# Ibrutinib and idelalisib in the management of CLL-associated autoimmune cytopenias: a study from the FILO group

Anne Quinquenel, Sophie Godet, Caroline Dartigeas, Loïc Ysebaert, Jehan Dupuis, Haykanush Ohanyan, Aude Collignon, Laurent Gilardin, Stéphane Lepretre, Marie-sarah Dilhuydy, et al.

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## ► To cite this version:

Anne Quinquenel, Sophie Godet, Caroline Dartigeas, Loïc Ysebaert, Jehan Dupuis, et al. Ibrutinib and idelalisib in the management of CLL-associated autoimmune cytopenias: a study from the FILO group. American Journal of Hematology, 2019, 94 (7), pp.E183-E185. 10.1002/ajh.25480. inserm-04798575

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CORRESPONDENCE

# Ibrutinib and idelalisib in the management of CLL-associated autoimmune cytopenias: a study from the FILO group

To the Editor:

Autoimmune cytopenias (AIC) are well-known complications of chronic lymphocytic leukemia (CLL).¹ There is no consensus regarding their optimal management. No prospective trial has ever been conducted in this particular setting, and patients with uncontrolled AIC are systematically excluded from clinical trials. The first-line therapy is usually based on corticosteroids, but in most cases, this treatment does not result in a long-term response of AIC. It is hypothesized that an optimal control of CLL should lead to a longer control of AIC. Novel drugs targeting B-cell receptor (BCR) signaling, such as ibrutinib and idelalisib have dramatically changed the outcome of patients with progressive CLL.²,³ They affect the malignant clone by disrupting the signaling pathway downstream of the BCR, but they also impact the ability of CLL cells to interact with the tumor microenvironment, which plays an important role in the onset of CLL-associated AIC. Thus, kinase inhibitors (KI) may represent a valuable option for the management of CLL-associated AIC. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from AIC and being treated with KI because of these autoimmune events.

Forty-four patients from 15 centers belonging to the FILO (French Innovative Leukemia Organization) were included in this study. First KI was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was autoimmune hemolytic anemia (AIHA) for 16 patients (64%), immune thrombocytopenia (ITP) for 5 (20%), Evans syndrome for 3 (12%), and pure red cell aplasia for 1 (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 for ITP (32%), and 1 for an Evans syndrome (5%). At the time of KI initiation, 70% of patients presented with active CLL disease requiring treatment by itself, regardless of AIC. When available, study of common prognostic factors revealed that most patients presented with adverse prognostic factors, as expected in CLL-associated AIHA. Details of the demographic, clinical, and biological characteristics of the patients by KI group and for each type of AIC (AIHA, ITP, and Evans syndrome) are available in Tables S1 to S4. Most patients (93%) were previously treated for either CLL

progression without AIC, AIC alone, or both (45%, 77%, and 34%, respectively). The median number of prior therapies was 3 (0-6). Previous lines of treatment are summarized in Table S5.

In most cases, KI were introduced at standard doses, 150 mg twice daily in combination with rituximab according to the French marketing authorization label in 18/19 patients for idelalisib (95%), and 420 mg daily for ibrutinib. Ibrutinib was associated with rituximab in five patients (20%). The majority of patients (66%) received concomitant short-term AIC therapy (corticosteroids or thrombopoietin receptor agonists, Table S6).

In nearly all cases, both ibrutinib and idelalisib resulted in satisfactory control of AIC. Response criteria are detailed in the supporting information. In terms of AIC, overall response rates (ORRs) to ibrutinib and idelalisib were 92% and 95%, respectively and were not correlated to the AIC type. Considering CLL, ORR, and CR were 100% and 24%, respectively for ibrutinib treated patients, and 95% and 37%, respectively, for idelalisib treated patients. Response rates of both AIC and underlying CLL for each type of associated AIC are detailed in Figure 1A. KI therapy allowed corticosteroids discontinuation in 86% of ibrutinib patients and in 67% of idelalisib patients.

In this specific population, it is of interest to consider the safety profile of ibrutinib and idelalisib as the frequent concomitant exposure to corticosteroids might increase the rate of infections.⁴ Twenty-one of our 44 patients (48%) experienced at least one grade from 3 to 5 adverse events while on KI therapy, 10 in the ibrutinib group (40%), and 11 in the idelalisib group (58%). The increased bleeding risk induced by ibrutinib should be considered especially for ITP patients. Four patients (16%), all 4 treated for AIHA, presented grade 3/4 hemorrhagic syndrome. No severe hemorrhagic event was reported in ibrutinib patients with ITP. Two patients (8%) developed atrial fibrillation. Four patients (16%) experienced severe infections. In the idelalisib group, four patients (21%) developed colitis, and hepatic toxicity was reported in four patients. Severe infections occurred in five patients (26%), mainly pneumonia (cytomegalovirus n = 1, *Pneumocystis jirovecii* n = 2, pneumococcus n = 1).

At the last follow-up, in the ibrutinib group, most patients were still receiving ibrutinib. Conversely, more than 60% of the patients had stopped idelalisib, mainly because of severe adverse events in accordance with the toxicity profile of the drug. Reasons for KI discontinuation are detailed in Table S7.

In our cohort, KI compared favorably with previously published data on immunochemotherapy in CLL-associated AIC.⁵,⁶ After a median follow-up of 27.8 months (range, 2.8-47.7), the estimated 2-year overall survival (2y-OS) of the whole cohort was 88%. The two-year progression-free survival (2y-PFS) was 75.3% for CLL and 65.1% for AIC. The AIC type did not significantly impact 2y-PFS (Figure S1). In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL (Figure 1B,C). In the idelalisib arm, 2y-OS was 80% and

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WILEY
<table><thead><tr><th rowspan="3"></th><th colspan="4">IBRUTINIB<br>(n = 25)<br>n (%) or median (min-max)</th><th colspan="4">IDELALISIB<br>(n = 19)<br>n (%) or median (min-max)</th></tr><tr><th>AIHA<br>(n = 16)</th><th>ITP<br>(n = 5)</th><th>Evans<br>(n = 3)</th><th>Total*<br>(n = 25)</th><th>AIHA<br>(n = 12)</th><th>ITP<br>(n = 6)</th><th>Evans<br>(n = 1)</th><th>Total<br>(n = 19)</th></tr></thead><tbody><tr><td>Median KI duration<br>(months)</td><td>24.3<br>(4.0-45.7)</td><td>5.9<br>(1.7-21.3)</td><td>8.7<br>(2.9-33.2)</td><td>18.0<br>(1.7-45.7)</td><td>5.9<br>(1.3-27.1)</td><td>15.9<br>(8.4-30.4)</td><td>6.2</td><td>11.4<br>(1.3-30.4)</td></tr><tr><td>AIC responses</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ORR (CR + PR)</td><td>14 (87.5%)</td><td>5 (100%)</td><td>3 (100%)</td><td>23 (92%)</td><td>11 (92%)</td><td>6 (100%)</td><td>1 (100%)</td><td>18 (95%)</td></tr><tr><td>CR</td><td>6 (38%)</td><td>4 (80%)</td><td>3 (100%)</td><td>13 (52%)</td><td>3 (25%)</td><td>5 (83%)</td><td>0 (0%)</td><td>8 (42%)</td></tr><tr><td>CLL responses</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ORR (CR + PR + PRI)</td><td>16 (100%)</td><td>5 (100%)</td><td>3 (100%)</td><td>25 (100%)</td><td>11 (92%)</td><td>6 (100%)</td><td>1 (100%)</td><td>18 (95%)</td></tr><tr><td>BM unconfirmed CR</td><td>5 (31%)</td><td>1 (20%)</td><td>0 (0%)</td><td>6 (24%)</td><td>6 (50%)</td><td>1 (17%)</td><td>0 (0%)</td><td>7 (37%)</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**FIGURE 1** Efficacy of KI therapy. A, Response rates on KI therapy. *One patient was treated with ibrutinib for pure red cell aplasia. B-C, Ibrutinib group: (B) Progression-free survival (PFS) of CLL. 2y-PFS = 94.4% [95% CI: 84.4-100]. C, PFS of AIC. 2y-PFS = 81% [95% CI: 62.8-100]. D-E, Idelalisib group: (D) Progression-free survival (PFS) of CLL. 2y-PFS = 55.6% [95% CI: 35.4-87.2]. Median PFS = 25.7 months. E, PFS of AIC. 2y-PFS = 48.6% [95% CI: 28.9-81.8]. Median PFS = 19.1 months. BM, bone marrow; CR, complete response; KI, kinase inhibitor; ORR, overall response rate; PR, partial response; PRI, partial response with lymphocytosis</figcaption></figure>

median PFS was 19 months for AIC and 25.7 months for CLL (Figure 1D,E). At the last follow-up, 66% of the whole cohort was still responding to treatment. Fifteen patients experienced progression of CLL, AIC, or both (CLL along with AIC progression n = 5, CLL without AIC progression n = 6, AIC without CLL progression n = 4). The nine AIC relapses all occurred in patients with AIHA, and not surprisingly after KI discontinuation in most cases, owing the suspensory effect of

these agents. Finally, it is important to note that this retrospective study was not designed to make a direct comparison between ibrutinib and idelalisib, and that shorter PFS in the idelalisib group may be linked to the shorter exposure to the drug.

Our results indicate that BCR inhibitors, such as ibrutinib and idelalisib, are able to induce sustained responses on AIC and may offer new therapeutics options for AIC.
## AUTHOR CONTRIBUTIONS

A.Q. and T.A. designed the study; A.Q., T.A., S.G., L.Y., C.D., J.D., A.C., L.G., S.L., M.S.D., M.V., S.D.G., N.D., E.D., D.G., D.R., E.T., F.M. included patients in the study, A.Q. and M.C.B. created the database, H.O. and V.L. performed statistics, A.Q., S.G., A.D. and T.A. wrote the manuscript.

### ORCID

Anne Quinquenel https://orcid.org/0000-0002-3666-3442

Loïc Ysebaert https://orcid.org/0000-0001-8478-5623

Eric Durot https://orcid.org/0000-0003-3463-0089

Damien Roos Weil https://orcid.org/0000-0002-7767-755X

Anne Quinquenel<fnref n="1" />,<fnref n="2" />

Sophie Godet<fnref n="1" />,<fnref n="2" />

Caroline Dartigeas<fnref n="3" />

Loïc Ysebaert<fnref n="4" />

Jehan Dupuis<fnref n="5" />

Haykanush Ohanyan<fnref n="6" />

Aude Collignon<fnref n="7" />

Laurent Gilardin<fnref n="8" />

Stéphane Lepretre<fnref n="9" />

Marie-Sarah Dilhuydy<fnref n="10" />

Marguerite Vignon<fnref n="11" />

Sophie de Guibert<fnref n="12" />

Natalia Dmytruk<fnref n="13" />

Eric Durot<fnref n="1" />

David Ghez<fnref n="14" />

Damien Roos Weil<fnref n="15" />

Marie-Christine Béné<fnref n="16" />

Elise Toussaint<fnref n="17" />

Fatiha Merabet<fnref n="18" />

Vincent Lévy<fnref n="6" />

Alain Delmer<fnref n="1" />,<fnref n="2" />

Thérèse Aurran<fnref n="7" />

### Correspondence

Anne Quinquenel, Hôpital Robert Debré, CHU Reims, rue du general Koenig, 51092 Reims, France.

Email: aquinquenel@chu-reims.fr

Anne Quinquenel and Sophie Godet contributed equally to this study.

### REFERENCES

1. Moreno C, Hodgson K, Ferrer G, et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. *Blood*. 2010;116(23):4771-4776. https://doi.org/10.1182/blood-2010-05-286500.

2. Brown JR, Hillmen P, O'Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. *Leukemia*. 2018;32(1):83-91. https://doi.org/10.1038/leu.2017.175.

3. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. *N Engl J Med*. 2014;370(11):997-1007. https://doi.org/10.1056/NEJMoa1315226.

4. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. *Blood*. 2018;131(17):1955-1959. https://doi.org/10.1182/blood-2017-11-818286.

5. Rossignol J, Michallet A-S, Oberic L, et al. Rituximab-cyclophosphamide-dexamethasone combination in the management of autoimmune cytopenias associated with chronic lymphocytic leukemia. *Leukemia*. 2011;25(3):473-478. https://doi.org/10.1038/leu.2010.278.

6. Quinquenel A, Willekens C, Dupuis J, et al. Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS). *Am J Hematol*. 2015;90(3):204-207. https://doi.org/10.1002/ajh.23909.

### SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Received: 4 April 2019

Accepted: 8 April 2019

DOI: 10.1002/ajh.25489

# Ruxolitinib treatment and risk of B-cell lymphomas in myeloproliferative neoplasms

### To the Editor:

Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders complicated mainly by vascular events and transformation to myelofibrosis or leukemia.<fnref n="1" /> Secondary malignancies, in particular lymphoproliferative disorders, are rare but occur at a higher frequency than found in the general population.<fnref n="2" />⁻<fnref n="4" />

<footnote n="1">¹CHU Reims, Hôpital Robert Debré, Hématologie Clinique, Reims, France</footnote>

<footnote n="2">²Université Reims Champagne Ardenne, UFR Médecine, Reims, France</footnote>

<footnote n="3">³CHU Tours, Hôpital Bretonneau, Hématologie Clinique, Tours, France</footnote>

<footnote n="4">⁴IUC Toulouse-Oncopole, 'Hématologie Clinique, Toulouse, France</footnote>

<footnote n="5">⁵Hôpital Henri Mondor, Hématologie Clinique, Créteil, France</footnote>

<footnote n="6">⁶Hôpital Avicenne, URC/CRC, Assistance Publique-Hôpitaux de Paris (APHP)</footnote>

<footnote n="7">⁷Institut Paoli Calmettes, Hématologie Clinique, Marseille, France</footnote>

<footnote n="8">⁸Hôpital Saint Louis, Hématologie Clinique, Paris, France</footnote>

<footnote n="9">⁹Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France</footnote>

<footnote n="10">¹⁰Hôpital haut-Leveque, Hématologie Clinique, Bordeaux, France</footnote>

<footnote n="11">¹¹Hôpital Cochin, Hématologie Clinique, Paris, France</footnote>

<footnote n="12">¹²CHU Rennes, Hématologie Clinique, Rennes, France</footnote>

<footnote n="13">¹³CHU Limoges, Hématologie Clinique, Limoges, France</footnote>

<footnote n="14">¹⁴Institut Gustave Roussy, Hématology Clinique, Villejuif, France</footnote>

<footnote n="15">¹⁵Sorbonne Universités, UPMC Univ Paris 06, AP-HP, GRC-11, Groupe de recherche clinique sur les hémopathies lymphoïdes (GRECHY), Hôpital Pitié-Salpétrière, Hématologie Clinique, Paris, France</footnote>

<footnote n="16">¹⁶CHU Nantes, Hématologie Biologique, Nantes, France</footnote>

<footnote n="17">¹⁷CHU Strasbourg, Hématologie Clinique, Strasbourg, France</footnote>

<footnote n="18">¹⁸CH Versailles, Hématologie Clinique, Versailles, France</footnote>