Low dose IL-2 in patients with steroid-dependent dysimmune manifestations associated with myelodysplastic syndromes: a three-case report

Abstract

Introduction

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) can be associated with systemic inflammatory and autoimmune diseases (SIADs), with a frequency ranging from 10% to 28% [1]. The dysregulation of the bone marrow could trigger an inappropriate immune cell activation and the secretion of inflammatory cytokines, but the pathophysiology of dysimmune disorders associated to MDS is largely unknown [2]. The management of these dysimmune manifestations consists in glucocorticoids, generally enabling a rapid response, but generating a high rate of steroid dependence. Conventional immunosuppressive therapy is limited in the context of MDS cytopenias and biologics (including rituximab, TNFa, IL1-R and IL6R inhibitors) have been reported to be less effective than in idiopathic autoimmune diseases [3]. MDS-specific therapy, especially azacitidine, has shown some efficacy in SIADs associated with MDS but only few data are available. Prospective studies are needed to confirm the efficacy of azacitidine in these situations [4] .

Regulatory T cells (Tregs) play an essential role in maintaining immunological tolerance, controlling inflammations and preventing the occurrence of dysimmune manifestations. MDS patients at early stages have decreased regulatory Treg proportions, associated with increased levels of cytotoxic CD8+ T cells and Th17 cells [5]. Treg expansion/activation could thus be interesting in early MDS, and particularly in patients with SIADs.

Recombinant IL-2 was initially used at high doses to treat cancer, with limited efficacy and with severe side effects [6]. IL-2 was subsequently repositioned at a low dose (ld-IL2) as a Treg activator for the treatment of autoimmune diseases [7] first in HCV-induced cryoglobulinemia vasculitis [8], and then in many autoimmune diseases including type 1 diabetes and lupus [8–10]. These clinical trials indicated that ld-IL-2 was safe, could activate and expand Tregs without activating effector T cells, and lead to clinical improvement in a wide range of autoimmune and inflammatory diseases [8–10]. These data are interesting but efficacy of ld-IL2 autoimmune diseases needs confirmation and the potential of ld-IL2 for the management of dysimmune manifestations in the subset of the paraneoplastic disease remained to be evaluated.

Here, we report a case series of three patients from the internal medicine department of Saint Antoine Hospital (Paris, France) with refractory or steroid-dependent MDS-associated SIADs treated by ld-IL-2.

Case reports

Patient 1

A 70-year-old woman without medical history presented wrists and belts inflammatory pain associated with acute-phase reactants, leading to the diagnosis of polymyalgia rheumatica in January 2010. She received oral glucocorticoids (0.25 mg/kg/day of an equivalent of prednisone) that led to partial clinical improvement, and remained steroid-dependent at 15–30 mg/day for over 2 years. Following a persistent anaemia, MDS with excess blasts-2 with trisomy 14 (Revised International Prognostic Scoring System, IPSS-R at 6, without somatic mutation) was diagnosed in January 2014 and six cycles of azacytidine were administered. Despite partial haematological response, there was no steroid-sparing effect of azacytidine and she presented a steroid dependence of at least 15 mg/day to prednisone and fractural osteoporosis. With regard to cytopenia (including neutropenia), the infectious risk of azacitidine limiting the use DMARDs or tocilizumab, ld-IL-2 was initiated in January 2016, concomitantly with a maintenance therapy of azacitidine. After 6 months of ld-IL-2, she was in clinical and biological remission and partial hematological response, with 5 mg/day of prednisone, and ldIL-2 was then discontinued (azacitidine was continued alone). Eight months after ld-IL-2 discontinuation, the patient progressed to acute myeloid leukaemia and died.

Patient 2

A 65-year-old man presented relapsing ear chondritis, skin lesions and arthalgias. Laboratory data revealed the presence of acute-phase reactants, and the complete immunological screening was negative. Skin biopsies showed the presence of leucocytoclasic vasculitis and lesions consistent with Sweet’s syndrome. Relapsing polychondritis associated with Sweet’s syndrome was diagnosed, and he received steroids associated with azathioprine. Due to a persistent anaemia, MDS was diagnosed: CRDM without excess of marrow blasts and cytogenetic abnormalities, IPSS-R at 2 and without somatic mutations. Because of a steroid dependence of 40 mg/day to a prednisone equivalent, he received various immunomodulatory therapies, which were either ineffective (colchicine, disulone, tocilizumab) or discontinued because of the side effects (anakinra with important reactions at infusion sites, infliximab complicated with recurrent pneumopathies). Because of the anaemia that was refractory to recombinant EPO, azacitidine was started and, after six cycles, helped decrease prednisone to 15 mg/day concomitant to complete hematological response. After 28 months on azacitidine treatment (21 cycles), we still observed an inflammatory clinical relapse when we tried to decrease steroids under 15 mg/d (fever, arthritis and neutrophilic dermatosis). Ld-IL-2 therapy was started because of the recurrent infectious complications and the inefficacy or intolerance of the other bDMARDs. Despite moderate side effects (skin reactions at infusion sites), Ld-IL-2 was maintained and made it possible to decrease prednisone to 5 mg/day after 5 months of Ld-IL-2 therapy and sustained remission without any infectious adverse events (Table 1). The intervals of azacytidine and Ld-IL-2 administration were progressively increased to every 6 weeks and 3 weeks, respectively.

Patient 3

In 2016, a 70-year-old man presented vascular purpura, arthralgia and fever. His medical history included type 2 diabetes and severe chronic renal insufficiency related to diabetic and vascular nephropathy. Skin biopsy showed leukocytoclastic vasculitis, without IgA deposits, and IgA plasma levels and autoimmune screening was negative. Because of a persistent anaemia, MDS was diagnosed 3 months later: MDS with single-lineage dysplasia, without cytogenetic abnormalities, with an IPSS-R score of 3, and the presence of ZRSR2 and SF3B1 mutations. The low risk MDS required recombinant EPO, which made it possible to bring haemoglobin levels back to normal. A diagnosis of vasculitis associated to MDS was made, and steroids at 0.5 mg/kg were started that led to rapid clinical and biological responses. Because of the steroid dependence at 15 mg/day to a prednisone equivalent and acute-phase reactants (CRP at 80 mg/l), IL-1R antagonist (anakinra) was initiated at 100 mg/day, but was discontinued because of severe skin reactions at the site of injection. Ld-IL-2 was initiated at 1 MUI/day, during five consecutive days, and then every 15 days for 3 months without efficacy on inflammatory parameters (purpura and persistent acute-phase reactants, CRP levels at 60 mg/l) (Table 1). No MDS progression was noted under ld-IL-2 and Hb levels remained stable with EPO.

Discussion

Here, we report the use of ld-IL-2 for the management of steroid-dependent dysimmune manifestations associated to MDS. Association of azacitidine and ld-IL-2 showed a transient effect on the control of the disease in two cases with steroid sparing effects. No serious adverse events were reported and there were grade 1 skin reactions at the site of injection in two cases.

These dysimmune manifestations constitute paraneoplastic syndromes and their management can be challenging, as underlying cytopenia and the risk of infectious adverse events can limit the use of conventional immunosuppressive therapies [11]. Azacitidine has shown benefit for the treatment of both MDS and SIADs [4], but is associated with infectious adverse events. Immunosuppressive or immunomodulatory therapies have been shown to be disappointing, as demonstrated in one of our patients treated by several lines of therapies. Steroids remain the best drug to control SIADs, as observed in our patients, but usually with high rates of steroid dependence as observed in all our patients. Consequently, alternative therapies without increased risks of infectious adverse events are highly warranted in the subset of SIADs associated to MDS.

Low concentrations of IL-2 selectively activate Tregs lymphocytes [7]. In vivo expansion and activation of Tregs using ld-IL-2 has shown promising results in several SIADs [10]. A recent randomized placebo-controlled trial using induction therapy of ld-IL-2 at 1 MUI has demonstrated its efficacy and safety in SLE [9].

In our patients, all presenting stable MDS, the need for steroid-sparing drugs and previous infectious adverse events motivated the use of low doses of IL-2. It allowed steroid-sparing effects in two out of the three cases, and was safe with regard to infectious complications and the underlying MDS. Although ld-IL-2 has not been shown to be effective in treating MDS [12], the use of this treatment could, therefore, be interesting in patients with SIADs.

Conclusion

In this case series, the use of ld-IL-2 in association with azacitidine was safe and allowed, at least temporally, steroid-sparing effects, without inducing any progression of the MDS in two of the three patients with dysimmune features associated to MDS. Use of ld-IL-2 could be an option for patients with a high level of steroid dependence and/or with treatment-related adverse events (as infections or osteoporosis). These results should prompt the evaluation of ld-IL2 in controlled trials.

Acknowledgements

Informed consent was obtained from the subjects. All the authors have access to the data and played a part in drafting the manuscript.

Funding: No specific funding was received from public bodies, commercial or not-for-profit sectors in order to carry out the work described in this article.

Disclosure statement: D.K. is the inventor of a patent claiming low doses of IL-2 in autoimmune diseases owned by his academic institution and licensed to ILTOO pharma for which he is a consultant. A.M. received various fees for speaking and for trials at APHP promotion with financial help from Roche Chugai, GSK and Sanofi. T.C. received meeting attendance grants from Novartis and Add Medica, received research grant from Novartis, was a member of the advisory/scientific board for Novartis and Bristol-Myers Squibb and received personal fees from Novartis, Bristol-Myers Squibb and AstraZeneca.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

References

Author notes