Abstract
Background
Autoimmune conditions in B‐cell lymphomas are frequent. Steroids are standard of care, but many patients require other immunosuppressive agents. Ibrutinib is a Bruton Tyrosine Kinase inhibitor that is approved for B‐cell indolent lymphoma treatment. We evaluated the use of ibrutinib in previously treated hematologic immune manifestations associated with B‐cell lymphomas.
Results
We conducted a retrospective multicentric observational study. Patients presenting with active, relapsed/refractory B‐cell lymphoma associated hematological immune manifestation (autoimmune cytopenia, acquired immune‐mediated bleeding disorders) were included. Twenty‐five patients were identified. Median age at ibrutinib introduction was 69 years (range 44–84) and median number of previous treatment lines before ibrutinib was 2 (1–7). Twenty‐two patients (88%) were on concomitant stable treatment at inclusion. Within a median exposure of 8 months (2–35), overall response rate to ibrutinib on immune manifestations was 76% (95% CI, 54.9–90.6); complete response rate 44%. Fourteen patients (63%) were able to be weaned from concomitant treatments. Fourteen patients (56%) presented treatment‐related adverse events, mostly Grade 1 or 2.
Conclusions
Ibrutinib in this setting provides good efficacy and safety profile. Clinical trials are needed to define subgroups of patients who will benefit from this strategy and establish its place in the therapeutic arsenal.
Keywords: B‐cell lymphoma, hematologic immune disorders, ibrutinib
1. INTRODUCTION
Autoimmune manifestations associated with B‐cell lymphomas are a well‐known and frequent event, with an incidence rate of 4%–8% based mostly on retrospective series. 1 , 2 , 3 Such manifestations can occur at any time during the course of the disease, either before B‐cell lymphoma onset, at the time of diagnosis or even several years after. 4 Hematologic immune disorders include autoimmune cytopenia such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), immune‐mediated neutropenia, pure red cell aplasia, Evans syndrome, or other acquired immune‐mediated bleeding disorders. Independently from the natural course of the lymphoma, those conditions can also appear after specific treatment such as targeted therapies 5 , 6 or purine analogs. 7 Steroids remain the first therapeutic option to treat these manifestations, but many patients become refractory, steroid dependent, or relapse, requiring other treatments such as anti‐CD20 or immunosuppressive agents. Efficacy and weaning of such treatments remain uncertain.
Common pathophysiological features exist between autoimmunity and lymphomagenesis, and B‐cell receptors seem to play an important role in downstream activation of kinases such as Bruton tyrosine kinase (BTK). 8 , 9 , 10 This enzyme activates intracellular pathways leading to formation of transcriptional factors favoring B‐cell development, survival over apoptosis, and immune tolerance breakdown. 11 Ibrutinib is a first‐in‐class BTK inhibitor approved for treatment of indolent B‐cell neoplasms such as chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal‐zone lymphoma (MZL). Few studies have described the use of this drug to treat immune conditions associated with lymphoma, mainly case reports or retrospective phase III subgroup analyses. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 Results are promising but focus mostly on CLL patients. Additionally, patients in clinical trials are not representative of routine clinical practice and patients with uncontrolled manifestations are often excluded. Imprecisions regarding previous therapeutic lines and missing safety‐related data were noted, limiting the interpretation of the results. To date, only two studies have reported real‐life use of ibrutinib as a treatment for refractory hematologic autoimmune condition in patients with CLL, yielding a 58% and 91% overall response rate, respectively, and few adverse events. 6 , 23 Similar studies concerning the efficacy of ibrutinib to treat hemolysis in secondary cold agglutinin disease (CAD) were also reported. 24
In this study, we evaluated the efficacy and safety of ibrutinib to treat patients presenting with active refractory/relapsed hematologic immune disorders associated with indolent B‐cell lymphomas in routine clinical practice.
2. METHODS
This retrospective observational study was conducted throughout the national network of the French reference center for adult immune cytopenia (CERECAI), including 12 departments of internal medicine/clinical immunology and clinical hematology, and was conducted in compliance with the Good Clinical Practice protocols and Declaration of Helsinki principles.
2.1. Study population
Patients aged ≥18 years were eligible if they had a diagnosis of indolent B‐cell lymphoproliferation associated with a hematologic immune disorder (isolated or combined autoimmune cytopenia or acquired immune‐mediated bleeding syndrome) and at least one prior therapeutic line for immune condition. Other eligibility criteria included ibrutinib introduction for the management of an associated immune disorder. The main exclusion criterion was the introduction of ibrutinib to treat a high‐burden tumor.
Diagnoses of lymphoproliferation and associated immune disorder were realized in each center. For immune manifestations, basal characteristics were collected. For AIHA, hemolysis parameters and direct antiglobulin test (DAT) specificity were searched. 25 Data on specific antibodies for ITP and immune‐mediated neutropenia were collected whenever available. 26 If needed, bone marrow examination was performed, especially for thrombocytopenia and neutropenia to be considered as immune‐mediated rather than secondary to a bone marrow involvement. Details of prior immunological therapeutic lines, defined by specific therapies to target immune conditions, were assessed. Particular attention to exposure to corticosteroids, anti‐CD20, or splenectomy was done. Additionally, stable concomitant therapy was allowed at ibrutinib initiation if necessary.
Concerning tumoral assessment, a basal evaluation (clinical and/or radiological per recommendation) was done and another assessment was performed at the end of observation or in the case of premature arrest of ibrutinib. We decided not to assess cytogenetic and molecular characteristics of each lymphoproliferation because of the heterogeneity of lymphoproliferations.
2.2. Outcomes
The primary outcome was the assessment of the efficacy of ibrutinib in the treatment of hematologic immune disorder associated with B‐cell lymphomas. Overall response rate (complete response [CR] plus partial response [PR]) was the primary endpoint.
As no immune response criteria to ibrutinib were available in the global literature, we created new criteria. CR was defined according to international recommendations 25 , 26 , 27 , 28 for each manifestation in the absence of concomitant treatment; PR was defined according to standard recommendations for each manifestation in the absence of associated treatment or if CR criteria were obtained for patients who could not be wean from concomitant treatment. Failure was defined as stable disease, the need to add another immunosuppressive therapy or if CR or PR criteria were not met (Supplemental Tables). Resolution of DAT or disappearance of immune specific antibodies (e.g., antiplatelet antibodies, antigranulocytic inhibitors or FVIII inhibitors) after treatment initiation was assessed per physician discretion.
Secondary outcomes included tumoral response assessment, safety assessment, and treatment weaning for patients with ongoing treatment at ibrutinib initiation. Response criteria for each B‐cell lymphoma were in accord with international recommendations for each lymphoproliferation. 29 , 30 , 31
2.3. Safety assessment and follow‐up
Ibrutinib dose followed standard recommendations (420 mg per day for CLL and WM; 560 mg per day for MZL or MCL) and adaptation was done at the physician's discretion. Safety assessment included evaluation of adverse events (AEs) described in the literature, especially cardiovascular, bleeding, and infectious. Other events were considered significant if they modified the ibrutinib dose or discontinuation. Particular attention was paid to emergent autoimmune cytopenia, a phenomena described after ibrutinib introduction. 5
Patients were monitored per physician discretion. Patients were censored: at the time of last follow‐up (e.g., June 2021); on discontinuation of ibrutinib (reason was documented); or death.
2.4. Statistical analysis
Categorical variables were expressed as numbers (percentage). Quantitative variables were expressed as median either by IQR (interquartile range) or range. Clinical immune response after treatment with ibrutinib and tumoral response were calculated with exact 95% confidence interval (95% CI) by using Clopper–Pearson method. Data were analyzed using the SAS software version 9.4 (SAS Institute, Cary, NC).
3. RESULTS
3.1. Patients
A total of 25 patients were included. Median age at ibrutinib introduction was 69 years (range 44–84 years). Most of the patients were male (17 patients, 68%) (Table 1). We identified mostly CLL (18 patients, 72%), followed by WM (four patients, 16%), two patients with MZL, and one patient with primary cold agglutinin disease (CAD). The majority of patients (16 patients, 64%) had low tumoral burden diseases and were treatment‐naive for tumoral condition. Those requiring treatment (nine patients, 36%) received mostly either fludarabin‐based regimen or anti‐CD20 based regimen.
TABLE 1.
Baseline demographic and clinical characteristics (n = 25)
| Demographic characteristics | |
|---|---|
| Age, years | 69 (44–84) |
| Male sex (%) | 17 (68) |
| Underlying lymphoproliferation (%) | |
| CLL | 18 (72) |
| WM a | 4 (16) |
| MZL b | 2 (8) |
| CAD | 1 (4) |
| Binet Stage, for CLL only (n = 18) | |
| A | 13 (72) |
| B | 3 (17) |
| C | 2 (11) |
| Associated Immune condition (%) | |
| AIHA | 15 (60) |
| ITP | 3 (12) |
| Evans' syndrome | 4 (16) |
| Immune mediated neutropenia | 1 (4) |
| Acquired immune‐mediated bleeding disorder | 2 (8) |
| Median time between lymphoproliferation and immune condition diagnosis | |
| Time for AIHA, months | 23 (0–48) |
| Time for ITP, months | 48 (0–64) |
| Time for Evans syndrome, months | 20.5 (2.5–114.5) |
| Time for autoimmune neutropenia, months | 15 |
| Time for acquired immune‐mediated bleeding disorder, months | 121.5 (69–174) |
| Prior immunologic therapeutics line (range) | 2 (1–7) |
| Number of systemic therapies for lymphoma, prior to ibrutinib (range) | 0 (0–4) |
| Therapies before ibrutinib (n = 9) | |
| Fludarabine‐based regimens | 6 (66) |
| Bendamustine ± Rituximab | 3 (33) |
| CHOP ± Rituximab | 3 (33) |
| DRC | 2 (22) |
Note: Values are expressed as median (interquartile range) or numbers (percentage) unless specified otherwise.
Abbreviations: AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; CLL, chronic lymphocytic leukemia; DRC, dexamethasone–rituximab–cyclophosphamide; ITP, immune thrombocytopenia; MZL, marginal zone lymphoma; WM, Waldenström macroglobulinemia.
All Waldenström diseases were considered as stage IV lymphomas according to Ann Arbor classification, due to bone marrow involvement.
One patient with marginal zone lymphoma had an isolated splenic involvement; data were missing for the second patient.
AIHA was by far the most frequent associated‐immune disease (n = 15 patients), followed by Evans syndrome (n = 4) and ITP (n = 3). We also identified one case of immune‐mediated neutropenia and two cases of acquired immune‐mediated bleeding disorder, one with acquired hemophilia due to an anti‐FVIII auto‐antibody and one case with acquired von Willebrand disease. Among AIHA, 13 patients had warm AIHA defined by a positive DAT with an IgG or an IgG + C3d positive pattern. Three patients diagnosed with Evans syndrome were revealed by ITP.
Median time elapsed between immune disorder diagnosis and ibrutinib introduction was 30 months and differed for each manifestation. Median number of prior therapies was two (range 1–7). Concerning prior specific immune therapies, 20 patients (80%) received steroids alone; 9 patients (32%) received rituximab monotherapy, and 18 (72%) received rituximab in association, mostly with alkylating agents or steroids. One patient underwent splenectomy (4%). All manifestations were active at inclusion, with relatively severe phenotypes (Table 2). At the time of introduction, 22 patients (88%) were already being receiving a treatment to control the immune manifestation.
TABLE 2.
Immune characteristics at ibrutinib introduction
| Patient | AIC | Lymphoma | Age, years | TTT, montHS a | WBC (×109/L) | ANC (×109/L) | ALC (×109/L) | Hb (g/dL) | Plts (×109/L) | FVIII activity, % | WF activity, % | Associated treatment b | Immune outcome | Tumoral outcome | Duration, c months |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | AIHA | CLL | 70 | 40 | 46.9 | 5.1 | 41.9 | 6.6 | 101 | / | / | GC | CR | CR | 13 |
| 2 | AIHA | CLL | 74 | 7 | 4.6 | 2.7 | 6 | 6.2 | 113 | / | / | GC | CR | CR | 27 |
| 3 | AIHA | CLL | 61 | 2 | 64.9 | 3.8 | 60.7 | 7.6 | 110 | / | / | Rituximab | PR | PR | 8 |
| 4 | AIHA | CLL | 63 | 16 | 105 000 | 93 | 7.0 | 93 | / | / | GC | PR | PR | 5 | |
| 5 | AIHA | CLL | 69 | 31 | 16 | 2.6 | 8.2 | 10.5 | 190 | / | / | GC | CR | PR | 5 |
| 6 | Immune neutropenia | CLL | 62 | 32 | 1.5 | 0.3 | 1.1 | 10.2 | 100 | / | / | GC | PR | PR | 3 |
| 7 | ITP | WM | 84 | 3 | 8.2 | 6.4 | 0.9 | 9.7 | 12 | / | / | TPO‐RAs | PR | / | 8 |
| 8 | ITP | CLL | 73 | 4 | 100 000 | 91 | 8.0 | 2 | / | / | GC | Failure | PR | 2 | |
| 9 | Acquired coagulopathy | CLL | 75 | 14 | 9.5 | 8.2 | 1.1 | 12.0 | 216 | 18 | / | GC | CR | CR | 25 |
| 10 | AIHA | CAD | 78 | 23 | 10.3 | 7.8 | 1.3 | 6.9 | 541 | / | / | Transfusion | Failure | PR | 12 |
| 11 | Acquired coagulopathy | WM | 75 | 68 | 4.8 | 3.2 | 0.8 | 9.4 | 212 | 31 | 25 | / | CR | PR | 4 |
| 12 | AIHA | MZL | 79 | 1 | 14 | 12.6 | 5.4 | 183 | / | / | GC | Failure | CR | 2 | |
| 13 | Evans Syndrome | CLL | 64 | 49 | 60.1 | 6.6 | 46.9 | 8.5 | 2 | / | / | TPO‐Ras | PR | SD | 10 |
| 14 | AIHA | MZL | 70 | 336 | 6.1 | 3.8 | 1.2 | 7.9 | 236 | / | / | Transfusion | Failure | SD | 9 |
| 15 | ITP | MW | 69 | 118 | 3.2 | 2.1 | 0.8 | 10.8 | 4 | / | / | GC | CR | PR | 25 |
| 16 | AIHA | CLL | 68 | 71 | 52.4 | 11.6 | 45.3 | 6.0 | 71 | / | / | GC | Failure | SD | 2 |
| 17 | AIHA | CLL | 74 | 5 | 3.2 | 0.1 | 2.2 | 4.7 | 29 | / | / | Rituximab | PR | PR | 10 |
| 18 | AIHA | CLL | 68 | 35 | 9.7 | 6.5 | 2.5 | 8.1 | 240 | / | / | / | CR | CR | 28 |
| 19 | Evans Syndrome | WM | 67 | 54 | 5.2 | 2.8 | 1.2 | 8.7 | 28 | / | / | GC | PR | SD | 5 |
| 20 | Evans Syndrome | CLL | 69 | 29 | 3.1 | 1.5 | 1.1 | 13.1 | 6 | / | / | TPO‐Ras | CR | CR | 7 |
| 21 | AIHA | CLL | 44 | 3 | 130 000 | 6 | 120 000 | 4.4 | 182 | / | / | / | Failure | PR | 2 |
| 22 | AIHA | CLL | 73 | 30 | 7.5 | 1.8 | 5.6 | 9.9 | 165 | / | / | Rituximab | CR | CR | 24 |
| 23 | Evans Syndrome | CLL | 63 | 46 | 28 | 5.7 | 21.3 | 7.1 | 246 | / | / | GC | CR | CR | 27 |
| 24 | AIHA | CLL | 70 | 1 | 96.4 | 8.7 | 84.3 | 9.5 | 152 | / | / | GC | CR | CR | 35 |
| 25 | AIHA | CLL | 76 | 189 | 8 | 3.5 | 3.5 | 10.7 | 86 | / | / | Transfusion | PR | CR | 8 |
Abbreviations: AIC, autoimmune condition; AIHA, autoimmune hemolytic anemia; ALC, absolute lymphocytic count; ANC, absolute neutrophilic count; CR, complete response; GC, glucocorticosteroids; Hb, hemoglobin; ITP, immune thrombocytopenia; Plts, platelets; PR, partial response; SD, stable disease; TPO‐RAs, thrombopoietin receptor agonists; TTT, time to treatment; WBC, white blood count; WF, Willebrand factor.
Defined by the time between autoimmune condition diagnosis and ibrutinib introduction.
At ibrutinib introduction.
Duration of ibrutinib.
Median duration of ibrutinib exposure at time of analysis was 8 months (IQR 5–24). Fourteen patients (56%) discontinued treatment. Reasons for discontinuation included severe AEs (Grade 3/4) in four patients (16%), continuous complete remission in three patients (12%), primary failure in two patients (8%), and relapse in four patients. Median time to relapse was 7.8 months (IQR 4.2–9.7).
3.2. Efficacy
In this specific population, the overall response rate (ORR) was 76% (95% CI, 54.9–90.6), consisting of 44% with a CR (11 patients) and 32% with a PR (eight patients) using our response criteria (Figure 1A). Among the six failures, three occurred in CLL patients, two in MZL patients, and one in the patient with CAD. Responses according to each autoimmune condition is reported in Figure 1B. For patients who were monitored for the disappearance of antibodies, resolution of DAT occurred in one patient and FVIII inhibitor disappeared for the patient with acquired hemophilia.
FIGURE 1.
Overall response rates to ibrutinib. For all manifestations (A) and according to each manifestation (B). AIHA, autoimmune hemolytic anemia
Responses did not differ regardless of the number of prior therapeutic lines, steroid response, or anti‐CD20 agent response. Naïve‐treatment patient for tumoral condition seemed to attain more frequently CR than pre‐treated patients (nine patients against two) but ORR were similar (respectively 75% and 77%).
For patients who had concomitant treatment at baseline, 13 could be weaned from this treatment and continued ibrutinib as a monotherapy (62%).
After a median follow‐up of 20 months (range 4–64), response was sustained in this relapsed/refractory population, with a median duration of 8 months (IQR 5–24), with long‐term response up to 35 months. At the end of observation time, 11 patients (44%) were still pursuing ibrutinib.
For patients with measurable disease, tumoral response was not strictly coincident with immunologic response (Table 2). After introduction of ibrutinib, the overall response rate of B‐cell lymphoma was 83.3% (IC 95%, 62.6–95.3). 41.7% B‐cell lymphoma achieved CR and 41.7% achieved PR (n = 24). Among patients with stable disease, two patients had CLL, one patient had WM and one patient had MZL. We did not observe any progressive disease in our cohort.
3.3. Safety
During treatment period and follow‐up, 14 patients (56%) presented at least one treatment related‐event (Table 3). Cardiovascular events (high blood pressure, palpitations, or heart rhythm disorders) were found in six patients (24%). Four patients presented bleeding events (16%), with exclusively Grade 1/2 transient bleeding. No discontinuation was observed due to this event and only one occurred in a patient with ITP. Infections occurred in nine patients (36%), mostly due to viral infection in five patients (20%), followed by bacterial infection in three patients (including an endocarditis) (12%), and one fungal event (cerebral aspergillosis) in one. Other adverse events leading to dose reduction or discontinuation were cytopenia and diarrhea with a cumulative incidence of five patients (20%). Discontinuation occurred for four patients (16%), mostly due to infectious related event (three patients) and one patient with diarrhea (one patient).
TABLE 3.
Adverse events (AEs) according to grade in all 25 patients
| Any grade a | Grade 1 | Grade 2 | Grade 3 or 4 | |
|---|---|---|---|---|
| High blood pressure | 3 (12) | 0 | 2 (8) | 1 (4) |
| Atrial fibrillation | 2 (8) | 0 | 2 (8) | 0 |
| Palpitation | 1 (4) | 1 (4) | 0 | 0 |
| Hemorrhage | 4 (16) | 2 (8) | 2 (8) | 0 |
| Bacterial infection | 3 (12) | 1 (4) | 1 (4) | 1 (4) |
| Viral infection | 5 (20) | 1 (4) | 3 (12) | 1 (4) |
| Fungal infection | 1 (4) | 0 | 0 | 1 (4) |
| Diarrhea | 2 (8) | 1 (4) | 1 (4) | 0 |
| Fatigue | 4 (16) | 4 (16) | 0 | 0 |
| Cramp | 1 (4) | 1 (4) | 0 | 0 |
| Neutropenia | 3 (12) | 0 | 1 (4) | 2 (8) |
| Thrombocytopenia | 1 (4) | 1 (4) | 0 | 0 |
Multiple events may have occurred in several patients.
We did not observe any case of emergent autoimmune cytopenia due to ibrutinib in our cohort.
One death due to pneumonia was reported during follow‐up, but the referring physician did not consider it to be related to the treatment.
4. DISCUSSION
Relapse and refractory primary or secondary immune disorders remain a therapeutic challenge. Concerning immune disorders associated with B‐cell lymphomas, relapse may affect the natural course of the disease and can lead to reduced quality of life or even death, independently of tumor progression. Ibrutinib is a BTK inhibitor developed to treat B‐cell indolent lymphoproliferation, initially CLL 32 then subsequently WM, 33 MCL, 34 and MZL. 35 It is an interesting alternative to other regimens and to chemoimmunotherapy, which can lead to toxicities in these populations.
In this multicenter study, we sought to evaluate the efficacy and safety of ibrutinib in B‐cell neoplasms associated with hematologic immune disorders. To date, few data support the use of ibrutinib in this setting. 6 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 Here, we report real‐world use of ibrutinib in the treatment of active, refractory/relapsed hematologic immune conditions associated with various B‐cell neoplasms. It is also one of the first description of ibrutinib used for the treatment of acquired hemophilia and acquired von Willebrand disease.
Demographic characteristics of our population were on par with the literature and lymphoproliferation in our cohort focused not only on CLL but also on WM, MZL, and CAD. Immune manifestation distribution was atypical, with a low rate of ITP which can partially be explained by a selection bias due to the putative bleeding risk of ibrutinib. All patients presented with a refractory/relapsing associated immune disease, defined by the failure of at least one prior therapeutic line, with a median rate of two (up to seven therapeutic lines). All manifestations were active at inclusion, either with persistent cytopenia or the need of additional treatment.
Our study showed a 76% ORR with 44% of CR (95% CI, 54.9–90.6). Those rates are not inferior to those found in the literature, which concerned mostly CLL patients and patients with either active or past manifestations. Among non‐responders, three patients were diagnosed with CLL, two with MZL, and one with CAD. We cannot draw conclusions concerning efficacy for MZL and CAD patients, but it is our opinion that BTK inhibitor in MZL patients seems to be less effective as a single agent concerning tumoral condition and may be less dependent on the BTK pathway for survival or autoimmunity. 35 Concerning CAD, promising results are emerging as shown by Jalink et al. 24 In a cohort of 10 patients, who obtained one PR and nine CRs with transfusion independence and low‐grade complications after a follow‐up of 20 months. In our study, among patients receiving a treatment before ibrutinib initiation (n = 22), 13 could be weaned from the associated treatment (62%), which suggests a steroid or immunosuppressive‐sparing role of ibrutinib. Also, response was sustained for this refractory population with a median duration of response of 8 months, including long‐term responses (up to 35 months).
We realized that the tumoral response and the immunological response were not strictly identical. This could be explained by several hypotheses. First, clonal evolution may drive evolutionary pressure linked to prior therapies with the emergence of multiples clones. For example, in CLL, it could be demonstrated that immune disorders tend to appear in patients with high cytogenetic or molecular risks (non‐mutated IgVH status, TP53 mutation) or exposure to anterior chemoimmunotherapy such as purine analogs. 7 , 36 , 37 However, we decided not to study cytogenetic and molecular characteristics because of the heterogeneity of our population, preventing verification of this hypothesis. Also, BTK inhibitors have an action targeted not only on B cells but also on micro‐environment cells such as T cells and macrophages. It could be demonstrated that patients with B‐cell neoplasms and immune disorders had perturbations in T‐cell subsets, notably on T regulatory cells and T helper cells (Th17). 38 , 39 Ibrutinib, by inhibiting intracellular T cells kinases in whose structure is close to BTK (e.g., SYK, ITK) can select proliferation of T cells with a Th1 profile over those with a Th17 profile, which favors immune tolerance and tumoral defense. These observations suggest that ibrutinib, and BTK inhibitors more generally, may not be limited to autoimmune phenomena associated with B‐cell neoplasms but could be used in primary autoimmune cytopenia or immune disorders associated with systemic diseases. 40 , 41
In our study, safety profiles of cardiovascular, infectious, and hemorrhagic events were similar to what has been previously reported. It is interesting to note that infectious events were mostly a result of reactivation of the herpes virus, but we also report Grade 3 hepatitis, infectious endocarditis, and cerebral aspergillosis which occurred in the neutropenic patient. Although rare, those events are important to consider because of underlying immunodepression due to prior therapeutic lines such as corticotherapy, immunosupressive agents, or a specific background. Specific prophylaxis should be started depending on the patient, with mandatory antiviral prophylaxis as recommended.
Another interesting point is that only four patients presented with hemorrhagic events considering that we had four patients treated for ITP, three for Evans syndrome with thrombocytopenia, and two for acquired bleeding disorders. These events occurred only in one patient with thrombocytopenia and were mostly low‐grade cutaneo‐mucosal bleeding and none of these events led to discontinuation. Finally, we did not observe any emergent autoimmune cytopenia after ibrutinib introduction. This specific event has a variable incidence of 1%–6% among different series 5 , 6 , 23 and can be found not only for ibrutinib but also for other targeted therapies such as BCL2 inhibitors or PI3K inhibitors. It is important to detect this event because it can modify the natural history of immune conditions and can have a non‐negligible impact, such as the management of targeted therapy. However, this data is limited because of the size of our cohort and a potential selection bias.
Several limitations must be pointed out. Besides the size of the cohort, our study is retrospective which may limit the results. We also decided not to collect intrinsic characteristics of lymphomas because of our population's heterogeneity, which can be another source of bias. For example, TP53 deletion in CLL could unconsciously guide a clinician to treat the patient with ibrutinib, independently of other variables.
To date, there is no clearly defined indication for ibrutinib in the management of secondary immune manifestations in clinical routine practice. In our opinion, regular immunosupressive treatment, as recommended per specific institution standard of care should be followed. Ibrutinib should be considered in cases of complications of immunosuppressive agents, absence of other available therapies available and/or in the case of predominant active B‐cell lymphoma with hematologic immune conditions. Ibrutinib as a weaning therapy may also be considered.
To conclude, ibrutinib as a treatment for refractory/relapsing hematologic immune disorders associated with B‐cell indolent lymphoproliferation seems to be an interesting and novel strategy to control both tumoral and immune condition with a relatively safe tolerance profile. Therapeutic applications may be even wider, with potential indication in primary autoimmune cytopenia, for example. Prospective studies including these specific populations should be planned to confirm these data, to investigate predictive factors of response, and to define the exact place of this strategy in clinical practice.
AUTHOR CONTRIBUTIONS
Adrien Daniel and Louis Terriou designed the study, wrote the paper and analyzed the data. Adeline Pierache made the statistical analysis. All authors revised critically, approved the manuscript, and contributed significantly to the work.
CONFLICT OF INTEREST
David Ghez received research grant for Janssen. Charles Herbaux declares conflict of interest with Janssen. No other potential conflict of interest relevant to this article was reported.
Supporting information
Appendix S1 Supporting information
ACKNOWLEDGMENT
The authors would like to thank all the participating patients and their families, study research nurses, study coordinators, and operations staff. We thank all members of the Department of Hematology/Oncology who participated in the treatment patients.
Daniel A, Ghez D, Ravaiau C, et al. Ibrutinib as a treatment of hematologic autoimmune disorders in patients with indolent B‐cell lymphoma. Eur J Haematol. 2022;109(6):719‐727. doi: 10.1111/ejh.13858
This article has not been previously published nor is being considered for publication elsewhere.
Contributor Information
Adrien Daniel, Email: adrien.daniel@chru-lille.fr.
Louis Terriou, Email: louis.terriou@chru-lille.fr.
DATA AVAILABILITY STATEMENT
Data supporting the findings of this study are available within the article and its Supplementary Materials. We present here the use of ibrutinib as a treatment of relapsed/refractory hematologic immune disorders associated to various B‐cell lymphoma, not only focusing on chronic lymphocytic leukemia, and in a real‐life experience. Ibrutinib as a single agent in this feature was associated with interesting response rate (ORR 76%, CR 42%) with acceptable tolerance. In our opinion, this treatment can be an interesting option in case of complications to immunosuppressive agents or in the absence of other available therapy agents, even if our results should be confirmed in wider and prospective studies.
REFERENCES
- 1. Jachiet V, Mekinian A, Carrat F, et al. Autoimmune manifestations associated with lymphoma: characteristics and outcome in a multicenter retrospective cohort study. Leuk Lymphoma. 2018;59(6):1399‐1405. [DOI] [PubMed] [Google Scholar]
- 2. Dührsen U, Augener W, Zwingers T, Brittinger G. Spectrum and frequency of autoimmune derangements in lymphoproliferative disorders: analysis of 637 cases and comparison with myeloproliferative diseases. Br J Haematol. 1987;67(2):235‐239. [DOI] [PubMed] [Google Scholar]
- 3. Váróczy L, Gergely L, Zeher M, Szegedi G, Illés A. Malignant lymphoma‐associated autoimmune diseases—a descriptive epidemiological study. Rheumatol Int. 2002;22(6):233‐237. [DOI] [PubMed] [Google Scholar]
- 4. Jardin F. Development of autoimmunity in lymphoma. Expert Rev Clin Immunol. 2008;4(2):247‐266. [DOI] [PubMed] [Google Scholar]
- 5. Rogers KA, Ruppert AS, Bingman A, et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia autoimmune cytopenias during ibrutinib treatment. Leukemia. 2016;30(2):346‐350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Vitale C, Salvetti C, Griggio V, et al. Preexisting and treatment‐emergent autoimmune cytopenias in patients with CLL treated with targeted drugs. Blood. 2021;137(25):3507‐3517. [DOI] [PubMed] [Google Scholar]
- 7. Myint H, Copplestone JA, Orchard J, et al. Fludarabine‐related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol. 1995;91(2):341‐344. [DOI] [PubMed] [Google Scholar]
- 8. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol. 2016;12(7):763‐773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Corneth OBJ, Klein Wolterink RGJ, Hendriks RW. BTK signaling in B cell differentiation and autoimmunity. Curr Top Microbiol Immunol. 2016;393:67‐105. [DOI] [PubMed] [Google Scholar]
- 11. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219‐232. [DOI] [PubMed] [Google Scholar]
- 12. Manda S, Dunbar N, Marx‐Wood CR, Danilov AV. Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia. Br J Haematol. 2015;170(5):734‐736. [DOI] [PubMed] [Google Scholar]
- 13. Cavazzini F, Lista E, Quaglia FM, et al. Response to ibrutinib of refractory life‐threatening autoimmune hemolytic anemia occurring in a relapsed chronic lymphocytic leukemia patient with 17p deletion. Leuk Lymphoma. 2016;57(11):2685‐2688. [DOI] [PubMed] [Google Scholar]
- 14. Montillo M, O'Brien S, Tedeschi A, et al. Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study. Blood Cancer J. 2017;7(2):e524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Vitale C, Ahn IE, Sivina M, et al. Autoimmune cytopenias in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2016;101(6):e254‐e258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Molica S, Levato L, Mirabelli R. Chronic lymphocytic leukemia, autoimmune hemolytic anemia and ibrutinib: a case report with review of literature. Leuk Lymphoma. 2015;4(57):1‐10. [DOI] [PubMed] [Google Scholar]
- 17. St Bernard R, Hsia CC. Safe utilization of ibrutinib with or without steroids in chronic lymphocytic leukemia patients with autoimmune hemolytic anemia. Ann Hematol. 2015;94(12):2077‐2079. [DOI] [PubMed] [Google Scholar]
- 18. Quinquenel A, Godet S, Dartigeas C, et al. Ibrutinib and idelalisib in the management of CLL‐associated autoimmune cytopenias: a study from the FILO group. Am J Hematol. 2019;94(7):E183‐E185. [DOI] [PubMed] [Google Scholar]
- 19. Goldschmidt N, Rund D. Refractory pure red cell aplasia associated with chronic lymphocytic leukemia successfully treated with ibrutinib. Leuk Lymphoma. 2017;58(2):498‐500. [DOI] [PubMed] [Google Scholar]
- 20. Nakamura M, Yoshioka S, Yamashita D, Hara S, Ishikawa T. Improvement of autoimmune cytopenia with ibrutinib in a chronic lymphocytic leukemia patient complicated by monoclonal immunoglobulin deposition disease. Rinsho Ketsueki. 2019;60(10):1449‐1454. [DOI] [PubMed] [Google Scholar]
- 21. Tripathi A, Steingart R. Resolution of Waldenström macroglobulinemia‐associated autoimmune hemolysis with ibrutinib. J Oncol Pract. 2016;12(5):490‐491. [DOI] [PubMed] [Google Scholar]
- 22. Galinier A, Delwail V, Puyade M. Ibrutinib is effective in the treatment of autoimmune haemolytic anaemia in mantle cell lymphoma. Case Rep Oncol. 2017;10(1):127‐129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Hampel PJ, Larson MC, Kabat B, et al. Autoimmune cytopenias in patients with chronic lymphocytic leukaemia treated with ibrutinib in routine clinical practice at an academic medical centre. Br J Haematol. 2018;183(3):421‐427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Jalink M, Berentsen S, Castillo JJ, et al. Effective treatment of cold agglutinin disease/cold agglutinin syndrome with ibrutinib: an international case series. Blood. 2020;136(Suppl 1):29‐30. [Google Scholar]
- 25. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the first international consensus meeting. Blood Rev. 2020;41:100648. [DOI] [PubMed] [Google Scholar]
- 26. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386‐2393. [DOI] [PubMed] [Google Scholar]
- 27. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780‐3817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kruse‐Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia a: updated review of evidence and treatment guidance. Am J Hematol. 2017;92(7):695‐705. [DOI] [PubMed] [Google Scholar]
- 29. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745‐2760. [DOI] [PubMed] [Google Scholar]
- 30. Kastritis E, Leblond V, Dimopoulos MA, et al. Waldenström's macroglobulinaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow‐up. Ann Oncol. 2018;29(Suppl 4):iv41‐iv50. [DOI] [PubMed] [Google Scholar]
- 31. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non‐Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059‐3068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213‐223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):1430‐1440. [DOI] [PubMed] [Google Scholar]
- 34. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle‐cell lymphoma: an international, randomised, open‐label, phase 3 study. Lancet. 2016;387(10020):770‐778. [DOI] [PubMed] [Google Scholar]
- 35. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129(16):2224‐2232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. De Back TR, Kater AP, Tonino SH. Autoimmune cytopenias in chronic lymphocytic leukemia: a concise review and treatment recommendations. Expert Rev Hematol. 2018;11(8):613‐624. [DOI] [PubMed] [Google Scholar]
- 37. Visco C, Barcellini W, Maura F, Neri A, Cortelezzi A, Rodeghiero F. Autoimmune cytopenias in chronic lymphocytic leukemia. Am J Hematol. 2014;89(11):1055‐1062. [DOI] [PubMed] [Google Scholar]
- 38. Lad DP, Varma S, Varma N, Sachdeva MUS, Bose P, Malhotra P. Regulatory T‐cell and T‐helper 17 balance in chronic lymphocytic leukemia progression and autoimmune cytopenias. Leuk Lymphoma. 2015;56(8):2424‐2428. [DOI] [PubMed] [Google Scholar]
- 39. Prabhala RH, Pelluru D, Fulciniti M, et al. Interleukin‐17 and TH17 pathway supports Waldenstrom's macroglobulinemia cell‐growth: potential therapeutic implications. Blood. 2010;116(21):446.20460503 [Google Scholar]
- 40. Kuter DJ, Efraim M, Mayer J, et al. Rilzabrutinib, an oral BTK inhibitor, in immune thrombocytopenia. N Engl J Med. 2022;386(15):1421‐1431. [DOI] [PubMed] [Google Scholar]
- 41. Zarrin AA, Bao K, Lupardus P, Vucic D. Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov. 2021;20:39‐63. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1 Supporting information
Data Availability Statement
Data supporting the findings of this study are available within the article and its Supplementary Materials. We present here the use of ibrutinib as a treatment of relapsed/refractory hematologic immune disorders associated to various B‐cell lymphoma, not only focusing on chronic lymphocytic leukemia, and in a real‐life experience. Ibrutinib as a single agent in this feature was associated with interesting response rate (ORR 76%, CR 42%) with acceptable tolerance. In our opinion, this treatment can be an interesting option in case of complications to immunosuppressive agents or in the absence of other available therapy agents, even if our results should be confirmed in wider and prospective studies.