scholarly journals Efficacy and Safety of Cyclosporine Treatment in Autoimmune Cytopenias: The Experience of Two Italian Reference Centers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3146-3146
Author(s):  
Bruno Fattizzo ◽  
Silvia Cantoni ◽  
Rachele Zavaglia ◽  
Juri Alessandro Giannotta ◽  
Nicola Cecchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Board Of Directors ◽  
Oral Drug ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Concomitant Treatment ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Autoimmune Cytopenias

Abstract Background: Autoimmune cytopenias (immune thrombocytopenia ITP, autoimmune hemolytic anemia AIHA, and chronic idiopathic neutropenia CIN) are a heterogeneous group of disorders characterized by the presence of autoantibodies directed against platelets (PLT), erythrocytes, and neutrophils (ANC). Frontline steroids are the mainstay of treatment, although most patients relapse and require 2 nd line therapies which slightly differ according to disease subtype. Rituximab is mainly effective in AIHA, although only a fraction of cases would experience long-term relapse-free. Splenectomy may be contraindicated due to age and risk of thrombotic and infectious complications and thrombopoietin-receptor agonists (TPO-RA), effective in more than 70% of ITP patients, may result in great PLT fluctuations and increased bone marrow reticulin fibrosis. Cyclosporine (CyA) is an immunosuppressant used for over 30 years in the post-transplant setting and in the treatment of aplastic anemia. It is a manageable oral drug with known toxicities and its plasma concentrations may be monitored to optimize treatment. However, few data exist about its efficacy in autoimmune cytopenias either used as single drug or in combination with other treatments. Aim: The aim of this study was to evaluate the efficacy and safety of CyA in a cohort of patients with ITP, AIHA, and CIN, followed at two reference hematology centers in Milan, Italy. Methods: Medical charts of consecutive patients treated with CyA 3-5 mg/ kg day in the last 20 years were evaluated. Responses were assessed at 3, 6 and 12 months, and divided into partial (PR, for Hb> 10 g/dL; PLT> 30x 109/L and ANC> 0.8 x 109/L) and complete (CR, for Hb> 12 g/dL; PLT> 100x109/L; ANC>1 x 109/L). Adverse events were recorded according to CTCAE criteria. Results: 41 patients, 27 ITP (66%), 11 AIHA (27%) and 3 CIN (7%), were included, 16 men (39%) and 25 women (61%), with a median age of 60 year (21-81). The median time from diagnosis to CyA start was of 10 years (5-15), with a median of 3 (1-8) previous therapy lines. Most patients were receiving concomitant treatment including steroids (N=13), IVIG (3), or TPO-RA (14). Reasons to start CyA included no response to previous treatments (N=27), platelets fluctuations (N=5) or bone marrow fibrosis (N=5) on TPO-RA, and contraindication for splenectomy (N=4). Median duration of CyA therapy was 5 years (1-9) and 34 patients (83%) responded: 34% CR, 44% PR at month+3; 39% CR and 39% PR at month+6; and 26%CR and 43%PR at month+12 (Figure 1). Specifically, median PLTs increased by 32 x10^9/L at month+3, by 121 x10^9/L at month+6, and by 43 x10^9/L at month+12. Median Hb improved by 0.5 g/dL at month+3, by 1 g/dL at month+6, and by 2,6 g/dL at month +12. Median ANC augmented by 0.7 x10^9/L at month +3, by 1.7 x10^9/L at month +6, and by 0.07 x10^9/L at month +12. Importantly, 9 patients could stop steroids, and 10 subjects discontinued or tapered TPO-RA (5 each). Better responses were observed in ITP patients with baseline bone marrow hypocellularity (p = 0.01), absence of reticulin fibrosis (p=0.02), and in those not previously splenectomized (p=0.04). Among AIHA cases, those with IgG+C direct antiglobulin test positivity showed higher percentage of non-response (67 versus 22% in IgG+). Adverse events were mainly G1-2, occurring in 52% of patients, and included asthenia, dyspnea, myalgia, nausea, vomiting, diarrhea and abdominal pain, epistaxis, petechiae and an Escherichia Coli cystitis. Three patients on concomitant long-term steroids developed a G3 event (1 pulmonary embolism, 1 Aspergillus lung infection and 1 bronchitis), and 1 died for Pneumocystis jirovecii pneumonia. Conclusion: Cyclosporine was effective in about 80% of highly pretreated patients and allowed tapering/discontinuation of concomitant treatments in 63% of cases. Responses were higher in those with ITP, and hypocellular bone marrow without reticulin fibrosis. The occurrence of infectious episodes, including a fatal pneumonia, warrants careful surveillance in this heavily pretreated patient population. Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals: Honoraria.

PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 56-56 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Lynda M Foltz ◽  
Vikas Gupta ◽  
John O. Mascarenhas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Negative Slope ◽  
Computer Assisted ◽  
Jak Inhibitor ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

Epoxyeicosatrienoic Acids Regulate Hematopoietic Stem/Progenitor Cell Fate Decision During Stress Response and Embryonic Hematopoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 860-860
Author(s):  
Pulin Li ◽  
Emily K Pugach ◽  
Elizabeth B Riley ◽  
Dipak Panigrahy ◽  
Garrett C Heffner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Marrow Transplantation ◽  
Mouse Bone Marrow ◽  
Zebrafish Embryos ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Equity Ownership ◽  
Runx1 Expression

Abstract Abstract 860 During bone marrow transplantation, hematopoietic stem/progenitor cells (HSPCs) are exposed to various stress signals, and undergo homing, rapid proliferation and differentiation in order to achieve engraftment. To explore how fate decisions are made under such stress conditions, we developed a novel imaging-based competitive marrow transplantation in zebrafish. The feasibility of handling hundreds of zebrafish for transplantation per day allowed us to screen a library of 480 small molecules with known bioactivity, aimed at identifying new drugs and pathways regulating HSPC engraftment. Two structurally related eicosanoids, 11,12-epoxyeicosatrienoic acid (EET) and 14,15-EET, were able to enhance GFP+ marrow engraftment compared to DsRed2+ engraftment in zebrafish. This remarkable effect of EETs on adult marrow prompted us to study the effect of EETs in embryonic hematopoiesis. Treating zebrafish embryos with 11,12-EET during definitive hematopoiesis increased the HSPC marker Runx1 expression in the AGM (Aorta-Gonad-Mesonephros), resulting in a significant increase of HSPC in the next hematopoietic site, caudal hematopoietic tissue, the equivalent of fetal liver/placenta in mammals. The same treatment condition also induced ectopic Runx1 expression in the tail mesenchyme, a non-hematopoietic tissue. Microarray analysis on EET-treated zebrafish embryos revealed an upregulation of genes involved in stress response, especially Activator Protein 1 (AP-1) family members. Genetic knockdown experiments confirmed AP-1 members, especially JunB and its binding partners, cFos and Fosl2, are required for Runx1 induction. Motif analysis also predicted several conserved AP-1 binding sites in the Runx1 enhancer regions. To understand how EETs induced AP-1 expression, a suppressor screen was performed in zebrafish embryos. The screen revealed that activation of both PI3K/Akt and Stat3 are required for induced AP-1 expression, and therefore Runx1 upregulation. Similarly, ex vivo treatment of mouse whole bone marrow with 11,12-EET resulted in a 2-fold increase of long-term repopulating units. Microarray data had previously shown that Cyp2j6, one of the cytochrome P450 enzymes involved in EET biosynthesis from arachidonic acid, is enriched in quiescent mouse long-term HSCs. To further increase the EET levels in HSPCs, human CYP2C8 enzyme was over-expressed in transgenic mice using the Tie2 promoter. These transgenic mice have a 4-fold increase of long-term multi-lineage repopulating unit compared to their wild-type siblings. In purified mouse HSPCs, EETs directly and cell-autonomously activate PI3K/AKT pathway. Co-treatment of mouse bone marrow with EET and a PI3K inhibitor, LY294,002, completely blocked EET-induced enhancement of mouse bone marrow engraftment. In conclusion, we performed the first competitive marrow transplantation-based chemical screen, leading to the discovery of arachidonic acid-cytochrome P450-EETs as a novel modulator of HSC cell fate decision. PI3K/Akt and Stat3 pathways activated by EETs are required for adult HSPC engraftment and/or embryonic HSC specification, partially through transcriptional regulation of AP-1. We also demonstrated the requirement of AP-1 family members for Runx1 expression during embryonic development. This discovery may have clinical application in marrow or cord blood transplantation. Disclosures: Daley: iPierian, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Verastem, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Solasia, KK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; MPM Capital, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Zon:Fate Therapeutics: Founder; Stemgent: Consultancy.

Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Selective Inhibitor ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

Excellent Outcome and Good Tolerability of Long-Term Imatinib in Patients with Chronic Myeloid Leukemia (CML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2794-2794
Author(s):  
Simone Claudiani ◽  
Nikhita Gupta ◽  
Ji Soo Baik ◽  
Simona Deplano ◽  
Renuka Palanicawander ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Board Of Directors ◽  
Advisory Committees ◽  
Optimal Response ◽  
Time Points ◽  
The Future ◽  
Sokal Score

Abstract Introduction: The introduction of the tyrosine kinase inhibitors (TKIs) into clinical practice in the late 1990s has considerably improved both survival and quality of life for patients with CML. Imatinib was the only TKI available for several years with no useful drug treatment for patients with resistance and/or intolerance. Despite the lack of alternative agents the 8-year follow-up of the IRIS trialshowed that only 55% of patients were still on imatinib. The majority of those who discontinued did so for lack or loss of response rather than intolerance, suggesting that imatinib is very well tolerated in the long-term. This is particularly pertinent today as controversy persists as to the best agent for newly diagnosed patients. There is not only increasing evidence that the second and third generation TKIs are associated with more severe adverse events, but generic imatinib is now available in many countries at considerably less expense. We report our experience of treating 45 patients with continuous imatinib for more than 10 years. Methods: We interrogated our single centre database of all patients treated with TKIs for CML at our centre from June 2000 to March 2015. From a total of 832 patients we identified 188 CML who had received only imatinib. Of these, 45 patients had received treatment for more than 10 years. Results: The median duration of imatinib therapy was 6 years in the total cohort of imatinib only patients and 11 years (range 10-14.7) in the study group. All 45 patients were in chronic phase at diagnosis: the median age was 45.4 years (range 26-72). Forty patients were evaluable for Sokal scoring, with 19, 13 and 8 identified as low, intermediate and high risk respectively. The median imatinib starting dose was 400 mg daily. The proportions of patients who achieved optimal responses (OR), as defined by the ELN at 3, 6 and 12 months from start of imatinib, were 88.2%, 78.8 and 56.1% respectively. At 10 years the probabilities of CCyR, MR3, MR4, MR4,5 and MR5 were 100%, 100%, 100%, 100%, 75.6% respectively. The 10 year probability of obtaining a sustained (at least 2 years) molecular response was 100%, 64.4%, 35.6% and 15.6% for MR3, MR4, MR4.5 and MR5 respectively. In patients who were not optimal responders at one or more time points (n=21), the median dose of imatinib was ≥400 mg in the first 12 months of treatment; for 13/21 higher dosages (range 600-800 mg daily) were prescribed. We found a significant correlation between a low or intermediate Sokal score at diagnosis and OR at 3 months (p=0.012). No correlation was found between Sokal score and OR at 6 or 12 months. No statistically significant association was found between an optimal response at 6 or 12 months and the future depth of responses. In fact, the overall rates of sustained MR4.5 for patients optimal responders at 6 and 12 months were 52% and 52% versus 41.6% and 50% for non optimal responders at the same time points. Grade 4 toxicities and secondary malignancies were not observed during the follow-up. Seven pts (15.5%) experienced grade 3 events, including 1 each of supraventricular tachycardia and anemia, and neutropenia, fatigue and hypophosphataemia were each seen in 2 patients. The most frequent adverse event of any grade was fatigue (36% of pts), followed by anemia (27%) and neutropenia (18%). The cumulative probability of common side effects increased over the time. Cardiovascular events were mostly grade 1-2 palpitations and hypertension. At last follow-up, all pts were alive. Conclusions: Our patient cohort analysis confirms long term safety and tolerability of imatinib after 10 years of therapy. The majority of side effects were grade 1-2 and some increased in incidence over the time. The most frequent adverse events were hematological. Imatinib continues to provide an excellent therapeutic outcome granting deep molecular responses even in some patients deemed to be poor risk at diagnosis. ELN optimal response status at 6 and 12 months was not associated with prediction of the future depth of response, in this very good risk population (majority of patients in optimal response at 3 months). Disclosures Milojkovic: BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Apperley:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Curing Multiple Myeloma (MM) with Total Therapy (TT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 195-195 ◽  
Author(s):  
Bart Barlogie ◽  
Alan Mitchell ◽  
Frits van Rhee ◽  
Joshua Epstein ◽  
Shmuel Yaccoby ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Phase 2 ◽  
Advisory Committees ◽  
Cure Fraction ◽  
Metronomic Therapy ◽  
Age And Sex

Abstract Intra-tumoral heterogeneity is a hindrance to curing malignant disease. By employing all MM-active drugs upfront, TT was designed to overcome such obstacle by targeting all potential MM sub-clones broadly. We are reporting on long-term results of phase-2 TT1, phase-3 TT2 and phase-2 TT3a trials, with median follow-up times of 21yr, 12yr and 9yr, respectively. Five year estimates of OS, PFS and CR duration (CRD) increased from 58%, 28% and 40% with TT1 to 65%, 42% and 50% with TT2’s control arm (TT2-), to 68%, 56% and 58% with TT2’s thalidomide arm (TT2+), and to 74%, 65% and 74% with TT3a (all p<0.0001). The 5-yr estimates of time to progression (TTP)/time to relapse (TTR) from CR decreased from 59%/58% in TT1 to 43%/42% in TT2-, to 28%/34% in TT2+, and to 22%/18% in TT3a (all p<0.0001). When examined in the era of gene expression profiling (GEP) of purified plasma cells, 5-yr estimates of TTP/TTR in GEP70 low-risk MM were 47%/46% with TT2-, 26%%/36% with TT2+, and 18%/16% with TT3a (all p<0.0001); the corresponding data for the 15% with high-risk MM were 60%/50% with TT2-, 62%/64% in TT2+, and 48%/35% in TT3a (NS). Relative survival (RS) was computed per year in relationship to age- and sex-matched controls. RS ratios approached 1 at 10–15 years for TT1 and TT2-, but earlier, at 5-10 years, for TT2+ and TT3a. A parametric mixture cure model was used to estimate PFS and CR duration for each protocol, from baseline and from a 5-year landmark. The cure model fits the data well and provides cure-fraction estimates that increase with later protocols (Figure 1). Importantly, when comparing data from GEP-defined low-risk and high-risk MM, plateaus for both PFS- and CRD-based cure fractions emerged at 10 years in the former and earlier, at 5 years, in the latter (data not shown). PFS-based cure-fraction estimates increasedsignificantly with successive TT trials: 9% in TT1, 16% in TT2-, 25% in TT2+, and 33% in TT3a (p=0.04). CRD-based cure-fraction estimates were 18%, 28%, 36%, and 49%, respectively (p=0.17) (Table 1). When a 5-year landmark was applied to exclude early myeloma-related events, PFS-based cure fraction estimates were 28% in TT1, 39% in TT2-, 51% in TT2+, and 70% in TT3a (p<0.001); in this setting, CRD-based cure fraction estimates were 32%, 47%, 56%, and 75%, respectively (p=0.007). MRD flow cytometry was available in 83 of 175 TT2 PFS patients, of whom 78% were MRD-. Our TT results are consistent with curability of MM. Solely novel agent-based trials without transplant lack the long-term follow-up to determine their cure potential. As MM usurps the bone marrow micro-environment (ME) for its growth and survival, we reasoned that ME alterations reflecting an angiogenic switch may persist beyond the state of clinical CR and even MRD. We therefore performed GEP analyses of bone marrow biopsies in CR and compared findings with age- and sex-matched controls. Indeed, biopsy “normalization” was linked to superior CR duration and is being developed as an early “cure surrogate” marker to help define the length of maintenance therapy in future trials. Although about 50% of CR patients treated with TT3a can be considered cured, the median PFS in high-risk MM of 2yr has not improved with successive TT trials. Reasoning that cytokine storms emanating after myelosuppressive therapies to restore normal hematopoiesis may be growth-stimulatory to MM cells, we applied non-myelotoxic metronomic therapy (Papanikolaou, Haematologica, 2014). Six newly diagnosed transplant-ineligible high-risk patients were offered an extended 28-day course of low-dose metronomic therapy with bortezomib, thalidomide, dexamethasone and continuous infusions of doxorubicin and cisplatin, to which were added arsenic trioxide and vincristine infusions. Remarkably, 5 of 6 achieved CR status after a single course and remain disease-free without further therapy 6-8 months later. Our results attest to the curability of MM with TT and, given the short PFS of 2yr in high-risk MM, such patients should be the focus of future novel interventions that yield information in a timely manner. Table 1 Cure fraction estimates Protocol PFS CR duration N Cure Fraction N Cure Fraction From start of therapy TT1 231 8.8% 79 17.9% TT2 -Thal 345 15.5% 146 28.2% TT2 +Thal 323 25.1% 200 35.6% TT3a 303 32.9% 189 48.8% From 5-yr landmark TT1 65 28.4% 33 32.3% TT2 -Thal 145 39.2% 84 47.4% TT2 +Thal 150 51.1% 134 55.9% TT3a 197 69.8% 148 74.7% PFS CR duration Figure 1 Cure fraction estimates from baseline Figure 1. Cure fraction estimates from baseline Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
N Rates

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Vorinostat Combined with Bortezomib In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Update on the Vantage Study Program

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1952-1952 ◽  
Author(s):  
David S Siegel ◽  
Sundar Jagannath ◽  
Roman Hajek ◽  
Meletios A. Dimopoulos ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Primary Objective ◽  
Advisory Board ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
Eortc Qlq

Abstract Abstract 1952 Background: Initial clinical response rates have improved significantly with current treatments for multiple myeloma (MM). However, most patients eventually relapse or become refractory to approved agents, prompting the development of additional targeted agents and combination regimens. Vorinostat is a first-in-class oral histone deacetylase inhibitor that regulates the expression of genes and proteins involved in tumor growth and survival, and is approved in the United States for the treatment of patients with advanced cutaneous T-cell lymphoma in whom prior therapies have failed. Bortezomib, a reversible proteasome inhibitor, is approved for the treatment of patients with MM who have received at least 1 prior therapy. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and confirmed in Phase I trials in patients with relapsed/refractory (RR) MM, producing objective response rates (ORRs; partial response or better) of up to 42% in all patients (including those with bortezomib-refractory disease) and overall clinical benefit of up to 90%. Methods: Vantage 088 is a global, Phase III, randomized, double-blind study to investigate the safety and efficacy of vorinostat vs placebo in combination with bortezomib in patients with relapsed MM and progressive disease after 1–3 prior antimyeloma regimens. The primary objective is to determine the duration of progression-free survival, with a planned enrollment of 742 patients. Overall survival, time to progression, ORR, tolerability, and patient-reported outcomes (PROs) will be included as secondary and exploratory outcomes. A distinctive aspect of this study design involves the evaluation of PROs using validated instruments, including quality-of-life (QoL) questionnaires for cancer patients (EORTC QLQ-C30) and myeloma patients (EORTC QLQ-MY20) and the EuroQoL-5D, presenting an opportunity to correlate PROs with efficacy and safety data. Interim analysis will take place when at least 126 events have occurred. Vantage 095 is a Phase IIB open-label study to investigate the efficacy and tolerability of vorinostat combined with bortezomib in patients with RR MM who had received ≥2 prior antimyeloma regimens; were refractory to bortezomib; and were relapsed, refractory to, intolerant of, or ineligible for other MM therapies, including immunomodulatory drugs (IMiDs). The primary objective is to determine the ORR, with a planned enrollment of 142 patients. In both studies, patients receive 21-day cycles of intravenous bortezomib (1.3 mg/m2; days 1, 4, 8, and 11) combined with oral vorinostat 400 mg (or matching placebo in Vantage 088) once daily on days 1–14. Efficacy is assessed using European Bone and Marrow Transplantation Group criteria. Adverse events (AEs; including clinical and laboratory events) are assessed and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Results: Vantage 088: As of June 11, 2010, 349 patients (range, 1–17 cycles) were randomized. Patients received a median of 2 prior regimens (range, 1–3 regimens; 25% prior bortezomib, 48% prior thalidomide, and 12% prior lenalidomide). Vantage 095: As of June 11, 2010, 108 patients were enrolled. Patients (median age, 62 y; 57% men; 67% with Eastern Cooperative Oncology Group performance status 1) were heavily pretreated (median prior regimens, 5 [range, 2–17]). Interim efficacy data were reviewed in January 2010 by an independent data monitoring committee (DMC) for the first 43 patients enrolled; the futility threshold was passed, and final results are expected to be available 2Q2011. Conclusion: 2 ongoing global, multicenter, investigational trials are evaluating the efficacy and safety of combined vorinostat and bortezomib in patients with RR MM and are rapidly accruing patients. The Vantage 088 trial has passed the initial safety evaluations by the DMC, while interim results from Vantage 095 suggest that combined vorinostat and bortezomib may have clinical activity in patients with RR MM who are refractory to bortezomib and IMiDs and ineligible for other regimens. Disclosures: Siegel: Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board, Consultancy. Off Label Use: Vorinostat Combined with Bortezomib for treatment in Multiple Myeloma. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Ortho Biotech: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Hajek:Janssen-Cilag: Honoraria; Celgene: Honoraria; Merck, Sharp, and Dohme: Honoraria. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Graef:Merck Research Laboratories: Employment. Pietrangelo:Merck Research Laboratories: Employment. Lupinacci:Merck Research Laboratories: Employment. Reiser:Merck Research Laboratories: Employment. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in Pediatric Patients with Tagraxofusp, a CD123-Targeted Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2317-2317
Author(s):  
Naveen Pemmaraju ◽  
Branko Cuglievan ◽  
Joseph L Lasky ◽  
Albert Kheradpour ◽  
Nobuko Hijiya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Plasmacytoid Dendritic Cell ◽  
Case Series ◽  
Complete Response ◽  
Retrospective Case ◽  
Advisory Committees

Abstract BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematological malignancy that overexpresses CD123, the interleukin-3 (IL3) receptor alpha subunit. Although BPDCN predominantly affects older adults (median age of 65 years at diagnosis), cases of BPDCN have been reported across all age groups, including infants and children. There is limited data available in the literature on the efficacy and safety of treatments for pediatric patients with BPDCN. Tagraxofusp (TAG, SL-401) is a CD123-directed targeted therapy consisting of recombinant human IL3 linked to a truncated diphtheria toxin payload. A published multicohort prospective study, with prespecified multisystem endpoints, demonstrated the benefit of TAG in adult patients with untreated or relapsed BPDCN. Among the untreated patients, 72% had a complete response and 90% overall response rate; of these patients, 45% were bridged to stem cell transplantation. Adverse events included transaminase elevations, hypoalbuminemia, thrombocytopenia, and capillary leak syndrome (CLS). In a previous case report including 3 pediatric patients with BPDCN, TAG was well-tolerated without significant toxicities and showed encouraging initial clinical responses. TAG was FDA approved in 2018 for BPDCN treatment in adult and pediatric (≥2 years) patients and was recently approved in the EU as monotherapy for first-line treatment in adults. METHODS Here, we report on a multicenter, retrospective case series investigation involving pediatric patients diagnosed with BPDCN at 3 centers in the United States. All patients were treated with TAG according to local institutional guidelines as either first-line treatment (1L) or as a therapy for relapsed/refractory disease (R/R). Data was collected retrospectively via chart review and summarized descriptively. Assessments included tumor response to therapy, survival and safety (adverse events and laboratory abnormalities). RESULTS A total of 6 pediatric patients diagnosed with BPDCN and treated with TAG were included in this analysis. The median age for patients in this study was 15.5 years (range 10 - 21 years), and 4 of the 6 patients were female. Three patients were R/R and received systemic therapy prior to TAG administration, while 3 patients were treatment-naive. Four patients had bone marrow involvement, 2 patients had lymph node involvement, and all 6 patients had skin lesions at diagnosis. All patients received a TAG dose of 12 mcg/kg, with the exception of 1 patient who received 9 mcg/kg. At the time of data cut off, the number of cycles administered ranged from 1 to 4. TAG was well tolerated in these 6 patients. One patient experienced headaches, hot flashes, fatigue, and mouth sores, and low albumin was observed in one patient. No other adverse events were reported and CLS was not observed in these patients. One patient had a complete response to TAG therapy (bone marrow minimal residual disease negative), 2 patients had stable disease, and 3 patients did not have an observed response. In the three 1L patients, one patient had stable disease (no progression after 4 TAG cycles), and 1 patient with extensive disease (skin, bone marrow and central nervous system) had a complete response. Three patients bridged to a stem cell transplant (SCT); 2 were R/R and 1 was 1L. Median survival data for this cohort will be presented (5 of 6 patients remain alive). CONCLUSIONS This multicenter, retrospective case series of 6 pediatric patients with BPDCN expands our base of knowledge of BPDCN treatment in younger individuals. At the time of data cut off for this abstract, TAG, an approved treatment for BPDCN, was well tolerated in all patients. Treatment with TAG was associated with promising efficacy, including half of the patients with responses that allowed for bridging to SCT. Disclosures Pemmaraju: CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Springer Science + Business Media: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Clearview Healthcare Partners: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau.

scholarly journals Daratumumab As a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2088-2088
Author(s):  
Galina Tsykunova ◽  
Pal André Holme ◽  
Hoa Thi Tuyet Tran ◽  
Tor Henrik Anderson Tvedt ◽  
Ludvig Andre Munthe ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Phase Ii Study ◽  
Rescue Therapy ◽  
Observational Period ◽  
Advisory Committees ◽  
Autoimmune Cytopenias

Abstract Background: Immune thrombocytopenia (ITP) is characterized by antibody-mediated platelet destruction and impaired platelet production. Residual long-lived autoreactive plasma cells may be a source of treatment resistance in autoimmune cytopenias. Antiplatelet-specific plasma cells have been detected in the spleen of the rituximab refractory ITP patients. These cells can also migrate and reside in bone marrow as long-lived plasma cells. Daratumumab, an anti-CD38 antibody, targets plasma cells and is approved for the treatment of multiple myeloma. Daratumumab has been successfully used to treat refractory autoimmune cytopenias in children and a few cases of post-transplant autoimmune cytopenias and refractory SLE in adults. We hypothesized that long-lived autoreactive plasma cells may be the source of treatment failure in some ITP patients. Based on that, we initiated a multicenter, open-label, dose-escalating phase II study with a safety run-in to evaluate the safety and efficacy of daratumumab in patients with ITP (NCT04703621). The first 3 patients were included in the safety run-in during Jan - May 2021. Study design and methods: Main inclusion criteria include age ≥18, primary ITP with a platelet count of ≤30X109/L, failure of corticosteroid therapy, and at least one second-line therapy including rituximab and/or TPO-RA. Main exclusion criteria include active bleeding, secondary ITP, concomitant autoimmune hemolytic anemia. Twenty-one patients will be included in the study. The safety run-in phase includes 3 patients who receive 4 weekly subcutaneous daratumumab injections followed by a 4-week observational period. Enrollment of the next patient in this phase occurs after the previous patient has completed treatment and an observational period. In cohort 1, 9 patients will receive 8 weekly injections. If the response rate is &lt;100% and no severe adverse events appear, the subsequent 9 patients will receive 8 weekly daratumumab injections followed by 2 injections administered every other week. Standard premedication before all daratumumab injections consists of antihistamine, corticosteroid (methylprednisolone 100 mg or equivalent before the 1 st daratumumab injection and 60 mg or equivalent before subsequent injections), and paracetamol. Rescue ITP medications are allowed during the first 8 weeks of the study. Steroid or TPO-RA (eltrombopag or romiplostim) dosing must remain stable during the 2 weeks preceding the inclusion. Dose escalation is not allowed during the study. The primary endpoint is a platelet count &gt;50x10 9/L in 2 measurements 12 weeks after treatment initiation for cohort 1, and 16 weeks for cohort 2, without rescue therapy after week 8. Safety will be assessed by the incidence and severity of adverse events. Secondary endpoints will include the number of weeks with platelet count &gt;50x10 9/L between the end of treatment and end of study without rescue therapy or dose increments of corticosteroids. Time to treatment failure (TTF) is defined as time to first platelet count &lt;30x10 9/L or administration of any platelet elevating therapy after achieving response. Exploratory endpoints include: role of anti-GPIIb/IIIa and Ib antibodies; serial characterization of various subsets of immunocompetent cells in the bone marrow and blood; measurement of HRQoL and fatigue Statistics: The primary outcome (treatment response) will be reported separately for each cohort and the entire study population, expressed by absolute numbers and rates with the corresponding 95% confidence interval. Daratumumab treatment will be considered "successful" if we observe a response rate of 30% or higher. Current enrollment status: As of July 10, 2021, 2 sites are open. Two patients have completed the safety run-in; one is close. One/two responded to treatment at week 12. Platelet response in all 3 patients is shown in Figure 1. No serious or grade 3 adverse events were reported. Cohort 1 will start in August 2021. Figure 1 Figure 1. Disclosures Tsykunova: Ablynx: Consultancy; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sobi: Consultancy; Sanofi: Consultancy. Holme: bayer, Octapharma, Pfizer: Other: support to institution, Research Funding; Bayer, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda, Sobi: Consultancy, Honoraria. Tran: Astra Zeneca: Consultancy; Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy. Tvedt: Ablynx,Alexion, Novartis: Membership on an entity's Board of Directors or advisory committees. Michel: Amgen,Novartis,UCB,Argenx,Rigel: Honoraria. Frederiksen: Novartis: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Bussel: CSL: Other: DSMB; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuter: Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Up-to-Date: Patents & Royalties: Up-To-Date. Ghanima: Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Bayer, BMS/Pfizer: Research Funding; Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy.

scholarly journals Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1256-1256
Author(s):  
Jorge Labrador ◽  
Adolfo de la Fuente ◽  
David Martínez-Cuadrón ◽  
Rebeca Rodríguez-Veiga ◽  
Josefina Serrano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Advisory Committees ◽  
Baseline Characteristics

Abstract INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count &lt; 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes &lt; 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts &lt; 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count &lt;20 x10 9/L (95% CI: 1.150 - 3.422) and those with eGFR ≥ 45 mL/min/1.73m 2 (95% CI: 1.040 - 2.059) did benefit for treatment with AZA compared to DEC (Figure 1D). CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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