A case of bone lesion in a patient with relapsed chronic lymphocytic leukemia and review of the literature
Francesca Bacchiarri1, Alessandro Gozzetti1, Nicola Mondanelli2, Stefano Lazzi3, Monica Bocchia1
1 University of Siena, Department of Hematology, Siena, Italy
2 University of Siena, Department of Orthopedic Surgery, Siena, Italy
3 University of Siena, Anatomic Pathology department, Siena, Italy
Corresponding author: Francesca Bacchiarri, MD
Email: francesca.bacchiarri@hotmail.it
Address: University of Siena, Viale Bracci 16, 53100- Siena, Italy
Phone: +39 0577586798
Fax: +39 0577586185
Keywords: chronic lymphocytic leukemia, hypercalcemia, osteolysis
ABSTRACT
Skeletal involvement in CLL is very rare. We present a case of ileum bone lesion during in a patient receiving 5th line of therapy. Despite radiotherapy and salvage therapies, subsequent bone lesions led to a fatal outcome. Further studies on the mechanism by which bone disease develops are currently needed.
KEY CLINICAL MESSAGE
The mechanism by which bone lesions develop in CLL is unclear, further studies are needed in this regard, with the aim of developing more effective therapies. This case aims to review the literature, the modality of presentation and pathogenesis.
INTRODUCTION
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with a predominance in the elderly and an increasing incidence with age.1 Characterized by heterogeneous clinical course, CLL has predominantly a B-cell origin, with a clonal expansion of mature CD5+ CD23+ B-lymphocytes that accumulate in the bone marrow and infiltrate lymphoid tissues such as the spleen and lymph nodes.2
Treatment has changed over the last 30 years from chemotherapy, to chemo-immunotherapy and lately to novel agents (i.e. BTK inhibitors and BCL-2 inhibitor).3-5
Rarely, patients can experience a skeletal progression, variously associated with hypercalcemia, as reported by some authors. Herein we present a case of skeletal progression in a patient with a 10-year history of CLL with del17p and unmutated IGHV, receiving venetoclax as 5th line of therapy.
CASE PRESENTATION
The patient was diagnosed with CLL in 2009: he presented with a mild lymphocytosis, diffuse lymphadenopathies (laterocervical and axillary lymph nodes of maximum diameter 2 cm), splenomegaly and left testicular swelling. Bone marrow aspiration was positive for CLL (CD5+ CD19+ CD23+ CD20+ CD38+); fluorescence in situ hybridization (FISH) analysis showed chromosome 17p delection (20% of nucleated cells), and unmutated IGHV. The patient underwent left orchiectomy, that confirmed CLL diagnosis. After 4 cycles of chemotherapy with fludarabine and alemtuzumab, he obtained a partial remission of the disease. Patient underwent maintenance therapy with rituximab until October, 2012. In December 2012, due to a disease relapse with anemia, splenomegaly and lymphadenopathy, 2nd line therapy with rituximab and bendamustine was started. After 4 cycles, patient was in stable disease, therefore a therapy with alemtuzumab and cyclophosphamide was administered from April to September 2013.
Patient remained asymptomatic until June 2014, when massive splenomegaly, anemia and lymphocytosis were again found. A therapy with BTK inhibitor (ibrutinib) was started. For an episode of autoimmune haemolytic anemia he required corticosteroids therapy. Patient obtained a partial remission and continued ibrutinib until March 2018, when a therapy with BCL-2 inhibitor (venetoclax) was started for massive lymph nodes enlargement. Patient had a complete remission until August, 2019 when he was admitted to the Emergency Unit for lower limbs pain complained for about 2 months. Radiographs and CT-scan demonstrated a left iliac bone pathological fracture due to a bone lesion that also affected the soft intrapelvic tissues, occupying and replacing the iliopsoas muscle (maximum diameter of the lesion 10 cm), as shown in Figure 1. A core needle bone biopsy performed under radiographic guidance confirmed CLL diagnosis (Figure 2). Physical examination revealed no lymphadenopathy nor organomegaly. Laboratory findings showed no lymphocytosis with WBC 2.3 x 109/L (lymphocyte count 15%), Hb 11.4 g/dL, platelets 137 x 109/L. Serum total proteins were low (5.6 g/dL), without monoclonal component. Uric acid (4.3 mg/dL) and serum alkaline phosphatase (125 U/L) were normal, with elevated calcium (14.6 mg/dL), β2-microglobulin (4.9 mg/L) and serum lactate dehydrogenase (250 U/L). PTH analysis was not performed. Bone marrow aspiration showed CLL infiltrate.
The fracture was treated conservatively, and radiotherapy was administered at the dose of 30 Gy, but other lytic lesions of the contralateral acetabulum, 3rd left rib and left clavicle leading to pathological fractures occurred. The patient was subsequently treated with 1 cycle of intravenous rituximab, continuing with venetoclax plus zoledronic acid as prophylaxis. Despite the radiotherapy and intensification of immunotherapy, patient developed multiple cranial lytic lesions, involving epidural and dural tissue and left occipitotemporal leptomeningeal infiltration, and he died 3 months later.
DISCUSSION
CLL is the commonest form of leukemia, presenting often with asymptomatic peripheral lymphocytosis. The clinical course can be very heterogenous with lymphadenopathy, increased incidence of infection, autoimmune phenomena (e.g., haemolytic anemia, thrombocytopenia), and B symptoms (fever, unintentional weight loss, night sweats, and severe fatigue). Active treatment is required with advanced disease stage, evidence of disease progression (e.g., cytopenias, lymphadenopathy of 10 cm, and/or splenomegaly), and/or in the presence of constitutional B symptoms. In case of relapse, the presentation can be identical or characterized by transformation to high-grade lymphoma (Ricther’s syndrome)6. Macroscopic skeletal involvement is extremely rare, being more frequent in other lymphoproliferative disease and some acute leukemias. Altered bone metabolism, resorption, and demineralization can lead to an increased risk of spine and pelvic fractures in untreated patients.7-9
Some cases in literature have already described the presence of lytic lesions in patients affected by CLL, and one of them was previously described by our group.10
In 11 on 22 cases of the literature, patients had the axial skeleton or proximal long bones involved 10-21 and in rare cases fractures were localized to the skull or facial bones.17,22,23Multiple fractures were reported in 8 cases.24-31
Like this one, other cases in the literature described pathological fracture due to CLL involving the spine and vertebral compression fractures.16,19,29,30 Of note, in 13 reports symptomatic osteolysis was the first presentation of a CLL. The cases reported in the literature are summarized in table 1. Interestingly, pathological fracture can be also the first presentation of a newly diagnosed CLL. Hypercalcemia is a frequent finding with osteolysis, and can be related to Richter’s transformation, or co-occurring multiple myeloma. The pathogenesis is not well understood, and can be related to primary hyperparathyroidism,32 increased serum immunoreactive parathormone (iPTH), or osteoclast activating factor (OAF).33
In a recent study34 bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and it was directly related to the number of RANKL + cells present in the circulating blood. Also, after denosumab administration to CLL cells in vitro the expression of RANK decreased and also cell proliferation, this could partially be explained by the interaction between CLL lymphocytes and stromal cells.
CONCLUSIONS
Our patient had a 10-year history of CLL, with several relapses, and eventually developed multiple osteolytic lesions associated with hypercalcemia. PTH analysis was not performed, however in an end-stage disease characterized by several skeletal lytic lesions hypercalcemia can be a common finding.
The pathogenesis of bone involvement in CLL is not completely understood, and it is associated with Richter disease in the majority of cases. Of note, in 13 cases patients developed bone metastases / presented symptomatic bone lesions as first presentation of a CLL.
Bone erosions in patient affected by CLL can be related to an increased expression of RANK or locally released osteoclast stimulating factors.
This overview suggests that bone lesion are not rare events in CLL and further investigation is required to clarify the underlying mechanism and to find suitable therapies for this group of patients, which often presents a high morbidity and mortality.
AUTORSHIP
FB wrote the manuscript, AG followed the patient, NM performed patient’s bone biopsy, SL analyzed bone biopsy, MB designed the study. All authors have contributed to, read and approved the manuscript and this submission.
ETHICS STATEMENT
relatives of the deceased patient were informed and agreed to the publication.
CONFLICT OF INTEREST
The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.
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