (pts) treated with ICIs. Methods: Cancer pts treated with ICIs between 01/2015 and 7/2019 at Cleveland Clinic Foundation were retrospectively reviewed. Platelets (plts) count and hemoglobin (hb) level at baseline, after one month and 3 months of treatment were reviewed. Thrombocytopenia was defined as plts count &lt; 150,000. In pts with thrombocytopenia at baseline, more than 50% drop in the plts count was considered significant. Pts were followed-up for one year after ICIs treatment initiation for significant bleeding. Results: We identified 555 cancer pts treated with ICIs. Of these pts 65% were males. Among all included pts, 53% had lung cancer, 23% had genitourinary cancers, 17% had melanoma, 3% had gastrointestinal cancers, and 5% had other cancer types. Nivolumab, pembrolizumab, ipilimumab, and atezolizumab were used in 62%, 27%, 14%, and 12% respectively. Clinically significant bleeding, thrombocytopenia after one month and 3 months of treatment were identified in 21%, 6%, and 7% respectively. Of all pts who developed bleeding, 8% had gastrointestinal bleeding, 5% had intracerebral hemorrhage, and 3 % had hemoptysis. Only 23% of the pts who developed bleeding were receiving anticoagulation therapy. In multivariate analysis, breast cancer as primary malignancy (p = .03) and atezolizumab (p = 0.02) were predictors of clinically significant bleeding. Also, nivolumab was associated with increased risk of significant thrombocytopenia after one month of treatment (p = .02). There was no significant association between the use of specific medication and the development of significant anemia. Median overall survival time was not statistically different in patients who had bleeding compared to no bleeding group, 12.6 months (95% CI:10.8-14.5) and 12.4 months (95% CI:10.3-15) respectively (p = .21). Conclusions: In this cohort study, atezolizumab and breast cancer were significantly associated with increased risk of bleeding. The use of nivolumab was associated with a greater risk of thrombocytopenia after one month of treatment. Prospective studies are needed for better understanding of the hematological side effects of ICIs.

Predicting chemotherapy-induced thrombocytopenia in cancer patients with solid tumors or lymphoma.

Chemotherapy-induced thrombocytopenia is a serious complication in chemotherapy-treated patients. Identification of patients at risk for chemotherapy-induced thrombocytopenia could have clinical value in personalized management of patients and optimized administration of prophylactic thrombopoietic agents. The aim of this study was to develop a predictive model for chemotherapy-induced thrombocytopenia (platelet count < 100,000/µl) in cancer patients undergoing chemotherapy. A total of 14 covariates were prospectively assessed as explanatory variables in a cohort of consecutive patients with solid tumors or lymphoma. A multivariable logistic regression model was developed after univariable analysis. A bootstrapping technique was applied for internal validation. Data from 305 patients during 1732 chemotherapy cycles were considered for analysis. Forty-eight patients (15.73%) developed chemotherapy-induced thrombocytopenia during their treatment course. The multivariable model exhibited three final predictors for chemotherapy-induced thrombocytopenia, including high ferritin (odds ratio, 4.41; bootstrap P = 0.001), estimated glomerular filtration rate <60 ml/min/1.73 m2 (odds ratio, 3.08; bootstrap P = 0.005), and body mass index <23 kg/m2 (odds ratio, 2.23; bootstrap P = 0.044). The main characteristics of the model include sensitivity 75%, specificity 65.4%, positive likelihood ratio 2.16, and negative likelihood ratio 0.382. Moreover, the model was well calibrated (Hosmer-Lemeshow P = 0.713) and the area under the receiver operating characteristic curve was 0.735 (95% confidence interval, 0.654-0.816; P < 0.001). We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical and laboratory factors. This study may provide a valuable insight to guide optimized treatment of cancer patients. Further studies with larger sample size are warranted.

Chronic thrombocytopenia in cancer patients: Impact on percutaneous coronary intervention and antiplatelet therapy.

e22092Background: Cancer patients with thrombocytopenia are at risk of developing significant bleeding complications during cardiac catheterization. Little data is currently available on the outcom...

3:27 PM Abstract No. 402 Partial splenic artery embolization in 35 cancer patients

Thrombocytopenia in cancer patients often contraindicates chemotherapy and/or surgery leading to suboptimal therapy and decreased overall survival. The purpose of our study was to determine safety and efficacy of partial splenic embolization to improve platelet count and to establish a standardized treatment plan to achieve ideal embolization endpoint and minimize postprocedural complications. Medical records of 35 cancer patients who underwent 39 splenic artery embolizations with 300-500 μm Embospheres were analyzed. The target embolization endpoint was 50-70% splenic infarct. Celiac plexus block was performed following 25 procedures for pain control. The spleen volumes were 1337 ± 1038 mL. The embolization led to 59 ± 16% splenic infarct. One mL of microspheres resulted in 272 ± 107 mL splenic infarct in patients with chemotherapy- or portal hypertension-induced splenomegaly and 582 ± 3 45 mL infarct in patients with hematologic malignancies. The spleen volumes decreased by 40.5 ± 11% in 1 year. The platelet count increased from 63.9 ± 29.6 (mean ± SD) to peak platelet count of 248 ± 118 in 2-4 weeks after embolization. Patients with follow-up period of >1 year had the last platelet count of 174 ± 113 (n = 12). The most common complication was moderate/severe pain which occurred in 92% of patients without celiac block and in 20% of patients with celiac block. There was non-occlusive portal vein thrombus in 2 patients, pulmonary embolus in 1 patient, focal pancreatitis in 1 patient, and increased ascites and pleural effusion in 7 patients. Procedure-related 30–day mortality was 25% amongst patients with hematologic malignancies and 0% amongst patients with chemotherapy- or portal hypertension-induced splenomegaly. Partial splenic embolization is effective to correct thrombocytopenia in cancer patients and provides improved platelet count for long-term. It is a low risk procedure in patients with chemotherapy- or portal hypertension-induced splenomegaly, but has high mortality in hematologic malignancies. The postprocedural pain was significantly reduced by celiac plexus block. Based on our data the required amount of beads can be calculated to achieve target splenic infarct.

34 Testing for Heparin-Induced Thrombocytopenia in Cancer Patients

34 Testing for Heparin-Induced Thrombocytopenia in Cancer Patients

Performance of 4T score and HIT Antibody in the Diagnosis of Heparin-Induced Thrombocytopenia in Cancer Patients

Objectives: Cancer patients may have relatively higher risk of HIT-related complications, yet data on HIT in cancer are limited. Though cancer patients have characteristics which significantly influence the 4T score and HIT antibody (ab), performance of these tests in this population is unknown. Our aim was to determine among cancer patients the rates of HIT-related thrombosis and the correlation of …

Is there a predictive significance of ABO blood group on chemotherapy-induced thrombocytopenia in patients with stage III colon cancer?

Chemotherapy-induced thrombocytopenia (CIT) is the most important cause of thrombocytopenia in cancer patients. In this paper, I discussed the effect of ABO blood group on CIT in patients with stage III colon cancer. In a pilot study, a total of 131 (72 men, 55%) eligible patients with stage III colon cancer were divided into two groups according to whether they had CIT. Both groups were compared using demographic, histopathological, and laboratory variables. CIT was detected in 51 (40%) of 131 patients. The incidence of CIT had a significant increased in patients with 0 blood group compared to other blood groups. It was concluded that the relationship between blood group 0 and the presence of CIT in patients with stage III colon cancer is independent of other study variables (P=0.035, OR 3.14, 95% CI 1.16-7.01). In conclusion, I hypothesized that 0 blood group may predict to differentiate high-risk patients for CIT.

Thrombocytopenia in cancer patients

Thrombocytopenia is a frequent complication of cancer and its treatment. The causes of thrombocytopenia in cancer patients can be diverse and multifactorial. Systemic chemotherapy is the most frequent cause of thrombocytopenia. The degree and duration thrombocytopenia depends upon whether the chemotherapeutic treatment is myeloablative, as used in stem cell transplants, or non-myeloablative, as typically used in solid non-hematologic malignancies. Additional causes of significant thrombocytopenia include tumor involvement of bone marrow and spleen; microangiopathic disorders such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura or hemolytic uremia syndrome. Lymphoproliferative malignancies can also be associated with secondary immune thrombocytopenia. Due to the broad differential diagnosis associated with cancer related thrombocytopenia, a careful diagnostic evaluation is indicated. The goal of treatment should be to maintain a safe platelet count to allow effective treatment of the underlying malignancy, prevent bleeding complications and to minimize the use of platelet product transfusion.

Supportive transfusion therapy in cancer patients with acquired defects of hemostasis

Bleeding occurs in approximately 10% of patients with cancer: supportive transfusion therapy with Platelets Concentrates (PC), Fresh Frozen Plasma (FFP) and plasma-derived or recombinant concentrates is often required for the cessation and prevention of the bleeding episodes. The most frequent causes of bleeding in cancer is thrombocytopenia followed by liver insufficiency with or without vitamin K deficiency, disseminated intravascular coagulation (DIC) and the inappropriate or excessive use of anticoagulants. Other acquired hemostatic defects such as acquired hemophilia (AHA) and acquired von Willebrand syndrome (AVWS) are rare but they can be life-threatening. Thrombocytopenia in cancer patients may be the consequence of marrow invasion, chemotherapy or platelet auto-antibodies; patients with severe hypoproliferative thrombocytopenia, must be treated with PC and carefully followed to assess refractoriness to PC. The management of the other acquired defects of hemostasis usually requires the use of FFP and specific plasma-derived or recombinant concentrates. PC, FFP and plasma-derived concentrates can induce complications and/or adverse events in cancer patients: these include mainly allergic (ALR) or anaphylactic reactions (ANR), Transfusion-Associated Graft-Versus-Host Disease (TA-GVHD), Trasfusion-transmitted bacteriemia (TTB), Transfusion-Related Acute Lung Injury (TRALI), Acute Hemolytic Transfusion Reactions (AHTR), Febrile Non Hemolytic Transfusion Reactions (FNHTR). Therefore, modifications such as leukocyte-reduction and irradiation of the blood components to be transfused in cancer patients are recommended to reduce the risk of these complications.

Posterior Reversible Encephalopathy Syndrome in Cancer Patients (P06.015)

Objective: To explore the clinical manifestations, radiologic features and clinical outcome of posterior reversible encephalopathy syndrome (PRES) in patients with cancer. Background The PRES is a clinical-radiologic entity characterized by headache (HA), altered mental function (AMS), seizures and visual-disturbances in association with imaging findings. Previous literature about the management and outcome of the patients with PRES is limited. Design/Methods: We identified 64 patients with cancer who developed PRES at M.D.Anderson-Cancer-Center between 01/2006 and 06/2011. Clinical and radiographic data were abstracted from their records. Results: The average age at the onset was 52±17.7 years. 44 patients (69%,p=0.003) were women with mean age at onset of 49.6±17.8 years compared to men (mean age at onset 58.8±16 years, p=0.055). Most common cancer diagnoses were leukemia (36%), Lymphoma (9%), gastrointestinal tumors (8%), central-nervous-system tumors (8%). 16 patients (25%) and 35 patients (55%) were treated with tacrolimus and chemotherapy respectively. 22 patients (35%) received bone-marrow transplant (BMT). Clinical presentation included AMS (72%), seizures (69%), HA (33%) and visual-disturbances (19%). PRES was associated with hypertension (HTN) in 57 patients (89%). The brain MRI demonstrated T2 signal abnormalities in all patients and 29 patients (59%) had some evidence of hemorrhage. Seventeen of these 29 patients (59%) were thrombocytopenic. Clinical symptoms fully recovered in 36 patients (57%). Of the 27 (43%) patients with neurological deficits, nine patients (33%) had intracranial hemorrhage and thrombocytopenia, sixteen patients (59%) had a significant delay in diagnostic imaging (11.4±2.5 days versus 1.1±0.3 days, p=0.025) and half of them did not receive a prompt intervention. Conclusions: PRES is an increasingly recognized occurrence in cancer patients undergoing therapy. HTN seems to be the most important co-existent risk factor for development of PRES. Delay in diagnosis can result in permanent residual deficits. Underlying thrombocytopenia in cancer patients with PRES is associated with hemorrhagic complications and increases the risk of incomplete recovery. Disclosure: Dr. Paker has nothing to disclose. Dr. Kamiya Matsuoka has nothing to disclose. Dr. Chi has nothing to disclose. Dr. Loghin has nothing to disclose.

Multicenter, randomized study of genetically modified recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in cancer patients receiving chemotherapy

The aim of this study is to evaluate the efficacy and safety of genetically modified recombinant human IL-11 (mIL-11), using original IL-11 as an active control, in a multicenter randomized trial involving 88 cancer patients undergoing chemotherapy Eighty-eight subjects who had platelets ≤ 75 × 10(9)/L during the prior chemotherapy were randomized to the MR or RM group. Cohort MR consists of subcutaneous injection of mIL-11 (7.5 μg/kg/day) for 10 days, beginning 72 h after chemotherapy for a 21-day chemotherapy cycle (cycle-1) followed by that of recombinant human interleukin-11 (rhIL-11) (25 μg/kg/day) for another 10 days (cycle-2). Cohort RM represents the reverse sequence. Intent-to-treat populations of mIL-11 (n = 73) or rhIL-11 (n = 80) were analyzed to evaluate the safety. The incidence of drug-related adverse events of mIL-11 (32.9%) was lower than that of rhIL-11 (51.3%) (p = 0.033). There were no unexpected ≥ grade-3 adverse events, and no subject developed antibodies to the mIL-11 protein. Sixty-two subjects were analyzed for efficacy by measuring average platelet levels. Both mIL-11 and rhIL-11 increased nadir platelet levels (62.6 ± 34.9 × 10(9)/L for mIL-11 vs. 60.2 ± 31.7 × 10(9)/L for rhIL-11) as compared with the untreated control group (41.2 ± 17.7 × 10(9)/L) (p < 0.0001). There was no statistical difference in average platelet levels and platelet recovery rate between mIL-11 and rhIL-11. This study shows that mIL-11 is well tolerated and has thrombopoietic activity equivalent to one third of the clinical dose of rhIL-11, indicating the potential of mIL-11 for use in the treatment of CIT.

Prevention of Chemotherapy-Induced Anemia and Thrombocytopenia by Constant Administration of Stem Cell Factor

Chemotherapy-induced apoptosis of immature hematopoietic cells is a major cause of anemia and thrombocytopenia in cancer patients. Although hematopoietic growth factors such as erythropoietin and colony-stimulating factors cannot prevent the occurrence of drug-induced myelosuppression, stem cell factor (SCF) has been previously shown to protect immature erythroid and megakaryocytic cells in vitro from drug-induced apoptosis. However, the effect of SCF in vivo as a single myeloprotective agent has never been elucidated. The ability of SCF to prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia was tested in a mouse model of cisplatin-induced myelosuppression. To highlight the importance of maintaining a continuous antiapoptotic signal in immature hematopoietic cells, we compared two treatment schedules: in the first schedule, SCF administration was interrupted during chemotherapy treatment and resumed thereafter, whereas in the second schedule, SCF was administered without interruption for 7 days, including the day of chemotherapy treatment. The administration of SCF to cisplatin-treated mice could preserve bone marrow integrity, inhibit apoptosis of erythroid and megakaryocytic precursors, prevent chemotherapy-induced anemia, and rapidly restore normal platelet production. Treatment with SCF increased the frequency of Bcl-2/Bcl-XL-positive bone marrow erythroid cells and sustained Akt activation in megakaryocytes. Myeloprotection was observed only when SCF was administered concomitantly with cisplatin and kept constantly present during the days following chemotherapy treatment. SCF treatment can prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia in mice, indicating a potential use of this cytokine in the supportive therapy of cancer patients.

Abstract B216: Exposure-response (E-R) relationship of ABT-263-induced thrombocytopenia in cancer patients in phase 1 studies

Abstract Background: ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity to multiple antiapoptotic Bcl-2 family proteins. The pharmacokinetics, safety and preliminary efficacy of ABT-263 in patients with relapsed or refractory lymphoid malignancies, CLL/SLL, SCLC and other non-hematological malignancies are being studied in three Phase 1/2a studies. Both a 14/21-day dosing schedule and a continuous dosing preceded with a 7-day lead-in period are being evaluated in these studies. Grade 4 thrombocytopenia has been the most prominent, mechanism-related, dose-limiting toxicity in patients in these studies. E-R relationship in this drug-induced thrombocytopenia may inform the selection of the dose and dosing schedule for a Phase 3 study in CLL patients. Methods: ABT-263 plasma concentrations and platelet data from more than 100 patients in the three ongoing Phase 1/2a studies were included in the analysis. ABT-263 plasma concentration data were described using a two-compartment model with first-order absorption and elimination. The relationship between the circulating platelet count and ABT-263 plasma concentration was described with a semi-physiological model that had been developed using data in dogs. Simulations were preformed to compare the 14/21-day dosing schedule and the continuous dosing schedule with a low-dose lead-in period and project the incidence rates of Grades 3 and 4 thrombocytopenia in the dose range of 200 and 350 mg. Results: The E-R relationship was generally well described by the semi-physiology model. Simulations indicated that, compared to the 14/21-day dosing schedule, continuous dosing preceded with a 7-day lead-in period minimizes platelet variability across cycles. The lead-in treatment appeared to blunt the initial sharp drop in platelet count according to the simulations with 250 mg dose. Although there seemed to be little difference in the incidence rate of Grade 4 thrombocytopenia, continuous dosing showed a trend of lower rate of Grade 3 thrombocytopenia than the 14/21-day dosing schedule. In terms of the rates of Grade 3 and 4 thrombocytopenia, the dose-response curve between 200 and 350 mg was quite shallow. Conclusions: A continuous dosing preceded with a 7-day lead-in period is superior to the 14/21-day dosing schedule because it minimizes platelet variability across cycles and blunts the initial sharp drop in platelet count. Drug-induced thrombocytopenia is not sensitive to the change in dose does not provide significant differentiation in the dose range of 200 mg and to 350 mg. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B216.

A prediction model for chemotherapy-associated thrombocytopenia in cancer patients

8616 Background: Thrombocytopenia (TP) can lead to serious complications, however, little is known about the incidence and risk factors for chemotherapy-associated TP. A prospective, nationwide cohort study was undertaken to better define the impact of TP in cancer treatment. Methods: 2,842 patients with cancer of the breast, lung, colon, ovary or lymphoma initiating a new chemotherapy regimen have been prospectively enrolled at 115 randomly selected US community oncology practices between 2002 and 2005. Risk factors for chemotherapy-associated TP were identified, a multivariate logistic regression model based on pretreatment characteristics was developed, and test performance characteristics were estimated. Results: Over a median of 3 cycles of chemotherapy, minimum recorded platelet counts were: ≥150K in 53% of patients; 100–150K in 26%; 75–100K in 8%; 50–75K in 6% and &lt;50K in 7%. Significant independent predictive factors for platelets &lt;75K include type of cancer (P&lt;.0001), type of chemotherapy including gemcitabine-based (P&lt;.0001), anthracycline-based (P&lt;.0001) and platinum-based (P&lt;.0001) regimens, prior chemotherapy (P&lt;.0001) or surgery (P=.005), age (P=.015), Caucasian ethnicity (P=.022), body surface area (P=.0001), planned relative dose intensity ≥85% (P=.082), diabetes (P=.018), pulmonary disease (P=.011), abnormal baseline platelets (P&lt;.0001), hematocrit (P=0.030), alkaline phosphatase (P=.072) or albumin (P=.017). Model fit was good (Chi-square, P&lt;.0001), R2 = 0.735 and c-statistic = 0.816 [95% CI: 0.792–0.840, P&lt;.0001]. Model test performance characteristics [95% CI] at a ≥20% risk of TP include: sensitivity 56% [51–61]; specificity 88% [87–89]; likelihood ratio positive 4.63 [4.02–5.33]; likelihood ratio negative 0.50 [0.45–0.57]; and diagnostic odds ratio 9.22 [7.23–11.75]. Validation of the model is underway. Conclusions: This prediction model based on pretreatment factors identifies with high specificity patients at risk for clinically important chemotherapy-associated thrombocytopenia early in the treatment course. It may provide a valuable tool for guiding chemotherapy and new supportive care measures. [Table: see text]

Thrombopoietin and interleukin 11 have different modulatory effects on cell cycle and programmed cell death in primary acute myeloid leukemia cells

The c-mpl ligand, thrombopoietin (TPO), is a physiologic regulator of platelet and megakaryocytic production, acting synergistically on thrombopoiesis with the growth factors interleukin 11 (IL-11), stem cell factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and granulocyte-macrophage colony-stimulating factor. Because some of these growth factors, especially TPO and IL-11, are now being evaluated clinically to reduce chemotherapy-associated thrombocytopenia in cancer patients, we evaluated 25 acute myeloid leukemia (AML) samples to test whether TPO, IL-11, and other early-acting megakaryocyte growth factors can affect leukemic cell proliferation, cell cycle activation, and programmed cell death (PCD) protection. TPO induced proliferation in the majority of AML samples from an overall mean proportion of S-phase cells of 7.8% ± 1.5% to 14.5% ± 2.1% ( p = 0.0006). Concurrent G 0 cell depletion was found in 47.3% of AML samples. TPO-supported leukemic cell precursor (CFU-L) proliferation was reported in 5 of 17 (29.4%) of the samples with a mean colony number of 21.4 ± 9.6 × 10 5 cells plated. In 13 of 19 samples, a significant protection from PCD (from an overall mean value of 13% ± 0.7% to 8.8% ± 1.8%; p = 0.05) was detected after TPO exposure. Conversely, IL-11–induced cell cycle changes (recruitment from G 0 to S phase) were detected in only 2 of 14 samples (14.2%). In addition, IL-11 showed little, if any, effect on CFU-L growth (mean colony number = 17.5 9.5) or apoptosis. Combination of TPO with IL-11 resulted in only a slight increase in the number of CFU-L, whereas IL-3 and stem cell factor significantly raised the mean colony numbers up to 119.2 ± 68.3 and 52.9 ± 22.1 × 10 5 cells plated, respectively. We conclude that TPO induces cell cycle activation in a significant proportion of cases and generally protects the majority of AML blast cells from PCD. On the other hand, IL-11 has little effect on the cell cycle or PCD. Combination of both TPO and IL-11 is rarely synergistic in stimulating AML clonogenic growth. These findings may be useful for designing clinical studies aimed at reducing chemotherapy-associated thrombocytopenia in AML patients.

THE THROMBOCYTOPENIA OF CANCER: Prospects for Effective Cytokine Therapy

The previous 10 years have witnessed the development of increasing needs for platelet transfusion in support of aggressive therapies of malignancy. Despite gains in our understanding of platelet preparation, storage, and transfusion, alternative therapies are clearly desirable. During the late 1980s at least six distinct cytokines that display effects on megakaryocyte growth and differentiation-IL-3, KL, GM-CSF, IL-6, IL-11, and LIF- and a synthetic growth factor, PIXY 321, were cloned and characterized. Although none of these cytokines fulfill all of the physiologic roles of thrombopoietin, in its absence several have undergone extensive preclinical and preliminary clinical testing. Of these, IL-11 and PIXY 321 hold promise for clinical amelioration of thrombocytopenia in cancer patients. With the recent cloning of thrombopoietin and its promise in preclinical trials, the role of each of these recombinant proteins in clinical medicine is undergoing careful evaluation. As with erythropoietin and G-CSF before it, given its normal role in the regulation of platelet production, Tpo would appear to provide the greatest physiologic stimulus to platelet production in states of natural and iatrogenic marrow failure. Careful clinical trials of the agent are needed to determine whether the hormone will fulfill this promise. The following decade will most certainly see the resolution of many of the complications of thrombocytopenia and its transfusional support.