Efficacy Of Eltrombopag In Patients Research Articles

Safety and efficacy of eltrombopag in patients with post-CAR T cytopenias.

While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post-treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post-CAR T cytopenias using the thrombopoietin mimetic eltrombopag. This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T-cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high-grade leukopenia and/or thrombocytopenia beyond 21 days post-CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag. Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre-existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients. The use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post-CAR T cytopenias might be effective in a high-risk patient population but requires further study.

POSTER: CT-216 Safety and Efficacy of Eltrombopag in Patients With Post-CAR T Cytopenias: Real-World Experience

POSTER: CT-216 Safety and Efficacy of Eltrombopag in Patients With Post-CAR T Cytopenias: Real-World Experience

CT-216 Safety and Efficacy of Eltrombopag in Patients With Post-CAR T Cytopenias: Real-World Experience

CT-216 Safety and Efficacy of Eltrombopag in Patients With Post-CAR T Cytopenias: Real-World Experience

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKI) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); with a median age of 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12 of 15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients five could re-escalate the TKI dose and nine improved their response. None of the six patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1,000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted (clinicaltrials gov. Identifier: NCT01428635).

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.

e18539 Background: Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic phase (CP) chronic myeloid leukemia (CML). Up to have patients with CML may develop grade ≥3 thrombocytopenia, leading to treatment interruptions and dose reductions. Similarly, management of thrombocytopenia in myelofibrosis (MF) can be challenging because the condition may result in dose adjustments and interruptions of ruxolitinib. Methods: We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia during therapy with a TKI or ruxoltinib. We enrolled 15 CML patients with persistent grade ≥3 thrombocytopenia (platelets ≤50 x 109/l) and six MF patients with platelets < 100 x 109/l after at least 3 months of therapy with a TKI or ruxolitinib. Patients received eltrombopag at a starting dose of 50 mg daily, with dose escalation to a maximum of 300 mg daily according to platelet response. Patients were followed with a weekly complete blood count until a stable platelet count was achieved. The target response was a complete response, defined as a platelet count ≥50 x 109/l for CML and ≥100 x 109/l for MF in at least 30% of subjects, sustained for 3 months while continuing TKIs or ruxolitinib therapy. Results: We enrolled 21 patients (CML = 15, MF = 6), with a median age of 60 years (range, 31-99 years). The median platelet count was 44 (range, 3-49) in patients with CML and 62 (range, 25-91) in those with MF. After a median duration of treatment of 18 months (range, 5-77 months), 11 of the 15 patients with CML achieved a complete platelet response at eltrombopag doses of 50–300 mg per day. The median peak platelet count among responders was 133 (range, 6-1225) x 109/l. Nine patients with CML experienced an improvement in cytogenetic response. In 5 patients with CML, the TKIs dose was increased and maintained while continuing eltrombopag. None of the 5 patients with MF had a sustained increase in platelet count to ≥100 x 109/l. No progression of disease was documented in any patient. Therapy was generally well tolerated. One patient (CML) discontinued therapy secondary to toxicity (persistent transaminitis with an accompanying lack of response). Conclusions: Eltrombopag demonstrated clinical efficacy in some patients with CML who were treated with TKIs. No similar benefit was observed in patients with MF who were treated with ruxolitinib. Eltrombopag might be a useful adjunct for patients with CML experiencing persistent thrombocytopenia. Clinical trial information: NCT01428635.

Eltrombopag for the Management of Thrombocytopenia Associated with Tyrosine Kinase Therapy in Patients with Chronic Myeloid Leukemia and Myelofibrosis

Background: Grade ≥ 3 thrombocytopenia occurs in 20-45% of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKI). While most instances resolve with TKI transient interruptions and dose reductions, persistent or recurrent thrombocytopenia may adversely influence TKI efficacy. Similarly, patients with myelofibrosis (MF) treated with ruxolitinib may experience thromobocytopenia requiring dose adjustments and interruptions, also potentially affecting efficacy.Methods: We initiated a pilot study to assess the efficacy of eltrombopag for patients with CML or MF with persistent or recurrent thrombocytopenia after ≥3 months of therapy with an approved TKI or ruxolitinib, respectively. The primary objective is recovery of platelet count. Secondary objectives include safety, TKI/ruxolitinib dose intensity and response to therapy after start of therapy with eltrombopag. Patients with grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) for patients with CML or platelets <100 x 109/L for patients with MF after at least 3 months of therapy with TKI or ruxolitinib, or those with prior grade 3 thrombocytopenia requiring TKI/ruxolitinib dose reductions or interruptions interfering with response, were enrolled.Starting dose for Eltrombopag is at 50 mg daily (25 mg for patients of East Asian ancestry) with dose escalation allowed every 2 weeks to a maximum of 300 mg daily according to platelet response. Safety monitoring includes liver enzymes and periodic evaluation of bone marrow fibrosis. Planned accrual is for 39 patients (29 patients with CML and 10 with MF). The target response is at least 30% of subjects to have a complete (platelet) response, which is defined as platelet count ≥50 x 109/L for CML, and ≥100 x 109/L for MF that is sustained for 3 months while continuing TKI therapy. This report is an interim analysis of futility and toxicity.Results: Nineteen patients have been enrolled (CML=14, MF=5). Median age is 58 years (range, 29-97 years); median duration of disease 2.1 years (range, 0.5-29 years) for patients with CML and 2 years (range, 0.3-3.6 years) for patients with MF. At the time of enrollment, patients with CML were treated with following TKIs: dasatinib (4), nilotinib (3), ponatinib (3), bosutinib (3), and imatinib (1). Median platelet count for patients with CML was 37 (range, 14-51), and 60 (range, 25 to 91) for those with MF. Cytogenetic response for patients with CML at baseline were: partial=3, minor=6, and none=5. After a median duration of treatment of 17 months (range, 3-48.4 months), 11 of 14 patients with CML achieved complete platelet response at eltrombopag doses of 50 - 300 mg per day. One additional patient with CML had a transient response. Median peak platelet count among responders was 224 (range, 123-424) x 109/L. In addition 7 patients with CML have had improvement in cytogenetic responses: 1 from none to complete, 3 from minor to partial, 1 minor to complete, 2 from partial to complete. None of the 5 patients with MF had a sustained increase in platelet count to ≥ 100 x 109/L. Two patients (1 each of CML and MF) had improvement in hemoglobin of over 2 gm/dL from baseline (from 8.2 g/dl to 10.6 g/dl, and from 9.4 g/dl to 11.4 g/dl, respectively), and 1 patient with CML had absolute neutrophil count recovery to >1x109/L (baseline neutrophils 0.71 x109/L). In 2 patients with CML, TKI dose could be increased and maintained while continuing eltrombopag. Grade3/4 toxicities irrespective of attribution include infection (n=5, 3 MF and 2 CML), elevated liver enzymes (n=5, all in CML), hyperglycemia (n=2), fatigue (n=2), chest pain (n=1), and myocardial infarction (n=1). One patient with MF showed increase in bone marrow fibrosis from grade 2 to grade 3. No progression of disease has been documented in any patient. One patient died on study from septic and hemorrhagic shock not related to study drug. Seven of the 19 patients enrolled are still on study. One patient discontinued therapy secondary to toxicity (persistent transaminitis with accompanying lack of response).Conclusion: Eltrombopag may alleviate thrombocytopenia in some patients with CML treated with TKI. This is frequently accompanied by a decrease in treatment interruptions, and improved response. No similar benefit has been observed in patients with MF treated with ruxolitinib. This study continues enrollment. DisclosuresCortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Celgene: Research Funding; BMS: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Significance of Anti-GPIIb/IIIa Antibody in Efficacy of Eltrombopag for Patients with Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired hemorrhagic condition of accelerated platelet consumption caused by antiplatelet autoantibodies, and glycoprotein (GP)IIb/IIIa is one of the major target antigens recognized by platelet-reactive CD4+ T cells. Patients with ITP often have few bleeding symptoms despite very low platelet counts, suggesting that ITP platelets are highly functional. Several factors may contribute to the prothrombotic state in ITP. We investigated the effect of thrombopoietin (TPO)-receptor agonist (RA) on the procoagulant state in ITP with or without anti-GPIIb/IIIa antibody. Long-term administration of eltrombopag resulted in stabilization of platelet numbers in many patients. On the other hand, when the analysis was carried out according to the presence of GPIIb/IIIa autoantibodies, the increase in platelet counts in ITP patients was more significant with than without anti-GPIIb/IIIa autoantibodies. In addition, there were significant differences in PDMP between cases in which platelet count was above or below 100x109/l. Our observation is possible to reflect the role of the anti-GPIIb/IIIa antibody in ITP patients who received TPO-RA.

Eltrombopag For The Management Of Thrombocytopenia Associated With Tyrosine Kinase Therapy In Patients With Chronic Myeloid Leukemia and Myelofibrosis

Incidence of grade ≥ 3 thrombocytopenia is 20-45% among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKI). While most thrombocytopenias resolve on continued TKI therapy with dose adjustments, sustained thrombocytopenia is cause for dose reductions and interruptions. Similarly among patients with myelofibrosis (MF), dose reduction of ruxolitinib is recommended for thromobocytopenia. As suboptimal dosing of TKI may lead to inadequate response, we initiated a study to assess the efficacy of eltrombopag for patients with CML or MF who are persistently thrombocytopenic after at least 3 months of therapy with an approved TKI. The primary objective is recovery of platelet count. Secondary objectives include safety, TKI dose intensity and response to TKI after start of therapy with eltrombopag. Patients with grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) for patients with CML and platelets<100 x 109/L for patients with MF after at least 3 months of therapy with TKI, are being enrolled.Starting dose for Eltrombopag is at 50 mg daily with dose escalation allowed every 2 weeks up to a maximum of 300 mg daily according to platelet response. For patients of East Asian ancestry, eltrombopag starting dose is 25 mg daily with dose escalation every two weeks. Safety monitoring includes liver enzymes and periodic evaluation of bone marrow fibrosis. Planned accrual is for 39 patients (29 patients with CML and 10 with MF). The target response is at least 30% of subjects to have a complete (platelet) response, which is defined as platelet count ≥ 50 x 109/L for patients with CML and ≥ 100 x 109/L for patients with MF that is sustained for 3 months while continuing TKI therapy. This report is of a planned interim analysis of futility and toxicity.Eleven patients have been accrued to the study (CML=7, MF=4). Median age is 59 years (range, 30-97 years) and median duration of disease was 2.5 years (range, 2-17 years) for patients with CML and 2.3 years (range, 0.4-3 years) for patients with MF. At the time of enrollment patients with CML were treated with following TKIs: nilotinib (2), ponatinib (2), dasatinib (2) and bosutinib (1). Median platelet count for patients with CML was 47 (range, 29-48) and was 60 (range, 25-72) for patients with MF. Cytogenetic response for patients with CML at baseline were; major=3, minor=2, none=2. After a median duration of treatment for 8 months (range, 3-12 months), 5 out of 7 patients with CML achieved complete platelet response at eltrombopag doses 50 – 300 mg per day. Median peak platelet count among responders was 115 (range, 64-205) x 109/L. In addition 3 patients with CML had improvement in cytogenetic responses; 1 minor to complete, 2 minor to major. Two out of four patients with MF had non sustained increases in platelet count to ≥ 100 x 109/L. In addition to improvement in platelet counts, 2 patients (1 each of CML and MF) had improvement in hemoglobin of over 2 gm/dL from baseline and 1 patient with CML had absolute neutrophil count recover to> 1x109/L. In 3 patients, 2 with CML and 1 with MF, TKI dose could be increased while continuing eltrombopag. Grade3/4 toxicities irrespective of attribution include infection (N=5, 4 MF and 1 CML), hyperglycemia, fatigue, chest pain, myocardial infarction, elevated liver enzymes (N=1 for each). Follow up bone marrow biopsies have not shown any increase in bone marrow fibrosis or evidence of disease acceleration.In conclusion, early evidence of activity of eltrombopag in alleviating persistent TKI induced thrombocytopenia in chronic phase CML is quite encouraging while its activity in MF appears to be limited. Disclosures:Borthakur:GSK: Research Funding.

Eltrombopag Treatment of Thrombocytopenia in Advanced Myelodysplastic Syndromes and Acute Myeloid Leukemia: Results of the 8-Week Open-Label Part of an Ongoing Study

AbstractAbstract 3822 Background:Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) commonly experience severe thrombocytopenia with a high risk for bleeding. Eltrombopag is an oral thrombopoietin receptor agonist indicated for treatment of chronic immune thrombocytopenia. Eltrombopag may reduce platelet transfusions and bleeding, and preclinical data suggest that it may have an anti-leukemic effect (Erickson-Miller 2008; Kalota 2010; Will 2009; Mavroudi 2010; Roth 2012). We present results of the 8-week, open-label part of an ongoing multicenter trial to evaluate the safety and efficacy of eltrombopag in patients with intermediate (int)-2 or high-risk MDS or AML (WHO criteria) with platelets <25,000/μL. Methods:Eltrombopag was administered daily at 3 escalating dose levels, with increases every 2 weeks in patients without a platelet response: Dose Level (DL)1, 100 mg (50 mg for East Asian [EA] patients); DL2, 200 mg (100 mg for EA patients), and DL3, 300 mg (150 mg for EA patients). Platelet response was defined as on-treatment platelets ≥2x baseline and >20,000/μL for patients with baseline platelets <20,000/μL or ≥2x baseline and ≥50,000/μL for patients with baseline platelets ≥20,000/μL. Treatment with hydroxyurea was permitted. Results:Seventeen patients with a median age of 72 years (range, 49–91) with int-2 or high-risk MDS (n=12) or AML (n=5) were enrolled. Baseline median platelet count was 12,500/μL (range, 6,000–35,000/μL). Sixteen of 17 patients had received ≥1 prior treatment for their disease. Five, 3, and 9 patients received DL1, DL2, and DL3 as their maximum daily dose. Nine of 17 patients completed 8 weeks of treatment, 6 of whom continued to receive eltrombopag in the extension part of the study. Of the 9 patients who completed all 8 weeks of therapy, 2, 2, and 5 were receiving DL1, DL2, and DL3 at the time they completed their treatment. Ten of 17 (59%) patients had reductions in platelet transfusions during treatment with eltrombopag compared with the 4-week pre-treatment period (Table). Platelet responses were observed in 4/17 (24%) patients. Post-baseline bone marrow examinations 1–3 months after starting eltrombopag (n=11) showed no clinically meaningful changes in blast counts. The most common adverse events (AEs) were pyrexia (n=4), alanine aminotransferase (ALT) increase, diarrhea, epistaxis, headache, and pneumonia (n=3 each). Two of 3 patients with increased ALT met protocol-defined liver-stopping criteria. Both elevations occurred while patients were receiving 300 mg eltrombopag and resolved following discontinuation of eltrombopag. Three deaths were reported (2 patients with fatal AEs of sepsis, considered not related to eltrombopag treatment; 1 patient died of disease progression). Conclusion:Preliminary data suggest that eltrombopag may reduce platelet transfusion requirements in thrombocytopenic patients with advanced MDS and AML. AEs were as expected for this patient population and for treatment with eltrombopag. Randomized studies assessing the potential benefits and risks of eltrombopag in this setting are ongoing.TableSummary of Clinical Benefit by PatientPatientBaseline DiseasePlatelet TransfusionsPlatelet ResponsecBone Marrow Blasts, %ScreeningaBest ResponsebBaselinePost-treatmentAMDS10Yesc1112BMDS10No1520CAML10 (3m)No2525DAML9Not evaluableNo20No post-baselineEMDS22No105FMDS00Yesc118GMDS20No0No post-baselineHMDS44No0No post-baselineIMDS12 (2m)No18No post-baselineJMDS3Not evaluableNo00KMDS21 (2m)Yesc1621LMDS84No178.6MMDS2Not evaluableNo19.420NAML114Yesc48.8No post-baselineOMDS114No00PAML10No36.2No post-baselineQAML10 (2m)No26.755.4aScreening platelet transfusions are the number of transfusions during the 4 weeks prior to Day 1bBest platelet transfusion response is the minimum number of transfusions received by each patient during any 4-week period during treatment with eltrombopag. In parentheses, is the duration in months (m) for the best transfusion response, if >1 month. Patients with <4 weeks of eltrombopag treatment were not evaluablecPlatelet counts for platelet responders: A: Baseline=12,000/μL, maximum=33,000/μL; F: Baseline=27,500/μL, maximum=114,000/μL; K: Baseline=12,500/μL, maximum=47,000/μL; N: Baseline=11,000/μL, maximum=26,000/μL. Platelet counts assessed within 3 days of a transfusion were not evaluable for a platelet response Disclosures:Off Label Use: Eltrombopag is an oral TPO agonist indicated for chronic ITP being studied in MDS/AML. Garcia Delgado:Celgene: Consultancy, Speakers Bureau. Mannino:GlaxoSmithKline: Employment. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Messam:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment.

Eltrombopag &amp;ndash; a novel approach for the treatment of chronic immune thrombocytopenic purpura: review and safety considerations

Eltrombopag is one of a number of novel agents recently developed for use in the treatment of patients with immune thrombocytopenia (ITP). Rather than preventing destruction of platelets, these agents increase the production of platelets, presumably overwhelming the immune system resulting in normal platelet counts in individuals refractory to or dependent on other therapies. These treatments are well tolerated and in randomized controlled trials show an improvement in platelet counts and a reduction in bleeding in refractory patients. This article summarizes the development of this new class of drug and evaluates the safety and efficacy of eltrombopag in patients with ITP.