Management of central nervous system involvement in chronic
lymphocytic leukaemia: a retrospective cohort of 30 patients
Anne Wanquet,1,* Rudy Birsen,2,* Charlotte Bonnet,3Marouane Boubaya,4 Sylvain Choquet,2Jehan Dupuis,5 Stephane Lepretre,6Daniel Re,7 Jonathan Fahri,8Anne-Sophie Michallet,9Lo€ıc Ysebaert,10 Richard Lemal,11Thierry Lamy,12 Richard Delarue,13Xavier Troussard,14 Florence Cymbalista,4Vincent Levy,4 Pierre-Yves Dietrich,15Veronique Leblond2and Therese
Aurran-Schleinitz1
1Department of Haematology, Institut
Paoli-Calmettes, Marseille,2Department of Haematol-ogy, H^opital La Pitie-Salp^etriere, AP-HP, Paris,
3Department of Neurological Surgery, CHU
Bordeaux, Bordeaux,4URC/CRC, H^opital
Avicenne, AP-HP, Bobigny,5Lymphoid
Malignancies Unit, Henri Mondor University Hospital, AP-HP, Creteil,6Department of
Haematology, Centre Henri Becquerel, Rouen,
7Department of Medicine 3, Centre Hospitalier,
Antibes,8Department of Haematology, CHU,
Angers,9Department of Haematology, Centre Leon Berard, Lyon,10Department of Haematology, CHU, Toulouse,11Service de therapie cellulaire et d’hematologie clinique adulte CHU Clermont-Ferrand, Clermont-Ferrand,
12Department of Haematology, CHU, Rennes, 13Department of Haematology, Hoˆpital Necker,
AP-HP, Paris,14Department of Haematology,
CHU, Caen, France and15Centre of Oncology,
Hoˆpitaux Universitaires, Geneva, Switzerland Received 8 May 2016; accepted for publication 20 July 2016
Correspondence: Therese Aurran-Schleinitz, Department of Haematology, Institut Paoli-Calmettes, 232 Bd Ste Marguerite 13273, Marseille Cedex09 France.
E-mail: aurrant@ipc.unicancer.fr
*AW and RB contributed equally to the study.
Summary
Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains chal-lenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of
the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological
symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Ini-tial treatment with fludarabine-based immuno-chemotherapy, with or with-out intra-CSF therapy, led to durable response in eight with-out of nine untreated patients. In contrast, 50% patients receiving various prior treat-ments needed additional therapy within a median of 4 months (1–16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From
CNSi, 5-year overall survival was 72% and 48% for treatment-na€ıve and
previously treated patients respectively (P= 006); 5-year progression-free
survival (PFS) was 43% and 0% (P = 0125). 17p deletion was significantly
associated with poor PFS (P= 0006). CNSi may be the only sign of
pro-gression of CLL and should be considered an initiation criterion of sys-temic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.
Keywords: chronic lymphocytic leukaemia, central nervous system,
cerebrospinal fluid, magnetic resonance imaging, treatment.
Chronic lymphocytic leukaemia (CLL) is the most common
leukaemia occurring in adulthood in the Western
hemisphere with a median age at diagnosis of 71 years
(http://seer.cancer.gov/statfacts/html/clyl.html, last accessed 3 January 2016). Prognosis is related to biological features that have been the subject of recent significant progress
ª 2016 John Wiley & Sons Ltd
both in terms of prognostic markers and of prediction of treatment response. Meanwhile, initiation treatment criteria still rely on initial bio-clinical Rai (Rai et al, 1975) and Binet (Binet et al, 1981) classifications. These criteria for treatment mostly depend on the tumour burden and the progressive status of the disease. CLL management may be determined by other complications, such as infec-tions, autoimmune haemolytic anaemia and Richter trans-formation. Other unusual manifestations, such as central nervous system involvement (CNSi) have been poorly described.
Although a consistent rate of CNSi has been reported in autopsy studies of CLL patients (Reske-Nielsen et al, 1974; Bojsen-Møller & Nielsen, 1983; Barcos et al, 1987), only a few clinical cases of symptomatic CNS infiltration by CLL have been reported (Cramer et al, 1996; Lopes da Silva, 2012; Moazzam et al, 2012; Strati et al, 2016).
A broad array of conditions can lead to neurological symptoms in patients with CLL, and specific CNSi has been involved in only 20% of cases (Strati et al, 2016). Heteroge-neous clinical presentation and inconclusive neurological investigations (including lumbar puncture and neuroimaging techniques) may result in difficulties in establishing a causal relationship between the CLL and the neurological symp-toms. Because CNSi with CLL is rare, there is no clear data available on the clinical and radiological presentation, and diagnostic modalities are not standardized. Treatment recom-mendations and outcome in this setting are poorly reported in the literature.
In order to better characterize this complication, we retro-spectively collected clinical, biological and radiological data and report here the outcome of the largest cohort of CLL patients with specific CNSi.
Subjects and methods
Patient selection
Data were retrospectively collected within centres of the French Innovative Leukaemia Organization (FILO), and Geneva centre (Switzerland). Detailed information was collected by chart review after the approval of the inde-pendent ethics committee and in accordance with the declaration of Helsinki. Six patients were reported else-where (Chantepie & Cornet, 2014; Rossi et al, 2014; Wan-quet et al, 2016).
All the patients met the International Workshop on CLL (IWCLL) diagnostic criteria for CLL (Hallek et al, 2008). Clinical and biological information were collected, including fluorescent in situ hybridization results for common CLL chromosome abnormalities, analysis of the mutation status of the immunoglobulin heavy chain variable gene (IGHV), CD38 expression by flow cytometry, beta-2-microglobulin and lactate dehydrogenase levels. Suspicion of CNSi with CLL was based on persistent peripheral or central
neurological symptoms associated with documentation of CLL infiltration either leptomeningeal, defined by positive cerebrospinal fluid (CSF) cytology and flow cytometry (FCM), or histopathological, defined by CNS biopsy. CSF analysis included basic chemistry (glucose and protein) and microbiology studies. Neuro-imaging was recorded but was not mandatory for a positive diagnosis. Specific CLL CNSi diagnostic was established after the exclusion of any other setting, such as infectious, autoimmune or inflammatory conditions, other cancer or treatment-related conditions. Patients with CNS localization of Richter transformation were excluded.
Response criteria
Response criteria for CNS involvement were defined as fol-lows: complete remission (CR) i.e. disappearance of neuro-logical clinical symptoms with CSF (and neuro-imaging when applicable) normalization; partial response (PR) i.e. partial clinical improvement with CSF normalization; pro-gressive disease (PD) was defined as progression of clinical symptoms, CSF involvement or neuro-imaging; patients not fulfilling PR or PD criteria were considered to have stable disease (SD).
Response for CLL was assessed according to the
IWCLL guidelines (Hallek et al, 2008) but bone marrow biopsy was not routinely performed. Patients meeting clinical and blood complete response criteria were described as achieving clinical complete response (Hallek et al, 2008).
Statistical analysis
Data were summarized by frequency and percentage for categorical variables. For continuous variables, the median and range were computed. Overall survival (OS) was mea-sured from the date of both CLL diagnosis and the begin-ning of treatment for CNSi until death from any cause, with observation ending at the date of last contact for patients’ last known to be alive. Progression-free-survival (PFS) was measured from the start of CNSi treatment to the date of the first event (i.e. progression, Richter trans-formation, next treatment line, death from any cause). Patients without events were censored at the date of the last follow-up. The median follow-up was estimated using the inverse Kaplan–Meier method. Follow-up was com-pleted by January 2016. OS and PFS were estimated by the Kaplan–Meier method. Factors associated with OS and PFS were analysed using univariate Cox models. The pro-portional hazards assumption was checked by examination of Schoendeld residuals. Given the number of events, no multivariate model was applied. All the tests were two-sided at a 005 significance level. Analyses were carried out using R statistical software version 3.1.2 (R Foundation for Statis-tical Computing, Vienna, Austria, http://www.r-project.org).
Results
Patients and CLL characteristics
Thirty CLL patients were diagnosed with CNSi at 16 centres between February 1996 and March 2015. One, 9 and 20 patients were diagnosed with CNSi before 2000, between 2001 and 2010 and between 2011 and March 2015, respectively.
Patients were diagnosed with CLL between January 1990 and February 2015. Median age at CLL diagnosis and at CNSi onset was 62 years (range 41–85) and 69 years (range 42–87), respectively. The male/female ratio was 15 (18/12). Median time from CLL diagnosis to CNSi positive diagnosis was 76 months (range 0–301). At CNSi onset, 13 (43%) patients were in Binet stage A and less than half of the patients had progressive CLL (n= 14, 47%). Twenty (67%) patients had never been treated for CLL. Fifteen patients were reassessed for cytogenetic abnormalities at the time of CNSi: complex karyotypes and 17p deletion were observed in 7 and 4 cases respectively. Characteristics of CLL patients both at CLL diagnosis and CNSi diagnosis are summarized in Table I.
Presenting symptoms of CNSi
Clinical presentation at diagnosis was remarkably heteroge-neous. Neurological symptoms were either central (related to supra-tentorial cortical infiltration) or peripheral (related to infra-tentorial meningitis, cranial or spinal nerves, nerve roots or plexus infiltration). Central symptoms included
cognitive dysfunction (n= 5), hemianopia (n= 1), encephalopathy (n= 1), headache (n = 5), expressive aphasia (n= 3), partial seizures (n = 2), pyramidal irritation (n = 6) and cerebellar syndrome (n= 2). Peripheral symptoms com-prised autonomic disorder (n= 1), diplopia (n = 6), hearing loss (n= 1), trigeminal neuralgia (n = 1) ophtalmoplegia (n= 1), optic neuritis (n = 2), facial palsy (n = 4), ptosis (n= 2), sensory ataxia (n = 3) and polyradiculopathy (n= 7). Clinical presentation for each patient is detailed in Table II. Two patients displayed paraneoplastic hypercalcemia.
Fourteen patients (47%) experienced a delay between their first neurological manifestations and a positive CNSi diagno-sis. Median delay was 6 months (range 1–90) and 5 patients were diagnosed more than 1 year after their first symptoms (19, 22, 50, 86 and 90 months).
Biological results
Twenty-nine patients underwent CSF analysis at CNSi diag-nosis – most of them had two or three lumbar punctures and one patient had a brain biopsy. Median CSF cell count was 36/ll (range 1–1980), with predominance of lympho-cytes (50–100%), and 86% of patients had >5 cells/ll. Med-ian CSF protein was 07 g/l (range 032–389), while 85% of patients had high CSF protein (>045 g/l). Median CSF glu-cose was 3 mmol/l (range 18–6), 8% of patients had hypo-glycorrhachia (<22 mmol/l). Immunophenotyping analysis of CSF was positive for monoclonal B CLL-like cells in all cases. The details of immunophenotyping were recorded for 25 patients (Table II). Median monoclonal B cell population was 25% (range 05–93). Of note, CD5 expression was par-tially lost on CSF CLL cells in 2 cases. T cells immunopheno-type was available for 10 patients and showed CD4+ lymphocytes predominance in all cases (median 61% of total lymphocytes; range 16–91%).
Five (17%) patients underwent a biopsy at diagnosis: brain mass (n= 1), vertex sub cutaneous tumour (n = 1), orbital mass (n= 1), vitrectomy (n = 1) and peripheral nerve (n= 1). They all showed lymphocytic infiltration without sign of Richter transformation.
Radiological findings
Twenty-seven patients (90%) had neuro-imaging by magnetic resonance imaging (MRI) for initial diagnostic work-up (Table II). Among the 26 brain MRI, 16 (62%) were infor-mative (Fig 1), showing either specific abnormalities, such as brain mass (n= 1), hydrocephalus (n = 1), leptomeningeal enhancement (n= 3) and brainstem enhancement (n = 1) or less specific diffuse white matter FLAIR (axial fluid-attenuated inversion recovery) hyperintensities diffuse white matter FLAIR hyperintensities (DWMFH) (n= 12); Three out of 6 medullar MRI were abnormal, with 2 myelitis and 1 spinal cord infiltration (Table II). Of note, a nodular
Table I. Clinical and biological patients’ characteristics at CLL diag-nosis and CNSi diagdiag-nosis.
At CLL diagnosis At CNSi diagnosis Median age, years (range) 62 (41–85) 69 (42–87) CLL Binet stage A/B/C/Richter 25/5/0/0 13/9/6/2 Cytogenetics n= 17 n= 21 Normal 5 6 Isolated 13q deletion 4 5 17p deletion 1 4 Trisomy 12 5 6 Complex karyotype 1 6 Other 1 1 IGHV status n= 12 Unmutated 6 Mutated 6 CD38 expression n= 18 >30% 8 b2-microglobulin n= 12 n= 18 High 7 14 Lactate dehydrogenase n= 26 Elevated 11
CLL, chronic lymphocytic leukaemia; CNSi, central nervous system involvement.
Table II. CN Si diagnostic work up: neurological symptoms, perip heral blo od ly mphocytos is, CSF results and neur o imaging , at dia gnosis and evolution on treat ment . Patient Age at CNSi diagnosis Clinical neurological presentation
Blood lypmhocyte count (9
10 9/l) CSF leucocyte count (l l) CSF lymphocyte rate (%) CSF CLL cells (%) CSF T CD4/ CD8 cells (%/%) CSF red cells (ll) CSF protein (g/l) Histological lymphocytic infiltration Cerebral and/or medullar MRI MRI evaluation under treatment Clinical neurological response
at last FU CSF response at last FU CLL systemic response at last FU 1 7 7 Vertex tumour without focal neurological symptoms 6 3 1260 –– – – 0 56 Vertex tumour Leptomeningeal enhancement with
sub cutaneous vertex tumour Stability ND CR PR 2 7 5 Cognitive disturbance, headache, sensory ataxia 0 84 231 – 78 – 01 42 – Normal – CR CR CR 3 6 5 Hypoesthesia related to an intra medullar lesion 180 3 331 90 25 – 80 –– Brainstem and medullar enhancement (T9, T10, T11) Regression CR ND CR 4 6 3 Cognitive disturbance, cerebellar syndrome, expressive aphasia, partial cauda equina syndrome 245 176 – 4 – 00 39 –– – CR CR PR 5 7 0 Diplopia, dysphonia, ptosis, i.e. cranial nerve neuropathy (III, VI, X) 40 25 88 81 – 30 7 – Normal – CR CR CR 6 7 5 Expressive aphasia 69 175 91 23 59/7 8 0 91 – Normal – SD MS PD 7 7 1 Hemianopia 4 46 –– – – – – Brain mass Brain mass – ND ND ND 8 6 6 Hearing loss, i.e. cranial nerve neuropathy (VIII), polyradiculopathy, uveitis (anterior and intermediate) 23 39 12 100 83 – 10 96 Vitrectomy DWMFH
Progression with nodular enhancement, eventual regression
PR then PD CR then PD PR 9 4 2 Headache, dizziness, meningeal syndrome, phopsphene, i.e. partial visual seizures 8 5 740 93 8 – 50 0 7 – Normal – CR CR CR 10 70 Peripheral facial palsy, i.e. cranial nerve neuropathy (VII) 5 35 32 85 1 7 –– 0 92 – DWMFH Stability CR CR PR 11 55 Diplopia, visual impairment, i.e. cranial nerve neuropathy (VI) 213 14 > 75 0 9 – 10 48 – Leptomeningeal enhancement Regression CR ND CR
Table II. (Continued ) Patient Age at CNSi diagnosis Clinical neurological presentation
Blood lypmhocyte count (9
10 9/l) CSF leucocyte count (l l) CSF lymphocyte rate (%) CSF CLL cells (%) CSF T CD4/ CD8 cells (%/%) CSF red cells (ll) CSF protein (g/l) Histological lymphocytic infiltration Cerebral and/or medullar MRI MRI evaluation under treatment Clinical neurological response
at last FU CSF response at last FU CLL systemic response at last FU 12 86 Dyschromatopsia, i.e. partial visual seizures, ophtalmoplegia, peripheral facial palsy, i.e. cranial nerve neuropathy (VI, VII); sensorimotor polyradiculopathy 8 54 564 97 29 62/13 61 3 89 – Normal – ND ND ND 13 69 Cognitive disturbance 12 6 6 100 49 – 10 55 – DWMFH Regression PR ND CR 14 51 Trigeminal neuralgia, i.e. cranial nerve neuropathy (V), headache, pyramidal irritation 36 63 790 99 32 – 50 0 96 – Normal – CR CR CR 15 77 Peripheral facial palsy, i.e. cranial nerve neuropathy (VII), polyradiculopathy 38 80 > 50 79 – 00 36 Peripheral nerve Spinal cord infiltration at
the L5, S1 levels Regression PD PD PR 16 58 Autonomic disorder, polyradiculopathy, pyramidal irritation 19 84 22 100 93 –– 0 53 – DWMFH
Progression with nodular enhancement, eventual regression Not evaluable CR PR 17 60 Optic neuritis 32 37 243 – 25 – 54 2 46 – Normal – CR CR CR 18 53 Optic neuritis 14 2 100 15 –– 0 5 Orbital mass Orbital mass Regression CR ND CR 19 87 Diplopia, peripheral facial palsy, i.e. cranial nerve neuropathy (VI, VII), pyramidal irritation 10 92 76 100 24 –– 1 87 – Normal – CR CR CR 20 66 Headache, dizziness, sensorimotor polyradiculopathy 24 4 – 15 – 00 61 – DWMFH – PR ND PR with lymphocytosis
Table II. (Continued ) Patient Age at CNSi diagnosis Clinical neurological presentation
Blood lypmhocyte count (9
10 9/l) CSF leucocyte count (l l) CSF lymphocyte rate (%) CSF CLL cells (%) CSF T CD4/ CD8 cells (%/%) CSF red cells (ll) CSF protein (g/l) Histological lymphocytic infiltration Cerebral and/or medullar MRI MRI evaluation under treatment Clinical neurological response
at last FU CSF response at last FU CLL systemic response at last FU 21 76 Cognitive disturbance, expressive aphasia, polyradiculopathy, pyramidal irritation 2 91 1 100 17 42/32 0 0 32 – DWMFH, hydrocephalus Stability PR CR PR 22 68 Fluctuating diplopia, i.e. cranial nerve neuropathy (VI) 84 51 8 9 9 – 00 41 – Normal – CR ND CR 23 85 Cauda equina syndrome, sensory ataxia, cerebellar syndrome 300 11 100 2 64/26 0 0 65 – DWMFH – PR CR PD 24 63 Cognitive disturbance, sensory ataxia 7 89 36 100 0 5 86/13 16 1 – DWMFH Regression PR CR CR 25 76 Headache, diplopia, i.e. cranial nerve neuropathy (VI) 15 41 62 – 30 40/11 –– – DWMFH – CR CR PR 26 78 Ptosis, diplopia, i.e. cranial nerve neuropathy (III, VI) 5 35 2 – 60 16/8 2 0 5 – DWMFH – CR CR CR 27 68 Diplopia, i.e. cranial nerve neuropathy (VI) 5 55 52 99 8 79/11 0 1 78 – DWMFH, leptomeningeal enhancement Progression with nodular enhancement, eventual regression
CR CR CR 28 71 Encephalopathy, polyradiculopathy 55 7 1980 95 –– – 1 28 –– – CR CR PR 29 79 Paraparesia, i.e. pyramidal irritation 44 81 2 –– – 01 44 –– – ND CR PR 30 64 Monoplegia, i.e. pyramidal irritation 8 6 3 0 9 8 3 40/ND 17 0 55 – DWMFH/ myelitis – SD CR CR CLL, chronic lymp hocytic leuka emia; CNSi, central nerv ous system involvement; CSF, cerebrospina l fluid; FLAI R, axial fluid -attenuated inversion recovery seq uence; DWM FH, diffuse white ma tter FLAIR hyper intensities; MRI, ma gnetic resonan ce imaging ; F U , follow-up; CR , com plete response; P R, partial response; PD, progre ssive disease; SD , stable dise ase.
enhancement arose in three patients along with progression of neurological symptoms and persistent CSF infiltration. One of these patients (patient 27) underwent a cerebral posi-tron-emission tomography-computed tomography (PET-CT), which found no sign of Richter transformation, i.e. no sus-pect hypermetabolism. Cerebral CT-scan was performed in 15 cases and found to be abnormal in 4.
Treatments for CNSi and responses
Initial therapy was heterogeneous, including systemic chemotherapy (n= 22, 73%) either with (n = 17, 77%) or without rituximab, CSF-directed chemotherapy (n= 16, 53%) or irradiation (n = 1). Fourteen (47%) patients
received a combination of systemic and intra-CSF
chemotherapy (IT). First line treatments are summarized in Table III.
Among the 20 treatment-na€ıve patients, 14 (70%) had a non-progressive CLL. Only 10 received systemic immuno-chemotherapy for CLL, consisting of either fludarabine, cyclophosphamide and rituximab (FCR) (n= 9) or ben-damustine and rituximab (BR) (n= 1) with (n = 6) or with-out (n= 4) IT. All ten achieved response, including 8 CR, and 9 are still in response after a median follow-up of 33 months (4–78). Only one patient relapsed and needed to be retreated.
The other 10 treatment-na€ıve patients received the hetero-geneous treatments listed in Table III, including systemic chemotherapy in 3 patients only i.e. high-dose methotrexate, cyclophosphamide, cytarabine or vincristine. Only four patients achieved a response after 1st line therapy, including 3 CR and 1 PR. Seven patients progressed within a median of 4 months (1–110).
Ten (33%) patients had already been treated for CLL before CNSi onset, with a median of 2 treatment lines (1–8). Previous therapy consisted mainly of fludarabine (n= 3), FCR (n= 6) or BR (n = 2). Two patients had refractory
disease and 8 were progressive at the time of CNSi. As first treatment for CNSi, they all received various combinations of systemic chemotherapy with (n= 7) or without (n = 3) IT. Only two patients achieved CR, one of whom relapsed 14 months later. Three patients achieved PR and 5 had SD or PD with one Richter transformation. Five patients needed additional therapy within a median of 4 months (1–16), and received a median 3 lines of treatment (2–7) (Table II).
Six (20%) patients received ibrutinib. Four (67%) were heavily pre-treated (median 6 lines, range 2–8), with CLL being refractory in 2 and progressive in 3. Cytogenetic analy-sis showed a complex karyotype and/or 17p deletion in 4 patients. All patients achieved response, with 3 CR and 3 PR. Both patients showing a brain mass at the time of ibrutinib initiation had normalization of neuro-imaging after 4 and 6 months on ibrutinib monotherapy, respectively (Fig 2). Five CR/PR patients are alive after a median of 8 months (4–14). One died in neurological CR after 9 months on ibrutinib.
Outcome
Median follow-up from CLL diagnosis was 97 years (09–257). Median follow-up from CNSi was 278 months (0–227).
At last follow-up, median number of treatment lines for CNSi was 1 (range 1–7), with 25 (83%) patients having received systemic chemotherapy, and 22 (73%) IT. Nineteen patients (63%) achieved CSF clearance, 21 (70%) neurological clinical response, either complete (n= 16, 53%) or partial (n= 5, 17%), and 27 (90%) achieved haematological response, either complete (n= 15, 50%) or partial (n = 11, 37%).
Median OS from CLL diagnosis was 242 months (range 11–308). Median OS from CNSi was not reached {643% at 5 years [95% confidence interval (CI); 43.5–95.3]}, while median PFS was 208 months (Fig 3).
(A)
a b a b
(B) (C)
Fig 1. Examples of brain MRI images in 3 chronic lymphocytic leukaemia patients with central nervous sytem involvement. (A) Patient with neurological progression and persistent positive cerebrospinal fluid (CSF) on therapy. (a) Axial brain magnetic resonance imaging post-contrast T1-weighted image showing a small area of enhancement in the juxtacortical region of left temporal lobe (white arrow) associated with (b) periventricular white matter hyper intensities on axial fluid-attenuated inversion recovery (FLAIR) sequence (white arrowhead). (B) Patient with neurological progression and persistent positive CSF on therapy. (a) Small hyperintense lesion in left parietal lobe in diffusion-weighted axial image (black arrow), associated with (b) periventricular white matter hyper intensities on FLAIR sequences (white arrowhead). (C) Patient at diagnosis, presenting with aphasia, peripheral neuropathy, cognitive disturbance and positive CSF examination. FLAIR sequence showing quadriventricular dilatation (white star) and periventricular white matter hyper intensities (white arrowhead).
Table III. Initial the rapy, resp onse and me dian time to next trea tment. Two groups wer e dist inguished: patients previously unt reated for the ir CLL and pa tient s previously treated. Treatme nt naive, n = 20 Previous ly treated, n = 10 Who le cohort, n = 30 1st line trea tment Respo nse (CR/ PR) after 1st line (n ) Need for a second line treatment (n ) Med ian time to next treatment , months (rang e) Progr essive disease 6 8 –– – Refra ctory diseas e 0 2 –– – Sys temic chemoth erap y IT 13 9 2 2 1 6 8 15 (1 –110 ) Flu darabine -based reg imen 9 5 14 11 4 1 1 (4 –21) Flu darabine /FR/FCR 0/0 /9 02/ 01/02 02/01/ 11 B endamust ine-rituximab + IT 1 1 2 2 0 – High dose MTX -based regimen + IT 2* 1 3 2 1 1 Oth er systemic chemoth erapy † IT 2 2 4 2 3 3 9 (14 –110) Ibru tinib + IT 0 1 1 1 0 – IV cor ticosteroids 2 0 2 0 2 4.5 (4 –5) IV Imm unogl obulins 1 0 1 0 1 4 Ritu xima b monotherapy 2 0 2 0 2 1 In tra CSF chemot herapy (IT) 9 7 16 IT alon e 1 0 1 1 –– Rad iotherapy (on fo cal lesions) 10 1 N D –– CLL, chronic ly mphocytic leuka emia; FR, flud arabine, rituximab; FCR, fludarabin e, cyclophosph amide, rituximab; MTX, methotrexa te; CSF , ce rebros pinal fluid ; IT, intra-CSF chem otherapy; IV, intravenous; CR, complete respons e; PR, partial respons e; ND, not don e. *Including one in comb ination with FCR. †In cluding alkyla ting agents other than FCR regimen (cy clophos phamide), anti-m etabolites (aracy-tine/gemcitabine), vinc a-alkaloids (vinb las tine/vincristine) and anthracyclines.
Again, we distinguished treatment-na€ıve patients from previously treated ones at the time of CNSi diagnosis. The 5-year OS was 72% [95% CI; 49–100] and 48% [95% CI; 19–100] respectively (P = 006). The 5-year PFS
were 43% [95% CI; 23–79] and 0% respectively
(P= 0125) (Fig 3).
Seven patients died. Causes of death were PD (n= 2, 1 systemic progression and 1 neurological progression), vascu-lar stroke caused by an atrial fibrillation on ibrutinib (n= 1), pulmonary infection (n = 1), pulmonary embolism (n= 1), pulmonary metastatic adenocarcinoma (n = 1) and undetermined cause (n= 1).
(A) (B) (C)
a a a
b b b
c c c
Fig 2. Brain magnetic resonance imaging (MRI) of a patient with central nervous system involvement (CNSi) who received ibrutinib. (A) Brain MRI scans at diagnosis of CNSi showing a nodular lesion (white arrow), with increased signal intensity. (a) Axial fluid-attenuated inversion recovery (FLAIR) sequence, (b) 3D neuronavigation sequence, (c) axial brain MRI post-contrast T1-weighted image. (B) The lesion was already partially reduced after two months of ibrutinib monotherapy, associated with negative cerebrospinal fluid study and no clinical progression. (a) FLAIR sequence, (b) 3D neuronavigation, (c) T1-weighted image. (C) The lesion was completely reduced after 6 months of ibrutinib, with persis-tent response at 9 months, associated with a complete clinical and biological response. (a) FLAIR sequence, (b) 3D neuronavigation, (c) T1-weighted image.
In univariate analysis, 1st line treatment for CNSi with immuno-chemotherapy was associated with a significantly improved PFS (P= 0002), whereas the presence of a 17p deletion was associated with a poorer outcome (P= 0006) (Table SI). No predictive factors for OS were identified.
Discussion
We present here the largest cohort of CLL patients with CNS involvement. The frequency of neurological complications in CLL has been described in two large series, occurring in 113% and 4% cases respectively, but related to direct CNSi by CLL in only 08% and 04% cases (Bower et al, 1997; Strati et al, 2016). Other aetiologies included Richter syn-drome, opportunistic or herpetic infection, autoimmune/in-flammatory conditions, other cancer- and treatment-related conditions. Moazzam et al (2012) listed only 80 cases of direct leukaemic CNS involvement in the literature during the last four decades. Our report of 30 consecutive cases with significant follow-up allowed us to systematically analyse their initial characteristics, diagnostic work-up, treatment effect and outcome.
We confirmed the variety and non-specificity of neurolog-ical manifestations in the clinneurolog-ical presentations. Indeed, both central and peripheral nervous system symptoms were observed, frequently with incomplete pictures, as reported in Bing Neel syndrome (Simon et al, 2015; Castillo et al, 2016). In more than half of our patients CNSi was not correlated
with systemic progression of CLL. These features, together with the scarcity of this complication in the literature, may explain the frequent diagnostic delay observed (median 6 months).
Cerebrospinal fluid cytology was positive in 97% of cases and immunophenotype in 100%. Low sensitivity of conven-tional cytology has been reported with 6–55% of false nega-tives (Glass et al, 1979). This is particularly true in CLL because of the mature morphology of CLL cells. Previous studies have shown that FCM enhanced the detection rate of malignant cells by 43–75% (Finn et al, 1998; French et al, 2000; Roma et al, 2002; Bromberg et al, 2007; Quijano et al, 2009). This technique may facilitate the differentiation between reactive polyclonal and malignant monoclonal pop-ulations. Meanwhile, we found a highly heterogeneous per-centage of clonal cells, as few as 2% or less in 4 cases. This is consistent with previous reports (Finn et al, 1998; French et al, 2000) but raises the issue of false positivity. Rupture of the blood–brain barrier was ruled out in one case of low CLL count in the CSF. Peripheral blood (PB) contamination of CSF was unlikely, given the low erythrocyte and neu-trophil cell count in CSF. However, even in the absence of PB contamination, CSF analysis may lack specificity for the diagnosis of CLL CNSi (Strati et al, 2016). Of note, all the patients of our cohort were symptomatic and large diagnostic work-up didn’t find any other cause of meningitis. The majority of non-progressive patients who did not receive sys-temic treatment for CLL as first line had neurological
Fig 3. (A) Overall survival (OS) and (B) progression-free-survival (PFS) for the whole cohort from the beginning of treatment for central nervous system involvement. (C) OS and (D) PFS for patients previously treated and untreated.
progression and most of them eventually improved after CLL treatment. Furthermore, three patients diagnosed with CSF infiltration progressed with worsening of neurological symp-toms and apparition of a cerebral nodular lesion on brain MRI. Brain biopsy was discussed but not done because of its invasive nature and the subsequent disappearance of the mass on CLL-specific treatment including ibrutinib for 2 of these cases. These observations argue retrospectively for the specific CLL origin of the CNS damage reported in our cohort but shouldn’t minimize the difficulty of positive diag-nosis and right therapeutic decision.
Finally, CSF FCM analysis found a majority of T cells with predominance of CD4+ T cells in most cases. This result is not specific for leukaemic involvement but may be related to the enhancement of regulatory T cells previously described in lymphomatous and carcinomatous meningitis (Haas et al, 2008).
Sensitivity of MRI is limited in the detection of lep-tomeningeal disease (K€uker et al, 2005; Kiewe et al, 2010; Pauls et al, 2012; Taylor et al, 2013). However, if CNSi with CLL is suspected, neuroimaging may be a valuable diagnostic tool. Cranial and/or spine MRI contributed to the diagnosis in 60% of our patients showing mass syndrome, leptomeningeal involvement, hydrocephalus or DWMFH. The specificity of DWMFH may be subject to discussion. The observation of two cases of secondary nodular enhancement from an initial iso-lated DWMFH, and their disappearance on ibrutinib treat-ment, suggests that this should be taken into account in patients with CLL who present neurological symptoms.
The therapeutic modalities were very heterogeneous, reflect-ing the lack of consensus regardreflect-ing treatment of CNSi in CLL. A wide range of therapeutic modalities have been reported in sporadic cases (Stagg & Gumbart, 1987; Garicochea et al, 1997; Hagberg et al, 1997; Miller et al, 1997; Elliott et al, 1999; Poplawska-Szczyglowska et al, 1999; Rye et al, 2001; Brick et al, 2002; Remkova et al, 2003; Knop et al, 2005; Mowatt et al, 2005; Watanabe et al, 2005; Hanse et al, 2008; Kakimoto et al, 2010; Cohen et al, 2012; Imitola et al, 2012; Moazzam et al, 2012; Strati et al, 2016), consisting of either IT, systemic immuno-chemotherapy or radiotherapy, combined or alone. Based on our results, FCR or BR with IT in first line seems an effective therapy, both for non-progres-sive and progresnon-progres-sive CLL. Indeed, in univariate analysis, receiving FCR or BR with or without IT as first line therapy for CNSi was associated with a significantly improved PFS (P = 0004). Interestingly, all 5 patients treated with FCR without IT showed neurological CR. On the contrary, all 5 patients initially treated with rituximab monotherapy, intra-venous immunoglobulin or corticosteroids progressed and subsequently needed systemic chemotherapy, suggesting CNSi should be considered a criterion for CLL systemic treatment initiation.
The results observed with ibrutinib in our series strengthen the place of this agent in the treatment of CNSi. Ibrutinib, an irreversible, oral, covalent, Bruton Tyrosine
kinase inhibitor, has shown remarkable efficacy in patients with relapsed refractory CLL or as initial therapy in patients with deletion of 17p (Byrd et al, 2013, 2014, 2015; Brown et al, 2015). In those large series, no data were available about the potential efficacy of ibrutinib in CLL patients with CNSi. Recent studies, including our own, have shown a clear clinical benefit of ibrutinib treatment in CNS localization of mantle cell lymphoma (Bernard et al, 2015), Waldenstr€om macroglobulinaemia (Cabannes-Hamy et al, 2015) and CLL (Wanquet et al, 2016). These results are supported by plasma and CSF pharmacokinetics showing ibrutinib penetration through the blood–brain barrier. In primary CNS lymphoma, the maximum concentration (Cmax) of ibrutinib in CSF was decreased by 2–3 logs in comparison to the plasma Cmax. But when corrected for protein binding, CSF penetration was 21–100% for ibrutinib (Dunleavy et al, 2015).
Central nervous system involvement is relatively frequent in acute lymphoblastic leukaemia (5%) (Lazarus et al, 2006) and aggressive systemic non-Hodgkin lymphoma (28–5%) (Haioun et al, 2000; Bernstein et al, 2009), either at diagno-sis or in relapse setting. Prognodiagno-sis is worse for patients with CNSi than for those without. Strikingly, the OS in our cohort was favourable and much higher than previously reported (Moazzam et al, 2012; Strati et al, 2016). Strati et al (2016) reported a median OS of only 12 months. Rigorous interpretation of this discrepancy is hampered by the lack of mention of previous CLL treatment in our report. Sixty-six per cent of our patients were treatment-na€ıve and this result may explain the better outcome we observed. Even if not sta-tistically significant, OS and PFS tended to be worse in previ-ously treated patients than in treatment-na€ıve patients. Univariate analysis found significant poorer outcome in patients showing a 17p deletion. These results argue that out-come may be related to the prognosis of CLL itself rather than to CNSi.
Still, our study has major limitations. This is a retrospec-tive study where diagnostic work-up and treatment were not standardized, leading to variability and missing values. Statis-tical analysis needs to be interpreted cautiously. In particular, the small size of our population limited the power to detect factors significantly associated with OS or PFS. Multivariate analysis couldn’t be performed.
Our study emphasizes the heterogeneity of CNSi in CLL, regarding clinical as well as biological or neuro-imaging pre-sentation. Establishing cause and effect between the CLL and the neurological symptoms may represent a significant clini-cal dilemma, hence the importance of establishing a careful diagnosis after systematic and rigorous diagnostic work up. When inconclusive, CSF analysis and neuroimaging should be repeated. Once the diagnosis of specific CNSi is deter-mined, it should be regarded as a criterion to start systemic immuno-chemotherapy even in non-progressive Binet stage A patients. Ibrutinib monotherapy seems to be an attractive alternative in patients with 17p deletion and/or refractory/re-lapsed disease.
Finally, our data suggest that the prognosis of CNSi in CLL is correlated to CLL natural history rather than CNS localization by itself.
Author contributions
AW and RB collected and analysed the data and wrote the paper, MB and VL (Vincent Levy) performed the statistical analysis, TAS designed the study, analysed the data and wrote the paper; all the other authors managed the patients.
Conflict of interest
The authors declare no conflict of interest in relation to this work.
Supporting Information
Additional Supporting Information may be found in the online version of this article:
Table SI. Univariate analysis of predictive factors for pro-gression-free survival (PFS).
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