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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