Phase 1/2 Study of AMG 531 in Thrombocytopenic Patients (pts) with Low-Risk Myelodysplastic Syndrome (MDS): Update Including Extended Treatment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 250-250 ◽  
Author(s):  
Hagop Kantarjian ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
Pamela Becker ◽  
Adam Boruchov ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase 1 ◽  
Blast Cell ◽  
Low Risk ◽  
Extension Phase ◽  
Severe Thrombocytopenia ◽  
Platelet Response ◽  
Baseline Platelet Count ◽  
Cell Counts ◽  
The Mean

Abstract Background: AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. This report updates outcomes in Part A of the study as of May 2007 on pts who continued into the extension phase of this ongoing phase 1/2, open-label, sequential-cohort, dose-escalation study to evaluate the safety and efficacy of AMG 531 in low risk MDS pts with severe thrombocytopenia (Kantarjian et al., ASCO, 2007). Methods: Pts with low- risk MDS (IPSS Low or Intermediate-1, excluding CMML), a mean baseline platelet count ≤50×109/L, and only receiving supportive care were eligible to enter this study. Pts were enrolled into sequential cohorts of 300, 700, 1000, and 1500μg, receiving 3 weekly subcutaneous injections of AMG 531. After evaluation of platelet response at week 4, pts could continue AMG 531 in an optional treatment extension at their assigned dose or dose adjust to achieve or maintain a response. Results: The mean duration of exposure to AMG 531 was 23±15.5 (SD) weeks. Of 44 pts enrolled, 40 continued into the extension phase; 16 pts remain on treatment. Eighteen pts (41%) achieved a durable platelet response (per IWG 2006 criteria for at least 8 consecutive weeks). Evaluation of durable responses based on baseline platelet count showed that responses occurred in 12/29 (41%) pts with a baseline count of ≥20×109/L, and in 6/15 (40%) pts with a baseline count of <20×109/L. The mean duration of the platelet response was 22.8±13.3 (SD) weeks. A total of 104 platelet transfusions were given to 17/44 (39%) pts during this study; of these transfusions, 7 were given in 3/18 (17%) pts who achieved a durable response. Treatment-related AEs were reported in 17 pts. There were 3 deaths unrelated to treatment. Two confirmed cases of transformation to AML were reported. These two pts received maximum doses of 300 and 1000μg. Six pts were confirmed to have temporary blast cell increases, three of whom had increases above 20%. Of the 6, 4 were receiving 1500μg and 2 were receiving 1000μg. In all 6 pts, blast cell counts were observed to have fallen upon follow-up assessments within 7 weeks after treatment discontinuation. In one case, treatment was reinitiated at 700μg. Conclusions: In this study, AMG 531 appeared to be well-tolerated in severely thrombocytopenic low-risk MDS pts, and resulted in increased and sustained platelet counts in the responding pts. AMG 531 may have a role in the treatment of low-risk MDS pts who are thrombocytopenic or have a history of bleeding. These data suggest that further exploration is merited in this pt population. Pt recruitment is ongoing until reaching the planned 84 pts.

Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7032-7032 ◽  
Author(s):  
H. M. Kantarjian ◽  
F. J. Giles ◽  
P. Fenaux ◽  
P. S. Becker ◽  
A. M. Boruchov ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase 1 ◽  
Low Risk ◽  
Platelet Response ◽  
Durable Response ◽  
Safety And Efficacy ◽  
Treatment Dose ◽  
Clinically Significant ◽  
Grade 3 ◽  
To Receive

7032 Background: The prevalence of thrombocytopenia in MDS ranges from 40% to 65%, hemorrhagic complications range from 3% to 53%, and hemorrhagic deaths range from 14% to 24% (Kantarjian 2006). Platelet transfusion can lead to reactions, infection, and alloimmunization. AMG 531 is a thrombopoiesis-stimulating peptibody that increases platelet production. This phase 1/2 study evaluated the safety and efficacy of AMG 531 in thrombocytopenic MDS patients. Methods: A minimum of 5 subjects with low risk MDS (IPSS low or intermediate-1) and a platelet count of = 50×109/L were enrolled to receive 3 QW SC injections of AMG 531 in each of 4 sequential dose cohorts. After evaluation at week 4, subjects could continue AMG 531 in an optional treatment extension at their assigned dose or escalated to a responding dose. Erythroid growth factors were allowed, but no other active treatment. Results: 28 subjects (9 transfusion-dependent) have been enrolled to date. All subjects were evaluable for response and entered the extension; 17 continue treatment. Dose-limiting toxicity (DLT) was defined as a drug-related grade 3 or 4 adverse event (AE) or a platelet count ≥ 600×109/L. Two DLTs occurred, both due to elevated platelet counts. No treatment-related severe AEs occurred. There was 1 treatment-unrelated death. Overall, 17 subjects (61%) achieved a platelet response. Median baseline platelet count for responders was 25×109/L with a median peak platelet count of 130×109/L during the 4 week treatment period. Of the 18 subjects to date completing at least 12 weeks of treatment, 11 (48%) achieved a durable response of at least 8 consecutive weeks (revised IWG criteria, Cheson 2006). A total of 90 clinically significant thrombocytopenic events (39 bleeding, 51 transfusions) were observed over both treatment phases. There were 16 such events (12 bleeding, 4 transfusions) in 6 subjects with a durable response, 6 events (6 minor bleeds, 0 transfusions) during the durable response period. There were 74 events (27 bleeding, 47 transfusions) in 11 subjects without a durable response. Conclusions: These preliminary data suggest that bleeding and transfusion events can be reduced in thrombocytopenic low risk MDS patients who respond to AMG 531. [Table: see text]

Long-Term Dosing of AMG 531 Is Effective and Well Tolerated in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 220-220 ◽  
Author(s):  
James B. Bussel ◽  
David J. Kuter ◽  
James N. George ◽  
Louis M. Aledort ◽  
Alan E. Lichtin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Platelet Response ◽  
Open Label ◽  
Baseline Platelet Count ◽  
First Response ◽  
The Mean

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the TPO receptor, resulting in increased production of platelets. This ongoing, open-label study assessed the safety and efficacy of long-term AMG 531 dosing in ITP patients. Eligible patients have completed a previous AMG 531 study in ITP, are ≥18 years of age, have a baseline platelet count ≤50 x 109/L, with no recent significant change in medical history. The AMG 531 starting dose is 1μg/kg by SC injection with dose adjustment to an original maximum of 30μg/kg, since reduced to 15μg/kg. Patients are treated weekly unless the platelet count is >400x109/L. Concurrent corticosteroids can be tapered when the platelet count is ≥50x109/L. Preliminary data are available for 26 patients treated for up to 24 weeks: 17 women and 9 men; mean age, 48.4±11.6 (SD) years; mean baseline platelet count, 18.5±12.3 (SD) x109/L. Twenty-one patients (80.8%) had undergone a splenectomy before study entry; 6 (23.1%) were receiving concurrent corticosteroids for ITP. Twenty-one of 26 patients (80.8%) had a protocol-defined platelet response to AMG 531 (doubling of the baseline platelet count and ≥50x109/L). The mean AMG 531 dose at the first response was 3.7±2.7 (SD) μg/kg (at median 5 weeks); the mean dose at week 24 was 7.2±4.2 (SD) μg/kg. Twelve of 26 patients (46.2%) had a durable platelet response (doubling of the baseline count and ≥50x109/L at 6 or more of weeks 17–24). Twenty patients (76.9%) had a platelet count ≥100x109/L at least once; 7 (26.9%) had a platelet count ≥400x109/L. Of 6 patients on concurrent corticosteroids, 3 discontinued treatment and 2 had a ≥25% dose reduction. At least 1 serious adverse event was reported in 4 patients: anal fistula (unrelated to treatment), adverse drug reaction (unrelated), multiple sclerosis relapse (unrelated), bone pain (related), and diffuse reticulin formation in the bone marrow reported as myelofibrosis (related). Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a bone marrow 3 months later showed improvement. One patient experienced adverse events (musculoskeletal pain and headache) resulting in withdrawal from the study. No neutralizing antibodies have been detected to date. In summary, repeated exposure to AMG 531 has been generally well tolerated in this ongoing study. A total 80.8% of patients achieved a platelet response, defined as doubling of the baseline count and ≥50x109/L. Individualized weekly doses of AMG 531 may provide a therapeutic option in ITP, potentially enabling patients to taper off long-term corticosteroid therapy.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 476-476 ◽  
Author(s):  
David Kuter ◽  
James Bussel ◽  
James George ◽  
Louis Aledort ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Sinus Thrombosis ◽  
Therapeutic Option ◽  
Subcutaneous Administration ◽  
Transverse Sinus ◽  
Platelet Response ◽  
Open Label ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1308-1308
Author(s):  
Yukari Shirasugi ◽  
Kiyoshi Ando ◽  
Satoshi Hashino ◽  
Toshiro Nagasawa ◽  
Yoshiyuki Kurata ◽  
...  
Keyword(s):  
Platelet Count ◽  
Dose Escalation ◽  
Japanese Patients ◽  
Phase 2 ◽  
Platelet Response ◽  
Phase 3 ◽  
Continuation Phase ◽  
Platelet Counts ◽  
Starting Dose ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response

Platelet Doubling After the First Azacitidine Cycle Is a Promising Predictor for Response in MDS, CMML and AML Patients in the Dutch Azacitidine Compassionate Patient Named Program,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3841-3841
Author(s):  
Geert A Huls ◽  
Lieke H. van der Helm ◽  
Canan Alhan ◽  
P.W. Wijermans ◽  
Marinus van Marwijk Kooy ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Fold Increase ◽  
Risk Groups ◽  
Low Risk ◽  
Logrank Test ◽  
Baseline Platelet Count ◽  
Routine Administration ◽  
Ortho Biotech ◽  
Chronic Myelomonocytic Leukaemia

Abstract Abstract 3841 The efficacy of azacitidine in the treatment of high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20–30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analyzed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate patient named program. Patients received azacitidine for a median of 5 cycles (range 1–19). The overall response rate (CR/PR/HI) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13.0 (9.8–16.2) months. In multivariate analysis we confirmed that circulating blasts (HR 0.48, 95% CI 0.24–0.99; p=.05) and poor risk cytogenetics (HR 0.45, 95% CI 0.22–0.91; p=.03) are independent predictors for OS. Interestingly, in this analysis we also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5.4, 95% CI 0.73–39.9; p=.10). Of the 90 treated patients, 14 (16%) had an at least two-fold increase in platelet count after the first cycle of azacitidine, which was associated with significant better OS (p=.01, according to logrank test) (figure). Of these 14 patients 13 could be classified according the azacitidine prognostic scoring system for OS as recently proposed by Itzykson et al. (Blood:2011;117:403); 6 patients belonged to the low risk and 7 to the intermediate risk group. Median baseline platelet count of these patients was 35 x109/L (range 2–290 x109/L). Characteristics of this subgroup of patients were not significantly different from the patients without platelet doubling. Interestingly, platelet doubling was observed in all cytogenetic risk groups, in patients with and without circulating blasts, and in patients who are transfusion dependent and independent. In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible and subgroups with distinct efficacy of azacitidine treatment can be identified. Disclosures: Wijermans: Centocor Ortho Biotech Research & Development: Research Funding.

scholarly journals Inherited Giant Platelet Disorder, Kashmiri Thrombocytopenia, a Common Syndrome Found in Srinagar, India

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4211-4211 ◽  
Author(s):  
Felipe R Lorenzo ◽  
Tsewang Tashi ◽  
Parvaiz Koul ◽  
Nicola J Camp ◽  
Perumal Thiagarajan ◽  
...  
Keyword(s):  
Platelet Count ◽  
Inclusion Bodies ◽  
Blood Donors ◽  
Autosomal Dominant ◽  
Sensorineural Deafness ◽  
Severe Thrombocytopenia ◽  
Red Cell ◽  
Kashmir Valley ◽  
Giant Platelet ◽  
The Mean

Abstract The causative genetic mutations of inherited giant platelet disorders (IGPD) encompass genes coding for the platelet glycoprotein Ib-IX complex (Bernard Soulier syndrome and its variants), myosin heavy chain 9 (MYH9 gene mutated in May-Hegglin anomaly and other IGPDs), GATA-01 (GATA-related thrombocytopenia), TUBB-1, ITGA2, ITGAB3, FLNA and some others. IGPDs are frequently associated with other disorders including renal disease, sensorineural deafness, and leukocyte inclusion bodies. Most are accompanied with variable degrees of bleeding diathesis, while others, like TUBB1 IGPD, do not have any bleeding manifestations. Harris platelet syndrome (HPS), previously called asymptomatic constitutional macrothrombocytopenia, is an autosomal dominant disorder characterized by low-normal to severe thrombocytopenia IGPD and absence of bleeding. HPS has also been observed in healthy blood donors from the northeastern part of India (Bengal) and some areas of Bangladesh, Bhutan and Nepal. We describe a high prevalence of an autosomal dominantly inherited form of IGPD with mild to severe thrombocytopenia in the Muslim population in Kashmir Valley in the northern Indian subcontinent. 830 voluntary, healthy, male blood donors from Kashmir Valley were included in the study. They were aged 15-55 years (median 31 years) and underwent ancillary screening as follows; CBC, peripheral smear, HBV, HCV, HIV, ANA and Anti-H pylori antibodies. 15% of the donors had thrombocytopenia (mean platelet count 109.6 compared to 189.9 in controls; p=<0.0001). No differences were noted in age between the 2 groups. The mean platelet volume (MPV) in thrombocytopenic subjects was higher (12.53 + 0.78 vs 9.52 + 1.03 fl). The red cell distribution width (RDW) in thrombocytopenic subjects was higher than in those with normal counts (15.6 + 1.61 Vs 13. 22 + 1.36, p=<0.001). Hematocrit and other red cell indices were not different in the 2 groups. None of the participants had a history of bleeding, renal disease, sensorineural deafness, or leukocyte inclusion bodies. Peripheral blood platelet morphology revealed large platelets in all subjects. In a pilot study of 7 families, Kashmiri thrombocytopenia was compatible with autosomal dominant inheritance affecting both genders. The congenital nature of Kashmiri thrombocytopenia was demonstrated by analyses of 34 consecutive neonates born in Sher-i-Kashmir Institute Hospital; among 20 girls and 19 boys, we found 18% (2 male and 5 female) to have low platelet count, the mean platelet count of the affected group when compared to unaffected group were 102.6 vs 234 (p=<0.001) respectively. We then searched for a causative mutation using the following approaches. We sequenced the MYH9 gene and no mutation was found. We then employed SNP array analyses using Shared Genome Segment (SGS) and Whole Genome Association Study (WGAS). We were able to exclude all previously reported IGPD-causing genes. SGS that overlapped with WGAS narrowed the target into 3 chromosome regions in Chr. 5 (rs6872531-rs100072476), Chr. 9 (rs11999541-rs12682912) and Chr. 10 (rs11013452-rs7083349). The performed SNP analyses included large genomic segments as candidates for a Kashmiri thrombocytopenia-causative gene. To further narrow down the cause of this disorder, we recruited 3 TRIO families (an affected parent and a child) for stronger linkage analysis and next-generation sequencing to continue the search for the cause of the Kashmiri thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2428-2428 ◽  
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.

Possible Severe Thrombocytopenia Associated with a Single Dose of Plicamycin

1992 ◽  
Vol 26 (11) ◽  
pp. 1369-1373 ◽  
Author(s):  
Weeranuj Yamreudeewong ◽  
Neil E. Henann ◽  
Anthony Fazio ◽  
Uma Rangaraj
Keyword(s):  
Platelet Count ◽  
Single Dose ◽  
Time Course ◽  
Clinical Status ◽  
Total Serum ◽  
Severe Thrombocytopenia ◽  
Close Monitoring ◽  
Contributing Factors ◽  
Baseline Platelet Count ◽  
Total Serum Calcium

OBJECTIVE: To report a case of possible severe thrombocytopenia associated with administration of a single dose of plicamycin. CASE SUMMARY: A 73-year-old man with prostate cancer was admitted to the hospital with hypercalcemia (total serum calcium concentration 4.02 mmol/L) and a low baseline platelet count (152 × 109/L). Because of his symptomatic hypercalcemia, he was treated with NaCl 0.9%, furosemide, oral inorganic phosphate, and a single dose of plicamycin (15 μg/kg). Five days after plicamycin administration his platelet count decreased to 52 × 109/L, and continued to decrease further even after the transfusion of four units of platelets to a nadir of 7 × 109/L (hospital day 20). A second transfusion produced a small increase in his platelet count. The patient's clinical status continued to deteriorate, however, and he subsequently died. DISCUSSION: Plicamycin and other drugs that may induce thrombocytopenia are reviewed. The time course between plicamycin administration and the development of thrombocytopenia in our patient is assessed. Other contributing factors such as a low baseline platelet count and advanced age are also addressed. CONCLUSIONS: It is likely that the severe thrombocytopenia experienced by our patient was caused by a single dose of plicamycin. Adjusting the dosage for a patient's renal function as well as close monitoring of the platelet count are necessary when administering this drug. We report this case to remind clinicians of the potential for the development of severe thrombocytopenia following administration of a single dose of plicamycin.

scholarly journals A Case of Immune Thrombocytopenia After COVID-19 Vaccination: Coincidental or Causal Effect? Running Title: ITP After COVID-19 Vaccination

2021 ◽  
Author(s):  
Ernesto Vigna ◽  
Daniele Caracciolo ◽  
Enrica Martino ◽  
Francesco Mendicino ◽  
Eugenio Lucia ◽  
...  
Keyword(s):  
Platelet Count ◽  
Side Effects ◽  
Intravenous Immunoglobulin ◽  
Vaccine Efficacy ◽  
Immune Thrombocytopenia ◽  
Causal Effect ◽  
High Dose ◽  
Severe Thrombocytopenia ◽  
Platelet Response ◽  
Normal Range

Abstract The discovery and the introduction of different vaccines in the therapeutic armamentarium against SARS-CoV-2 represents a big hope in the fight against the pandemic. However, safety of SARS-CoV-2 vaccination is continuously monitored for the emergence of potential new side effects, such as recently reported thrombotic events, after the use of certain types of vaccines. In this context, we report a case of 31-year-old woman who developed immune thrombocytopenia (ITP) after 3 weeks from receiving SARS-CoV-2 vaccine. She developed significant widespread petechiae and gum bleeding, with severe thrombocytopenia documented at her hemogram. Over a 10-day period, thrombocytopenia was treated first with high dose corticosteroids, intravenous immunoglobulin and platelet transfusions, without a platelet response. Two days later, she received the TPO-mimetic and after three days, his platelet count began to rise reaching the normal range 18 days from her admission to our Hematology department. These findings cannot actually elucidate if vaccination was causal or coincidental effect of ITP, but further highlights the need of additional pharmacovigilance studies to empower SARS-CoV2 vaccine efficacy.

Outcomes of Referrals for Mild and Moderate Thrombocytopenia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 41-41
Author(s):  
Charles Schlappi ◽  
David McCall ◽  
Prasannalaxmi Palabindela ◽  
Christy Bemrich Stolz ◽  
Lee Hilliard ◽  
...  
Keyword(s):  
Platelet Count ◽  
Chart Review ◽  
Univariate Analysis ◽  
Retrospective Chart Review ◽  
Severe Thrombocytopenia ◽  
Platelet Counts ◽  
Pediatric Hematology ◽  
Normal Platelet Count ◽  
Normal Platelet ◽  
The Mean

Abstract Thrombocytopenia is a common reason for referral to a Pediatric Hematologist Oncologist. However, the need for acute intervention in patients with mild or moderate thrombocytopenia is likely a rare event. Because mild and moderate thrombocytopenia is less likely to need intervention and could resolve, the potentially stressful impact of referral to an Oncology center needs consideration. But with minimal literature to support the hypothesis that mild to moderate thrombocytopenia is unlikely associated with severe or progressive hematologic diseases, our ability to provide evidence based recommendations for need for referral is limited. To better understand the course for patients with mild and moderate thrombocytopenia, we conducted a retrospective chart review to assess the prevalence, outcomes, and need for intervention among patients referred for thrombocytopenia. Methods: We conducted a retrospective chart review of 1,140 patients referred to a large Pediatric Hematology Oncology program over a three year period (2012-2014). The diagnosis and demographics were recorded for every patient. Platelet counts at time of referral, lowest platelet count, and current platelet count were recorded and categorized as mild (plt: 100-149x103/mL), moderate (plt: 50-99 x103/mL), severe (plt: 20-49 x103/mL), and very severe (plt: <20 x103/mL). Therapeutic interventions and reason for intervention were recorded. Finally, ANA, platelet antibody and IgG levels were recorded. Descriptive statistics and univariate analysis were conducted using JMP10. Results: In a three year period (2012-2014), 1140 patients were referred to Pediatric Hematology Oncology, 902 of these patients for hematologic diagnoses. One hundred and three (11.4%) of 902 Hematology patients were referred for thrombocytopenia. The mean age of patients with thrombocytopenia was 9.2 years (s.d. 5.8yrs) and 58% were male. At the time of referral, 29% were categorized as mild, 33% were moderate, 17% severe and 21% very severe. The mean platelet count was 68 x103/mL (range 3-143). Younger patients had lower platelet counts (p<0.001), but no differences in mean platelet count were identified by gender (F:M 59 vs. 75 x103/mL, p=0.06). Thirty patients were categorized as mild thrombocytopenia at the time of referral. Only 2 (6%) patients needed eventual treatment (Crohn's disease and SLE treated by subspecialist) and 7 (23%) patients had at least one episode of moderate thrombocytopenia. On their most recent platelet count, 17 (57%) patients remained categorized as mild, 1 (3%) was moderate, and 12 (40%) had a normal platelet count. Thirty four patients were categorized as moderate thrombocytopenia at the time of referral. Only 5 (15%) patients needed eventual treatment (3 ITP patients for QOL/bruising/petechiae, one for SLE and one for NAIT) and 4 (12%) patients had at least one episode categorized as severe thrombocytopenia. On their most recent platelet count, 9 (26%) patients remained categorized as moderate, 10 (29%) were mild, and 15 (44%) had a normal platelet count. At time of diagnosis, 9 of 17 (53%) patients with severe thrombocytopenia and 19 of 22 (86%) of patients with very severe thrombocytopenia required interventions. Currently, 19 of the 39 (49%) patients have normal platelet counts. Other known diagnoses for the 103 patients include: rheumatologic diagnoses (n=5), drug induced (n=5), NAIT (n=3), ADP deficiency (n=1), X-linked thrombocytopenia (n=1), HSP (n=1), HIV (n=1), and Crohn's (n=1) Conclusion: Mild and moderate thrombocytopenia does not often progress or require interventions. Pediatricians should evaluate for Rheumatologic disorders in their initial work-up for mild to moderate thrombocytopenia as well as consider medication-induced thrombocytopenia. A safe and cost-effective approach to a patient with mild to moderate thrombocytopenia could be to observe repeat laboratory data (including ANA) in lieu of any other co-morbid condition. This approach could save families time, money, effort, and emotional stress in making appointments at large referral institutions. Disclosures No relevant conflicts of interest to declare.

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