Common‐sense combination therapy in refractory immune thrombocytopaenia

This is the authors' abstract. We don't add key points for this paper.

In 1979, two boys with Wiskott–Aldrich syndrome in Switzerland were given intravenous immunoglobulin (IVIG) to help treat a viral illness. To everyone's surprise, the platelet counts of both boys increased dramatically. Drs. Imbach, Barandun and others recognized this and Dr. Imbach subsequently gave IVIG to one of his patients with chronic immune thrombocytopaenia (ITP). This patient's platelet count also improved, and eventually the first publication on the successful use of IVIG in 13 children with acute and chronic ITP appeared in June 1981.1 IVIG has become a well-known and widely accepted treatment in ITP and now other autoimmune diseases, but the relevance of the story is that this was the last ITP treatment 'discovered' serendipitously. Since then, essentially all attempts to treat patients have been largely mechanism-of-action-driven. This is not to say that the exact mechanism of effect is completely known for each therapeutic; far from it, but there is at least reasonable understanding as to the aspect of the disease pathophysiology that is being primarily targeted. Thus, when considering simultaneous multidrug therapy (so-called "combination therapy") in ITP, prospects for success may be optimized when there is a 'method to the madness' rather than simply combinations of convenience. This is what we see in the study by Crickx and colleagues in this issue of BJH2: high rates of success in treating 'refractory' ITP may be achieved with a common-sense combination of one treatment to reduce platelet destruction via immunosuppression with another to increase platelet production via thrombopoietic stimulation. In their study, Crickx and colleagues retrospectively evaluated the outcomes of combination thrombopoietin receptor agonist (TPO-RA; romiplostim or eltrombopag) plus immunosuppressant (mycophenolate mofetil [MMF], azathioprine, cyclosporine, everolimus or cyclophosphamide) therapy of 39 adults with refractory ITP treated at 17 centres in France. Refractory ITP was defined as failure to respond to romiplostim, eltrombopag, splenectomy and rituximab. Importantly, single-agent TPO-RA therapy was previously ineffective in all patients, and approximately half had also received single-agent immunosuppressive therapy with no response. Defining platelet response according to International Working Group definitions (with the added requirement of a minimum response duration of three consecutive months), Crickx and colleagues observed at least a response in 77% of the cohort. This included a response in 6 patients and a complete response in 24 patients, with responses maintained for a median duration of 15 months. While adverse events were not infrequent, as would be expected in a population of patients with refractory ITP, they also did not appear to be consistently related in any significant way to overlapping drug toxicity of the two agents being used to treat the patient (i.e. they were primarily toxicities associated with one drug or the other). While 37% of the responders ultimately relapsed and their combination therapy discontinued due to loss of response, the rates of response and the durability of this response in most responders is quite promising and meritorious of confirmation in future studies of patients with refractory ITP. Given the failures of single-agent therapies prior to the success of the employed mechanistically diverse common-sense combination therapy in these patients, the authors conclude that the high response rates they observed may be attributable to this diversity. Of course, many other factors contribute to selection of certain combinations of treatment. Perhaps the two major ones beyond the ideal mechanism-driven circumstance are in fact convenience driven: availability of a certain treatment in a given location and the cost of the treatments. In this regard, the authors note that fostamatinib, a regulatory agency-approved ITP therapy, was not included as a potential immunosuppressant because it was not available in France over the duration of the cohort. Additionally, combining two novel but relatively expensive agents may not always be possible because of cost. This is probably one reason that corticosteroids have relatively frequently been combined with TPO-RAs,3-5 or that the FLIGHT trial combined two inexpensive agents in MMF and corticosteroids.6 These restrictions may simplify the task of choosing combination treatments, which might otherwise be challenging because of the relatively large number of choices. It is worth noting that combining agents with similar mechanisms can also be productive. IVIG plus intravenous anti-Rh D immune globulin appears to be at least additive, possibly because they interfere with platelet destruction via different pathways. Similarly, dual-agent TPO-RA therapy can be effective where single-agent therapy fails since each TPO-RA is believed to exert its effects in differing ways. If a recently published provocative study describing clonal CD8 cytotoxic T cells in ITP7 leads to a need to treat patients for this pathophysiology, it may well be that anti-thymocyte globulin and cyclosporine are used together as they are in severe aplastic anaemia. Despite the occasional publications describing combination therapy, monotherapy has been the persisting dominant treatment paradigm in ITP for decades in both the first- and later-line settings. In later-line settings, in particular more refractory patients, the paradigm of monotherapy continues to be supported by the development of novel therapeutics, most of which are developed as monotherapies in patient populations who have previously failed multiple lines of therapy. However, the promise of combination therapy leveraging multiple diverse mechanisms of action has begun to enter even novel therapeutic development in ITP and in studies repurposing newer biologic drugs. As one example, the combination of the anti-B-cell activating factor (BAFF) receptor monoclonal antibody belimumab (a biologic currently approved to treat systemic lupus erythematosus) in combination with rituximab has promising preliminary results in ITP8 and is under active investigation. Belimumab targets plasma cells and B cells and may prevent rebound responses to rituximab as suggested by the investigations to date completed by Mahevas and colleagues. Similarly, an investigational BAFF inhibitor, ianalumab, is currently under evaluation in combination regimens with corticosteroids in first-line ITP (NCT05653349) and eltrombopag in second-line ITP (NCT05653219). Additionally, ianalumab itself has a dual mode of action, as in addition to BAFF receptor blockade it is additionally engineered for direct ADCC-mediated B-cell depletion.9 With approaches like this in the novel therapy space along with well-done real-world studies like the one from Crickx and colleagues in this issue of BJH, the evidence base for use of combination therapy in ITP may mature such that certain combination approaches could eventually be recommended in evidence-based ITP practice guidelines and ultimately adopted in routine clinical practice in both early and later-line, refractory settings.10 Hanny Al-Samkari and James B. Bussel contributed equally to all aspects of the manuscript, from conception to completion. H. Al-Samkari is funded by the National Heart, Lung, and Blood Institute (1K23HL159313) and is the recipient of the American Society of Haematology Scholar Award. Dr. Al-Samkari reports research funding to his institution (Agios, Sobi, Novartis, Vaderis, Amgen) and consultancy (Agios, Sobi, Moderna, Novartis, Rigel, argenx, Forma, Pharmacosmos). Dr. Bussel reports advisory fees from Amgen, argenx, AstraZeneca, Janssen, Novartis, Rigel, Sanofi, Sobi, and UCB; and data and safety monitoring fees from UCB.