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. Author manuscript; available in PMC: 2019 Nov 1.
Published in final edited form as: Br J Haematol. 2018 Aug 16;183(3):421–427. doi: 10.1111/bjh.15545

Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukaemia Treated with Ibrutinib in Routine Clinical Practice at an Academic Medical Centre

Paul J Hampel 1, Melissa C Larson 2, Brian Kabat 2, Timothy G Call 3, Wei Ding 3, Saad S Kenderian 3, Deborah Bowen 3, Justin Boysen 3, Susan M Schwager 3, Jose F Leis 4, Asher A Chanan-Khan 5, Eli Muchtar 3, Curtis A Hanson 6, Susan L Slager 2, Neil E Kay 3, Kari G Chaffee 2, Tait D Shanafelt 7, Sameer A Parikh 3
PMCID: PMC6234062  NIHMSID: NIHMS983196  PMID: 30117139

Summary:

The effects of ibrutinib on the natural history of autoimmune cytopenias (AIC) among chronic lymphocytic leukaemia (CLL) patients treated in routine clinical practice require further investigation. Using the Mayo Clinical CLL Database, 193 CLL patients treated with ibrutinib between November 2013 and January 2017 outside the context of a clinical trial were identified; complete review of their medical records was performed for details of past history of AIC and treatment-emergent AIC. We identified 29/193 (15%) patients with history of AIC prior to ibrutinib start. Of 12 patients requiring AIC therapy at ibrutinib start, 8 (67%) were able to discontinue or de-escalate AIC treatment, and no patient had worsening of their AIC after initiating ibrutinib. Eleven (6%) patients developed treatment-emergent AIC after a median of 59 (range, 6–319) days following the initiation of ibrutinib, 7 of whom (64%) were able to continue ibrutinib. Overall and event-free survival from time of ibrutinib start were not significantly different between patients with history of AIC and those with no history of AIC. Treatment-emergent AIC were seen exclusively in patients with unmutated IGHV and were associated with a shorter EFS. These results suggest a low rate of treatment-emergent AIC and improvement in patients with existing AIC.

Keywords: Autoimmune Haemolytic Anaemia (AIHA), Immune Thrombocytopenia (ITP), Pure Red Cell Aplasia, Aplastic Anaemia, Ibrutinib

Introduction

Autoimmune cytopenias (AIC) are the most frequently encountered autoimmune complication of chronic lymphocytic leukaemia (CLL), occurring in ~5–10% of patients at some point during their disease course (Barcellini et al., 2006, Hamblin et al., 1986, Kyasa et al., 2003, Zent et al., 2009, Zent et al., 2008). Although the vast majority of these cytopenias occur due to CLL per se, a small proportion, particularly autoimmune haemolytic anaemia (AIHA), has been reported to occur associated with or following therapy with purine nucleoside analogues (Leporrier et al., 1993, Weiss et al., 1998). The impact of novel therapies, such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), phosphatidylinositol 3-kinase inhibitors (e.g., idelalisib) and BCL2 antagonists (e.g., venetoclax) on the occurrence of AIC requires further investigation.

Ibrutinib is a first-in-class BTK inhibitor approved in the United States for treatment of CLL patients, both in the relapsed/refractory and frontline settings (https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf). The effects of ibrutinib treatment on the natural history of AIC among CLL patients treated on clinical trials suggests a low rate of treatment-emergent AIC (Montillo et al., 2017, Rogers et al., 2016). In addition, ibrutinib has also been shown to decrease the need for ongoing immunosuppressive therapy among CLL patients who have pre-existing or active AIC at the time of initiation of therapy (Rogers et al., 2016, Vitale et al., 2016). However, these reports have all been conducted in the context of patients receiving ibrutinib therapy under the evaluation and monitoring rigor of a clinical trial. Additionally, most clinical trials exclude patients with uncontrolled AIC, defined as requiring >20 mg of prednisone daily or equivalent at the start of ibrutinib therapy (Burger et al., 2015, Byrd et al., 2014). Confirmation of these findings in CLL patients treated in routine clinical practice requires further investigation given that the outcomes of CLL patients treated outside clinical trials may be different from those who are treated on clinical trials (Datla et al., 2016, Hodskins et al., 2014, Manda et al., 2015, Rider et al., 2016, St. Bernard and Hsia, 2015).

Using the Mayo Clinic CLL Database, we analysed the incidence, clinical manifestations, management and outcomes of AIC among CLL patients who were treated with ibrutinib outside the context of a clinical trial (i.e., in routine clinical practice). We also evaluated risk factors for treatment-emergent AIC and compared the clinical outcomes of these patients to ibrutinib-treated CLL patients who did not develop AIC. Given the importance of T cells, particularly T-regulatory cells, in the pathogenesis of AIC in CLL patients, we performed limited peripheral blood flow cytometry analysis to investigate circulating T cells from a small cohort of patients enrolled on this study (Dubovsky et al., 2013, Lad et al., 2015, Schliffke et al., 2016).

Methods

Study Population

The study was approved by the Institutional Review Board of Mayo Clinic and was conducted in accordance with the principles of the Declaration of Helsinki. Between November 2013 and January 2017, all CLL patients treated with ibrutinib outside the context of a clinical trial with regular follow-up in the Division of Hematology at Mayo Clinic were identified. Since patients enrolled in this study were treated per physician discretion, follow-up was not uniform on all patients. In general, patients were seen monthly for the first 3 months after starting ibrutinib and then once every 3–4 months while they continued active therapy. The Clinical CLL Database and the electronic health records of these patients were reviewed to identify all patients with AIC and were subsequently categorized into: 1) past history of AIC at ibrutinib start; 2) active but controlled [<20 mg prednisone or equivalent daily] AIC at ibrutinib start; and 3) active and uncontrolled [≥20 mg of prednisone daily or equivalent] AIC at ibrutinib start (NCT01578707). Based on Rogers et al (2016), treatment-emergent AIC was defined as the occurrence of AIC on ibrutinib therapy in patients with 1) no past history of AIC, OR 2) past history of a different AIC on ibrutinib therapy compared to the AIC prior to ibrutinib therapy, OR 3) past history of the same AIC not on therapy at the time of ibrutinib initiation (referred to relapsed). Based on the treating physician’s diagnoses, AIC was categorized as follows: AIHA, immune thrombocytopenia (ITP), pure red cell aplasia (PRCA), aplastic anaemia and autoimmune neutropenia.

Details on the timing of AIC diagnosis and prior therapy in relation to ibrutinib treatment were ascertained. Additional information, including additional AIC therapies required after ibrutinib initiation and changes to dosage of ibrutinib as a result of AIC, were recorded. CLL-specific characteristics, such as white blood cell count, haemoglobin, platelet count, Rai stage, prognostic markers such as immunoglobulin heavy chain (IGHV) mutation status, cytogenetics by fluorescence in-situ hybridization (FISH), ZAP70 and CD38 expression, direct antiglobulin test (DAT) positivity, B-cell receptor stereotypy and treatment received, were also abstracted from the medical record. In patients with treatment-emergent AIC where a peripheral blood research sample was available for analysis prior to the start of ibrutinib therapy, we analysed the ratio of regulatory T cells (Tregs) (CD4+CD127dimCD25+) to T-helper 17 (Th17) cells (CD4+CXCR3-CCR6+). We then compared this ratio to matched control patients who received ibrutinib and did not develop treatment-emergent AIC; these patients were matched for the following characteristics: treatment status, IGHV mutation status and FISH.

Statistical Methods

Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of history of treatment-emergent AIC with event-free (EFS) and overall (OS) survival. OS was calculated from the time of ibrutinib start to date of death, regardless of the cause of death. For EFS, progression of disease (either CLL progression or Richter syndrome), subsequent therapy, or death, which ever occurred first, was considered an event. Time-dependent Cox regression models were used to look at the association of treatment-emergent AIC with clinical variables, namely EFS and OS. All statistical analyses were conducted using the SAS 9.4 software package (SAS Institute, Cary, NC).

Results

Patient Demographics

One hundred and ninety-three CLL patients were treated outside the context of a clinical trial during the study period. One hundred and sixty-one (83%) patients received therapy for relapsed CLL and 32 (17%) patients received ibrutinib for previously untreated CLL. The median age at ibrutinib start was 69 years, and 69% were males. Overall, 28 (18%) patients had TP53 disruption [either del(17p) or TP53 mutation], and 123 (76%) had unmutated IGHV genes. Table I describes additional baseline characteristics at the start of ibrutinib therapy. Of the 32 previously untreated patients, 1 had uncontrolled AIC at ibrutinib start and 2 developed treatment-emergent AIC (detailed in subsequent sections).

Table I:

Characteristics of patients with chronic lymphocytic leukaemia at time of ibrutinib start

Characteristic Number (%) or median [range]
Total number of patients 193
Age, years 69 [45–93]
Males 134 (69)
Haemoglobin (g/l) 12 [7–16]
Total WBC (x10⁹/l) 70 [1.4–424.8]
Absolute lymphocyte count (x10⁹/l) 60 [0–408]
Platelet count (x10⁹/l) 143 [4–517]
Treatment naïve 32 (17)
History of AIC Any 29 (15)
AIHA 11
ITP 8
Evans syndrome 5
PRCA 3
Aplastic anaemia 1
Autoimmune neutropenia 1
Rai stage 0 32 (19)
I 66 (38)
II 31 (18)
III 19 (11)
IV 24 (14)
Missing 21
CD49d Negative (<30%) 85 (49)
Positive (>30%) 87 (51)
Missing 21
CD38 Negative (<30%) 104 (57)
Positive (>30%) 79 (43)
Missing 10
ZAP70 Negative (<20%) 71 (40)
Positive (>20%) 106 (60)
Missing 16
Stereotyped BCR Yes 21 (20)
No 82 (80)
Missing 90
IGHV mutation status Mutated 38 (24)
Unmutated 123 (76)
Missing 32
FISH Normal 26 (20)
Other 2 (1)
13q- 38 (29)
Trisomy 12 31 (23)
11q- 18 (14)
17p- 17 (13)
Missing 61
TP53 Disruption [either del(17p) or TP53 mutation] Negative 124 (82)
Positive 28 (18)
Missing 41
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AIC: autoimmune cytopenia; AIHA: autoimmune haemolytic anaemia; BCR: B-cell receptor; FISH: fluorescence in situ hybridization; IGHV: immunoglobulin heavy chain gene; ITP: immune thrombocytopenia; PRCA: pure red cell aplasia; WBC: white cell count

Twenty-nine/193 (15%) patients had a history of AIC prior to starting ibrutinib. Of these 29 patients, 17 (59%) had a past history of AIC and were not on any AIC treatment at the time of ibrutinib start, while 12 (41%) patients were receiving AIC-directed therapy at the time of ibrutinib start (5 with uncontrolled AIC receiving ≥20 mg prednisone or equivalent daily and 7 with controlled AIC receiving <20 mg prednisone or equivalent daily).

Patients with history of AIC prior to ibrutinib start

Of the 29 patients with a history of AIC prior to ibrutinib start, 11 patients had AIHA, 8 patients had ITP, 5 patients had AIHA and ITP either concomitantly (Evans syndrome) or sequentially, 3 patients had PRCA, 1 patient had autoimmune neutropenia and 1 patient had aplastic anaemia. Of the 12 patients who were receiving AIC therapy at ibrutinib start, 3 (25%) were able to discontinue AIC therapy after a median of 2 months (range, 0–25) of ibrutinib, an additional 5 (42%) patients were able to reduce the intensity of AIC directed-therapy, and 4 (33%) patients continued AIC therapy with no changes. None of these 12 patients on AIC therapy had worsening of their underlying AIC as a consequence of initiating ibrutinib. See Figure 1 for flow diagram of patient disposition. The one previously untreated patient had uncontrolled ITP at ibrutinib start and subsequently achieved a complete response with ability to taper off corticosteroids while continuing on ibrutinib.

Figure 1:

Figure 1:

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Flow diagram of patient disposition

* Controlled AIC: receiving < 20 mg prednisone or equivalent daily

† Uncontrolled AIC: receiving > 20 mg prednisone or equivalent daily

‡ In an additional 1 of the 11 patients, while ibrutinib was held due to refractory AIHA, there was progression of CLL necessitating a change in therapy.

AA: aplastic anaemia; AIC: autoimmune cytopenia; AIHA: autoimmune haemolytic anaemia; ITP: immune thrombocytopenia; PRCA: pure red cell aplasia.

Patients with treatment-emergent AIC

Eleven (6%) patients developed treatment-emergent AIC. The types of treatment-emergent AIC include: AIHA (n=5), ITP (n=3), PRCA (n=1), aplastic anaemia (n=1) and autoimmune neutropenia (n=1). These treatment-emergent AIC occurred a median of 59 days following initiation of ibrutinib (range, 6–319 days). Three of the 11 patients with treatment-emergent AIC had a past history of AIC: 2 with a history of AIHA who developed treatment-emergent AIHA (relapsed) and 1 with a history of PRCA who developed treatment-emergent AIHA. Seven of the 11 patients with treatment-emergent AIC were able to continue ibrutinib after either temporarily holding ibrutinib (n=5), ibrutinib dose reduction (n=1) or no modification to ibrutinib therapy (n=1). The median duration of holding ibrutinib was 17 days (range 3–61 days). Four of the five patients who had ibrutinib held also received additional AIC pertinent therapies: steroids (n=2), steroids and rituximab (n=1) and steroids and obinutuzumab (n=1). In addition to receiving appropriate AIC-directed therapy, ibrutinib was discontinued as a result of the AIC event in 3 of the 11 patients (ITP n=2, aplastic anaemia n=1). In an additional 1 of the 11 patients, while ibrutinib was held due to refractory AIHA, there was progression of CLL necessitating a change in therapy. Two of the patients (PRCA [n=1] and aplastic anaemia [n=1]) with treatment-emergent AIC were previously untreated and neither had a history of AIC. The patient with PRCA achieved complete response to corticosteroids and rituximab and was able to continue ibrutinib after a 15-day hold. The patient with aplastic anaemia permanently discontinued ibrutinib but achieved a complete response to corticosteroids, intravenous immunoglobulin, cyclophosphamide, anti-thymocyte globulin and eltrombopag.

Outcomes of AIC patients

After a median follow-up of 2.4 years, the median OS of the entire cohort was not reached, and the median EFS was 2.9 years. The median OS and EFS from time of ibrutinib start were not significantly different between patients with a past history of AIC and those with no history of AIC (Figure 2 and Figure 3). After adjusting for age and sex, TP53 disruption (HR 1.95 [95% CI, 1.12–3.40]; p=0.02) and treatment-emergent AIC (HR 2.70 [95% CI, 1.21–5.84]; p=0.01) were associated with shorter EFS; however, unmutated IGHV (p=0.11) and del11q (p=0.87) were not. There was no association between age, sex, TP53 disruption, IGHV mutation status, IGHV gene family usage, past history of purine nucleoside analogue therapy, DAT positivity or B-cell receptor stereotypy and the development of treatment-emergent AIC. Treatment-emergent AIC was noted to occur exclusively among unmutated IGHV patients (9/123 unmutated IGHV patients developed treatment-emergent AIC compared to 0/38 patients with mutated IGHV; p=0.09). Stored sample analyses of pre-ibrutinib Treg/Th17 ratio was not significant between cases of treatment-emergent AIC (n=4) and those patients who did not develop treatment-emergent AIC (n=8) (Figure 4).

Figure 2:

Figure 2:

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Overall survival in patients with and without history of autoimmune cytopenia

AIC: autoimmune cytopenia

Figure 3:

Figure 3:

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Event-free survival in patients with and without history of autoimmune cytopenia

AIC: autoimmune cytopenia

Figure 4:

Figure 4:

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Ratios of regulatory T cells to Th17 T cells prior to ibrutinib initiation: treatment-emergent autoimmune cytopenia cases versus controls (all patients treated with ibrutinib)

* Three values present: 0.39, 0.38, 0.37.

Discussion

This retrospective cohort study provides complementary data to support clinical trial literature regarding the effect of ibrutinib treatment on the natural history of AIC among CLL patients (Montillo et al., 2017, Rogers et al., 2016). Our study found that ~1 out of 17 patients treated with ibrutinib in routine clinical practice developed treatment-emergent AIC. Treatment-emergent AIC occurred at a median of ~2 months following ibrutinib therapy, occurred exclusively among patients with unmutated IGHV, and was associated with shorter EFS, although there was no apparent impact on OS. Although no risk factors for treatment-emergent AIC were identified, the majority of these patients (64%) were ultimately able to continue ibrutinib treatment. Additionally, two-thirds of patients on AIC-directed therapy at ibrutinib initiation were able to discontinue or de-escalate their AIC treatment.

How do these results compare to the existing literature? Among 301 CLL patients treated on clinical trials at The Ohio State University, Rogers et al (2016) showed that 19 (86%) of 22 patients receiving therapy for their AIC at the time ibrutinib was started were able to discontinue AIC therapy. In another study involving patients treated on the RESONATE study (comparing ibrutinib to ofatumumab in previously treated CLL), Montillo et al (2017) reported rising haemoglobin and platelet counts among the 21 patients with ongoing AIHA and 12 patients with ongoing ITP at study entry. Vitale et al (2016) similarly found 9 (69%) of 13 patients with signs of AIC at ibrutinib initiation ultimately had controlled or resolved AIC on ibrutinib alone. The results from our study support these findings, that ibrutinib may be successfully able to ameliorate the need for ongoing immunosuppressive therapies in patients with active AIC. Contrary to some published reports that suggest a “flare” of AIC with the start of ibrutinib therapy among patients with active AIC (Vitale et al., 2016), we did not observe any worsening signs of AIC disease during close follow-up in the weeks after ibrutinib initiation in any of the 12 patients with active AIC.

Clinical trial literature also suggests a low rate of treatment-emergent AIC with ibrutinib initiation. Rogers et al (2016) reported 6 (among 301) cases of treatment-emergent AIC, after a median follow-up of 1.8 years. Montillo et al (2017) reported that of 195 CLL patients treated with ibrutinib for a median duration of 18.3 months from 11 participating centres around the world, there were no cases of treatment-emergent AIC. Our study of 193 CLL patients treated outside of a clinical trial found ~6% patients developed treatment-emergent AIC a median 59 days after starting ibrutinib. Ibrutinib was able to be continued in 64% of these patients after management with AIC-directed therapy, supporting the findings in clinical trial and case literature that most patients who develop treatment-emergent AIC are ultimately able to safely reintroduce and continue ibrutinib (Datla et al., 2016, Hodskins et al., 2014, Rider et al., 2016, Rogers et al., 2016). Although additional immunosuppressive therapies, most commonly steroids, are often utilized initially for episodes of treatment-emergent AIC, these can frequently be tapered and discontinued.

A higher incidence of AIC has been previously associated with advanced stage CLL and unfavourable prognostic markers (Maura et al., 2013, Moreno et al., 2010). As expected in the patient population eligible for ibrutinib therapy, the cohort in our study did have features that would predict a higher incidence of AIC, including unmutated IGHV in 76%. Although all cases of treatment-emergent AIC in this study occurred among patients with unmutated IGHV, other studies have found more heterogeneity in IGHV mutation status amongst cases of treatment-emergent AIC (Rogers et al., 2016, Vitale et al., 2016). AIC secondary to CLL has been shown to not confer the same propensity for shortened survival as cytopenias secondary to bone marrow failure; however, the prognostic impact of AIC on outcomes compared to patients with no AIC remains controversial (Kyasa et al., 2003, Mauro et al., 2000, Moreno et al., 2010, Visco et al., 2008, Zent et al., 2008). In our study, patients treated with ibrutinib had no significant difference in EFS or OS with respect to their past history of AIC, possibly suggesting that ibrutinib was able to abrogate the inferior outcome associated with AIC. Additionally, this may reflect the lack of effective treatment options for CLL-related AIC in the past as well.

Ibrutinib affecting AIC is mechanistically plausible due to its varied effects on the immune system. Beyond BTK inhibition in B cells, ibrutinib also irreversibly binds interleukin-2-inducible kinase (ITK), inhibiting Th2 cell activation and tilting towards a Th1 response (Dubovsky et al., 2013, Podhorecka et al., 2017, Yin et al., 2017). Previously, an imbalance in the Treg/Th17 ratio has been associated with AIC or progression (Lad et al., 2015). We did not find any differences Treg/Th17 ratio among patients who developed treatment-emergent AIC and those who did not, although our analysis is limited secondary to the small number of research samples available in this retrospective study of patients treated outside the context of a clinical trial. Outside of the traditional mechanisms considered for AIHA and ITP, an abnormal T cell environment was also proposed as a driver in cases involving PRCA and autoimmune neutropenia that improved with ibrutinib and documented T-cell immune environment normalization (Schliffke et al., 2016). As the next generation of more specific BTK inhibitors arrive, the importance of the effect of ibrutinib on ITK in the setting of AIC may become clearer.

Limitations of our study include its retrospective nature and that it was conducted in a single-centre. Additional studies of larger cohorts of ibrutinib-treated CLL patients who receive therapy outside the context of a clinical trial need to be done to confirm our findings.

In summary, in this retrospective cohort of ibrutinib-treated CLL patients at an academic medical centre outside the context of clinical trials, we found that ~1 out of every 17 patients developed treatment-emergent AIC. Improved control of AIC with the start of ibrutinib allowing for discontinuation or de-escalation of AIC treatment in two-thirds of patients supports previous findings. Past history of AIC was not associated with a difference in EFS or OS from time of ibrutinib start; treatment-emergent AIC were associated with shorter EFS, as expected.

The results of our study, obtained from careful follow-up of patients treated outside the context of a clinical trial, provide important information to practicing clinicians about the incidence, clinical manifestations and management of AIC in ibrutinib-treated patients.

Acknowledgements

SAP and SSK are recipients of the K12 CA090628 grant from the National Cancer Institute (Paul Calabresi Career Development Award for Clinical Oncology).

Footnotes

Disclosures

SAP has participated in advisory boards and received research support from Pharmacyclics and AstraZeneca and AbbVie; he was not personally compensated for the advisory board or the research support. TDS has received research funding from Pharmacyclics, Janssen, Genentech, Glaxosmithkline, Celgene, Cephalon, and Hospira; he was not personally compensated for the research support. NEK has received research funding from Pharmacyclics, Tolero and he is on DSMC for Gilead, Morpho-Sys, Infinity Pharm, Celgene and Cytomyx Therapeutics; he was not personally compensated for the research support or the DSMC work. All other authors have no conflicts of interest to declare.

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