Use of Low Molecular Weight Heparin (LMWH) in Thrombocytopenic Patients with Hematologic Malignancy-Associated Venous Thromboembolism (VTE)

Abstract Introduction: The management of hematologic malignancy-associated VTEin patients with moderate to severe thrombocytopenia is unclear. Clinical trials of anticoagulants in VTE exclude such patients, hence do not inform the risk of bleeding or clot progression. Consensus-based guidelines recommend case-by-case consideration for either platelet transfusion to maintain platelet count >50,000/µL and therapeutic anticoagulation, or 50% dose reduction in LMWH (J Thromb Haemost. 2013 Jan;11(1):56-70.; Curr Oncol. 2015 Apr;22(2):144-55). At our institution, our approach is to use prophylactic dose LMWH for patients with platelet count ≤50,000/µL. Method: This is a single-center retrospective study of 128 adult patients with hematologic malignancies, who were diagnosed with VTE. Patients were identified from hospital research database. The diagnoses were verified after the review of medical records. The platelet count was assessed during the period of anticoagulation for VTE. The outcomes of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Bleeding and clot recurrence was assessed until the last follow-up (median of >1 month). Fisher's Exact test was used to test the association between two categorical variables, and Analysis of Variance (ANOVA) was used to test the association between a continuous variable and a categorical variable. Results: Characteristics of the study population were as follows: 51% male, 47% non-Hodgkin lymphoma, 20% acute leukemia/myelodysplastic syndrome, 40% status-post hematopoietic stem cell transplant, 9% with creatinine >2 mg/dl, 36% with pulmonary embolism and 28% with catheter-related VTE. Forty six patients (36%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 9000/µL( range 2000-45,000/µL) versus 166,000/µL (range 50,000-389,000/µL) in those without (p<0.001). The median duration of significant thrombocytopenia in the first group was 10 days (range 1-68 days). Therapy during the period of significant thrombocytopenia included prophylactic dosing of LMWH (46%), therapeutic dose of LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%) and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At last follow-up, the risk of bleeding (p=0.65) and clot progression (p=0.81) were similar in the two groups (Table 1). Conclusion: Within the limits of this retrospective study, cautious use of dose-adjusted LMWH in thrombocytopenic patients with hematologic malignancy-associated VTE may be safe. A prospective trial of prophylactic dose LMWH in patients with VTE during thrombocytopenia is required to confirm the safety and, to some extent, efficacy of such an approach. Table 1. Outcome of patients with VTE Outcome Thrombocytopenic cohort (Platelet count ≤50,000/µL) Patients without significant thrombocytopenia (Platelet count >50,000/µL) p-value Bleeding after VTE treatment 0.65 No 38 (82.6%) 75 (91.5%) Minor (without significant clinical implications) 1 (2.2%) 1 (1.2%) Clinically significant (causing drop in hemoglobin; requiring transfusion or other interventions) 4 (8.7%) 5 (6.1%) Missing 3 (6.5%) 1 (1.2%) Clot progression or recurrence at last follow-up 0.81 No 35 (76.1%) 67 (81.7%) Yes 9 (19.6%) 15 (18.3%) Missing 2 (4.3%) 0 Disclosures Vose: Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage:Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

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Rituximab Plus Three Cycles of Dexamethasone In the Treatment of Immune Thrombocytopenia (ITP): a Pilot Study.

Blood ◽

10.1182/blood.v116.21.3697.3697 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3697-3697

Author(s):

Rebecca Elstrom ◽

Soo Y. Lee ◽

James B. Bussel

Keyword(s):

Platelet Count ◽

Pilot Study ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Advisory Committees ◽

Equity Ownership ◽

Almost All

Abstract Abstract 3697 Introduction: Rituximab has been a useful treatment for patients with ITP; many hundreds of patients have been treated. 30–40% of patients will achieve a complete remission (CR: platelet count >150 × 109/l) with initial treatment and, of this group, the CR will last at least a year in almost all patients. However, emerging data suggests that at least 40% of these patients in CR will relapse between 1 and 3 years from initial treatment suggesting that long-term “cures” only occur in 20% of the initial patients. Therefore it would be desirable if CR's could be achieved in more patients and especially if these would be durable in more than 20%. One approach would be to use rituximab maintenance, however it results in suppression of B-cells for more than 2 years. Dexamethasone has also been used to achieve “cure” in ITP especially in adults at or near diagnosis. Cheng's study suggested that approximately 50% of patients would achieve a long-term response with only one 4-day cycle of high dose (40 mg/day) dexamethasone (N Engl J Med, 2003). A follow up study from GIMEMA suggested that 3–4 cycles of dexamethasone would be better than 1 cycle (Blood, 2007). Finally, Zaja's study suggested that rituximab plus one cycle of dexamethasone was superior to dexamethasone alone with a > 50% CR rate at 6 months (Blood, 2010). Therefore, we elected to perform a pilot study to explore the combination of rituximab with three cycles of dexamethasone at 14 day intervals. Methods: Patients with ITP with platelet counts < 30,000 off therapy and in need of treatment were enrolled. The standard dose (4 infusions of 375mg/m2) rituximab was given on days 1, 8, 15 and 22 and dexamethasone 40 mg (adjusted for size) on days 1–4, 15–18, and 29–32. Results: Fourteen patients between the ages of 4 and 53 years with ITP were treated with rituximab and dexamethasone (R&D) (Table 1). All had received previous steroid therapy as well as other treatments. The median platelet count was 40,000 at initiation of rituximab (range 7,000-230,000); several patients with low counts started with dexamethasone prior to initiating Rituximab to sustain their counts during initial treatment. Patients received rituximab weekly for between 2 and 4 doses and dexamethasone for either 2 or 3 courses at intervals between 1 and 8 weeks (median 2 week intervals). A summary of the results is shown in table 2 demonstrating short-lived platelet increases in response to dexamethasone in almost all patients. With short follow up, there were 7 CR's, 3 PR's and 4 NR's. If this was divided by duration of ITP prior to R&D, there were 4 CR's and 1 NR for ≤ 12 months and 3 CR, 3 PR, and 3 NR for > 12 months. More of the children who were treated had chronic disease than did adults explaining their apparently poorer response. Observed toxicities included hyperglycemia, grade 1 and 2 liver function abnormalities, weight gain, and 1 episode of colitis requiring hospitalization. Three patients opted to skip the third cycle of dexamethasone. Conclusion: A regimen of rituximab + 2–3 courses of dexamethasone is active in patients with pretreated ITP with appreciable but usually manageable toxicity. It appears to yield superior results if administered to patients within one year of diagnosis. This combination merits further exploration in a prospective clinical trial. Disclosures: Bussel: Portola: Consultancy; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc.: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Genzyme: Research Funding.

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Long Term Follow up of a Phase 2 Study of Ruxolitinib in Patients with Splanchnic Vein Thrombosis Associated with Myeloproliferative Neoplasm

Blood ◽

10.1182/blood.v126.23.2803.2803 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2803-2803 ◽

Cited By ~ 2

Author(s):

Lisa Pieri ◽

Chiara Paoli ◽

Umberto Arena ◽

Fabio Marra ◽

Fabio Mori ◽

...

Keyword(s):

Platelet Count ◽

Weight Gain ◽

Board Of Directors ◽

Phase Ii ◽

Esophageal Varices ◽

Research Funding ◽

Advisory Committees ◽

Splanchnic Vein Thrombosis ◽

Vein Thrombosis

Abstract Background: Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT). Ruxolitinib, a JAK1/2 inhibitor, efficiently reduced spleen volume and improved symptoms in patients (pts) with MF and PV in the COMFORT-I/II and RESPONSE phase III trials, and in ET pts in a phase II study. We reported (Blood 2014 124:3192) that ruxolitinib was safe in pts with MPN associated to SVT and effective in reducing spleen size at the planned primary endpoint analysis at 24 weeks (w) in a phase II clinical trial. Herein we present follow up data with cut off at 1 year after core period (a total of 72 w of treatment). Methods: Main enrolment criteria included diagnosis of PV, ET, PMF or PPV-/PET-MF associated with SVT, splenomegaly >5 cm below costal margin (bcm), active anticoagulant or antiaggregant thrombosis prophylaxis, platelet count (plt) >100 x109/L, neutrophils count >1x109/L, normal hepatic and renal function, absence of esophageal varices >grade 2. Pts who completed the 24 w of study treatment and tolerated well the drug and had evidence of clinically-significant improvement were allowed to enter an extension phase aimed at collecting and reviewing safety and efficacy data. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. Results: Diagnosis of MPN were: PMF 8 (38.1%), PV 5 (23.8%), ET 4 (19.1%), PPV-MF 3 (14.3%), PET-MF 1 (4.8%). Nineteen pts had spleno-porto-mesenteric thrombosis and 3 Budd-Chiari syndrome (BCS); one pt had both sites involved. Initial dose of ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with baseline (bl) platelet count of 100 to 200x109/L and 20 mg BID for platelet count >200x109/L. Currently 17/21 pts are on active treatment, 14 completed w72; final data for all 17 pts will be available at meeting. One pt with MF discontinued from the study being shifted to commercial ruxolitinib at w60, one ET and one MF pt discontinued for inefficacy at w24 and one MF pt for an unrelated adverse event after w72. Efficacy: 13/21 (61.9%) pts obtained a ≥50% spleen length (sl) reduction by palpation at w24, that was maintained at w72 in 8/14 pts (57.1%). Median sl reduction at w72 was 63% (range 0-100). No significant differences in resistive or pulsatility index of splanchnic artery were noted, nor in esophageal varices status evaluated at w72. 10/11 evaluated pts with echocardiography at w72 showed a median reduction of the cardiac output of 20.1% (range 2.3-42.2) mainly due to a reduction of heart rate and of cardiac index (-21.9%, range 8.8-44.3) due to increase in body surface area. The first effect could be attributed to decrease of proinflammatory cytokines, the second to weight gain associated with ruxolitinib. Symptomatology was evaluated by MPN-SAF up to w24, showing a median total symptom score reduction from 65 to 42. Safety: regardless of drug relationship, the most common adverse events (AE) (% any grade, % grade ≥3) were thrombocythopenia (57.1%; 14.3%) and anemia (33.3%, 19%) that were the main reasons for dose adjustments. Other AE included AST or ALT increase (42.9%, 0%), diarrhea (28.6%, 0%), abdominal pain (23.8%, 0%), ascites (19%, 0%), fever (23.8%, 0%), neutropenia, (9.5%, 9.5%), upper airways infection (19%, 0%), weight gain (14.3%, 4.8%), muscle cramps (14.3%, 0%). Three serious AE occurred: one case of hepatocarcinoma in a pts with BCS, one grade 2 pneumonia and one grade 2 haematemesis not related to esophageal varices. Median ruxolitinib total daily dose at w72, after dose adjustments, was 19.1 mg for MF, 16 mg for PV and 28.3 mg for ET. Median hemoglobin reduced from 12.9 gr/dL (range 9.4-16.7) at bl to 10.7 (8.4-14.4) at w16 and recovered at w72 (12.1, range 10.8-14.7). No pts received transfusions. Median platelet count was 212 x109/L (100-389) at bl, reached to the lowest level at w4 (139, range 48-252) and improved to 160 (69-285) at w72. Median leukocyte count decreased from 7.3 x109/L (1.8-16.4) at bl to 4.08 (1.2-21.7) at w 24, and remained substantially stable through w 72 (4.96; range 2.45-17.3). Median reduction of JAK2 allele burden at w72 was 9% (range 0-38). Conclusions: At w 72 follow up, ruxolitinib continues to be safe in pts with MPN associated to SVT and maintains efficacy against splenomegaly in 57% of the pts. Disclosures De Stefano: Roche: Research Funding; GlaxoSmithKline: Speakers Bureau; Bruno Farmaceutici: Research Funding; Novartis: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding; Celgene: Speakers Bureau; Shire: Speakers Bureau; Amgen: Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Safety and Efficacy of Venetoclax-Based Treatment in Elderly CLL Patients: A Retrospective Study from the Filo Group

Blood ◽

10.1182/blood-2021-149640 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3747-3747

Author(s):

Charlotte Doublet ◽

Marie-Sarah Dilhuydy ◽

Emmanuelle Ferrant ◽

Pierre Feugier ◽

Alexandra Fayault ◽

...

Keyword(s):

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Oncology Nurses ◽

Advisory Committees ◽

Free Survival ◽

Daily Dose ◽

History Of

Abstract Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

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Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽

10.1182/blood-2018-99-109763 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2428-2428 ◽

Cited By ~ 1

Author(s):

Michael D. Tarantino ◽

Jenny M. Despotovic ◽

John Roy ◽

John Grainger ◽

Nichola Cooper ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Platelet Response ◽

Open Label ◽

Advisory Committees ◽

Baseline Platelet Count ◽

Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

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A Retrospective Multicenter Case Study Evaluating the Characteristics, Management and Outcome of Acquired Amegakaryocytic Thrombocytopenia

Blood ◽

10.1182/blood-2021-153388 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3167-3167

Author(s):

Anais Roeser ◽

Guillaume Moulis ◽

Mikael Ebbo ◽

Louis Terriou ◽

Elsa Poullot ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Aplastic Anemia ◽

Board Of Directors ◽

Bone Marrow Biopsy ◽

Research Funding ◽

Advisory Committees ◽

Overall Response ◽

Acquired Amegakaryocytic Thrombocytopenia

Abstract Introduction Acquired amegakaryocytic thrombocytopenia (AAT) is an extremely rare disease characterized by acquired megakaryocytic aplasia or hypoplasia with no other lineage abnormalities. Given limited evidence, the first aim of this study was to describe the characteristics, management and outcome of patients with AAT, the second aim was to examine the therapeutic response through a systematic review of published case reports. Patients and Methods We carried out a retrospective multicenter study through the French Reference Network for Adult Autoimmune Cytopenias, including patients aged > 18 years with acquired thrombocytopenia with a platelet count < 50 x 10 9/L, associated with a megakaryocytes / granulocytes ratio < 50 % on bone marrow, diagnosed from July 2007 to February 2020. Exclusion criteria were: abnormal granular lineage, evidence of dysplasia, bone marrow infiltration by tumor cells or hematologic malignancy, significant karyotype abnormality, and significant paroxysmal nocturnal hemoglobinuria clone. Bone marrow biopsy were centrally reviewed. Patients' medical charts were collected using the standardized form of the referral center for adult immune thrombocytopenia (ITP). Response to treatment was defined according to standardized international criteria for ITP: response (R) and complete response (CR) were respectively defined as platelet count of > 30 × 10 9/L with at least a doubling of the baseline value, and platelet count of > 100 × 10 9/L ; overall response as either R or CR. We performed a systematic review conducted through Medline and Scopus databases from 1970 to April 2021. Cases were included in the analysis if initial platelet count was < 50 x 10 9/L and bone marrow examination was available, demonstrating a megakaryocyte hypoplasia or aplasia with no alternate diagnosis. Results We screened 23 patients reported as thrombocytopenia with absence or decreased megakaryocytes. Eleven patients were excluded because of: presence of megakaryocytes on bone marrow biopsy despite megakaryocytic aplasia on bone marrow aspirate (n=2), absence of bone marrow biopsy (n=4), aplastic or hypoplastic bone marrow (n=3), moderate thrombocytopenia > 50 x 10 9/L (n=1), lack of data (n=1). Twelve patients were included in the analysis. AAT patients had a median age of 52.5 years, 5/12 (41.7%) were female, 6/12 (50%) had a preexisting autoimmune disease (Table 1). All bone marrow biopsies reviewed to date contained CD8+ T-cell infiltrates. Eight patients received a first line treatment with corticosteroids and/or intravenous immunoglobulins (IVIg), a single response was observed. Ten patients received cyclosporine in monotherapy resulting in 4CR, and 1R or in combination with diverse agents with heterogenous responses. Six had received a single therapy with thrombopoietin receptor agonists (TPO-RAs) inducing 4 CR. Eventually, 9 patients (75%) achieved a CR under therapy, obtained with ciclosporin alone in 3 cases, ciclosporin in association with TPO-RA or ATG in 2 cases, cyclophosphamide followed-up by mycophenolate mofetil in 1 case, and TPO-RAs alone in 4 patients (of whom 3 had previously received at least on immunosuppressive therapy). After a median follow up time of 4.0 years (range 1.2 - 11.9), 2 (16%) patients eventually developed an aplastic anemia, 7 and 41.5 months respectively after initial AAT diagnosis. The literature search yielded 108 articles, of which 75 articles reporting 85 cases were included in the final analysis. The pooled analysis of newly reported and historic cases included 97 cases. Overall response rates to corticosteroids and IVIg were respectively 22.4 % and 5.3 % (Table 2). Ciclosporin was used as single agent in 37.1 % of patients, with an overall response rate of 66.7 %. TPO-RAs were used in 9 cases, with a CR in 7 patients (77.8%). Overall, 9/97 patients (9.3 %) experienced an aplastic anemia during the follow-up. The presence of a thymoma was associated with a higher risk of aplastic anemia (OR 6.83 (95%CI 1.22-34.00, p=0.020)). Conclusion Distinguishing AAT from ITP is of significance as the outcome and response to therapy strongly differ. Aplastic anemia may occur in the follow-up but remain rare. Corticosteroids and IVIg are inefficient in most cases, ciclosporin appear to be very effective, TPO-RA could also be an option, as single therapy or in associations. Further data will be needed to define the respective place of these treatments. Figure 1 Figure 1. Disclosures Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenix: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Amgen: Honoraria; Sobi: Other: Attendance Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haioun: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Michel: Amgen,Novartis,UCB,Argenx,Rigel: Honoraria. Godeau: Amgen: Consultancy; Novartis: Consultancy; Grifols: Consultancy; Sobi: Consultancy. Mahevas: GSK: Research Funding; Amgen: Honoraria.

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Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood.v130.suppl_1.lba-1.lba-1 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 1

Author(s):

Marie Scully ◽

Spero R Cataland ◽

Flora Peyvandi ◽

Paul Coppo ◽

Paul Knöbl ◽

...

Keyword(s):

Platelet Count ◽

Drug Treatment ◽

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Thromboembolic Event ◽

Study Drug ◽

Adamts13 Activity ◽

Advisory Committees

Abstract Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets. Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine. Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were >50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 - 2.20, p <0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p <0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p <0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still <10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug. Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity <10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. (clinicaltrials.gov: NCT02553317) Disclosures Scully: Ablynx: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Novartis: Honoraria; Alexion: Honoraria. Cataland:Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau;Freeline, Kedrion, LFB, Octapharma: Consultancy. Coppo:Ablynx: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Kremer Hovinga:Baxalta/Shire: Other: unrestricted grant hereditary TTP registry; Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Metjian:Ablynx NV, Shire, Omeros: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Other: Honoraria; Celgene: Other: Honoraria; Janssen: Other: Honoraria. Pavenski:Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding. Callewaert:Ablynx NV: Employment. Biswas:Ablynx NV: Employment. De Winter:Ablynx NV: Employment. Zeldin:Ablynx NV: Employment.

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COVID-19 in Patients with Lymphoma: A Grupo De Estudio Latinoamericano En Linfoproliferativos (GELL) Retrospective Study

Blood ◽

10.1182/blood-2020-142787 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Guilherme Fleury Perini ◽

Juan Alejandro Ospina Idarraga ◽

Maria Alejandra Torres Viera ◽

Brady E Beltran ◽

Denisse A. Castro ◽

...

Keyword(s):

Latin America ◽

Monoclonal Antibodies ◽

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Current Treatment ◽

Advisory Committees ◽

Active Disease

Introduction: SARS-COV-2 pandemic has infected approximately 20 million people worldwide and more than 700.000 fatalities have been reported. Patients with malignant hematological diseases are at particular risk for unfavorable outcomes, including intensive care unit (ICU) admission, need for mechanical ventilation (MV) and death. There is paucity of data of the outcome of cancer patients with COVID-19 in low- and middle-income countries. GELL is a collaborative network of hematological centers in 13 countries in Latin America. In this retrospective study, we aimed to look at the outcome of lymphoma patients diagnosed with COVID-19 in Latin America. Methods: This is a retrospective study including patients with a diagnosis of lymphoma and COVID-19 infection. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were excluded from the analysis. COVID-19 diagnosis was done by RT-PCR in all but 3 patients, in whom the diagnosis was done by serology. Active disease was defined as patients with detected disease in any setting (prior to therapy, relapse) or patients currently on treatment. Survival curves were plotted using Kaplan Meier method. Results: A total of 117 patients were available for analysis. Median age was 60 years old, and 44% of patients had at least one comorbidity, including 32% with hypertension, 17% with obesity, 11% with cardiovascular disease and 17% with diabetes. Most patients had aggressive lymphomas (67%), including 46% of patients with diffuse large B-Cell lymphoma (DLBCL). Follicular lymphomas was observed in 13% of patients and Hodgkin's lymphoma in 10% of patients. 84% of patients had active disease, and 70% of patients were currently on treatment. With a median follow up of 17 days from COVID-19 diagnosis, 78% were admitted to Hospital, 30% needed ICU support, and 27% needed MV. Importantly, 26% of patients died, most of them within 20 days from diagnosis (Fig. 1). There was no relation between active disease (p=0.23), current treatment (p=0.65) or use of monoclonal antibodies (p=0.24) with death. COVID-19 treatment data was available in 107 patients, and 72 of them received any treatment, being steroids, the most common treatment used (n=59). Conclusion: We confirm the dismal prognosis of patients with hematological malignancies and COVID-19 infection. In our cohort of Latin America patients with lymphoma and COVID-19, 26% of patients died with a median follow up of 17 days. No impact of current treatment or use of monoclonal antibodies were observed. Figure Disclosures Peña: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; BindingSite: Research Funding. Idrobo:Amgen: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Abello:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; Dr. Reddy's: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Rojas:Novartis: Consultancy; Abbvie: Honoraria; Sandoz: Honoraria; Roche: Honoraria. Castillo:Beigene: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kymera: Consultancy; Janssen: Consultancy, Research Funding. Villela:amgen: Speakers Bureau; Roche: Other: advisory board, Speakers Bureau.

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Outcomes in Multiple Myeloma Patients Progressing on Lenalidomide Maintenance

Blood ◽

10.1182/blood-2019-128441 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1779-1779

Author(s):

Larysa Sanchez ◽

Erin Moshier ◽

Alexander Coltoff ◽

Ali Mustafa ◽

Darren Pan ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Total Change ◽

Advisory Committees ◽

Line Of Therapy

Introduction: Lenalidomide (R) maintenance therapy in multiple myeloma (MM) has been shown to improve progression-free survival (PFS) and overall survival (OS) after autologous stem-cell transplantation (ASCT). Even in the transplant ineligible population, R until progression is associated with improved PFS. The ever-increasing use of R maintenance therapy, however, eventually leads to refractoriness to R at maintenance doses. Moreover, clinical trials with len-dex (Rd) backbone regimens including daratumumab, elotuzumab, ixazomib, and carfilzomib have all excluded such patients (pts). This is particularly an issue for elotuzumab and ixazomib, which have no single agent approval. There are currently no published data on the outcomes of full dose Rd or Rd backbone containing regimens in pts refractory to R maintenance. A prospective randomized trial would be difficult to perform given variability in pt factors (i.e. R tolerance, age, renal function) and disease factors (i.e. molecular risk and clinical vs biochemical progression). We therefore performed a retrospective study to characterize outcomes of pts on R maintenance therapy. Methods: This is a single-institution, retrospective study in which we reviewed the records of all consecutive pts with a diagnosis of MM at the Mount Sinai Hospital between February 2010 and October 2016. There were 465 pts identified who had maintenance R as a single agent or in combination with low-dose dexamethasone or prednisone. Pts were excluded if insufficient data were available or < 3 month (mo) follow up from time of initiation of R maintenance. Time to progression (TTP) on R maintenance, next line of therapy, and PFS on next line of therapy were determined using Kaplan Meyer analysis. Results: A total of 350 pts were included in this study. Baseline characteristics are summarized in Table 1. The median follow up time was 59 mos and median time on R maintenance was 21.0 mos. 172 pts (49%) progressed while on R maintenance or within 60 days of R discontinuation. 51 pts (15%) remain on R maintenance as of last follow up. The remaining 127 pts (36%) discontinued R for reasons other than progression and either progressed after 60 days (median 658 days, range 91-2053 days) or have not progressed. The median TTP on R maintenance was 34.2 mos (Fig 1A) and the majority of these were characterized by the treating physician as biochemical (65% during maintenance and 56% after R discontinuation). Of the patients with serologic and symptomatic progression, the majority were by bone disease (24% and 37%, respectively). 234 pts had data available on next line of therapy and the median PFS on this next line was 16.8 mo (95% CI: 13.2-20.1), however the PFS was shorter for those who had progressed while on R maintenance versus those who had progressed after R maintenance had been discontinued (13.2 mos vs. 28.9 mos, respectively, p 0.0001). The median PFS according to next line of therapy for those who received an increase in R dose + dex vs 3rd agent added to Rd backbone vs total change in therapy was 9.5 mos vs 21.0 mos vs 14.2 mos, respectively (Fig 1B). The most common drugs added to an Rd backbone were bortezomib and elotuzumab with an associated PFS of 19.0 and 40.1 mos, respectively. The majority of those receiving elotuzumab + Rd had progressed on R maintenance (15/18 = 83%). The most common regimens for those with a total change in therapy are summarized in Table 2. Conclusions: The median TTP on R maintenance was 34.2 mos and while most progression was felt to be biochemical, of those with symptomatic progression as well, the primary manifestation was bone disease (approximately 30% of patients), highlighting the importance of surveillance osseous imaging in MM. While an increase in R dose with steroids was associated with an additional 9.5 mos PFS and a total change in regimen with 14.2 mos PFS, those who received an Rd containing triplet had impressive results. In particular, Rd + elotuzumab resulted in a PFS of 40.1 mos. Multivariate analysis accounting for the potential confounding patient and disease factors inherent to treatment selection in retrospective studies will be presented at the meeting. Disclosures Cho: BMS: Consultancy; GSK: Consultancy; Takeda: Research Funding; The Multiple Myeloma Research Foundation: Employment; Genentech: Honoraria, Research Funding; Agenus: Research Funding; Celgene: Honoraria, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy. Madduri:Abbvie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; undation Medicine: Consultancy. Parekh:Celgene Corporation: Research Funding; Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy. Richter:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, 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, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Chari:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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An Ongoing, Observational Cohort Study in Multiple Myeloma (PREAMBLE): Preliminary Efficacy Analyses in Patients with 1 Line of Prior Therapy

Blood ◽

10.1182/blood.v128.22.2403.2403 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2403-2403

Author(s):

Brian Durie ◽

David J Kuter ◽

Catherine Davis ◽

Teresa Zyczynski ◽

Hartmut Goldschmidt ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Outcomes ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hematologic Malignancy ◽

Research Assessment ◽

Advisory Committees ◽

Prior Therapy

Abstract Introduction: Multiple myeloma (MM) is an incurable hematologic malignancy associated with high disease burden and relapse rates. In recent years, several treatment options for MM have become available that have improved patient outcomes. However, robust data on real-world treatment outcomes associated with these MM treatments are sparse. PREAMBLE (Prospective REsearch Assessment in Multiple myeloma: an oBservationaL Evaluation; NCT01838512) is an ongoing multinational observational study that aims to increase understanding of real-world clinical effectiveness of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and combination therapy for relapsed/refractory MM (RRMM). Here, we present preliminary efficacy analyses on data from patients with 1 line of prior MM therapy both with and without prior transplantation experience. Methods: Eligible patients had a confirmed diagnosis of RRMM with 1 prior treatment and started treatment with an IMiD, PI, or IMiD+PI 90 days prior/30 days following study enrollment. Patient data were collected at each healthcare provider visit for a follow-up period of 3 years. Vital status was recorded every 6 months for all patients. Response rates (defined as minimal response or better) were assessed using cumulative incidence function, with progression as competing risk. Time in response, progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Results: Of 855 treated patients, 367 (43%) had 1 prior line of therapy (median age 70 years, 56% male). In this group, 71 (19%) had refractory disease, with even distribution among International Staging System stages I, II, and III. Index therapy was IMiD (n=193, 53%), PI (n=148, 40%), or IMiD+PI (n=26, 7%). At data cut-off (April 2016), median (Q1-Q3) follow-up was 16.7 (9-27) months, and 225 (61%) patients were still on study; the most common reasons for discontinuation were death or entering into a randomized clinical trial. Discontinuation was attributed to death for 92 (25%) patients; 69 (75%) of these deaths were due to disease progression. Approximately one-third of patients (128/367; 35%) had prior transplantation experience: 5% of patients had 2 prior transplantations, 99% of transplantations were autologous, and 83% were received after frontline (first) therapy. In patients without transplantation experience (n=238), the response rate (95% CI) was 46% (39-53) at 6 months, 58% (50-65) at 12 months, and 60% (53-67) at 18 months, versus 43% (34-53), 60% (50-70), and 60% (50-70), respectively, in those with prior transplantation. Median time in response was 14.6 months in patients without prior transplantation versus 20.3 months in those with prior transplantation. In patients with and without prior transplantation, time in response was longer in patients who had received an IMiD as index therapy (Table). Median PFS was 11.5 months in patients without transplantation and 14.1 months in those with transplantation; PFS rates (with/without prior transplantation) was: 6 months, 71%/67%; 12 months, 56%/49%; 18 months, 41%/32%. OS rate at 12 months was 81% in patients without prior transplantation and 82% in those with prior transplantation. In patients (≥6 months on study) who responded within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 93%/91%; 18 months, 85%/78%. In patients (≥6 months on study) who progressed within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 84%/69%; 18 months, 56%/64%. Conclusions: In patients with MM and 1 line of prior therapy either with or without prior transplantation experience, approximately 45% achieved a response, with approximately 40% of these patients maintaining their response at 18 months. Regardless of index therapy type or prior transplantation experience, loss of response was observed over time, highlighting the continuing unmet medical need in RRMM. Collectively, these data exemplify the importance of novel therapies that have potential to provide durable responses and improve treatment outcomes for patients with RRMM. Further analyses exploring any impact of prior transplantation and type of frontline therapy on treatment outcomes with subsequent lines of therapy are ongoing, and will be included in the final presentation. Study support: Bristol-Myers Squibb (BMS). Medical writing assistance was provided by K Rees, of Caudex, funded by BMS. Disclosures Durie: Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Kuter:Amgen: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Shionogi: Consultancy; Shire: Consultancy; 3SBios: Consultancy; Bristol-Myers Squibb: Research Funding; Protalix: Research Funding; Rigel: Research Funding. Davis:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Goldschmidt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Vij:Amgen: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Karyopharm: Honoraria. Popov:Bristol-Myers Squibb: Consultancy. Cella:Abbvie, Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bayer Pharmaceuticals, Inc.: Consultancy, Research Funding; Alexion, Inc., Astellas, Biogen Idec, Celgene, Clovis Oncology, Inc., Daiichi Sankyo, Eli Lilly, Evidera, Inc., Exelixis, Fiborgen, Genetech, Helsinn Therapeutics, Inc., Immunogen, Ipsen Pharma, Janssen, Lexicon Pharmaceuticals, Inc., Merck, Novartis, Onc: Consultancy, Research Funding; Facit.org: Other: President; Bristol-Meyers Squibb: Consultancy, Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Comparison of Splenectomy and Treatment Failure Incidence in Nonsplenectomized Patients with Immune Thrombocytopenia (ITP) Receiving Romiplostim or Medical Standard of Care: 1-Year Treatment and 6-Month Safety Follow-up.

Blood ◽

10.1182/blood.v114.22.679.679 ◽

2009 ◽

Vol 114 (22) ◽

pp. 679-679 ◽

Cited By ~ 2

Author(s):

David J Kuter ◽

Mathias J Rummel ◽

Ralph Vincent Boccia ◽

B. Gail Macik ◽

Ingrid Pabinger ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Actual Incidence

Abstract Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count <50 × 109/L. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. Patients received romiplostim or SOC for 52 weeks, and those who did not subsequently transfer to another romiplostim study completed a 6-month off-treatment safety follow-up. Co-primary endpoints of the study were: the incidence of splenectomy and the incidence of treatment failure (defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms). Patients who discontinued study during the treatment period were counted as having had splenectomy or treatment failure. To assess the impact of treatment discontinuation on the primary endpoints, a sensitivity analysis was conducted to determine the actual incidence of splenectomy or treatment failure. A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p<0.0001), and the incidence of treatment failure was 12% (18/157) in the romiplostim group compared to 30% (23/77) in the SOC group (OR, 0.31; 0.15, 0.61; p=0.0005). Sensitivity analyses confirmed the primary endpoint analyses: the actual incidence of splenectomy was significantly lower in the romiplostim group (2/157, 1%) than the SOC group (15/77, 20%) [p<0.0001], and the actual incidence of treatment failure was significantly lower in the romiplostim group (6/157, 4%) than the SOC group (10/77, 13%) [p=0.009]. The incidence of bleeding events with a worst grade score ≥3 appeared lower for patients in the romiplostim group (3%) than the SOC group (7%). Safety analyses included only patients who received ≥1 dose of romiplostim or 1 type of SOC. During the 52-week treatment period, adverse events occurred in 96% (147/154) of patients receiving romiplostim and 92% (69/75) of patients receiving SOC. Serious adverse events occurred in 23% (35/154) of romiplostim and 37% (28/75) of SOC patients; serious adverse events were considered treatment-related in 5% (7/154) of romiplostim and 8% (6/75) of SOC patients. During the 6-month safety follow-up period, 36% (11/31) of romiplostim and 43% (18/42) of SOC patients experienced an adverse event; treatment-related adverse events occurred in none of the romiplostim patients and 2 of the SOC patients. Overall, 6 patients died: 1 (1%) in the romiplostim group and 5 (7%) in the SOC group. None of the deaths were considered related to study treatment or the underlying ITP. No patients tested positive for neutralizing antibodies to romiplostim or TPO. One romiplostim-treated patient showed an increase in bone marrow reticulin that was still within the normal range (Grade 2). In summary, romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to SOC. The safety profile of romiplostim was similar to SOC. Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

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