Dual Mechanism of Severe Bleeding Diathesis in a Patient with CLL: Acquired Von Willebrand Syndrome and Ibrutinib - Mediated Platelets Dysfunction

Case Presentation

Ann Hematol Oncol. 2020; 7(3): 1290.

Dual Mechanism of Severe Bleeding Diathesis in a Patient with CLL: Acquired Von Willebrand Syndrome and Ibrutinib - Mediated Platelets Dysfunction

Bürki S* and Novak U

Department of Medical Oncology, Bern University Hospital, Switzerland

*Corresponding author: Bürki S, Department of Medical Oncology, Bern University Hospital, Bern, Switzerland

Received: February 16, 2020; Accepted: March 10, 2020; Published: March 17, 2020

Abstract

We here report an informative case of severe bleeding diathesis in a patient with Chronic Lymphocytic Leukaemia (CLL), due to Acquired Von Willebrand Syndrome (AVWS) and impaired platelets aggregation under the treatment with Ibrutinib.

Keywords: CLL; Acquired von Willebrand syndrome; Ibrutinib; Bleeding

Introduction

The diagnosis of Acquired Von Willebrand Syndrome (AVWS) might be challenging because of the broad spectrum of its clinical and laboratory features. The AVWS is a rare bleeding disorder caused by a structural or functional defect in von Willebrand Factor (vWF) that can be associated with autoimmune conditions, neoplasia, lymphoproliferative, myeloproliferative and cardiovascular disorders [1,2]. A variety of pathogenic mechanisms have been described, and include the formation of antibodies to the von Willebrand Factor (vWF) (antibodies to vWF are shown in vitro in only a minority of the cases), its absorption from the surfaces of transformed cells or platelets and its mechanical destruction under the shear-stress [3].

The bleeding history is usually characterized by spontaneous mucocutaneous and/or gastrointestinal haemorrhage, occurring in patients without a family history of bleeding disorders [4]. The diagnosis is based on the detection of low of a plasma concentration or impaired activity of vWF [5].

Bruton Tyrosine Kinase (BTK) functions downstream of multiple surface receptors in hematopoietic cells. Its constant activation via B-cell antigen receptor signalling in various B-cell malignancies leads to downstream activation of essential cell survival pathways such as NF-B and MAPK [6,7]. Reversible inhibition of BTK by Ibrutinib disrupts proliferation, differentiation and migration of normal and malignant B-cells, rendering it an effective therapeutic agent in B-cells neoplasms [8-10].

BTK activation via several platelet transmembrane receptors, including the platelet collagen receptor glycoprotein VI is required for a normal platelet activation. BTK blockage by Ibrutinib also leads to an impaired platelets aggregation, and can cause a severe hemorrhagic diathesis, including subdural hematomas and gastrointestinal bleedings [6,11-15]. Additionally, in vitro and in vivo studies show that Ibrutinib can affect platelet adhesion to the vWF via inhibition of the GPIb-receptor signaling [16,17].

We here describe the case of patient with Chronic Lymphocytic Leukaemia (CLL) that presented with both, a severe persistent hemorrhagic diathesis due to the combination of an AVWS as well as an impaired platelets function under the treatment with Ibrutinib.

Case Description

65-year old male patient with a past medical history of arterial hypertension and a Deep Vein Thrombosis (DVT) on the left low extremity presented in October 2012 with constitutional symptoms, generalized lymphadenopathy and lymphocytic leucocytosis.

Immunophenotyping of peripheral blood lymphocytes by flow cytometry and immunohistochemistry on a bone marrow biopsy reveal a typical B-CLL phenotype: CD5+, CD23+, CD20weak, and FMC7 and Cyclin D1 negativity. Investigations revealed a Binet B and Rai I. Neither cytogenetic nor molecular (mutation TP53) analysis is available as this was not routinely performed at the time in the external hospital.

The patient received six cycles of Rituximab/Bendamustin as a first line treatment, and achieved a good partial remission. Seven months later, he presented with new and significant B-symptoms. Richter’s transformation to Diffuse Large B-Cell Lymphoma (DLBCL) was excluded by a repeated lymph node biopsy. R-CHOP to treat this early progression lead to a minor response only. Treatment intensification was initiated with O-DHAP. Unfortunately, autologous stem cell collection with Navelbine failed.

Response after this treatment lasted only a couple of weeks, and the patient again presented with progressive disease with generalized lymphadenopathy and anemia (Hb 90-110g/l, thrombocytes 150- 200G/l). A treatment therapy with Ibrutinib was started. This resulted in a partial remission, as confirmed by CT-scan two months after treatment initiation. A dose reduction to 140 mg/day was needed due to grade 3 diarrhoea.

Furthermore, recurrent muco-cutaneous bleedings, rated by 9 points according to the ISTH-Bleeding-score standardized questionnaire occurred. The platelet number was normal at that time. The coagulation tests revealed the only mild aPTT (activated Partial Thromboplastin Time) prolongation (44sec). Further investigation showed normal values of Fibrinogen, Factor II, V, VII, IX, XI and XII. However, both the vWF and VIII-factor activities were reduced to 35% and 44%, respectively, in this patient with of 0 (Rh+) blood group.

The advanced platelet function analysis showed prolonged closure time with both collagen and epinephrine. The platelet aggregation test revealed an impaired platelet aggregation in response to collagen and a Ristocetin test revealed a biphasic platelet activation curve. The normal platelet aggregation could be restored in presence of ADP and arachidonic acid. Altogether, the findings were consistent with the diagnosis of an AVWS.

He experienced a severe epistaxis in August 2015. Emergency embolization of the A. maxillaris bilateralis was needed. Imaging revealed an epipharyngeal mass as a possible source of the bleeding, a biopsy showed an infiltration by the small lymphocytic lymphoma. Radiation therapy with 20Gy was given to the nasopharyngeal cavity.

Due to progressive disease, Ibrutinib was stopped in August 2015. The bleeding tendency, however, persisted, and therapy with the PIK3A inhibitor Idealisib was initiated.

Repetitive hemostasis tests showed a progressive decline of the von Willebrand factor and factor VIII:C. The clearance test of vWF clearly shows a higher activity of 72% after the Haemate substitution (Table 1).

Table 1: Results of hemostasis test during the treatment in the CLL patients.





  

    
    
    
vWF ACT%

    
vWF AG%

    
FV111%

  

  

    
During Ibrutinib

    
13 Months

    
35

    
44

    
49

  

  

    
    
14 Months

    
16

    
25

    
18

  

  

    
    
1 h after 3000 E Haemate

    
72

    
185

    
87

  

  

    
    
5 h after Haemate

    
18

    
93

    
77

  

  

    
    
24 h after Haemate

    
11

    
55

    
92

  

  

    
After Ibrutinib

    
    
16

    
25

    
18

  

  

    
During Idealisib

    
    
19

    
35

    
39

  










Table 1: Results of hemostasis test during the treatment in the CLL patients.

Two months after the initiation of Idelalisib therapy, the patient presented a severe mucositis. He also developed a significant and further deterioration of his performance status. A CT-scan confirmed a further disease progression, and the patient died shortly after.

Discussion

This patient’s history is informative as it includes a multifactorial aetiology of persistent severe bleeding diathesis and illustrates a possible therapeutic dilemma when treating such patients.

The AVWS was of origin of the disease-related hemostatic failure in this patient. The main supposed mechanism in CLL is a destruction of vWF by autoantibodies that are secreted by malignant B-lymphocytes [2]. The treatment approach here is based on the malignant clone eradication. Since CLL in our case was primary resistant, the hemorrhagic diathesis due to the vWF exhaustion correlated positively with the disease progression.

The second mechanism that played an important role in the bleeding persistence in our case was the qualitative (thrombopenia) and quantitative (impaired aggregation) platelet function perturbation.

The defective platelet aggregation was a manifestation of AVWS, and a consequence of inhibition of platelets signal transduction by Ibrutinib. Since the BTK-inhibitor can influence the platelet activation via blockage of vWF/GPIb-IX-V signalling, the platelet aggregation assay was not specific enough to distinguishing AVWSfrom Ibrutinib-mediated platelets function perturbation.

The PIK3A-inhibitor Idealisib could apparently ameliorate platelet function in patients with CLL, as it was shown by platelet aggregation essay [18].

In our case, we did not observe any improvement in the bleeding syndrome after Idealisib introduction. We believe that it could be explained by concomitant progressive AVWS, which levelled all possible positive effects of Idealisib on platelet aggregation. Moreover, and with regard to the bleeding problems, Idealisib was probably introduced too late, already in setting of a highly resistant disease associated with severe secondary thrombopenia. An earlier switch from Ibrutinib to Idealisib could probably have been a better strategy, at least for bleeding symptoms improvement.

Concerning the possible approach to the underlying progressive AVWS, Intravenous Immune Globulins (IVIG) could also have been an option as previously shown, especially in the cases with anti-vWF autoantibodies. The IVIG association with AVW concentrates may be even more beneficial [19].

We believe that the thorough work-up of a case like ours could help to better understand the aetiology and the management of a bleeding diathesis in patients with lymphoproliferative disease under Ibrutinib, and thus, help to better define possible therapeutic strategies.

Acknowlegments

We thank Julia Engels and Michael Nagler for valuable comments. We also thank the Department of Hematology and Center of Laboratory Medicine (ZLM) for the lab analyses.

Authorship Contributions

SB analyzed data and wrote the paper; UN contributed vital material, had the idea, designed research, analyzed data, and wrote parts of the paper.

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Citation: Bürki S and Novak U. Dual Mechanism of Severe Bleeding Diathesis in a Patient with CLL: Acquired Von Willebrand Syndrome and Ibrutinib - Mediated Platelets Dysfunction. Ann Hematol Oncol. 2020; 7(3): 1290.