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\begin{document}

\title{Treatment strategy in chronic lymphocytic leukemia with symptomatic
central nervous system involvement : a case report}



\author[1]{Rosina Dewaide}%
\author[1]{Kirsten Saevels}%
\affil[1]{University Hospital Antwerp}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Treatment strategy in chronic lymphocytic leukemia with
symptomatic central nervous system involvement : a case report}

Author: Rosina Dewaide, M.D. University Hospital Antwerp: Universitair
Ziekenhuis Antwerpen Antwerpen, BELGIUM

Co-author: Kirsten Saevels, , M.D. University Hospital Antwerp:
Universitair Ziekenhuis Antwerpen Antwerpen, BELGIUM

Corresponding author: Rosina.Dewaide@uza.be

The author and co-author state that they have no conflict of interest.

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.



\textbf{Treatment strategy in chronic lymphocytic leukemia with
symptomatic central nervous system involvement : a case report}

Chronic lymphocytic leukemia (CLL) is a rather common disease in daily
hematology practice, with an incidence in Belgium in 2018 of 6,8 new
cases for every 100.000 person years (1). Symptomatic central nervous
system (CNS) involvement in patients with CLL on the other hand is very
rare. However, according to autopsy studies, CNS localization may be
underestimated, with some reports showing a prevalence up to 71\% (2).
Diagnosis is often a strenuous process because of the heterogenic
clinical presentation. Moreover, upon finding a monoclonal B-cell
population in the cerebrospinal fluid (CSF), it can be challenging to
differentiate between contamination by peripheral blood, presence of
leukemic cells due to other conditions such as inflammatory/infectious
disease and clinical significant CNS involvement by CLL. The specificity
of flowcytometry analysis on CSF for distinguishing symptomatic CLL
involvement from other conditions is limited to 42\% (3). Even when
diagnosis of CNS involvement by CLL is made, there are no established
guidelines on how to treat this entity.

We present a case of a 76 year old man with known chronic lymphocytic
leukemia since 1993. He received chlorambucil at the time of diagnosis
after which he stayed in a durable remission, occasionally needing
intravenous immunoglobulins because of secondary hypogammaglobulinemia
with respiratory infections. In 2005 a bone marrow examination was
performed, revealing a complex FISH pattern with a trisomy 12 in 14/60
interphase nuclei, a deletion 17p13.1 in 5/100 interphase nuclei and
deletion 13q14 or monosomy 13 in 14 and 3/60 interphase nuclei. In 2017
he developed progressive lymphadenopathy in his left groin. Biopsy
revealed invasion of CLL without signs of transformation. Peripheral
blood stayed normal without lymphocytosis or cytopenia. Cytogenetics
revealed a trisomy 12 and 19 and fluorescence in situ hybridization
(FISH) analysis showed a deletion 13q14. The presence of 3 cytogenetic
abnormalities (complex karyotype) is associated with poor prognosis (4).
Molecular analysis was not performed. He was started on treatment with
ibrutinib 420 mg with very rapid involution of the palpable
lymphadenopathy. Unfortunately, the patient was admitted two months
later with an out of hospital cardiac arrest due to ventricular
fibrillation, likely related to ibrutinib. Treatment was discontinued.
Bone marrow examination cytogenetics still showed the same trisomy 12
and 19 and FISH analysis showed the deletion 13q14, indicating absence
of cytogenetic response. However due to the severity of the adverse
event and no apparent treatment indication after ibrutinib
discontinuation, a watch and wait approach was maintained.

In 2021, at the age of 76 years, the patient presented at the emergency
department with progressive cognitive impairment as well as a balance
disorder and a peripheral facial nerve palsy of unclear onset and was
hospitalized on the neurology ward for further investigations. Anamnesis
revealed no recurrent fever or night sweats but there was unintentional
weight loss of 17 kg over the course of one and a half year
(\textgreater{}10\% of his normal body weight over a period of 6
months). There were no apparent palpable lymphadenopathies nor
splenomegaly on clinical examination. Magnetic resonance imaging of the
brain showed staining of multiple cranial nerves with focal
leptomeningeal staining in the right sulcus callosi, suspect for
leptomeningeal lymphoma deposits (fig 1). Blood test again did not
reveal progression of lymphocytosis nor development of cytopenia.
Cerebrospinal fluid (CSF) showed a high white cell count of 40/\selectlanguage{greek}µ\selectlanguage{english}l
without erythrocytes (\textless{}1000/\selectlanguage{greek}µ\selectlanguage{english}l), excluding contamination by
peripheral blood. There was an increased protein level and decreased
glucose level. Flowcytometry on the CSF revealed a monoclonal B-cell
population with CLL phenotype. An infectious etiology was ruled out by
negative viral PCR's for Varicella Zoster, Herpes simplex and
Enterovirus as well as negative PCR for Listeria and negative cultures.
PET-CT showed no evidence of FDG-avid lymph nodes but did show diffuse
heterogenic uptake in the left liver lobe. Liver biopsy surprisingly
showed infiltration of CLL, without signs of Richter's transfomation.
The diagnosis of CNS involvement of CLL with systemic relapse (liver
localization) was made.

Because of its ability to penetrate through the blood brain barrier and
its effectiveness in high risk (del17p) CLL, a bruton kinase inhibitor
would be the preferred treatment option for this 76 year old patient
with a CLL with poor cytogenetics with established CNS involvement (5).
Unfortunately, the previous history of ventricular fibrillation leading
to an out of hospital arrest was regarded as a strict contraindication
for ibrutinib.

We report on a different treatment strategy used in this case consisting
of venetoclax in combination with intrathecal dexamethasone (4 mg),
methotrexate (15 mg) and cytarabine (40 mg). Te patient was first
started on intrathecal (it) chemotherapy alone on a weekly basis because
of his frailty profile. A total of 6 it regimens were administered
before initiating venetoclax ramp up to 400 mg once daily. Minimal
residual disease was still detected by flowcytometry on the CSF before
start of venetoclax. After one month of (ramp up) venetoclax, the CSF
was cleared. Because of a (low symptomatic) covid 19 infection Rituximab
was not associated as per initial plan. Over the next months the patient
improved considerably with clear improvement of the neurologic symptoms
and Montreal Cognitive Assessment and he had a weight gain of 10 kg.
Overall, the treatment regimen was very well tolerated. Repeated
flowcytometry on the CSF showed a durable response almost one year after
start of treatment. Follow up PET-CT after one year showed no more
aberrant uptake in the liver nor anywhere else.

Our rational for choosing the BCL-2 inhibitor venetoclax as treatment
strategy for our patient was based on few reports in the literature.
Venetoclax is briefly discussed in Blood (2018) as an interesting agent
for primary central nervous system lymphoma (PCNSL) (6). Also in Blood
in 2020, the passage of venetoclax into the CNS was characterized in 33
pediatric patients with relapse/refractory acute leukemia. Because
venetoclax has a high molecular weight and is a substrate of the efflux
transporters P- glycoprotein (P-gp) and breast cancer resistance protein
(BCRP) expressed by endothelial cells at the BBB, its passage through
the BBB was long thought to be limited. The investigators showed the
ability of venetoclax to pass the BBB by measuring venetoclax
concentration in the CSF (with a broad range \textless{}0.1 and 13
ng/mL). However they observed a lower than expected disposition in
humans compared to mice-studies where there is a higher expression of
P-gp. This suggests that other factors are involved in venetoclax
disposition to the CSF (7).

In a case report from 2019, a patient was treated with the combination
of venetoclax and intrathecal cytarabine 70 mg plus methotrexate 15 mg
and showed a sustained response. The authors observed that venetoclax
crossed the blood brain barrier (BBB) with a concentration close to the
half the maximal inhibitory concentration (IC50) established in vitro in
a cultured CLL cell line exposed to venetoclax for 24 hours. This
suggest that venetoclax taken orally can effectively inhibit tumor
growth at the CNS site (8). Few other case reports mention the use of
venetoclax in CNS involvement of CLL. One discusses a patient with CNS
involvement of CLL treated with ibrutinib, who experienced a relapse of
neurological symptoms and reappearance of monoclonal B-cell population
in the CSF after 4 years. Venetoclax was added to ibrutinib and this
resulted in an ongoing complete response (9). In another report, a
patient was treated with ibrutinib 560 mg but was unable to achieve CSF
clearance and, after 6 months of ibrutinib treatment, also had a
symptomatic relapse with returning headaches and development of cervical
adenopathy. Venetoclax was added and within 2 months the CSF was
cleared. Due to reemerging headaches, thought of as mitigated by
venetoclax, the bcl-2 inhibitor was discontinued after the 2 months and
the patient stayed on ibrutinib monotherapy. More than one year after
initiation of venetoclax, the CSF remains cleared (10).

Currently, there are also two clinical trials running using venetoclax
in combination with other treatment modalities in CNS lymphoma. The
first trail evaluates venetoclax plus obinutuzumab for
relapsed/refractory PCNSL (VENOBI-CNS). This is a phase IB study to
assess the pharmacokinetics in the CSF (11). The second trail aims to
determine the safety and tolerability of venetoclax, ibrutinib,
prednisone, obinutuzumab, and revlimid with nivolumab (VIPOR-Nivo) in
participants with PCNSL or an aggressive B-cell lymphoma with secondary
involvement of the CNS (SCNSL). This trial is temporarily suspended due
to a life-threatening acute liver toxicity observed in one of the
participants (12).

In this case report, the clinical response as well as the durable
response in CSF clearance attribute to the potential importance of
venetoclax in patients with CLL with associated symptomatic CNS
involvement. It offers support for treatment approaches in this
historically rare and very difficult to

treat CLL patient population with no established guidelines.

\textbf{Figure legend}

Figure 1a. Staining of multiple cranial nerves.

Figure 1b. Focal leptomeningeal staining in the right sulcus callosi.

\textbf{References}

1. Belgian Cancer Registry. Obtained via kankerregister.org

2. Cramer SC, Glaspy JA, Efird JT, Louis DN. Chronic lymphocytic
leukemia and the central nervous system: A clinical and pathological
study. Neurology. 1996;46(1):19--25.

3. Strati P, Uhm JH, Kaufmann TJ, Nabhan C, Parikh SA, Hanson CA, et al.
Prevalence and characteristics of central nervous system involvement by
chronic lymphocytic leukemia. Haematologica {[}Internet{]}.
2016;101(4):458--65.

4. Thompson PA, O'Brien SM, Wierda WG, Ferrajoli A, Stingo F, Smith SC,
et al. Complex karyotype is a stronger predictor than del(17p) for an
inferior outcome in relapsed or refractory chronic lymphocytic leukemia
patients treated with ibrutinib-based regimens. Cancer.
2015;121(20):3612--21.

5. Lv L, Sun X, Wu Y, Cui Q, Chen Y, Liu Y. Efficacy and Safety of
Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant
Single-Arm Meta-Analysis. Front Oncol. 2021;11(July):1--14.

6. Illerhaus G, Schorb E, Kasenda B. Novel agents for primary central
nervous system lymphoma: Evidence and perspectives. Blood.
2018;132(7):681--8.

7. Salem AH, Badawi MA, Place AE, Palenski TL, Arrendale R, Kim SY, et
al. Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic
Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients.
Blood {[}Internet{]}. 2020;136(Supplement 1):30--1.

8. Reda G, Cassin R, Dovrtelova G, Matteo C, Giannotta J, D'incalci M,
et al. Venetoclax penetrates in cerebrospinal fluid and may be effective
in chronic lymphocytic leukemia with central nervous system involvement.
Haematologica. 2019;104(5):e222--3.

9. Soumerai JD, Takvorian RW, Sohani AR, Abramson JS, Ferry JA.
Venetoclax activity in a patient with central nervous system involvement
by chronic lymphocytic leukaemia. Lancet Haematol {[}Internet{]}.
2022;9(10):e796.

10. Karbhari N, Lara-Martinez H, Hill, JM. Venetoclax: A Novel
Therapeutic Agent for CLL with CNS Involvement. Case Rep Oncol.
2022;15(1):345--50.

11. ClinicalTrials.gov {[}Internet{]}. Bethesda (MD) NL of M (US).
Venetoclax and Obinutuzumab for Relapsed/Refractory Primary CNS Lymphoma
(VENOBI-CNS). Identifier: NCT04073147 {[}Internet{]}. 2019;

12. ClinicalTrials.gov {[}Internet{]}. Bethesda (MD) NL of M (US).
Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid With
Nivolumab (VIPOR-Nivo) for Diffuse Large B-cell Lymphoma Involving the
Central Nervous System {[}Internet{]}. Identifier: NCT05211336. 2022.\selectlanguage{english}
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