New Approaches Are Shifting the Landscape in Immune Thrombocytopenia | OncLive

New Approaches Are Shifting the Landscape in Immune Thrombocytopenia

June 24, 2019

During a recent OncLive Peer Exchange discussion, a trio of immune thrombocytopenia specialists review clinical trial data that led to approval of the second-line agents, talk about efforts to refine first-line treatment, and discuss how they approach therapy selection for refractory patients. Finally, they highlight emerging therapies for ITP and the need to expand the pipeline.

Ivy P. Altomare, MD

Although upfront management of immune thrombocytopenia (ITP) in adults has not changed much over the years, advances in the treatment of refractory ITP have some clinicians looking for guidance. In 2018, the FDA approved fostamatinib (Tavalisse) as a second-line treatment for adults with chronic ITP, making it the first new drug marketed for adults with ITP since approvals of romiplostim (Nplate) and eltrombopag (Promacta) a decade earlier.1-3 The FDA is also considering a request to expand indications for avatrombopag (Doptelet) to include refractory ITP in adults, with a decision expected by June 30, 2019.4

During a recent OncLive Peer Exchange® discussion, a trio of ITP specialists agreed the anticipated approval of avatrombopag would further complicate decision making. “We don’t have randomized head-to-head trials of any of these modalities to help,” said moderator Ivy P. Altomare, MD. Despite the challenges, the benefit of having more choices for patients is undeniable. Splenectomy and its attendant risks are now often delayed until much later in the disease course.

The panelists reviewed clinical trial data that led to approval of the second-line agents and talked about efforts to refine first-line treatment to prolong responses and minimize adverse effects (AEs). They also discussed how they approach therapy selection for refractory patients. Finally, they highlighted emerging therapies for ITP and the need to expand the pipeline.

“We have some newer agents where it looks like the control of the disease will be significantly longer, and we have a fraction of patients who, once they come off therapy, will maintain their responses, but we still haven’t hit the bullseye yet,” said Ralph V. Boccia, MD.

Initial Treatment of Adult Immune Thrombocytopenia

ITP is a rare autoimmune disorder characterized by an increased risk of bleeding due to below-average platelet counts,5 and Boccia said the primary goal of treatment is to reduce bleeding risk or stop ongoing bleeding “in as safe and convenient and nontoxic a way as possible.”

Guidelines for managing ITP from the American Society of Hematology (ASH) recommend starting treatment for patients with newly diagnosed disease who have a platelet count <30 x 109/L (<30,000/μL) even when mucosal bleeding is absent.6,7 Boccia said the heterogeneity of ITP makes it difficult to apply a strict platelet threshold to treatment decisions. “Patients may present with very low platelet counts and have no bleeding whatsoever or they may have moderate platelet counts and have significant bleeding,” he explained.

Amit Mehta, MD, and Altomare acknowledged that they do not adhere to the recommended platelet count. “In practice, many of us feel comfortable with a platelet count that’s lower for patients, as long as their bleeding is under control and doesn’t go beyond simple transient epistaxis or very mild mucocutaneous bleeding,” Mehta said. He said the patient’s perspective is also important and someone with only mild bleeding might still be concerned about constitutional symptoms like fatigue. Altomare said factors she considers besides platelet count are the patient’s age, lifestyle, and access to care.

First-line treatment for acute ITP is typically oral corticosteroids, which rapidly increase the platelet count by slowing platelet destruction.8 Mehta said the traditional approach of starting with 1 mg/kg/d of oral prednisone and tapering it over several weeks was giving way to a newer strategy known as pulsed-dose highdose dexamethasone (HD-DXM), which involves administering 40 mg/d of HD-DXM for 4 days and repeating the cycle every 1 to 2 weeks if the response is inadequate. He said clinical trials comparing pulsed-dose HD-DXM with traditional prednisone have observed higher response rates with HD-DXM. All 3 panelists said they had switched from prednisone to HD-DXM.

“I find that it works just as well and is a little better tolerated,” Altomare said. For acute bleeding, Boccia said he first administers intravenous immunoglobulin followed by platelets and corticosteroids, which produces a faster response than corticosteroids alone.

An abstract presented at the 2018 ASH Annual Meeting suggested that 12 weeks of eltrombopag (25-75 mg/d), an oral thrombopoietin receptor agonist (TRO-RA), plus 1 to 3 cycles of pulsed-dose HD-DXM might achieve sustained responses in patients with newly diagnosed ITP.9 The 6-month response rate was 56% (19/34), which the authors indicated was more than double the approximately 25% 6-month response rate observed in studies of HD-DXM monotherapy.9 The median platelet count at 6 months was 150 x 109/L.9 Boccia said longer-term data were needed before incorporating the regimen in clinical practice.

Recombinant human thrombopoietin (rhTPO), a drug approved in China for ITP,10 has also been studied in combination with HD-DXM. In a Chinese study, 90% of patients with newly diagnosed ITP treated with rhTPO and D-DXM had an overall response at 14 days compared with 67% of patients randomized to HD-DXM alone.11 In the combination arm, the complete response rate was 75% and the 6-month sustained response rate was 51% compared with 43% and 37%, respectively, in the dexamethasone-only arm.11

Second-Line Therapies

The ASH guidelines for ITP were published in 2011 and recommend splenectomy as the preferred second-line option for patients who fail corticosteroid therapy.6 Proposed updates to the guidelines, which were open for public comment in late 2017,12 include making TPO-RA an equivalent second-line option to splenectomy for adults with ITP lasting more than 3 months who are corticosteroid-dependent or do not respond to corticosteroids.12 Currently, the suggested revisions do not include fostamatinib, which was not yet approved when they were developed. ASH is expected to publish updated guidelines in 2019.

Older Treatments

A systematic review of clinical trials of second-line treatments for ITP found that approximately 71% of patients achieved remission with splenectomy but that 20% relapsed.13 “One of the problems is that we don’t have a reliable way to really predict who will have a long-term durable response after splenectomy, so it’s hard to go through an elective procedure with no guarantee that it’s going to work,” Altomare said. Because splenectomy is potentially curative, the panel agreed clinicians should always discuss it with patients and inform them that ITP drugs do appear to be active in patients who relapse post splenectomy.

Since the FDA approved the TPO-RAs eltrombopag and romiplostim in 2008, they have become standard second-line therapies for adult ITP.2,3 Boccia explained that they target myeloproliferative leukemia protein, the thrombopoietin receptor, on platelets and megakaryocytes to stimulate platelet production but with slightly different mechanisms. Eltrombopag is administered orally, whereas romiplostim is delivered subcutaneously.2,3 The drugs have been around more than 10 years, and data from the trials that led to their approval have been widely disseminated. Boccia said the TPO-RA trials included splenectomized and nonsplenectomized patients and defined response as a platelet count ≥50 x 109/L.14

In the pivotal phase III trials of romiplostim, 88% of nonsplenectomized patients and 79% of splenectomized patients who received the TPO-RA achieved a response, and 51% and 31%, respectively, had a durable response.15 Similar overall response rates have been reported for patients treated with 50- and 75-mg doses of eltrombopag in clinical trials.13 In the phase III RAISE trial, 58% of splenectomized and 66% of nonsplenectomized patients treated with eltrombopag achieved a durable response.16 Altomare said she has patients who “have been on these agents for years with continued response.”

“As far as choosing between the two, usually it’s determined more by patient factors… We don’t have a lot of guidance about one versus the other directly,” Mehta said. Boccia noted that a recent study by Al-Samkari et al found patients with modest elevations in thrombopoietin (TPO) level were more likely to respond to romiplostim than eltrombopag, and patients with extreme TPO elevations did not respond to either drug.17 If the findings are confirmed, TPO level might be a useful predictive biomarker.

Altomare said a small percentage of patients who respond to TPO-RAs maintain their response after discontinuing treatment. “I think it’s up to 30% of patients who may be able to come off and have a sustained response,” she said. Monoclonal antibodies that target CD154 and CD40 are also being studied, but concerns have emerged about their prothrombotic effects.8

Mehta said eltrombopag and romiplostim have slightly different safety profiles, which might influence selection. He said his patients taking romiplostim frequently experience transient arthralgias, aches and pains, and injection-site reactions, whereas his eltrombopag-treated patients more often report gastrointestinal-type symptoms and headaches. Boccia said other differences are a slightly increased risk of bone marrow fibrosis with romiplostim and liver enzyme increases with eltrombopag. He said headache is frequently observed with all the ITP drugs, including fostamatinib and avatrombopag and, in his experience, “tends to be more common during the first month.” Altomare said arterial and venous clots are another potential complication of romiplostim and eltrombopag.

Although rituximab (Rituxan) is not approved for ITP, it is frequently used for adult patients with refractory ITP before or after splenectomy, and between 18% and 35% of patients will achieve a long-term response with rituximab lasting more than 1 year.6 Altomare said she used to see patients who had received several courses of rituximab, a trend that has sharply declined. “In general, studies have shown…that retreatment with rituximab has diminishing returns,” Mehta said.

“It’s a very good drug… and the nice thing about it, compared with the other agents, is that it’s done in 4 weeks, so in that sense, I like it,” Boccia said. The panelists agreed, however, that rituximab also has drawbacks and that they typically only use it today for patients who previously had a good response to rituximab or who have another autoimmune disorder.

New and Emerging Approaches

Fostamatinib targets the SYK tyrosine kinase within activated macrophages to inhibit downstream signaling and prevent platelet destruction, which is a different mechanism from TPO-RAs. Boccia said although switching from one TPO-RA to another is unlikely to provoke a response, fostamatinib’s novel mechanism means “you can switch therapies.”

“The FDA-approved dosing is 100 mg by mouth twice a day, but it can be increased to 150 mg twice a day if the clinician is not satisfied with the response to the 100-mg dose,” Mehta said. He added that fostamatinib can be taken with or without food,1 whereas eltrombopag must be taken on an empty stomach.2 Boccia, who was involved in the phase III clinical trials of fostamatinib, said more than 80% of trial participants treated with fostamatinib required the higher dose.18

The randomized, double-blind, placebo-controlled phase III FIT1 and FIT2 trials included heavily pretreated patients who had chronic or persistent ITP.18 A combined analysis showed 43% of patients treated with fostamatinib arm responded and 18% achieved stable responses, which was significantly better than rates for patients randomized to placebo (14% and 2%, respectively).18 In a subset of 60 patients assayed for autoantibodies, the sustained response rate was even higher for fostamatinib-treated patients with detectable antibodies (36% vs 9% for placebo), which Boccia said could suggest a different pathophysiology and possibly serve as a predictor of fostamatinib response.18

Boccia said diarrhea and hypertension are the 2 most frequently observed AEs with fostamatinib and occurred, respectively, in 35% and 20% of patients treated with fostamatinib in the phase III clinical trials and open-label extension study.19 Most cases were mild or moderate and easily managed.

Avatrombopag, an experimental TPO-RA, was evaluated in a phase III randomized study of adults with previously treated chronic ITP.20 Approximately 34% of patients in the avatrombopag arm achieved a durable platelet response compared with none in the placebo arm.20 There was no significant difference in the need for rescue therapies between the groups.20 Common treatment-related AEs included headache, contusion, upper respiratory tract infection, arthralgia, epistaxis, fatigue, gingival bleeding, and petechiae.20

“I think it may give eltrombopag a run for the money,” Boccia said.

Another novel agent being evaluated for ITP is rozanolixizumab, an antineonatal Fc receptor recycling agent.8 In a phase II dosefinding trial, rozanolixizumab demonstrated significant activity and was well tolerated.21 PRN1008 is an oral Bruton tyrosine kinase inhibitor in development for ITP.

“The nice thing about this particular drug is that it does not inhibit collagen-activated platelet aggregation,” said Boccia, who is an investigator for a single-arm clinical trial of PRN1008. In a mouse model, PRN1008 reduced platelet destruction and inhibited autoantibody production.22 Altomare also mentioned a study of low-dose decitabine in patients with refractory ITP; she said the results showed encouraging activity. The overall response rate was 50%, which included 2 complete responses.23

The panelists agreed that many robust treatment options were available for ITP but that, as Altomare put it, “We need some newer stuff,” especially for newly diagnosed disease. Boccia expressed optimism that some of the newer agents may enable clinicians to move away from corticosteroids and their terrible AEs.

References

  1. Tavalisse [prescribing information]. South San Francisco, CA: Rigel Pharmaceuticals, Inc; 2018. www.accessdata.fda.gov/drugsatfda_ docs/label/2018/209299lbl.pdf. Accessed May 28, 2019.
  2. Promacta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008. www.accessdata.fda.gov/drugsatfda_ docs/label/2008/022291lbl.pdf. Accessed May 28, 2019.
  3. Nplate [package insert]. Thousand Oaks, CA: Amgen, Inc; 2008. www.accessdata.fda.gov/drugsatfda_docs/label/2008/125268lbl. pdf. Accessed May 28, 2019.
  4. Dova Pharmaceuticals announces FDA acceptance of supplemental new drug application for DOPTELET (avatrombopag) for the treatment of chronic immune thrombocytopenia (ITP) [news release]. Durham, NC: Dova Pharmaceuticals; November 5, 2018. investors. dova.com/node/7251/pdf. Accessed May 28, 2019.
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  9. Zhang L, Zhang M, Du X, Cheng Y, Cheng G. Eltrombopag plus pulsed dexamethasone as first line therapy for subjects with immune thrombocytopenic purpura (ITP). Blood. 2018;132(suppl 1):733. bloodjournal.org/content/132/Suppl_1/733?sso-checked=true.
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  11. Wang M, Qin P, Zhou H, et al. Recombinant human thrombopoietin (rhTPO) and high-dose dexamethasone (HD-DXM) versus high-dose dexamethasone monotherapy as frontline treatment in newly diagnosed adult immune thrombocytopenia (ITP): a prospective, multicentre, randomised, controlled trial. Blood. 2017;130(suppl 1):13- 13. bloodjournal.org/content/130/Suppl_1/13?sso-checked=true.
  12. ASH draft recommendations for immune thrombocytopenia. American Society of Hematology website. hematology.org/Clinicians/Guidelines- Quality/Documents/9106.aspx. Accessed May 28, 2019.
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  14. Vishnu P, Aboulafia DM. Long-term safety and efficacy of romiplostim for treatment of immune thrombocytopenia. J Blood Med. 2016;7:99-106. doi: 10.2147/JBM.S80646.
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  20. Jurczak W, Chojnowski K, Mayer J, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479-490. doi: 10.1111/bjh.15573.
  21. Robak T, Jarque I, Musteata V, et al. Phase II, multiple-dose study of anti-FcRn antibody, rozanolixizumab (UCB7665), in patients with primary immune thrombocytopenia: interim analysis. Blood. 2017;130(suppl 1):15. bloodjournal.org/content/130/Suppl_ 1/15?sso-checked=true.
  22. Langrish CL, Bradshaw JM, Owens TD, et al. PRN1008, a reversible covalent BTK inhibitor in clinical development for immune thrombocytopenic purpura. Blood. 2017;130(suppl 1):1052. bloodjournal. org/content/130/Suppl_1/1052?sso-checked=true.
  23. Zhou H, Qin P, Yuan C, et al. A prospective multicenter single-arm study of low-dose decitabine in adult patients with immune thrombocytopenia. Blood. 2016;128(22):3744.

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