PDSA E-News: December 29, 2016



ash2016signNews from the 2016 American Society of Hematology (ASH) Annual Meeting

Each year the annual American Society of Hematology (ASH) meeting attracts thousands of clinicians and scientists, worldwide, to learn about and report on the latest hematology research. This year’s 2016 ASH meeting, held December 3 - 6 in San Diego, CA featured more than 10 hours of presentations and more than 80 pages of abstracts about ITP and related diseases. In this issue of the e-news, we report some trends. Watch for additional ASH findings in the 2017 winter and spring issues of the PDSA quarterly newsletter, The Platelet News.

The ASH abstract numbers are shown in parentheses. You can search on the number and read the complete abstract at: https://ash.confex.com/ash/2016/webprogram/start.html after you ‘agree’ with the terms.


Learning More about Current ITP Treatments

Several Important Factors Determine Physicians’ Treatment Decisions in Selecting Second-Line Therapies for Children with ITP

Using collected data from physicians experienced in treating ITP researchers developed a conceptual model of factors that led doctors to choose treatments. This study was a part of ICON1, a longitudinal study of second-line treatments for childhood ITP that was carried out by the Pediatric ITP Consortium of North America (ICON). Doctors who enrolled pediatric patients in ICON1 were asked to rank the top three reasons they chose a particular treatment. Choices ranked 1, 2, or 3 were weighted to develop the scoring model. The physicians were asked about the range of factors that influenced their choice of a second-line therapy for ITP.

Mom and child with doctor

ICON1 enrolled 118 patients (101 with primary ITP, 53 receiving their first second-line treatment). Factors found most important in guiding doctors’ treatment decisions included: patient/parental preference (40%), treatment-related factors: possibility of remission (38%), side effects profile (37%), how well the treatment worked (27%), long-term toxicity (33%), and ease of administering the treatment (30%). Physician factors such as experience and following published guidelines for ITP, rarely influenced the doctors’ treatment decision (just 2% of doctors gave published guidelines as a reason for their choice). About 28% of doctors said their comfort level with a treatment strongly influenced their choice. More than a third (38%) of doctors did not endorse any patient clinical factors (e.g. bleeding frequency, expected treatment compliance, insurance approval, or patient’s distance to nearest medical center).

Treatments were placed into five groups: oral immunosuppressants, rituximab (Rituxan®), romiplostim (Nplate®), eltrombopag (Promacta®), or splenectomy. Oral agents were more likely to be chosen for ease of administration and expected adherence. The doctors indicated “this agent is most efficacious” most frequently for romiplostim, but not for eltrombopag. The researchers in this first analysis of what determines physician choice in second-line ITP treatment showed that patient preference and physician perception of treatment characteristics (efficacy, side effects, and possibility of long remission) were chosen much more than published guidelines, clinical characteristics, and health system factors.

See (1008) Lambert MP, Grace RF, Neunert C, et al. “Physician Factors Determining Treatment Decisions in Selecting Second-Line Agents for Pediatric ITP.”


Eltrombopag When Compared to Rituximab Improved the Probability of Response in Chronic ITP Adult Patients

EltrombopagWhen ITP patients are first diagnosed, hematologists tend to treat first with steroids or IVIg. When first-line treatments are unsuccessful at raising the platelet count, hematologists often turn to a range of second-line treatments with no official consensus on which therapy is most effective. Researchers from healthcare consulting firm WG Access and Novartis pharmaceuticals set out to create a hypothetical simulation model for the probability of response rates in adult chronic ITP patients treated with two common second-line treatments: Promacta® (eltrombopag) and Rituxan® (rituximab).

The model utilized results from the “RAISE” and “EXTEND” studies on Promacta and a systematic literature review for Rituxan. The researchers analyzed response rates, bleeding events, and mean time to treatment failure, and simulated hypothetical prognoses with treatments over one year. The model demonstrated that patients using Promacta had close to a 68% chance of responding to treatment, compared to a 38% response rate for Rituxan. Splenectomized patients responded 57% of the time to eltrombopag and 36% to Rituxan. Patients who failed to maintain an elevated platelet count stopped responding to therapy between 7.7 and 6.8 months when treated with Promacta, and between 5.3 and 5.0 months with Rituxan. Patients on Promacta experienced between 31-45% fewer bleeding events than patients undergoing Rituxan therapy. Overall, the researchers discovered that second-line treatment with Promacta yielded better and quicker response rates as well as fewer bleeding events compared with treatment with Rituxan.

See (2334) Hirst A, Wang-Silvanto J, Shephard C, et al. “Eltrombopag Compared to Rituximab Improves the Probability of Response in Adult Chronic ITP Patients.”


Eltrombopag, Low-Dose Rituximab, and High-Dose Dexamethasone Combination Works Well as First Line Treatment for Newly Diagnosed ITP Patients

Recently, steroids such as prednisone and dexamethasone have been used in conjunction with other ITP therapies in order to elevate and stabilize a patient’s platelet count. Dexamethasone and low-dose Rituxan® (100 mg/m2) seem to yield the same response rates as dexamethasone and standard-dose Rituxan (375 mg/m2), with approximately 58-76% of patients elevating their platelet counts. Promacta® and dexamethasone taken together have exhibited 100% response rates in some studies. Considering this information, hematologists at the Dr. José Eleuterio González Hospital in Mexico piloted a “total therapy” study in order to examine the efficacy, safety, and response duration of low-dose Rituxan, high-dose dexamethasone (40 mg), and Promacta (50 mg) taken together in newly diagnosed, previously untreated ITP patients.

All patients enrolled in the study were able to elevate their platelet count from a median count of 7x109/L to 30×109/L, at a median of four days (range 3-14) after initiating treatment. Nine out of 10 patients raised their counts to 100×109/L within a month of initiating treatment, and maintained their response for the duration of treatment (range 1-13 months). One patient’s platelet count dropped after one month after achieving an initial complete response; the patient received a second treatment of high-dose dexamethasone and was able to maintain a responsive platelet count. The researchers concluded this therapy combination can now be considered a practical front-line treatment for ITP, demonstrating minimal side effects and quick and sustainable response rates.

See (1369) Gomez-Almaguer D, Cantu-Rodriguez O, Guitterrez-Aguire C, et al. “Eltrombopag, Low-Dose Rituximab, and High-Dose Dexamethasone Combination for Patients with Newly Diagnosed Immune Thrombocytopenia: A Pilot “Total Therapy” Study.”


Understanding More about TPO Treatments

Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with ITP Finds 80% of Children Had a Platelet Response Over the Course of the Study

Nplate logoUse of the TPO receptor agonist romiplostim (Nplate®) in children with ITP has been evaluated in phase 1 / 2 and 3 studies. In this study, children with ITP will receive open-label SC romiplostim for up to three years. Eligible children were recruited from 16 countries worldwide, had ITP for 6 months or longer, had received at least one prior ITP treatment, and had platelet counts of 30,000 or less. Children in the study received weekly SC (subcutaneous) dosing started at 1 µg/kg and raised in increments to 10 µg/kg to target a platelet level of 50,000. Results as of March 2016 showed that 145 patients received one or more doses of romiplostim. Median age was 10 (range 2 - 17) years, 51% were female, 4% had prior splenectomy, median ITP duration was 1.9 years, and median platelet count was 13,000.

The median percentage of time with a platelet response in the first six months on the study was 50%; in the next 7 – 12 months it was 92%. Over the course of the study 80% (114/143) of patients had a platelet response. Median average weekly romiplostim dose was 6.1 (0.4 – 9.0) µg/kg. Thirty-two (22%) patients discontinued treatment because of lack of efficacy, 5 patients required other therapy, and 2 patients experienced adverse events (lung disease unrelated to treatment in one patient and abdominal pain, vomiting and headache in the other patient). After 12 weeks on treatment, median platelet counts were 50,000 or higher. The most frequently reported adverse events (AEs) were headache (27.6%), epistaxis (nosebleed) (22.8%), and nasopharyngitis (23%). Grade 3 bleeding was seen in 8 (6%) patients, and no grade 4 or 5 bleeding was observed.

The study found that one year into this ongoing, open-label study of romiplostim in children with ITP the % of time during the first six months with a platelet response was 50%, with 80% of children having a platelet response at some point in the study. The median dose of romiplostim reached was 10 µg/kg. There were no new safety signals. No effects of romiplostim were found in the subset of patients who received bone marrow biopsies. Future findings for years 2 and 3 of the study, the largest of romiplostim in children with ITP, is expected to provide additional information on dosage, platelet response, and safety.

See (869) Grainger J, Bussel J, Cooper N, et al. “A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP).”


Patient-Reported Health-Related Quality of Life Improves over Time in Patients with Chronic Immune Thrombocytopenia Receiving Long-Term Treatment with Eltrombopag

EXTEND was an open-label dose-adjustment extension study (June 2006 to July 2015) that evaluated safety and efficacy of eltrombopag (Promacta) for treatments of chronic ITP patients enrolled in a previous eltrombopag trial. Chronic ITP may lead to fatigue and interfere with patients’ daily activities, which affects their health-related quality of life (HRQoL). This study using final EXTEND data assessed patient-reported HRQoL changes over time while receiving long-term eltrombopag.

Bicycling on a trail in the desert

Four standard validated HRQoL instruments for measuring chronic disease were used in this study. These instruments were SF-36v2 (including the Physical Component Summary [PCS] and Mental Component Summary [MCS] that measure general physical and mental health state); MEI-SF (Motivation and Energy Inventory Short form), which measures motivation and energy; Fatigue Subscale of FACIT (FACIT-F), which measures symptoms of fatigue; and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6), which measures concerns about bruising and bleeding and their impact on daily activities. These instruments were used at baseline (start of the study) (BL) and every 3 months until the last on-treatment assessment was done. Patients were blinded as to their current platelet level before completing the questionnaires.

Of 302 patients enrolled in EXTEND, 289 – 293 patients had a BL and at least one on-treatment HRQoL assessment. Median treatment duration was 2.4 years. All four HRQoL instruments showed positive mean changes from BL over time. Noticeably, improvements from BL continued through five years of treatment for FACIT-F and FACT-Th6 (fatigue and bleeding, respectively). Most patients experienced an improvement from BL. The best improvement occurred at a median of 6 – 10 months from BL. The researchers concluded that 80% of patients treated with eltrombopag experienced improvement from BL, with positive, meaningful changes from BL in all HRQoL scores. Improvements from BL persisted over time for fatigue, bleeding, bruising, and physical health status.

See (3750) Khelif A, Saleh MN, Salama A, et al. “Patient-Reported Health-Related Quality of Life Improves over Time in Patients with Chronic Immune Thrombocytopenia Receiving Long-Term Treatment with Eltrombopag.”


Splenectomy Findings

Second-Line Treatment of Refractory ITP Patients with Splenectomy Achieved Higher Complete Response (CR) Compared to Treatment with Rituximab

Adult ITP is initially treated with steroids, IVIg, and/or anti-D, but about 80% of patients eventually relapse and don’t respond to the treatments. There is no universally agreed upon second-line therapy and ITP guidelines recommend either rituximab (R) or splenectomy (S) as acceptable choices. Long-term responses to second-line S has been reported around 60% and 25% for R. This study evaluated the impact of sequence of second and third-line therapy with rituximab or splenectomy. Researchers identified 222 patients with ITP (treated from 1990 to 2015 at the three Mayo Clinic sites (Arizona, Florida, and Minnesota) who received rituximab and/or splenectomy. Patients under age 18, those with uncontrolled infections, or with uncontrolled autoimmune disorders were excluded. Primary endpoints were freedom from relapse (FFR) and second and third-line treatments with R or S. Researchers evaluated treatment response, defined as a platelet count of 30,000 or higher.

Overall, patients treated with S as their second-line therapy were more likely to achieve complete response (CR) (86.6% vs 44%) and had a higher freedom from relapse at 5 years. Patients treated with S, followed by R (S to R) had a trend toward higher 2-year freedom from relapse than those treated with R followed by S (R to S) (69.4% vs 58.4%). The data were similar for both primary ITP and secondary ITP. The researchers indicated their results support that splenectomy provides higher freedom from relapse (FFR) at 5 years compared to rituximab as second-line treatment. It also suggests that, when needed, S followed by R (as opposed to R followed by S) might have a slight advantage.

See (3735) Hammond WA, Rodriguez EM, Li Z, et al. “Splenectomy or Rituximab in Steroid-Refractory Immune Thrombocytopenia (ITP): The Mayo Clinic Experience.”



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