Predictive Factors for Thrombopoietin Receptor Agonist Free Responses in Chronic ITP Patients: A Multicenter Retrospective Study with Long-Term Follow-up

Abstract

Background . In clinical practice, tapering off thrombopoietin receptor agonists (TPO-RA) in immune thrombocytopenia (ITP) is considered if therapy is no longer needed due to a decrease in the disease activity favoring sustained treatment-free responses (TFR). To date, there are no predictors to identify when this approach is likely to be successful, other than earlier start of TPO-RA, and robust platelet responses. Aim. To evaluate clinical predictors of TFR in a real-world cohort of ITP patients treated with TPO-RA by dealing with confounding variables that could be minimized at the stage of the analysis. Methods. In this retrospective, multicenter study from 19 secondary and tertiary Spanish hospitals, patients aged >18 years with chronic ITP who had initiated TPO-RA (eltrombopag [EPG] or romiplostim [ROM]) between January 2012 and December 2014 were included. Data were collected from medical records (November 2016 to January 2018) on patient characteristics, history of disease and previous therapies, TPO-RA administration, response and discontinuation. Results. A total of 82 patients with a median age of 63 years (range 19-90 years), 59.9% females initiated TPO-RA (ROM, n=37; EPG, n=45). The median time from diagnosis of ITP to therapy with TPO-RA was 5.5 years (1.1-50.3 years). In all cases the TPO-RA was started with intention to treat indefinitely; the median initial doses of EPG were 350 mg/week (175-525 mg/week), and those of ROM 2.0 μg/kg/week (1.0-7.0 μg/kg/week). The median time on TPO-RA treatment was 2.9 years (0.1 to 5.6 years), and the median follow-up from start of TPO-RA until collection of data was of 3.9 years (1.3 to 5.6 years). A total of 29 patients (35.4%) switched TPO-RA during follow-up. The most frequent cause for switching was lack of efficacy (44.8% of cases -in all cases the initial TPO-RA was EPG-). Due to switching, 58 patients received ROM, and 53 were treated with EPG, yielding 122.3, and 100.8 patient-years of total exposure, respectively. During follow-up almost one half of the patients (47.6%, n=39) stopped TPO-RA. After a median of 1.4 years (0.1-3.3 yrs) under TPO-RA treatment, 19 patients (23.2% of the whole cohort) maintained TFR defined as platelet counts >50x109/l for a median follow-up of 2.8 years (1.5-4.4 years) in the absence of any platelet increasing drug. Remarkably, while the specific TPO-RA that was discontinued did not influence the probability to achieve TFR (P=0.582), there was a trend towards receiving ROM as first TPO-RA and attaining sustained responses (P=0.073), while switching TPO-RA negatively predicted TFR (P=0.010). In univariate analysis with logistic regression, switching TPO-RA was associated with a 6.4 risk of not achieving TFR (P= 0.019). The overall comparison of the Kaplan-Meier curves indicated an association (log-rank P=0.041) among the initial TPO-RA that was prescribed and the probability of TFR (Fig 1A), but the estimated median time to achieve TFR was not reached for either TPO-RA. When switching and initial TPO-RA were considered, patients receiving ROM and not experiencing switching were the best performing group in terms of achieving TFR; the median time to taper off the drug and sustain platelet responses was 3.3 years (95% CI 2.7-4.0 years) (Fig. 1B). Conclusion. In this observational research analysis, we have tried to minimize the possible bias of some studies that could mistakenly attribute TPO-RA induced TFR, when in fact it may be the natural course of the underlying disease. By analyzing a group of chronic ITP patients with a particularly poor baseline prognosis (median time from diagnosis 5.5 years) we address potential confounding variables by disease severity. Our data show that assuring that long duration under TPO-RA therapy is provided (median of 3.3 years), one half of chronic ITP patients treated with ROM and not undergoing switching can achieve TFR. Disclosures Mingot-Castellano: Roche: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novonordisk: Consultancy; CSL Behring: Consultancy. Jarque:Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau. Campos:Novartis: Speakers Bureau; Amgen: Speakers Bureau. Lopez Fernandez:Amgen: Consultancy, Speakers Bureau. Casado:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Álvarez Roman:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Takeda: Research Funding; NovoNordisk: Consultancy, Speakers Bureau.

A Review of Romiplostim Mechanism of Action and Clinical Applicability

“…In contrast, late or progressive ITP is often associated with irreversible autoimmunity, as characterized by lasting cytokine imbalance, loss of immune tolerance, and the generation of difficult-totarget long-lived plasma cells. 95 Other events occurring in later stages of ITP that may justify the need for early intensive medical treatment include B-cell clonal expansion, antibody affinity maturation, epitope spreading, the functional diversification of autoantibody effector functions, and the generation of long-lived memory populations that differ from primary B cells. 96 Newly diagnosed patients who received more intensive initial treatment regimens appeared to show improved initial and late response rates, 88,[97][98][99] which is consistent with the theory that earlier treatment in any disease is potentially more curative than later treatment.…”

“…In contrast, late or progressive ITP is often associated with irreversible autoimmunity, as characterized by lasting cytokine imbalance, loss of immune tolerance, and the generation of difficult-to-target long-lived plasma cells. 95 Other events occurring in later stages of ITP that may justify the need for early intensive medical treatment include B-cell clonal expansion, antibody affinity maturation, epitope spreading, the functional diversification of autoantibody effector functions, and the generation of long-lived memory populations that differ from primary B cells. 96 …”