Short-term dose-escalated romiplostim for preparing an adult patient with persistent newly diagnosed primary immune thrombocytopenia for splenectomy

Murray, Nigel P; Minzer, Simona; López, Marco Antonio; Muñoz, Lorena

doi:10.1016/j.htct.2019.07.009

Cited by 2 publications

(3 citation statements)

References 10 publications

(19 reference statements)

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“…Romiplostim may also have been initiated with the intention of temporarily bridging to another therapy or prior to splenectomy. 22,23 Finally, we conducted an intent-to-treat analysis, and thus did not censor for treatment discontinuation, treatment augmentation, or switching. The intent-to-treat analysis was specified as the primary analysis in the proposed randomized trial and was thus the estimand that we targeted.…”

Section: Discussion Of Comparative Effectiveness Study Resultsmentioning

confidence: 99%

“…A lower than expected durable response rate among the romiplostim group (36%) in our RWE study compared with that from integrated clinical trial data (53%) 17 is likely to be explained by a shorter duration of romiplostim exposure (median duration: 14 weeks (RWE), 52 weeks (trial)) and lower romiplostim dose (median weekly dose: 2.1 μg/kg (RWE), 3.0 μg/kg (trial)) ( Table ), 17 possibly due to capturing patients early in the dose escalation phase. Romiplostim may also have been initiated with the intention of temporarily bridging to another therapy or prior to splenectomy 22,23 …”

Section: Discussionmentioning

confidence: 99%

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Lessons Learned Using Real‐World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia

McGrath¹,

Nielson

Saul³

et al. 2021

Clin Pharma and Therapeutics

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Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 10 9 /L (95% CI: −59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.

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Section: Discussion Of Comparative Effectiveness Study Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lessons Learned Using Real‐World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia

McGrath¹,

Nielson

Saul³

et al. 2021

Clin Pharma and Therapeutics

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“…To further investigate this mechanism, we performed splenectomies, which are clinically used to inhibit the clearance of platelets or red blood cells, 41 with the aim of eliminating platelet and MK degradation by phagocytosis. In both WT and SMS1-KO mice, the number of circulating platelets appeared to increase at 4 days’ post-splenectomy compared with that pre-splenectomy (on day 0) ( Figure 4D ; supplemental Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency

Fujii¹,

Taniguchi²,

Nagaya

et al. 2021

Blood Advances

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Sphingomyelin synthase 1 (SMS1) contributes to the generation of membrane sphingomyelin (SM) and affects SM-mediated physiological functions. Here, we describe the hematologic phenotypes, such as reduced circulating platelets and dysfunctional hemostasis, in SMS1-deficient (SMS1-KO) mice. SMS1-KO mice display pathologic manifestations related to idiopathic thrombocytopenia (ITP), including relatively high amounts of peripheral blood reticulated platelets, enhanced megakaryopoiesis in the bone marrow and spleen, and splenomegaly. Deficiency of SMS1, but not SMS2, prevented SM production and enhanced phosphatidylserine (PS) externalization on the plasma membranes of platelets and megakaryocytes. Consequently, SMS1-KO platelets were excessively cleared by macrophages in the spleen. Multimer formation in the plasma membrane of TMEM16F, a known calcium (Ca2+)-activated nonselective ion channel and Ca2+-dependent PS scramblase, was enhanced; the result was PS externalization to outer leaflets through increased Ca2+ influx in immortalized mouse embryonic fibroblasts established from SMS1-KO mice (SMS1-KO tMEFs), as seen with SMS1-KO platelets. Thus, SMS1 deficiency changed the TMEM16F distribution on the membrane microdomain, regulating Ca2+ influx-dependent PS exposure. SMS1-KO tMEFs in which TMEM16F was knocked out by using the CRISPR/Cas9 system lacked both the Ca2+ influx and excess PS exposure seen in SMS1-KO tMEFs. Therefore, SM depletion on platelet membrane microdomains due to SMS1 deficiency enhanced PS externalization via a Ca2+ influx through TMEM16F activation, leading to elevated platelet clearance and causing hemostasis dysfunction through thrombocytopenia. Our current findings show that the SM-rich microdomain generated by SMS1 is a potent regulator of thrombocytopenia through TMEM16F, suggesting that its dysfunction may be a novel additional mechanism of ITP.

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Short-term dose-escalated romiplostim for preparing an adult patient with persistent newly diagnosed primary immune thrombocytopenia for splenectomy

Cited by 2 publications

References 10 publications

Lessons Learned Using Real‐World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia

Lessons Learned Using Real‐World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia

A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency

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