ABSTRACT

Conclusion:

Ibrutinib therapy causes a quite high overall response in steroid resistant chronic patients with GVHD and appears to be a good option in these patients.

Results:

A total of 10 steroid resi-stant chronic patients with GVHD who received ibrutinib was included. While 50% of the patients had more than one organ involvement, 50% had a single organ involvement. The most commonly affected organs were the skin and liver. The patients received a median of three lines of systemic therapy before ibrutinib. After a median of 210 days of ibrutinib usage, the complete response rate of patients was 40% and the partial response rate was 40%. Corticosteroids were completely discontinued in 30% of patients after ibrutinib were initiated. Before ibrutinib, patients were given a median of 0.3 mg/kg methylprednisolone. The median methylprednisolone dose after ibrutinib was 0.03 mg/kg.

Methods:

The characteristics and clinical outcomes of steroid-resistant chronic patients with GVHD receiving ibrutinib were retrospectively reviewed.

Introduction:

Chronic graft-versus host disease (GVHD) is a serious complication that develops in 35-50% of patients in the late period after allogeneic hematopoetic stem cell transplantation. About half of the patients are resistant to corticosteroids, which is the first-line treatment of chronic GVHD, and therefore new treatment options that can be effective in chronic GVHD are needed. In the present study, we aimed to share our experience with the use of ibrutinib therapy in patients with steroid-resistant chronic GVHD who have previously received multiple lines of systemic therapy.

Keywords:

Steroid-resistant graft-versus host disease, ibrutinib, corticosteroids, allo-HSCT, chronic GVHD

Introduction

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) is a curative treatment option for many hematological diseases such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, aplastic anemia and paroxysmal nocturnal hemoglobinuria. However, early (<3 months) and late (>3 months) complications that cause transplant-related morbidity and mortality are observed in many patients after allo-HSCT.

Early complications of allo-HSCT include graft-versus host disease (GVHD), bacterial, viral and fungal infections, engraftment syndrome, hemorrhagic cystitis, capillary leak syndrome, graft failure, hepatic sinusoidal obstruction syndrome, pulmonary complications and transplant-related thrombotic microangiopathy (1,2). The mortality rate due to early complications varies between 5% and 40%, depending on factors such as transplantation from donor, pre-transplant regimen, age, and comorbidities of the patient (3).

Late complications following allo-HSCT include chronic GVHD, idiopathic pneumonia, bronchiolitis obliterans, pulmonary and nonpulmonary infections, hypogonadism, osteopenia, hypertension, hypothyroidism, dyslipidemia, diabetes mellitus, chronic kidney disease, cardiomyopathy, heart failure, and secondary malignancies (4). Although allo-HSCT is a curative option for treating many hematological diseases, life expectancy after allo-HSCT is still lower (5,6). The most common causes of mortality in the late period following allo-HSCT are recurrence of primary malignancy, chronic GVHD, infections, secondary malignancies, pulmonary complications, and cardiac toxicity, respectively (6).

Chronic GVHD is a severe difficulty that improves in 35-50% of patients in the late period after allo-HSCT and is the second most common cause of mortality in patients with allo-HSCT (6,7). In patients with chronic GVHD, the most commonly involved organ is the skin, but other organs such as the mouth, eyes, liver, gastrointestinal system, lungs, joints, fascia, genital organs, and hematopoietic system can also be involved (8,9). In recent years, with the increasing number of patients with allo-HSCT, the number of patients with chronic GVHD has also increased. Approximately half of the patients are resistant to corticosteroids, which are the first choice for treating chronic GVHD; thus, new treatment options that can be effective in chronic GVHD are needed.

The guidelines recommend that patients should participate in well-designed clinical trials because there is no standard second-line treatment for chronic GVHD (10,11). In the absence of a clinical trial option, guidelines recommend the administration of one of the following agents: ibrutinib, ruxolitinib, abatacept, imatinib, calcineurin inhibitors, alemtuzumab, extracorporeal photopheresis, hydroxychloroquine, low-dose methotrexate, mTOR inhibitors, bortezomib, mycophenolate mofetil, pentostatin, rituximab. Ibrutinib has been approved by the US Food and Drug Administration for the treatment of chronic GVHD patients who are resistant to one or more lines of systemic therapy.

Due to the uncertainty of optimal therapy in corticosteroids resistant chronic GVHD patients, we aimed to present our experience in chronic GVHD patients who have previously received multiple lines of systemic therapy.

Methods

Patients who developed chronic GVHD between February 2011-2021 and who were started on ibrutinib after at least two lines of treatment were included in the study. After the study was approved by the İnönü University Ethics Committee (decision no: 2022/2946), demographic, clinical, and laboratory data of the patients were retrospectively analyzed using the hospital electronic information system. Written informed consent was obtained from the patients included in the study.

Within the framework of the criteria recommended by the National Institutes of Health (NIH), chronic GVHD was defined as a complication occurring at any time after allo-HSCT and differentiated from acute GVHD with its clinical features (12). Chronic GVHD severity was defined as mild, moderate, and severe within the framework of the criteria recommended by the NIH (13). While systemic treatment was initiated with corticosteroids in patients with moderate to severe chronic GVHD, it was not preferred in patients with mild chronic GVHD.

Ibrutinib was initiated at a dose of 420 mg per day and continued at this dose until grade 3 or 4 toxicity occurred. We reduced the ibrutinib dose to 140 mg in patients who were given posaconazole as antifungal prophylaxis.

Ibrutinib-related adverse events were classified according to the Common Toxicity Criteria for Adverse Events version 5.0 (12).

As recommended by the NIH, patients with a resolution of all symptoms in all involved organs were considered to have a complete response to treatment. Patients with improvement in at least one involved organ without progression in other organs were considered to have a partial response to treatment. The overall response rate was considered as the sum of the complete response rate and the partial response rate (12).

Statistical Analysis

IBM SPSS 25.0 was used as the statistics program. Normality analysis of the data was performed using the Shapiro-Wilk test, and the data were given as median, range, and percentage.

Results

A total of 10 patients with steroid-resistant chronic GVHD who received ibrutinib were included in this study. Steroid resistant chronic GVHD developed in seven patients with AML, two with ALL, and one with beta thalassemia major. While 50% of the patients had more than one organ involvement, 50% had a single organ involvement. The most frequently involved ones are skin (60%) and liver (60%) (Table 1). All patients with skin involvement (n=6) had non-sclerotic features. There were no patients with sclerotic involvement.

All patients included in the study received myeloablative regimen before allo-HSCT. In our patients, chronic GVHD was diagnosed a median of 165 (50-500) days after allo-HSCT. Ibrutinib was initiated in a median of 150 (102-660) days after the diagnosis of chronic GVHD. Before ibrutinib, patients had received a median of 3 (2-4) lines of systemic therapy, including corticosteroids, cyclosporine, mycophenolate mofetil, and extracorporeal photopheresis.

Although the median follow-up time for 10 patients was 394 (100-750) days, it was 210 (30- days) under receiving ibrutinib. After a median of 210 days of treatment with ibrutinib, the complete response rate of patients was 40% and the partial response rate was 40% (Table 2).

Median time to onset of a response to ibrutinib in 8 patients was 52 (25-125), and median response duration of patients to ibrutinib was 143 (70-415) days. Organ involvement features of patients are given in Table 3.

After a median follow-up of 394 days, median failure-free survival could not be achieved in both the entire population and those who responded to ibrutinib (Figure 1, 2). No association was found between the severity of GVHD and the ibrutinib response (p=0.378). When those who received ≤3 lines of treatment before ibrutinib and those who did not receive more than 3 lines of treatment were compared, no difference was found between the GVHD response and OS of the two groups (p=1 and p=0.537, respectively).

We observed ibrutinib-related adverse events in two (20%) of 10 patients. In one patient (patient 2) with liver GVHD, ibrutinib was discontinued because of elevated liver enzymes (grade 3 alanine aminotransferase elevation) 30 days after initiation. This adverse event resolved 20 days after ibrutinib was discontinued. In another patient (patient 3), we observed grade 4 thrombocytopenia 50 days after initiation. Ibrutinib was discontinued for 27 days, the adverse event disappeared, and we continued ibrutinib at the same dose.

Corticosteroids were completely discontinued in 30% of patients after ibrutinib were initiated. Before ibrutinib treatment, patients were given a median of 0.3 mg/kg methylprednisolone. The median methylprednisolone dose after ibrutinib was 0.03 mg/kg. The median time to reduce the steroid dose was 43 (15-295) days. In 3 patients, steroid was completely discontinued after a median of 96 (50-115) days.

Discussion

Chronic GVHD is the most important cause of non-relapse mortality and affects quality of life in the late period following allo-HSCT (6,14). The treatment approach is not standard in steroid resistant chronic patients with GVHD because well-designed comparative studies of in these patients are lacking.

In retrospective studies that evaluated the efficacy of mycophenolate mofetil, sirolimus, rituximab, pentostatin, and ruxolitinib in steroid resistant chronic GVHD patients, overall response rates ranged from 55-81% (15-19). In phase 2 studies evaluating the efficacy of imatinib, sirolimus (in combination with tacrolimus), rituximab, and pentostatin in steroid resistant chronic GVHD patients, overall response rates ranged from 27-63% (20-22). Because of the uncertainty of the optimal agent to be chosen in second-line therapy, treatment should be determined according to affected organs (eg. sirolimus for joint, ruxolitinib for skin), patient renal and liver functions, side effects of the agents, patient preferences and clinician's experience (7).

Ibrutinib has been shown to inhibit Bruton’s tyrosine kinase and interleukin-2-inducible T-cell kinase, which play an important role in the pathogenesis of chronic GVHD, thereby reducing the activation of T- and B-cells in the murine chronic GVHD model (23). Based on this data, researchers designed a phase 1b/2 study to determine the safety and efficacy of ibrutinib in chronic GVHD patients who received at least 1 line of systemic corticosteroids therapy. Eighty-six percent of patients had mouth, 81% had skin, 36% had gastrointestinal system, 7% had liver, and 5% had a lung involvement. In this study, after the initiation of ibrutinib, a complete response was obtained in 21.4% (9/42) of patients and a partial response was obtained in 45.2% (19/42) of them in addition, 47.6% of patients (20/42) had a sustained response to ibrutinib for 20 weeks or longer (24). In the present study, two-thirds of the patients responded to ibrutinib, whereas the response rate was found to be slightly higher (%80) in our study evaluating fewer chronic GVHD patients.

In a retrospective single-center study in a total of 22 pediatric patients with chronic GVHD, a partial response was achieved in 54.5% of patients with ibrutinib at a dose of 250 mg/m². Ibrutinib was reduced by 50% in 16 patients who received voriconazole or posaconazole concomitantly. Of the 12 patients who responded to ibrutinib, the corticosteroids dose was reduced in 9 of them, and corticosteroids were discontinued in 2 of them (25). In our study, corticosteroids were completely discontinued in 3 of 8 patients who responded to ibrutinib, and the corticosteroids were reduced in 3 of them.

In a retrospective study of adult GVHD patients, a total of 17 patients with pulmonary chronic GVHD who received an average of 4 lines of treatment before ibrutinib and had an average of 5 organ involvement were included. Of the 14 patients who continued ibrutinib for 180 days, 2 (14.3%) had a partial response, 9 (64.3%) had a stable disease, and 3 (21.4%) had a disease progression (26). In this study, response rates to ibrutinib may have been found to be low because of the evaluation of the responses of patients with severe pulmonary chronic GVHD with multiple organ involvements and resistant to four lines of therapy. Patients in our study had less organ involvement and none the patients had the pulmonary involvement. Therefore, the response rate to ibrutinib in our study was found to be much higher than that in this study.

Study Limitations

The main limitations of the study are its retrospective design and the small number of patients.

Conclusion

Ibrutinib causes a quite high overall response in steroid resi-resistantnic patients with GVHD and appears to be a good option in these patients. However, prospective trials comparing the effectiveness of ibrutinib with other drugs used in chronic GVHD are needed, especially in lung involvement and/or multiorgan involvement.

Ethics Committee Approval: İnönü University Scientific Research and Publication Ethics Committee (date: 11.01.2022/decision no: 2022/2946).

Informed Consent: Written informed consent was obtained from the patients included in the study.

Peer-review: Externally peer reviewed.

Authorship Contributions

Concept: A.S., İ.K., E.K., A.K., L.H.T.; Design: A.S., M.A.E., E.K., E.H., A.K., Ö.F.B., S.G.Ö.; Data Collection or Processing: A.S., M.A.E., İ.K., E.K., İ.B., E.H., A.K., Ö.F.B., L.H.T.; Analysis or Interpretation: A.S., M.A.E., İ.B., S.B., E.H., A.K.; Literature Search: A.S., İ.K., İ.B., S.B., E.H., A.K.; Writing: A.S., S.B., L.H.T.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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The Experience of Ibrutinib in Chronic Graft-Versus-Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Experience