scholarly journals Efficacy and Safety of a Combination of Thrombopoietin Receptor Agonist with an Immunosuppressant Therapy for the Management of Multirefractory Adult ITP: Results from a Retrospective, Multicenter, Observational Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Etienne Crickx ◽  
Guillaume Moulis ◽  
Marc Ruivard ◽  
Bouchra Asli ◽  
Jean Pierre Marolleau ◽  
...  
Keyword(s):  
Platelet Count ◽  
Mycophenolate Mofetil ◽  
Observational Study ◽  
Median Duration ◽  
Research Funding ◽  
Biological Data ◽  
Efficacy And Safety ◽  
Immunosuppressant Therapy ◽  
Multicenter Observational Study ◽  
Thrombopoietin Receptor

Introduction Multirefractory adult ITP, defined as no response to splenectomy, rituximab, and thrombopoietin receptor agonists (TPO-Ra), is associated with high morbidity and mortality. In a previous study, we have shown that combining an immunosuppressant therapy with one TPO-Ra could be a promising therapeutic strategy for managing patients with multirefractory ITP. Objective The aim of this study was to assess the efficacy and safety of such combination in multirefractory ITP on a larger series of patients. Patients and methods We conducted a retrospective, multicenter, observational study in France. Adult patients treated by a combination of a TPO-Ra with an immunosuppressant therapy (i.e., mycophenolate mofetil, azathioprine, ciclosporin, everolimus, or cyclophosphamide) for chronic (> 12 months) or persistent (> 3 months) multirefractory ITP, were included through the national reference center for adult immune cytopenia (CERECAI) network. Multirefractory ITP was defined as disease not responding to rituximab, to splenectomy (or contraindication to splenectomy), and to the 2 TPO-Ras licensed in France (romiplostim and eltrombopag) administered at the maximal approved dose. Clinical and biological data were retrospectively collected using a standardized form. Complete response (CR) was defined by a platelet count >100 x109/L and response (R) by a platelet count between 30-100 x109/L with at least a 2-fold increase from baseline, according to the international recommendations. Results Thirty-one patients (65% female, median age 57 years [range 23 - 82]) were included. Five (16%) of them had secondary ITP (Evans syndrome (n=2), systemic lupus (n=1) with antiphospholipid syndrome (APS), primary APS (n=1), and Waldenstrom macroglobulinemia (n=1). Four patients had a monoclonal gammopathy of undetermined significance, and 11 (35%) had antinuclear antibodies (titer >1/160) without definite clinical autoimmune disease. All patients had previously received corticosteroids and 16/31 (52%) were corticosteroid-refractory. Previous treatments lines also included intravenous immunoglobulin (28/31, 90%) and at least one immunosuppressant therapy (16/31, 52%). Splenectomy was performed in 25 patients (81%), and not performed in the remaining 6 patients because of advanced age and comorbidities (n=3), underlying APS (n=2), or patient refusal (n=1). At the time of treatment combination initiation, median ITP duration was 57 months [3 - 393], with 28/31 (90%) chronic ITP and 3/31 (10%) persistent ITP. Bleeding symptoms were present in 23 patients (74%) and the median platelet count was 10 x109/L [range 1 - 35]. The combination regiment included eltrombopag (n=18) or romiplostim (n=13), associated with either mycophenolate mofetil (n=15), azathioprine (n=12), cyclophosphamide (n=2), ciclosporine (n=1), or everolimus (n=1). Median duration of combination therapy was 12 months [range 1 - 103]. Nineteen patients (61%) had no therapeutic intervention other than the combined treatment, while 10 patients were also given corticosteroids (either short course of high dose steroids [n=5], or on a long-term at low dose [n=5]), and/or hydroxychloroquine (n=5). Overall, 81% of patients (25/31) achieved at least a R, including 19/31 (61%) CR. Among responders, the median time to response was 30 days [range 7 - 270], and the median duration of the response was 12 months [4 - 55]. Response rates were similar in patients who did not receive concomitant corticosteroids (59% CR, 12% R), and in patients that were previously exposed to immunosuppressant therapy given alone (63% CR, 25% R). Regarding safety, 13/31 (42%) patients experienced at least one adverse event potentially related to treatment, including 7 severe adverse events. Three patients without APS but who were splenectomized had a thromboembolic event, including 3 deep vein thrombosis/pulmonary embolism, and 1 cerebral venous thrombosis; Three patients had an infection (one cholecystitis, one herpes zoster, and one dental abscess). After a median follow-up of 18 months [6-103], one patient died (from a previously diagnosed adenocarcinoma). Conclusion In summary, these data show that most of the patients managed for multirefractory ITP may benefit from the combination of TPOra with an immunosuppressant therapy by achieving a durable response. The safety profile of this combination in this population seems acceptable. Disclosures Moulis: Novartis SAS: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance grant, Research Funding; Amgen: Other: meeting attendance grant; Grifols: Research Funding. Michel:Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. Godeau:LFB: Honoraria; Amgen: Research Funding; Amgen: Honoraria; Novartis: Honoraria. Mahevas:GSK: Research Funding. OffLabel Disclosure: Some immunosuppressant drugs were given off-label for adult ITP.

Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura

Blood ◽  
2010 ◽  
Vol 115 (1) ◽  
pp. 29-31 ◽  
Author(s):  
Donald M. Arnold ◽  
Ishac Nazi ◽  
Aurelio Santos ◽  
Howard Chan ◽  
Nancy M. Heddle ◽  
...  
Keyword(s):  
Platelet Count ◽  
Mycophenolate Mofetil ◽  
Adverse Events ◽  
Observational Study ◽  
Immune Thrombocytopenic Purpura ◽  
Treatment Options ◽  
Initial Response ◽  
Immunosuppressant Therapy ◽  
Thrombocytopenic Purpura ◽  
Refractory Itp

Abstract Treatment options for patients with chronic refractory immune thrombocytopenic purpura (ITP) are limited. Because combination immunosuppressant therapy appeared to be effective in ITP and other disorders, we used this approach in patients with particularly severe and refractory ITP. In this retrospective, observational study, we determined the response (platelet count above 30 × 109/L and doubling of baseline) among 19 refractory ITP patients. Treatment consisted of azathioprine, mycophenolate mofetil, and cyclosporine. The patients had failed a median of 6 prior treatments, including splenectomy (in all except 1). Of 19 patients, 14 (73.7%) achieved a response lasting a median of 24 months, after which time 8 (57.1%) relapsed. Of the 8 relapsing patients, 6 responded to additional treatments. Of the 14 patients who achieved an initial response, 2 (14.3%) remained in remission after eventually stopping all medications. Severe adverse events did not occur. Combination immunosuppressant therapy can produce a rise in the platelet count that is sometimes sustained in refractory ITP patients.

Hemophilia Liver Transplant Observational Study (HOTS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3782-3782
Author(s):  
Margaret V. Ragni ◽  
Abhinav Humar ◽  
Peter G. Stock ◽  
Emily A. Blumberg ◽  
Bijan Eghtesad ◽  
...  
Keyword(s):  
Platelet Count ◽  
Liver Disease ◽  
Observational Study ◽  
Research Funding ◽  
Proportional Hazards ◽  
Bleeding Risk ◽  
Hcv Infection ◽  
Transplant Survival ◽  
Post Transplant ◽  
Transplant Candidates

Abstract Introduction: Hepatitis C is the leading cause of liver disease in individuals with hemophilia (H). HIV co-infection in 80% accelerates HCV disease progression. Although antiretroviral therapy improves HIV survival and slows HCV progression, some ultimately require transplantation. In contrast to non-hemophilic (NH) risk groups, H have 1) longer duration HCV infection with HCV acquisition via clotting factor in the first year of life; and 2) greater bleeding risk due to factor VIII (IX) deficiency in the setting of thrombocytopenia in end-stage liver disease. These risks are important as 1) duration of HCV infection is a significant predictor of liver disease progression; and 2) increased bleeding risk, including gastrointestinal bleeding, increases post-transplant mortality. Several studies have shown that, while post-transplant survival is similar, pre-transplant survival is shorter in HIV/HCV+ H than NH candidates. These studies were small, limiting analysis for predictors of pre-transplant survival. Methods: We conducted a retrospective observational study utilizing United Network for Organ Sharing (UNOS) national transplant registry data, comparing HCV+ H and HCV+ NH candidates. A 7-item case report form was completed on each subject by eight respective transplant centers including 1) hemophilia status (hemophilia A, ICD 286.0; hemophilia B, ICD 286.1); 2) hepatocellular carcinoma status; 3) HIV status; 4) CD4+ count; 5) HIV RNA PCR; 6) HCV RNA PCR; and 7) platelet count, the latter four variables at listing and at transplantation. We performed univariate proportional hazards models for pre-transplant mortality within 90 days of listing, including group and baseline factors. Variables with p<0.1 from univariate models were included in an initial multivariate model. Kaplan-Meier time to-event curves were constructed for transplant candidates, including time to death, time to transplant, and time to MELD 25; and for transplant recipients, including time to death and time to graft loss. Statistical analysis was by SAS version 9.3, Cary NC. Results: We identified 2,502 HCV+ liver transplant candidates, including 144 (5.8%) with HIV infection, 36 (1.4%) with hemophilia, and 1,213 (48.5%) undergoing liver transplantation from eight U.S. university-based transplant centers for the period January 1, 2004 to December 31, 2010. Other than male predominance, 100% vs. 78.0%, and younger age, 41 vs. 48 years, both p<0.0001, baseline data were similar between H and NH. A total of 1,289 candidates were not transplanted; 771 remained alive or were removed from listing pre-transplant; and 518 expired pre-transplant. The most common causes of pre-transplant death included multi-organ failure in 113 (21.8%) and sepsis or infection in 86 (16.6%). Among transplant candidates, the overall pre-transplant patient survival at 90-days and 6-months from listing did not differ between H and NH. In the first 90 days post-listing, time-to-event curves for death and elevated MELD 25 were significantly different between H and NH groups, log-rank, p=0.0001 and 0.02, respectively. In univariate proportional hazards models, pre-transplant mortality within 90-days of listing was associated with higher baseline MELD, HR=1.15, p<0.001, and lower platelet baseline platelet count, HR=1.11 per 25k/µL, p=0.04, and HIV+ status, p=0.003. The hazard of pre-transplant mortality was marginally worse in HIV+ H than HIV+NH candidates, HR=2.8, p=0.08. In multivariate analysis, higher MELD score was significantly associated with pre-transplant mortality (p<0.0001), and the hazard of pre-transplant mortality remained marginally worse in HIV+ H than HIV+ NH, HR=2.0, p=0.24. Conclusion: This observational study confirms MELD is a significant predictor not only of post-transplant survival, but also pre-transplant survival. Despite longer duration HCV infection and greater bleeding risk, there was no significant difference in pre-transplant survival between HIV+ H and NH, likely due to small numbers of hemophilia candidataes missed by retrospective ICD classification. We suggest implementing ICD classification for H in the UNOS system, to enable robust data collection to determine the impact of HCV antiviral therapies on pre- and post-transplant outcomes, and the potential utility of a combination MELD classification that incorporates age at HCV acquisition and platelet count. Disclosures Ragni: Alnylam Pharmaceuticals: Consultancy, Research Funding; SPARK: Research Funding; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Genentech: Research Funding; Novo Nordisk: Research Funding; Shire: Consultancy; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Sherman:BMS: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Merck: Consultancy, Research Funding.

Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3169-3169
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Follo ◽  
Marta Stanzani ◽  
Sarah Parisi ◽  
...  
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Phase Ii ◽  
Median Duration ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Randomized Phase Ii ◽  
Microrna Profile

Abstract Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade > 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to > 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. Disclosures Finelli: Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Ipilimumab in real-world clinical practice: efficacy and safety data from a multicenter observational study

2017 ◽  
Vol 29 (4) ◽  
pp. 245-251 ◽  
Author(s):  
Alberto Russi ◽  
Vera Damuzzo ◽  
Marco Chiumente ◽  
Jacopo Pigozzo ◽  
Marco Cesca ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Observational Study ◽  
Real World ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Multicenter Observational Study

scholarly journals Association between Megakaryocyte Abnormalities on Bone Marrow Smear and Response to Thrombopoietin Receptor Agonists in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3160-3160
Author(s):  
Ondine Walter ◽  
Agnès Ribes ◽  
Johanne Germain ◽  
Jean-Baptiste Rieu ◽  
Thibault Comont ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Adult Patients ◽  
Second Line ◽  
Bone Marrow Smear ◽  
Advisory Committees ◽  
Thrombopoietin Receptor

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count &lt;100 x 10 9/L and exclusion of other causes of thrombocytopenia). The study population consisted in all patients included in the CARMEN registry between June 2013 and March 2018 with primary ITP, treated by TPO-RA and with a BMS before initiating TPO-RA. We excluded the patients with a number of MKs &lt;10 MK on the BMS. Morphological abnormalities were established based on literature and defined by consensus among 3 expert cytologists (AR, JBR and VDM). All MKs present on each smear were analyzed. MKs were categorized by the presence of dysplasia (monolobed MK and/or separated nuclei and/or microMKs), and according to their stage of maturation (basophilic, granular and thrombocytogenic). All patients' medical charts were reviewed by two experts in ITP (OW and GM) to determine the response to TPO-RAs. Response was defined by a platelet count between 30 and 100 G/L with at least a doubling of basal platelet count according to the international definition. In case of subsequent exposure to both TPORAs in a single patient, response was defined by response to at least one TPO-RA in the main analysis. We performed a subgroup analysis by TPORAs. Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Thrombopoietin Receptor Agonists for Severe Thrombocytopenia after Allogeneic Stem Cell Transplantation: Experience of a Multicenter Study from the Grupo Español De Trasplante Hematopoyético (GETH)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 200-200 ◽  
Author(s):  
Leyre Bento ◽  
Jose Maria Bastida ◽  
Irene García-Cadenas ◽  
Estefania García-Torres ◽  
Daniel Rivera ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Multicenter Study ◽  
Efficacy And Safety ◽  
Platelet Recovery ◽  
Thrombopoietin Receptor Agonists ◽  
Thrombopoietin Receptor

Abstract Introduction Thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Underlying mechanisms are poorly known and usually multifactorial. Its treatment is not well defined, mostly based in platelet transfusion. Thus, is important to identify new strategies to manage this important post-SCT complication. Romiplostim and Eltrombopag are currently available thrombopoietin receptor agonists (TPO-RAs) that stimulate platelet production. Some studies with very small number of cases have reported their potential efficacy in the allo-SCT setting. For this reason, the aim of our study is to analyze the efficacy and safety of TPO-RAs for severe and persistent thrombocytopenia after allo-SCT. Patients and methods We performed a retrospective multicenter study including patients from centers of GETH with prolonged isolated thrombocytopenia (PT) or secondary failure of platelet recovery (SFPR) after allo-SCT. PT was defined as the engraftment of all peripheral blood cell lines but with platelet count ≤20000/µL for 7 consecutive days or requirement of transfusion for more than 60 days after allo-SCT. SFPR was defined as a decline of platelet counts to ≤20000/µL for 7 consecutive days or requirement of transfusion after achievement platelets ≥50000/µL without transfusion for 7 days post-SCT. The primary endpoint was platelet recovery to ≥50000/µL. Results Eighty-six patients with thrombocytopenia after allo-SCT were included. The characteristic of the patients, are summarized in table 1. Sixteen (19%) of the patients had PT and 71 (82%) SFPR. TPO-RA was started at a median time of 127 days (27-1177) after allo-SCT (41% Romiplostim / 59% Eltrombopag). Median initial and maximum administered doses were 50 mg/daily (25-150) and 75 (25-150) for Eltrombopag and 1 µg/kg (1-7) and 5 (1-10) for Romiplostin, respectively. Eighteen patients (21%) were previously treated with cell infusion (67% mesenchymal cells and 33% CD34+ boost). Median platelet count before TPO-RA onset was 14000/µL (1000-57000). Platelet recovery to ≥50000/µL was 60% and the response was achieved at a median time of 56 days (2-247). Responses were similar considering all potential causes of thrombocytopenia evaluated. 81% of the patients had decrease number of megakaryocytes prior to treatment showing a worse response to therapy: median time to ≥20000/µL platelets 43 days versus 28 days (p=0.011), with also a lower rate of platelet recovery to ≥50000/µL (62% versus 85% if normal megakaryocytes). In patients treated with Eltrombopag, 27% had neutropenia <1000/µL and 74% achieved >1000/µL after therapy. The median treatment duration was 62 days (7-700) and 62% discontinued TPO-Ra maintaining response. Grade 3-4 adverse events (hepatic and asthenia) were observed in only 2% of the cases. At last follow up with a median of 10 months (1-59), 72% of the patients maintained the response and 61 (71%) were alive. Death rate was significantly lower in responder-patients to TPO-RAs, 15% versus 53% in non-responders (p<0.001). Causes of death were disease progression (28%), infections (48%), graft versus host disease (GvHD) (16%) and others (8%). Conclusion To our knowledge this is the biggest series analyzing the use of TPO-Ra after allo-SCT. Our results support the efficacy and safety in this new setting with responses around 60% and a low number of side effects. Additional studies to identify predictors of response are needed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and safety of lenvatinib in combination with everolimus in metastatic renal cell carcinoma resistant to antiangiogenic targeted therapy: Russian multicenter observational study ROSLERCM.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 644-644 ◽  
Author(s):  
Maria Volkova ◽  
Ahmed Abdelgafur ◽  
Zurab Amoev ◽  
Magomed Aivazov ◽  
Ksenia Gennadievna Babina ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Observational Study ◽  
Renal Cell ◽  
Response Rate ◽  
Objective Response ◽  
Tumor Control ◽  
Efficacy And Safety ◽  
Multicenter Observational Study ◽  
Grade 3

644 Background: an assessment of efficacy and safety of lenvatinib in combination with everolimus in unselected patients with metastatic renal cell carcinoma (mRCC) progressed during or following ≥1 line of antiangiogenic targeted therapy. Methods: Russian multicenter observational study included 73 consecutive patients with morphologically verified mRCC progressed during or following ≥1 line of antiangiogenic targeted therapy, treated with lenvatinib (18 mg/d) and everolimus (5 mg/d) in 20 Russian centers. Median age of the patients was 59 (23-73) years, a male-to-female ratio - 3:1. Most common histological type of kidney cancer was clear-cell RCC (71 (95.8%)). More than 2 lines of previous treatment were administered in 45 (61.6%) cases. Most patients were diagnosed with multiple metastases (71 (97.3%)) in >1 site (61 (83.6%)). Nephrectomy was performed in 87.7% (64/73) of cases. At the combined therapy start ECOG PS 2-4 was registered in 16 (20.5%), poor prognosis according to IMDC score – in 33 (45.2%) patients. Median follow-up was 9.7 (1-26) months. Results: objective response rate was 11% (8/73); tumor control was reached in 93.2% (68/73) of cases. Median objective response duration was 10.5 (4.3-16.8) months, tumor control duration – 10.0 (2.5-17.5) months. Median progression-free survival (PFS) achieved 16.9 (95% confidence intervals (CI): 12.1-20.6), overall survival (OS) – 20.8 (95% CI: 15.7-25.9) months. Any adverse events (AE) developed in 83.6% (61/73), AE grade 3-5 - in 23.3% (17/73) of cases. Most frequent AE grade 3-4 were diarrhea (10 (13.6%)) and arterial hypertension (6 (8.2%)). Unacceptable toxicity demanded treatment cancellation in 4.2% (3/73), therapy interruption – in 30.1% (22/73) and dose reduction – in 32.9% (24/73) of patients. Conclusions: unselected mRCC patients administered with combined targeted therapy in the real world practice were registered with lower objective response rate, similar survival and better tolerability comparing with population assigned for lenvatinib plus everolimus in the randomized phase II trial.

scholarly journals Efficacy and safety of lenvatinib in combination with everolimus in metastatic renal cell carcinoma resistant to antiangiogenic targeted therapy: Russian multicenter observational study ROSLERCM

2019 ◽  
Vol 15 (3) ◽  
pp. 56-69 ◽  
Author(s):  
M. I. Volkova ◽  
A. M. Abdelgafur ◽  
M. T. Aivazov ◽  
Z. V. Amoev ◽  
K. G. Babina ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Adverse Events ◽  
Observational Study ◽  
Response Rate ◽  
Objective Response ◽  
Tumor Control ◽  
Efficacy And Safety ◽  
Multicenter Observational Study ◽  
Grade Iii

Objective: an assessment of efficacy and safety of lenvatinib in combination with everolimus in unselected patients with metastatic renal cell carcinoma (mRCC) progressed during or following ≥1 line of antiangiogenic targeted therapy.Material. Russian multicenter observational study ROSLERCM included 73 consecutive patients with morphologically verified mRCC progressed during or following ≥1 line of antiangiogenic targeted therapy, treated with lenvatinib (18 mg/d) and everolimus (5 mg/d) in 20 Russian centers. Median age of the patients was 59 (23–73) years, a male-to-female ratio – 3:1. Most common histological type of kidney cancer was clear-cell RCC (71 (95.8 %)). More than 2 lines of previous therapy were administered in 45 (61.6 %) cases. Most patients were diagnosed with multiple metastases (71 (97.3 %)) in >1 site (61 (83.6 %)). Nephrectomy was performed in 87.7 % (64/73) of cases. At the combined therapy start ECOG PS 2–4 was registered in 16 (20.5 %), poor prognosis according to IMDC score – in 33 (45.2 %) patients. Median follow-up was 9.7 (1–26) months.Results. Median progression-free survival achieved 16.9 (95 % confidence intervals (CI) 12.1–20.6), overall survival – 20.8 (95 % CI 15.7–25.9) months. Objective response rate was 11 % (8/73); tumor control was reached in 93.2 % (68/73) of cases. Median objective response duration was 10.5 (4.3–16.8) months, tumor control duration – 10.0 (2.5–17.5) months. Any adverse events developed in 83.6 % (61/73), adverse events grade III–V – in 23.3 % (17/73) of cases. Most frequent AE grade III–IV were diarrhea (10 (13.6 %)) and arterial hypertension (6 (8.2 %)). Unacceptable toxicity demanded treatment cancellation in 4.2 % (3/73), therapy interruption – in 30.1 % (22/73) and dose reduction – in 32.9 % (24/73) of patients.Conclusion. Unselected mRCC patients administered with combined targeted therapy in the real world practice were registered with similar survival, lower objective response rate, and better tolerability comparing with population assigned for lenvatinib plus everolimus in the randomized phase II trial.

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