The Effect of Tumor Necrosis Factor (TNFα) Inhibition on Platelet Counts in Adults and Children with Persistent ITP.

Abstract Immune Thrombocytopenic Purpura (ITP) is hematologic disorder caused by autoimmune opsonization and premature destruction of platelets. Approximately 20% of children and the majority of adults will have a chronic course of ITP with antibody-mediated destruction of platelets and the inability to clear immune complexes. Pro-inflammatory cytokines IL-2, TNF-α and IFN-γ are secreted following a Th1 response and are elevated in patients with chronic ITP. Recent treatments for chronic ITP in adults and children have focused on quelling dysregulated T and B lymphocyte activity. We conducted a pilot clinical trial of etanercept, a fusion peptibody composed of the soluble TNF-α receptor and the Fc portion of Ig. Hematologic and immunologic responses were measured before, during (blood counts only) and after a 12-week regimen of 0.4mg/kg/dose (max dose 25 mg) of subcutaneous etanercept, given twice weekly. Only fixed-dose prednisone or danazol were allowed as concomitant ITP medications. Cytokine concentrations were measured pre- and post-treatment from plasma and cultured lymphocytes (unstimulated or PHA- [2.5ng/ml] stimulated). Sixteen patients (9 male, 7 female), with chronic ITP (8 post-splenectomy) an initial platelet concentration < 30 × 109/L were enrolled with data evaluable for 15. The mean age of the patients was 31 years (median 32, min/max 7/52 years). One patient withdrew due to dizziness thought related to the study drug. One patient developed autoimmune hemolytic anemia, was diagnosed with Evans syndrome at treatment week 3 and withdrew from the study. Otherwise, no severe or serious related adverse events were observed. Two patients had a complete platelet response (CR, plt count > 150 × 109/L at least 6 weeks post treatment), 6 had a partial response (PR, plt count > 30 × 109/L and double baseline plt count), one had a minimal response (MR, plt count > 30 × 109/L) and 5 had no platelet response (NR). Two of the patients with PR had a platelet count rise that lasted at least until the end of the 8 week post-treatment observation period. The platelet response rate in nonsplenectomized and splenectomized patients was 67% and 28%, respectively, p = 0.1. Concentrations of IL-1β, IL-4, IL-6, IL-10 IFN-γ and TGF-β, before and at the end of the 12-week treatment course, showed marked inter-patient variation and did not predict the platelet count outcome. Both patients that had a CR had a reduction in PHA-stimulated TNF-α of 33 and 30%, respectively. Others with NR to treatment had similar declines in TNF-α, however. Although the precise mechanism of action is unclear, etanercept treatment led to at least a partial platelet response in 50% of patients with persistent ITP and was well-tolerated.

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SEROPOSITIVITY FOR ASCARIOSIS AND TOXOCARIOSIS AND CYTOKINE EXPRESSION AMONG THE INDIGENOUS PEOPLE IN THE VENEZUELAN DELTA REGION

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652015000100007 ◽

2015 ◽

Vol 57 (1) ◽

pp. 47-55 ◽

Cited By ~ 7

Author(s):

Zaida Araujo ◽

Sietze Brandes ◽

Elena Pinelli ◽

María A. Bochichio ◽

Andrea Palacios ◽

...

Keyword(s):

Indigenous Population ◽

Intestinal Parasites ◽

Ascaris Suum ◽

Toxocara Canis ◽

Hymenolepis Nana ◽

Blastocystis Hominis ◽

Tnf Α ◽

Blotting Technique ◽

Adults And Children ◽

Ifn Γ

The present study aimed at measuring seropositivities for infection by Ascaris suum and Toxocara canis using the excretory/secretory (E/S) antigens from Ascaris suum (AES) and Toxocara canis (TES) within an indigenous population. In addition, quantification of cytokine expressions in peripheral blood cells was determined. A total of 50 Warao indigenous were included; of which 43 were adults and seven children. In adults, 44.1% were seropositive for both parasites; whereas children had only seropositivity to one or the other helminth. For ascariosis, the percentage of AES seropositivity in adults and children was high; 23.3% and 57.1%, respectively. While that for toxocariosis, the percentage of TES seropositivity in adults and children was low; 9.3% and 14.3%, respectively. The percentage of seronegativity was comparable for AES and TES antigens in adults (27.9%) and children (28.6%). When positive sera were analyzed by Western blotting technique using AES antigens; three bands of 97.2, 193.6 and 200.2 kDas were mostly recognized. When the TES antigens were used, nine major bands were mostly identified; 47.4, 52.2, 84.9, 98.2, 119.1, 131.3, 175.6, 184.4 and 193.6 kDas. Stool examinations showed that Blastocystis hominis, Hymenolepis nana and Entamoeba coli were the most commonly observed intestinal parasites. Quantification of cytokines IFN-γ, IL-2, IL-6, TGF-β, TNF-α, IL-10 and IL-4 expressions showed that there was only a significant increased expression of IL-4 in indigenous with TES seropositivity (p < 0.002). Ascaris and Toxocara seropositivity was prevalent among Warao indigenous.

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Use of Post-Treatment Clinical Data To Predict Response to Decitabine.

Blood ◽

10.1182/blood.v110.11.1448.1448 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1448-1448

Author(s):

Elihu Estey ◽

J.-P. Issa ◽

Guillermo Garcia-Manero ◽

Stefan Faderl ◽

Hagop Kantarjian

Keyword(s):

Platelet Count ◽

Clinical Data ◽

Neutrophil Count ◽

Median Number ◽

Post Treatment ◽

Newly Diagnosed ◽

Platelet Response ◽

Best Response ◽

Blast Count ◽

To Receive

Abstract Best response of AML or MDS to decitabine (DAC) may require > 3 courses. Identification of pts whose response to initial courses suggests they are unlikely to respond further to subsequent courses would allow such pts to receive other therapies more expeditiously. 104 pts, median age 69, received DAC (20 mg/m2 IV daily × 5 days every 5 weeks) for newly- diagnosed MDS (80, 76 IPSS int-2 or high) or AML (24) from 9/00-5/07. After 3 courses, 33 of the 104 were in CR, 6 were dead, and 32 had been removed from study, with the remaining 32 receiving more DAC. The probability of CR decreased to < 10% on all courses after the 5th: Course# Pts Receiving CR Deaths/Off Study Received Next Course after course Course 1 104 7 (7%) 2/15 80 2 80 16 (20%) 4/12 48 3 48 10 (21%) 0/6 32 4 32 5 (16%) 0/5 22 5 22 3 (14%) 0/3 16 6 16 1 (6%) 1/3 11 7–15 11 1 (9%) 1/9 0 Results were qualitatively similar for AML and MDS. We divided the 32 pts who received ≥ 4 courses according to whether after course 3 their: marrow showed a response, defined as a p < 0.05 difference between the pre-Rx and post course 3 blast count, platelet count increased > 30, 000 if < 100,000 pre-Rx, or neutrophil count increased > 500 if < 500 pre Rx; criteria 2 and 3 were adapted from those of the IWG. 8/14 pts with vs. 1/11 without a marrow response after course 3 entered CR on subsequent courses (p = .02, 6/10 vs. 1/10 considering only MDS). The corresponding figure for platelet response/no response was 5/8 vs. 2/11 (3/5 vs. 2/9 for MDS). The median number of courses after the 3rd given pts with marrow response was 2 (range 1–10) vs. 3 (range 1–12) for pts without marrow response. Our data suggest that if CR is the goal, pts should not receive more than 5 courses of DAC and no more than 3 if marrow response has not occurred after the 3rd.

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A Multi-Centre, Single-Arm, Open-Label Study Evaluating the Safety and Efficacy of Fixed Dose Rituximab in Patients with Refractory, Relapsing or Chronic Idiopathic Thrombocytopenic Purpura (R-ITP1000 Study) and Exploring Rituximab Response with the FcGammaR3A Polymorphisms

Blood ◽

10.1182/blood.v118.21.1157.1157 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1157-1157

Author(s):

Huyen Tran ◽

Jamie P Nourse ◽

Rod Lea ◽

Timothy A. Brighton ◽

Andrew Grigg ◽

...

Keyword(s):

Platelet Count ◽

B Cells ◽

Autoimmune Disease ◽

Idiopathic Thrombocytopenic Purpura ◽

Response Rate ◽

Fixed Dose ◽

Contingency Table Analysis ◽

Open Label ◽

Thrombocytopenic Purpura ◽

Chronic Itp

Abstract Abstract 1157 Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding. Approximately 25–30% of adult patients with acute ITP develop chronicity; 30% of chronic ITP patients become refractory to corticosteroids and require additional therapy. As B-cells play an important pathophysiological role in autoimmune disease, rituximab, a chimeric anti-CD20 monoclonal antibody which depletes CD20+ B-cells has been used in chronic ITP. A dosing regimen based on lymphoma therapy (375 mg/m2 weekly × 4) has shown efficacy (∼38% Overall Response Rate-ORR) in adults in this context. Whether this schedule is optimal in autoimmune disease, in which the burden of pathological B-cells is low, is unknown. In this study we explored an abbreviated rituximab schedule, consistent with the approved rheumatoid arthritis dosing. We also explored inherited polymorphisms in FcGammaR3A (FCGR3A) as it has been shown to correlate with response to rituximab. AIM: The primary objective of this study was to determine the ORR, at week 8, among adults (≥ 18 years) with chronic or relapsing ITP (platelet count > 10 × 109/L and ≤ 50 × 109/L) according to the ASH guidelines, who received rituximab 1000 mg intravenous (IV) on days 1 and 15. A laboratory sub-study investigated the relationship between the FCGR3A-V/F158 polymorphisms and response to rituximab. METHOD: Patients received planned doses of rituximab and were followed-up for a minimum of 12 weeks. Assessments and procedures at mandatory follow-up visits occurring on weeks 8, 12, 26, 39 and 52 included physical examination, vital signs, FBC and serum chemistry. ORR was defined as the proportion of patients achieving a Complete Response (CR, platelet count > 150×109/L) or Partial Response (PR, > 50 × 109/L) at weeks 8 and 12 with 2 consecutive measurements, confirmed at least 2 weeks apart. Simon's 2-stage design was used to determine if the ORR was more likely to be ≤ 38% or ≥ 50%. At least 50 out of 108 responders (46%) were required to conclude, with 95% confidence and 80% power, that the ORR was likely to be ≥ 50%. FCGR3A-V/F158 genotyping was performed using allele specific polymerase chain reaction (PCR) techniques previously described (Koene HR, et al. Blood 1997;90:1109–1111). Distribution of polymorphisms was correlated according to response rate, as pre-defined in the study protocol and the frequencies compared using the standard chi-squared test for independence via contingency table analysis. Results: Out of the 124 patients recruited, 2 did not receive study medication and 14 did not have a platelet count ≤ 50 × 109/L within 7 days of first rituximab dose and were excluded from analysis. At week 8, the confirmed ORR was 44% (47/108 patients); 9% and 34% of whom achieved CR and PR respectively. At week 12, 9 patients had a missing platelet count value and therefore response rate data was available for 99 patients; ORR=46% (45/99). Treatment was well tolerated with no safety signals reported. Genotyping data was available for 87 patients. Correlations between FCGR3A-V/F158 polymorphisms and response to rituximab showed that 32% (16/50) non-responders [minor or no response] and 19% (7/37) responders [CR or PR] were homozygous for the FCGR3A-F/F158 genotype; p=0.21. Conclusion: The ORR is comparable with published studies using a more frequent rituximab schedule. Although not statistically significant, non-responders were more likely to be homozygous for the FCGR3A-F/F158 genotype than responders. Further investigations are warranted to determine whether the same response can be achieved with single/lower dosing rituximab, if longer/ more intense dosing might improve ORR and if maintenance rituximab may improve durability of responses. Disclosures: Thurley: ROche Products Australia: Employment.

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Anti-Leukemia Immune Responses in CML Patients Treated with Imatinib Mesylate.

Blood ◽

10.1182/blood.v106.11.1108.1108 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1108-1108

Author(s):

Christiane I.-U. Chen ◽

Holden T. Maecker ◽

Wesley H. Neal ◽

Rhoda Falkow ◽

Peter P. Lee

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Post Treatment ◽

Leukemia Cells ◽

Tnf Α ◽

Ifn Γ ◽

Cytogenetic Remission ◽

Pre Treatment

Abstract Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of patients with chronic myelogenous leukemia (CML). Most CML patients in chronic phase achieve hematologic remission with imatinib, while some achieve cytogenetic remission. As imatinib is an oral agent with few side effects, it has rapidly become the first-line therapy for most CML patients. However, this therapy does not represent a cure, as patients who discontinue the drug invariably relapse. Furthermore, imatinib resistance is beginning to emerge in some patients. Hence, the need to find alternate, potentially curative, therapies for CML remains. To date, the only curative treatment for CML is allogeneic bone marrow or stem cell transplantation (ABMT). A major mechanism of the curative potential of ABMT is immunological, as evidenced by the poor clinical outcome with T cell-depleted ABMT, and the efficacy of donor lymphocyte infusions (DLI) upon relapse. We hypothesized that an effective anti-leukemia immune response may emerge in patients entering remission on imatinib which may contribute to its clinical effectiveness. If so, strategies to further enhance this anti-leukemia immune response may lead to a potential cure. To determine if CML patients in remission on imatinib develop anti-leukemia immune responses, blood and bone marrow samples from patients before and after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia immune responses in post-treatment samples in IFN-g ELISPOT assays. Pre-treatment samples alone, post-treatment samples alone, and when available, serial post-treatment samples mixed together served as controls. In 9 of 14 patients investigated, IFN-g release was detected in pre- and post-treatment samples together with a median response of 22 spots above background (range 10 – 56 dots, p<0.01), whereas serial post-treatment samples together in 8 patients yielded results similar to background (median 5, range 5 – 20). In 6 of these patients in hematologic (or cytogenetic) remission, sufficient cells were available to allow additional analyses via intracellular staining for IFN-g, TNF-a, and IL-2 in autologous leukemia stimulated T cells (CD4 and CD8) and NK cells. In 4 of 6 patients, leukemia-reactive T cells were detected, most prominently in CD4+ T cells expressing TNF-a (1.4 – 37%), followed by IL-2 (0.3 – 12%) and IFN-g (0.1 – 4.6%). NK cells did not show significant expression of these cytokines upon stimulation with autologous leukemia cells. In pre-treatment and post-treatment samples alone, IL-2, TNF-a, and IFN-g expression was not detectable (0 – 0.5%). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia immune response, most notably in CD4+ T cells. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML as well as other leukemias, and raises the hope that immunotherapy may be combined with imatinib to eradicate residual leukemia cells for a durable cure of the disease. intracellular cytokine staining CD4+ T Cells CD8+ T Cells IL-2 IFN- γ TNF- α IL-2 IFN- γ TNF- α pt 1 0.3 0 0.8 0.1 0.1 0.5 pt 1 0.3 0.1 1.4 0.1 0.1 0.4 pt 2 2.6 0.8 10.3 2.2 2.1 6.1 pt 3 21 2 37 2.3 0.7 1.7 pt 4 12 4.6 19 6.3 1.8 5.8

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Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 2-Year Update.

Blood ◽

10.1182/blood.v110.11.568.568 ◽

2007 ◽

Vol 110 (11) ◽

pp. 568-568 ◽

Cited By ~ 2

Author(s):

James B. Bussel ◽

D.J. Kuter ◽

J.Th.M de Wolf ◽

T.H. Guthrie ◽

A. Newland ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Neutralizing Antibodies ◽

Drug Exposure ◽

Therapeutic Option ◽

Platelet Response ◽

Initial Report ◽

Chronic Itp ◽

Long Term Treatment

Abstract AMG 531, a novel thrombopoiesis-stimulating peptibody, increases platelet production by stimulating the TPO receptor. This study is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, SC administration of AMG 531 in patients with chronic ITP who completed a previous AMG 531 study. Patients previously treated with AMG 531 received the same starting dose as the final dose given in the previous study; placebo-treated patients began the extension at 1μg/kg. Doses could be adjusted based on platelet response. As of an April 2007 analysis, 137 patients were enrolled and 136 had received AMG 531. The longest treatment duration was 122 weeks; 22 patients were followed for 96 weeks or longer. At baseline, 91 women and 46 men had a mean age of 53±15(SD) years and a median (range) platelet count of 18(1–50)x109/L; 82 patients (60%) had undergone splenectomy. The most frequently reported adverse events (AEs) were headache (overall incidence 31%), contusion (27%), fatigue (24%), diarrhea (24%), epistaxis (23%), nasopharyngitis (21%), and arthralgia (20%). Exposure-adjusted analysis showed no trend for AEs to increase in frequency with increased drug exposure (table). Eleven patients had serious AEs judged by investigators as treatment-related including 3 withdrawn from study (vaginal hemorrhage, increased reticulin in the bone marrow reported as myelofibrosis, and initial report of multiple myeloma later reclassified as monoclonal gammopathy of undetermined significance - 1 report each) and 8 who continued on-study (bone marrow disorder/reticulin fibrosis - 3, unacceptably high platelet count - 2, thrombosis - 2, and cerebral thrombosis/papilloedema/temporary blindness - 1). One patient developed neutralizing antibodies to AMG 531 (absent on retesting 4 months after drug cessation), with no clinical sequelae and no cross-reactive antibodies to TPO. Overall, 112 patients (82%) achieved a platelet response (≥50x109/L and doubling of baseline). From week 4 onward, weekly incidence of platelet response ranged from 52–73% (figure). Median number of weeks to first response was 2 (median dose 3μg/kg). Of 30 patients with baseline use of concurrent ITP therapies, 13 were able to discontinue them and 6 additional patients had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for long-term treatment of chronic ITP. The safety profile has been acceptable, and most patients have been able to maintain a platelet response and discontinue or reduce concurrent ITP therapies. Exposure-Adjusted incidence of AEs with Overall Incidence ≥ 20% Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week

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Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program

Blood ◽

10.1182/blood-2011-03-340166 ◽

2011 ◽

Vol 118 (16) ◽

pp. 4338-4345 ◽

Cited By ~ 70

Author(s):

Mehdi Khellaf ◽

Marc Michel ◽

Philippe Quittet ◽

Jean-François Viallard ◽

Magda Alexis ◽

...

Keyword(s):

Platelet Count ◽

Clinical Practice ◽

Immune Thrombocytopenia ◽

Intravenous Immunoglobulins ◽

Interquartile Range ◽

Concomitant Treatment ◽

Platelet Response ◽

Compassionate Use ◽

Chronic Itp ◽

Bleeding Score

Abstract Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 109/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 109/L (interquartile range, 75-167 × 109/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 109/L (interquartile range, 35-44 × 109/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.

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Decitabine-Induced Early Platelet Response, a Predictor of Favorable Outcome during Hypomethylating Treatment of MDS, Is Associated with In Vivo Megakaryocytic Differentiation

Blood ◽

10.1182/blood-2019-128141 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4265-4265

Author(s):

Julia Stomper ◽

Annette M. May ◽

Tina E. Joeckel ◽

Peter Bronsert ◽

Martin Werner ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Treatment Cycle ◽

Post Treatment ◽

Platelet Response ◽

Absolute Increase ◽

Bone Marrow Biopsies ◽

Pre Treatment

Introduction Despite broad use of hypomethylating agents (HMAs) in MDS/AML treatment, the number of established outcome predictors is still very limited (Stomper and Lübbert, Sem Hematol 2019). One of them, the early, isolated and sometimes massive increase of platelets, is recurrently observed in patients with MDS treated with HMAs. It is not observed with non-HMA cytidine analogs such as low-dose cytarabine. In HMA-treated MDS patients, an early platelet increase is a predictor of overall and leukemia-free survival (van den Bosch et al., Leuk Res 2004; van der Helm et al., Br J Haematol 2011). HMAs induce cellular differentiation in vitro, by gene reactivation in the malignant cells. However, evidence for HMA-induced in vivo differentiation is still very limited. We hypothesized that the megakaryocytic cell lineage in MDS is a target for HMA-induced cellular maturation in vivo. Methods We systematically analyzed the bone marrow morphology of 34 higher-risk MDS patients (median age: 71.5 years, range 51-79) before and after 1 cycle of treatment with the HMA decitabine (DAC). All patients had been treated at a single center within 3 prospective clinical trials (Wijermans et al., Ann Hematol 2005; Lübbert et al., J Clin Oncol 2011). One treatment cycle consisted of 45 mg/m2 DAC per day (15 mg/m2 intravenously over 4 hours every 8 hours) for 3 consecutive days, repeated 6 weeks later. The early platelet response was evaluated after 1 cycle of DAC treatment. Based on the criteria of the International Working Group, an absolute increase in platelet count of 30x109/l or more compared to the pre-treatment count was defined as a platelet response. The histological analysis of the bone marrow specimens was performed by an experienced hematopathologist blinded to the treatment timepoints. Up to 200 megakaryocytes (MK) per sample were quantified at a magnification of 400 x using chloroacetate esterase staining. Results Thirteen of 34 patients (38%) showed a platelet response already after 1 cycle of DAC treatment, 21 (62%) did not. The median pre-treatment platelet count did not differ in patients with or without an early platelet response (median of 34x109/l in both groups, range 7-169 and 8-265, respectively). After 1 cycle of DAC treatment, patients with a platelet response had a median platelet count of 117x109/l (range 78-281), patients without this response had a median platelet count of 32 x109/l (range 4-155). Overall survival (OS) was measured from the time of early platelet response assessment after completion of 1 treatment cycle, i.e. after 6 weeks. The presence of a platelet response after 1 DAC cycle was associated with a longer OS compared to the absence of this early platelet response: median of 26.6 versus 14.0 months (p=0.04). Both pre- and post-treatment bone marrow biopsies of patients with an early platelet response showed higher numbers of MK, as well as significant differences in MK morphology compared to biopsies from patients without an early platelet response. Regarding MK numbers, increased MK density in specimens of patients with an early platelet response was observed both before (mean MK number per high power field 6.2 vs. 2.6, p=0.02) and after the application of DAC (mean MK number 10.4 vs. 3.1, p=0.01). Regarding MK maturation stage, more pre-treatment juvenile MK (on average 32.4% vs. 20.5% of all MK, p=0.03) and MK with typical myeloproliferative stigmata (present in 5/13 vs. 2/21 biopsies) were observed in patients with an early platelet response, compared to patients without this response. Regarding the induction of megakaryocytic maturation during this early treatment phase, more post-treatment "naked", mature MK nuclei indicative of active platelet shedding (on average 9.5% vs. 3.8% of all MK, p=0.01), were noted in patients with an early platelet response than in patients without an early platelet response. Conclusions This is, to the best of our knowledge, the first systematic hematopathological analysis of changes in quantitative and morphological MK features in bone marrow specimens of MDS patients during HMA treatment. DAC, which has in vitro differentiation-inducing effects on megakaryoblastic cells, induced maturation also of dysplastic MK in vivo in higher-risk MDS patients with an early platelet response to this HMA. The predictive value of an early platelet increase, a very easy-to-determine parameter, during this type of treatment is confirmed. Disclosures No relevant conflicts of interest to declare.

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Safety and Efficacy of Romiplostim in Immune Thrombocytopenia (ITP) in the “real-life” : Result of the French Experience in 72 Adults.

Blood ◽

10.1182/blood.v114.22.3519.3519 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3519-3519 ◽

Cited By ~ 1

Author(s):

Mehdi Khellaf ◽

Philippe Quittet ◽

Jean-Francois Viallard ◽

Magda Alexis ◽

Stéphane Cheze ◽

...

Keyword(s):

Platelet Count ◽

Rescue Medication ◽

Real Life ◽

Sustained Response ◽

Platelet Response ◽

Compassionate Use ◽

Safety And Efficacy ◽

Chronic Itp ◽

One Year

Abstract Abstract 3519 Poster Board III-456 Introduction Romiplostim is a thrombopoietic agent that has been unequivocaly demonstrated as highly effective in adult's ITP in prospective studies and has recently been licensed for adults with chronic ITP in USA, Europe, Canada, and Australia. France has been the only country where romiplostim could be given for a compassionate use outside clinical studies from January 2008. The official indication for obtaining romiplostim in this setting was: chronic ITP according to the international criteria and failure or relapse after at least one previous line of therapy regardless the status towards splenectomy. We report here the data on safety and efficacy of the first consecutive 80 ITP patients who have been registered by the French health authorities as receiving the treatment “off-label” and with at least one-year of follow up. Patients and methods The data were retrospectively reviewed using a standardized form. The protocol was approved by local ethical committee. Patients who did not fulfil official indication criteria of compassionate use were excluded (i.e. secondary-ITP). Platelet count was monitored at least monthly during the follow-up. Platelet response was defined as platelet count of 50×109/L or more and a doubling of the pre-treatment count in the absence of any rescue medication within the last 8 weeks. One-year sustained response was defined as a platelet response on at least 2 of the last 3 platelet determinations at month-10-11 and 12. Patients who received rescue medication at any time during the study could not be counted as having a one-year sustained response. Report of adverse events was captured using a standardized form. Results Among the 80 patients, 8 were actually excluded from the analysis (6 with secondary ITP and 2 have been misdiagnosed as having ITP). The analysis was then conducted on 72 patients (43 females) with a median age of 60 years (20 to 91). The median duration of ITP prior to romiplostim administration was 8.7 years (0.1 to 49) and the patients had received a median of 5 (2 to 12) treatment-lines before romiplostim including: corticosteroids (100%), rituximab (65/72, 90%) and splenectomy (39/72, 54%). Among the 33 non-splenectomized patients, 13 patients were reluctant to undergo splenectomy whereas splenectomy was considered as contra-indicated in 20 of them. At time of romiplostim first administration, median platelet count was 16×109/L (1 to 60) and 48 patients (66%) were receiving a concurrent treatment for ITP, including mainly steroids (n=29) ± immunosuppressive drugs (n=8). A platelet response was observed at least once in 76% (55/72) of the patients. On average, patients who responded at any point during the study had a platelet response during 64% of the time (range: 37 to 100%). Romiplostim was stopped in 28 % (20/72) of patients for either lack of efficacy (n=16), for intolerance (n=1) or because it was administered only transiently in preparation for surgery (n=3). Two patients had died respectively from a septic shock and from an ITP-related intracranial hemorrhage. At one-year of follow up, 52 patients were still receiving romiplostim at a median dose of 6.5 μg/kg per week. This dose remained relatively stable as after the first 12 weeks of treatment, romiplostim could be pursued at a stable dose ± 2 μg/kg in 82% of the cases. Twenty % (14/72) of patients received a rescue medication during the study and 50% (36/72) of the patients had a one-year sustained response. The percentage of one-year sustained response was similar in splenectomized and non splenectomized groups [respectively 54% (21/39) and 45% (15/33), NS)]. Among the 29 patients who responded to romiplostim and who were receiving a treatment at time of romiplostim initiation, 86 % (25/29) had discontinued this medication and a further 7% (2/29) had reduced the dose by at least 25%. Only one patient stopped romiplostim because of an adverse event (headache). The most frequent otherwise reported adverse events were: arthralgia (26%), fatigue (13%) and nausea (7%). A transient thrombocytosis > 400×109/L and > 1000×109/L has been observed in respectively 19% (14/72) and 4% (3/72) of patients. A transient stroke occurred in 2 elderly patients (age > 70 yrs). No deep vein thrombosis occurred. Myelofibrosis was not observed. Conclusion Our study confirms in “real-life” that romiplostim is definitely an effective and safe treatment for severe chronic ITP in both non-splenectomized and splenectomized adults. Disclosures: Godeau: AMGEN: Consultancy.

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A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3092 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3092-3092

Author(s):

Manish R. Patel ◽

Todd Michael Bauer ◽

Antonio Jimeno ◽

Ding Wang ◽

Patricia LoRusso ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Solid Tumor ◽

Human Study ◽

Post Treatment ◽

Tumor Shrinkage ◽

Tumor Patients ◽

Combination Methods ◽

Tnf Α ◽

Ifn Γ ◽

Pro Inflammatory Cytokines

3092 Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931 .

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Therapeutic Effect of Platelet Transfusion in Patients with Acute Lymphocytes Treated with CART Therapy

Blood ◽

10.1182/blood-2018-99-120108 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5073-5073

Author(s):

Liu Yan ◽

Xie Jue ◽

Yongxian Hu ◽

He Huang

Keyword(s):

Platelet Count ◽

Acute Lymphoblastic Leukemia ◽

Platelet Transfusion ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Bleeding Tendency ◽

Maximum Benefit ◽

Tnf Α ◽

Ifn Γ ◽

The Relationship

Abstract Background: CART therapy is the most effective method for the treatment of acute lymphoblastic leukemia (ALL) right now, which accompanied with severe cytokine storms (CRS) during treatment, resulting in severe platelet destruction and reduction. So the treatment of platelet transfusion is particularly important to the CART therapy. However, there is no clinical consensus on when given platelet transfusion can patients obtain the maximum benefit. Methods: In the study, 14 ALL patients were enrolled for the CART treatment. The patients with platelet transfusion refractoriness (PTR) were excluded for non-immune factors such as large spleen and high fever. Blood routine and cytokines such as IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A were monitored during treatment. Body temperature should be less than 38 degrees before transfusion of platelets. Analyze the efficacy of platelet transfusion in patients before the CART treatment, the time with CRS, and after the CRS. The platelet transfusion effect was determined by 24-hour corrected count increment (CCI) (greater than 7.5 considered as effective, otherwise as invalid). Results: All the patients in the study were treated with platelet transfusion before CART treatment. There was a CSR-3 level in every patients during the treatment. Four of them didn't get platelet transfusion as the lowest platelet count is more than 10×109/L without bleeding tendency. Ten of them received platelet transfusion treatment during CRS and the average of the cytokine were higher than before (IL-2 (12.65±21.08 pg/ml), IL-6 (8540.57±6791.91 pg/ml), IL-10 (1547.46±2939.45 pg/ml), IFN-γ (2846.49±2480.88 pg/ml),P<0.01). The 24 hour CCI of the 10 patients before CART treatment were 10.91±3.27, during CRS were 4.18±4.28, and after CRS were 8.72±2.93 (P<0.01). During the CRS, 24 hour CCI is higher in patients with platelet count below 5×109/L than patients with platelet count between 5-10×109/L(P<0.01). Conclusion : CRS during CART treatment accelerated platelet consumption, resulting PTR. Platelet transfusion could not be given to patients when they were experiencing the most serious CSR without bleeding tendency, but it can be considered when the platelet count is less than 5×109/L, Key Words: acute lymphoblastic leukemia, severe cytokine storms, platelet transfusion. Fig 1: the relationship between 24 hour CCI and the highest IL-6: The IL-6 is so high that we reduced it by one thousand times in the figure. The 24 hour CCI is negatively correlated with IL - 6, P<0.01, R=-0.92. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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