Chronic lymphocytic leukemia with central nervous system ...

J Neurooncol (2012) 106:185–200 DOI 10.1007/s11060-011-0636-z

CASE REPORT

Chronic lymphocytic leukemia with central nervous system involvement: report of two cases with a comprehensive literature review Alan A. Moazzam • Jan Drappatz • Ryan Y. Kim Santosh Kesari

•

Received: 3 January 2011 / Accepted: 17 June 2011 / Published online: 17 July 2011 Ó Springer Science+Business Media, LLC. 2011

Abstract Central nervous system (CNS) involvement is a rare complication of chronic lymphocytic leukemia (CLL) with varied outcomes. We contribute two additional cases of CLL with CNS involvement. The clinical course and response to treatment are described. All 78 previously reported cases of CLL with CNS involvement are presented in this comprehensive review of the literature. CNS involvement of CLL is a rare complication that does not seem to correlate with any evident risk factors. Resolution of CNS symptoms can often be accomplished with intrathecal chemotherapy or irradiation. Early detection and treatment may result in better outcomes in this rare complication. Keywords Leukemia Chronic lymphocytic leukemia CNS Leptomeningeal metastases Brain

Introduction Chronic lymphocytic leukemia (CLL) is a common lympho-proliferative malignancy in the United States, which occurs in older age (average age of 63) with an annual incidence of 2.7 cases per 100,000 [65]. The median survival is about 6 years, with infections being the most common cause of death [59]. Although initially believed A. A. Moazzam R. Y. Kim S. Kesari (&) Department of Neurosciences, Moores UCSD Cancer Center, University of California at San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA e-mail: [email protected] J. Drappatz Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA

to be a single entity, recent advances in the understanding of CLL have led clinicians to view the disease as a heterogeneous group of malignancies, all derived from antigen-stimulated mature lymphocytes [11]. Specifically, variations in the extent of immunoglobulin V gene mutation have prompted scientists to categorize CLL into two broad categories: a ‘‘mutated’’ CLL group, involving greater than 2% mutation in the VH gene from native clones, and an ‘‘unmutated’’ CLL group, with fewer or no mutations [13]. Based on these cytogenetic criteria, CLL cases have been shown to follow profoundly divergent clinical courses: the ‘‘mutated’’ group tending to survive for many years without therapy, and the ‘‘unmutated’’ group tending to have a rapidly fatal course, despite aggressive therapies. It is theorized that antigenic stimulation, believed to be the promoting factor in clonal expansion, occurs much more efficiently in the unmutated subgroup, thus inducing a more malignant course [13]. One of the single most discriminating genes that separate these two CLL subgroups is ZAP-70 [62], also currently noted as the most useful marker for clinical differentiation [13]. Neoplastic infiltration of high grade CLL has been found in skin, lung, pleura, kidney and gastrointestinal tract tissues. However, involvement of the central nervous system (CNS) is very rare. Reported cases of CNS involvement of CLL have demonstrated a diverse and non-specific spectrum of symptoms: headaches, acute or chronic changes in mental status, cranial nerve abnormalities, optic neuropathy, weakness of lower extremities, and cerebellar signs. Our review of the English literature revealed a total of 78 reported cases of CLL with intracranial involvement. We present two additional cases as part of a review of all previously published reports of CLL with CNS involvement.

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186

Methods We included all English language case reports of CLL with CNS involvement (Table 1) and also summarized features (Table 2). We included all cases that met the following criteria: (1) CLL diagnosed systemically, (2a) monoclonal population of lymphocytes demonstrated on CSF study or (2b) imaging findings suggestive of CNS process, and (3) well-described clinical course, including symptoms at presentation, diagnostic work-up, treatment, and response. Cases involving a malignant derivative of CLL manifesting as a primary CNS lesion are also included.

Case 1 Patient 1 is a 53-year-old female first diagnosed with CLL in March 2002 when she presented with right facial numbness and gait disturbance. At that time, a magnetic resonance imaging (MRI) of the brain revealed a subtle 7 mm medullary lesion with enhancement (Fig. 1a). CSF studies revealed glucose of 67 mmol/l, protein of 25 g/l, 2 9 109/l white cells, 29 9 1012/l red cells, and was negative for cytology and oligoclonal bands. She had diffuse adenopathy, which upon biopsy revealed CLL. Records of her peripheral cell count are unavailable. At the time, the medullary lesion was deemed unlikely to be CLL, and it was decided she be observed with serial imaging. By September 2002, she showed progression of her systemic adenopathy. She underwent cyclophosphamide/vincristine/ prednisolone (CVP) chemotherapy with modest response in her disease. Serial brain MRIs showed decreasing size of the medullary lesion. Her CNS symptoms resolved and remained in remission. By December 2002, her systemic response to therapy declined, so she was converted to a fludarabine and rituximab protocol. Her brain lesion regressed entirely. She relapsed in May 2007 and required another cycle. By March 2008, she again relapsed, and it was decided she undergo alemtuzumab (anti-CD52) therapy followed by consolidation with allogenic stem cell transplantation. Her white count was 16,000 9 1012/l, hematocrit 36%, and platelets 210,000 9 109/l. She had lymphadenopathy, but no organomegaly (Rai Stage I). Peripheral blood flow cytometry revealed a population of B cells positive for B lymphoid markers CD19, CD20, CD5, CD23, CD22, CD38, with no definitive demonstrable staining for surface immunoglobulin, and negative for CD10, CD11c, and other T cell markers. It was during the course of her alemtuzumab therapy that she began noticing disturbances in vision, which started as a minor disturbance in her field of vision in the right eye, followed by progressive central field loss in bilateral eyes. She was referred to a neuro-ophthalmologist;

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upon examination, there was no retinal detachment or hemorrhage, although the optic nerve head had pallor. A repeat MRI showed thin enhancement along the optic nerves bilaterally, there were no other signs of parenchymal or leptomeningeal disease. One of two lumbar punctures was positive for a monoclonal population of B-cells [WBC = 2/mm3 (70% lymphocytes), RBC = 13/mm3, protein = 24, glucose 163] that was similar to CD profile of the systemic CLL. Orbital radiation, steroids, and temozolomide were added to her chemotherapeutic treatment regimen. 36 Gy were given over 18 fractions. Her vision continued to decline despite this escalation of therapy. However, repeat CSF studies were negative for malignant cells. Intrathecal methotrexate was initiated and she experienced partial improvement in vision. In August 2008, she was admitted to the hospital for chest pain and shortness of breath. Bilateral pleural effusions were found. She subsequently developed multiple organ failures, lactic acidosis, and eventually expired upon that admission. On postmortem, cross-sections of the optic nerves showed thickening of the leptomeninges and bilateral multi-focal dystrophic calcification. However, there were no signs of active lymphoproliferative disease anywhere else in the CNS.

Case 2 Patient 2 is a 52-year-old male diagnosed with ZAP-70 positive B-Cell CLL in 2004. In late 2006, his white cell counts rose from 15 to 120 9 1012/l. His platelets dropped to 94,000 9 109/l and his hematocrit was 39%. He had lymphadenopathy and splenomegaly. This prompted chemotherapy treatment. Due to a hypersensitivity reaction to rituximab, he was treated with fludarabine alone. He responded well, with resolution of all his symptoms and did well till July, 2007. He began to experience malaise, abdominal discomfort and became unresponsive. A contrast MRI of his head was negative. A lumbar puncture revealed a white blood cell count of 58 9 1012/l with 98% lymphocytes. Infectious disease studies of his CSF were negative for bacteria and viruses. He slowly recovered spontaneously and he was discharged home. After discharge, he experienced a prolonged recovery course: he was intermittently confused, having difficulty with memory and was always tired. On July 30th, his wife witnessed a seizure, and he was returned to the hospital. His cell count at that time was white cells 14,000 9 1012/l, hemoglobin 11 g/l, hematocrit 31%, and platelets 128,000 9 109/l. Flow cytometry revealed a population of B-cells positive for B lymphoid markers CD19, CD20, CD5, CD23, and monotypic staining for surface immunoglobulin light chain kappa. It was negative for CD10, CD11c, CD38, and other

Dysphasia, CN palsy

Encephalopathy

52M

72F

57F

60F

89F

73M

65M

70M

Present study (2011)

Garofalo et al. (1989) [22]

Cash et al. (1987) [12]

Conesa et al. (1999) [14]

AkintolaOgunremi et al. (2002) [1]

Rubin and Harris (1993) [56]

Perez et al. (1998) [49]

Marmont (2000) [40]

Paresthesia, encephalopathy

Headache, diplopia, dysphagia

Facial pain, vision loss, EOM paresis

Sensory loss, gait disturbance

Encephalopathy, headache

Encephalopathy, dementia, seizures

Vision changes

53F

Present study (2011)

CNS symptoms

Age/ sex

Reference

12 years

Upon presentation

Upon presentation

Upon presentation

5.5 years

Upon presentation

5 years

3 years

4 years

Time interval from diagnosis of CLL to first CNS symptoms

Table 1 All previously reported cases of CLL with CNS involvement

0

0

0

0

0

0

0

IV

I

Rai stage at time of CNS symptoms

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

Type

Clearance of CSF: yes Survival: ?1 year

Response: resolution of CNS symptoms XRT

Cause of death: pneumonia

Survival: several weeks

Clearance of CSF: yes

Response: resolution of CNS symptoms

Cause of death: progression of CLL, stroke

Survival: 3 weeks

Clearance of CSF: No

Response: N/A

Cause of death: progressive neurologic decline due to CLL

Survival: 0.5 years

Clearance of CSF: no

Response: N/A

Cause of death: CLL infiltration of CNS

IT: MTX

IT: MTX

MRI—negative

MRI—positive

Systemic: COP

None

None

Survival: 2 months

Clearance of CSF: not reported

Response: none

Survival: not reported


Systemic: CHOP


XRT

Cause of death: CLL infiltration of CNS

Survival: 1 week


Response: N/A

Cause of death: progression of CLL

Survival: 0.5 years


Response: none

Cause of death: sepsis

Survival: 0.5 years


Response: partial response of CNS symptoms

Response to therapy

IT: MTX, cytarabine

None

None

XRT

IT: MTX

Systemic: alemtuzumab, rituximab

Treatment

CT—negative

MRI—positive

CT—positive

N/A

MRI—positive

CT—positive

CT—negative

Parenchymal infiltration

CT—positive

MRI—positive

MRI—positive

Imaging

J Neurooncol (2012) 106:185–200 187

123

123

Visual disturbance, headaches, paresthesia

CN palsy, vertigo, n/v

62F

64F

44M

74M

64F

78F

59F

34M

78M

Cramer et al. (1996) [15]

Majumdar (1998) [39]

Miller et al. (1997) [41]

Boogerd and Vroom (1986) [7]

Patton et al. (1992) [48]

Remkova et al. (2003) [53]

Cash et al. (1987) [12]

Oshimi et al. (1985) [46]

Bayliss et al. (1990) [5]

Encephalopathy

Optic neuropathy, cerebral hemorrhage

Vision loss, CN palsy, lower ext weakness

Headache, n/v

Syncope, dementia

Lower ext weakness, dysarthria

Hearing loss, weakness, gait disturbance

Lower ext weakness

52M

Elliott et al. (1999) [19]

CNS symptoms

Age/ sex

Reference

Table 1 continued

Upon presentation

Upon presentation

Upon presentation

Upon presentation

3 years

Upon presentation

Upon presentation

2 years

2 years

Upon presentation


0

0

0

0

0

0

0

0

0

0


Richter’s

B-cell

T-cell

T-cell

T-cell

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

Type

Survival: ?0.5 years

Response: none, stable course

CT—positive

CT—negative for CLL lesions

CT—negative


IT: MTX, dexamethasone

Surgical resection

IT: hydrocortisone


Survival: \1 month


Response: none

Cause of death: progression of CLL, herniation

Survival: 7 years


Response: none

Survival: ?2 years


XRT Systemic: dexamethasone


IT: MTX, cytarabine



Systemic: chlorambucil

Survival: ?2 years CT—negative

Clearance of CSF: yes XRT

Response: resolution of CNS symptoms IT: MTX



Clearance of CSF: not reported Systemic: chlorambucil

None

Survival: ?1 year


Response: resolution of CNS symptoms, except vision loss


CT—positive

CT—negative

IT: MTX, Ara-C

XRT

Systemic: chlorambucil, prednisone


XRT

MRI—negative



Cause of death: progression to large cell lymphoma

Survival: 4 years


Response: resolution of CNS symptoms, relapse

CT—positive

IT: MTX, cytarabine

XRT


Systemic: fludarabine Clearance of CSF: yes

Response to therapy

Treatment


CT—negative


MRI—positive

Imaging

188 J Neurooncol (2012) 106:185–200

Ext weakness, lethargy

Lower ext weakness

62M

71M

72F

73M

68F

68M

61F

77M

78M

Kalac et al. (2007) [29]

Schmidt-Hieber et al. (2005) [59]

Hagberg et al. (1997) [25]

Hagberg et al. (1997) [25]

Knop et al. (2005) [31]

Poplawska et al. (1999) [52]

Knop et al. (2005) [31]

Brick et al. (2002) [10]

Hanse et al. (2008) [26]

Headache

Headache, CN palsy

Headache

Ext weakness, aphasia

CN palsy, lower ext weakness

SIADH

SIADH

Encephalopathy

70M

Mahe et al. (1994) [38]

CNS symptoms

Age/ sex

Reference

Table 1 continued

N/A

Upon presentation

Upon presentation

Upon presentation

8 years

0.25 years

Upon presentation

0.5 years

Upon presentation

Upon presentation


I

I

I

I/II

I

I

I

I

I

0


N/A

N/A

PLL

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

Richter’s

B-cell

Type

MRI—negative

CT—negative

MRI—positive

MRI—positive

Clearance of CSF: no Survival: ?2.5 years



Clearance of CSF: yes Survival: ?0.5 years



Survival: 2 years

Clearance of CSF: yes, but recurrence


Cause of death: CLL lung infiltration

Survival: 0.5 years




Survival: 0.5 years


Response: partial resolution of CNS symptoms, relapse

Survival: ?3 years



Survival: ?2 years



Cause of death: pulmonary emboli

IT: MTX, cytarabine

IT: cytarabine

IT: MTX, corticosteroid

Systemic: fludarabine

Systemic: CCNU, procarbazine, dexamethasone

XRT

IT: MTX, cladribine

MRI—negative


CT—negative

Maintenance: chlorambucil

XRT

IT: MTX, hydrocortisone

Survival: 1 week


Response: none

Survival: ?1 month


IT: MTX, Ara-C


IT: dexamethasone

Survival: ?1 year


Response: none

Response to therapy


XRT

Treatment

MRI—negative

CT—negative

MRI—negative

CT—negative

CT—positive

Imaging

J Neurooncol (2012) 106:185–200 189

123

123

Headache, nausea, visual disturbance, seizure

CN palsy, coma

61F

57F

45M

83M

74F

42M

69M

42M

56M

Lange et al. (2007) [35]

Fain et al. (1992) [20]

Lane et al. (1988) [34]

Knop et al. (2005) [31]

Knop et al. (2005) [31]

Knop et al. (2005) [31]

Hoffman et al. (1995) [27]

Wang et al. (2000) [69]

Singh and Thompson (1986) [60]

Headache, encephalopathy

None

Paresthesia

Visual disturbance

Headache, visual disturbance, n/v

Visual disturbance, hypopituitary

Lower ext weakness

Lower ext weakness, CN palsy

57M

Hanse et al. (2008) [26]

CNS symptoms

Age/ sex

Reference

Table 1 continued

0.75 years

2 years

0.5 years

N/A

0.25 years

2.5 years

Upon presentation

Upon presentation

3 years

N/A


II

II

II

II

II

II

II

II

II

I


PLL

B-cell

PLL

B-cell

B-cell PLL

B-cell

B-cell

B-cell

B-cell

B-cell

B-cell

N/A

Type

Survival: ?3 years

CT—negative

CT—negative

N/A

MRI—negative

MRI—negative

XRT


Clearance if CSF: yes



Survival: 0.25 years IT: MTX

Clearance of CSF: yes XRT


Survival: ?2 years



Survival: ?2 years


Response: N/A


Response: partial resolution of CNS symptoms, relapse Clearance of CSF: no Survival: 0.5 years

Cause of death: infection

IT: MTX

Systemic: CHOP

IT: thiotepa

IT: cytarabine—partial response


IT: MTX, cytarabine

Systemic: temozolomide

Survival: 1 month


Response: N/A


None

IT: MTX MRI—negative

Clearance of CSF: yes, relapse

XRT

Richter’s


Survival: not recorded



Cause of death: progression of CLL, not reported

Survival: 0.75 years


Systemic: BVDC

Surgical resection

IT: MTX, cytarabine

Response: partial resolution of CNS symptoms, relapse


XRT: whole body Systemic: COP



Response to therapy

IT: MTX, cytarabine

Treatment

CT—negative

Parenchymal involvement

CT—positive

MRI—positive

MRI—positive

Imaging

190 J Neurooncol (2012) 106:185–200

Proptosis, lethargy

SIADH

64M

71M

64M

58M

53F

38M

66F

68M

Mahe et al. (1994) [38]

Yamamoto et al. (2004) [71]

Korsager et al. (1982) [32]

Korsager et al. (1982) [32]

Knop et al. (2005) [31]

Steinberg et al. (1984) [63]

Stagg and Gumbart (1987) [61]

Kuwabara et al. (2003) [33]

Headache

Paresthesias

Encephalopathy, hypersomnolence

Encephalopathy

Encephalopathy, gait disturbance

Headache, visual disturbance

Seizures

65M

Almhanna et al. (2009) [2]

CNS symptoms

Age/ sex

Reference

Table 1 continued

3 years

Upon presentation

2 months

12.5 years

1 year

Upon presentation

5 years

Upon presentation

6 years


III

III

III

III

II

II

II

II

II


B-cell PLL

B-cell

B-cell

B-cell

N/A

N/A

B-cell Richter’s

Richter’s

B-cell

Richter’s

B-cell

Type

N/A

N/A

Optic nerve

CT—positive

MRI—positive

CT—negative

CT—negative

MRI—positive

CT—positive

MRI—positive

Imaging

Clearance of CSF: yes Cause of death: progression of CLL


Response: resolution of CNS symptoms IT: MTX, cytarabine, hydrocortisone

Cause of death: cardiovascular complication

Survival: 1 year




Survival: 1 year






Response: partial resolution of CNS symptoms

Cause of death: CNS infiltration of CLL

Survival: short-term


Response: N/A

Cause of death: progressive neurologic decline due to CLL

Survival: 0.5 years

Clearance of CSF: yes, but recurrence


Systemic: CHOP

IT: MTX


IT: MTX

XRT

Systemic; chlorambucil, prednisone

IT: MTX, cytarabine, dexamethasone

None

IT: later MTX

XRT

Survival: ?1 year

Clearance of CSF: No



Systemic: THP-COP




Cause of death: withdrawal of treatment

Survival: 1 month


Response: none

Response to therapy

IT: MTX, Ara-C, prednisolone

XRT

IT: MTX, cytarabine

Systemic: MTX, VM26, BCNU

XRT

Systemic: ABVD

Treatment

J Neurooncol (2012) 106:185–200 191

123

123

Headache, insomnia

Lower ext weakness

75F

71M

45F

76M

53M

59M

81M

65F

Pastor (1997) [47]

Hanse et al. (2008) [26]

Currie et al. (1988) [16]


Kaiser (2003) [28]

Garicochea et al. (1997) [21]

Wang et al. (2000) [69]

Getaz and Miller (1979) [23]

Headache, vertigo, tinnitus

Jacksonian seizure

Vision loss

Vision loss

Diplopia, n/v, ext weakness, vertigo

Vertigo, diplopia, CN palsy

Headache

53M

Gobbi et al. (1985) [24]

CNS symptoms

Age/ sex

Reference

Table 1 continued

2 years

2.5 years

9 years

Upon presentation

2 years

11 years

N/A

2 weeks

5 years


IV

IV

III/IV

III

III

III

III

III

III


Bcell

Bcell

N/A

N/A

N/A

N/A

N/A

PLL

Bcell

PLL

Bcell

Type

CT—negative parenchyma infiltration

CT—negative

N/A

CT—positive parenchymal involvement

CT—positive

CT—positive

MRI—negative

Survival: 3 weeks

XRT

IT: MTX




Response: death prior to response


Clearance of CSF: not reported XRT Systemic: chlorambucil, streptonigrin, prednisone


Cause of death: gastric adenocarcinoma

Survival: 2 years



Survival: ?1 year



Survival: ?4 years


Response: partial improvement of visual symptoms

Cause of death: fall, subdural hemorrhage

Survival: 2 years


Response: partial improvement of visual symptoms



IT: dexamethasone


XRT

XRT: orbital

XRT: orbital

Clearance of CSF: no Survival: 0.5 years


IT: MTX, cytarabine

Cause of death: progression of CLL, neuro decline

Survival: 0.5 years



Survival: ?1 year

XRT

IT: MTX, cytarabine, prednisone

Systemic: CHOP


IT: MTX, cytarabine CT—negative

Response: not reported

Systemic: COP

N/A

Response to therapy

Treatment

Imaging

192 J Neurooncol (2012) 106:185–200

Encephalopathy

Lethargy, headache

68F

79M

61M

61M

49M

53M

70F

65F

68M

56M

Mowatt et al. (2005) [43]

Ruiz et al. (1992) [57]

Rye et al. (2001) [58]

Morrison et al. (1998) [42]

Sullivan et al. (1978) [64]

Lopez et al. (1989) [37]

Watanabe et al. (2005) [70]

Ng et al. (1991) [44]

Hanse et al. (2008) [26]

Liepman and Votaw (1981) [36]

Gait disturbance, headache, n/a

Headache, tinnitus, encephalopathy

Headache, n/v

Paresthesia, CN palsy

Vertigo, headache, gait disturbance

SIADH

Vision loss

Vision loss

Acute ischemic stroke

60F

Robak et al. (2004) [55]

CNS symptoms

Age/ sex

Reference

Table 1 continued

2.5 years

N/A

0.25 years

1 year

3 years

0.25 years

1 month

Upon presentation

14 years

9 years

8 years


IV

IV

IV

IV

IV

IV

IV

IV

IV

IV

IV


N/A

N/A

B-cell Richter’s

B-cell PLL

B-cell PLL

T-cell

B-cell

B-cell

B-cell

B-cell

B-cell

Type

N/A

MRI—negative

CT—negative initially, then positive

CT—negative MRI—negative

N/A

N/A

MRI—positive

CT—negative

N/A

N/A

CT—positive

Imaging


Clearance of CSF: yes IT: MTX, dexamethasone


XRT


IT: MTX


XRT


Survival: 0.5 years


IT: MTX

Survival: ?2 years


Systemic: CHOP



Response: none

IT: MTX

Survival: ?2 years

Response: resolution of CNS symptoms Systemic: rituximab


Response: resolution of CNS symptoms IT: MTX, cytarabine




Systemic: CHOP

XRT

IT: MTX


Survival: ?1 year




IT: MTX


Survival: several weeks


Response: none

XRT


Systemic: chlorambucil, pred (failed to respond)

Not reported

Survival: ?4 years


Not reported

Response: partial resolution of CNS symptoms

IT: MTX




Response to therapy


Surgical resection XRT

Treatment

J Neurooncol (2012) 106:185–200 193

123

123

Diplopia, CN palsy

Upper ext weakness

Lower ext weakness

Hearing loss, diplopia

Headache

68F

67F

70F

63F

78F

67M

69M

47F

51F

Liepman and Votaw (1981) [36]


Diwan et al. (1982) [18]

Pohar et al. (1993) [50]

Po´łtorak et al. (1983) [51]

Thiruvengadam and Bernstein (1992) [66]

Hanse et al. (2008) [26]

Kernoff and Coghlan (1983) [30]

Bousmell et al. (1981) [8]

N/A

Dysarthria, gait disturbance

Headache, n/v, weakness, nystagmus

Vision loss

CNS symptoms

Age/ sex

Reference

Table 1 continued

5 years

1 year

N/A

0.5 years

Upon presentation

3 years

0.75 years

12 years

5.5 years


N/A

N/A

N/A

N/A

N/A

N/A

IV

IV

IV


B-cell

B-cell PLL

N/A

PLL

T-cell (CNS) B-cell (sys)

N/A

N/A

N/A

N/A

Type

N/A

CT—negative

N/A

CT—negative

N/A

MRI—positive parenchymal infiltration

CT—positive parenchymal infiltration

CT—positive

N/A

Imaging

Survival: 7 years

XRT: Whole Body

Systemic : CHOP

IT: MTX





Cause of death: renal failure

Survival: several months



Cause of death: radiation leuko-encephalopathy


IT: MTX, cytarabine

Systemic: CHOP



Cause of death: renal failure





Clearance of CSF: yes IT: MTX, cytarabine


Survival: ?3 years



Survival: ?2 months



Cause of death: general deterioration of health

Survival: 1 year


Response: partial improvement of visual symptoms, sustained




Response to therapy


XRT


XRT


XRT: orbital


IT: MTX


Treatment

194 J Neurooncol (2012) 106:185–200

CN cranial nerve; IT ntrathecal; MTX methotrexate; XRT radiation therapy; CHOP cyclophosphamide, adriamycin, vincristine, prednisone; COP cyclophosphamide, oncovin, prednisone; ext extremity; n/v nausea and vomiting; CCNU lomustine; PLL prolymphocytic leukemia; BVDC bleomycin, vincristine, doxorubicin, cyclophosphamide; ABVD adriamycin, bleomycin, vincristine, dacarbazine; VM26 teniposide; BCNU carmustine; THP-COP pirarubicin, cyclophosphamide, oncovin, prednisone

Cause of death: deterioration of CNS

Survival: 2 months

Response: none

Survival: ?2 years

Clearance of CSF: not reported XRT

Surgical resection CT—positive N/A Richter’s N/A 8 years 70M

O’Neil et al. (1989) [45]

Ext weakness, aphasia


Survival: ?1 month


XRT CT—positive N/A Richter’s N/A 3 years 64M O’Neil et al. (1989) [45]

Headache, encephalopathy


Response: resolution of CNS symptoms 58F

Badic et al. (2007) [3]

XRT

IT: dexamethasone


CT—positive MRI—positive B-cell, Richter’s N/A 3 years

Age/ sex

Ext weakness, ataxia, ear pain

195

Reference

Table 1 continued

CNS symptoms



Type

Imaging

Treatment

Response to therapy

J Neurooncol (2012) 106:185–200 Table 2 Summary of reported cases from Table 1 Average age of CLL onset

63.41 years

Average latency period between CLL diagnosis and first signs of CNS involvement

2.62 years

Average overall survival from time of CLL diagnosisa

3.79 yearsa

Average overall survival from time of CNS onsetb

12.06 monthsb

% B-Cell leukemia

93.5%

% T-Cell leukemia

6.5%

% with positive imaging % Stage 0

40.0% 25.0%

% Stage I

15.2%

% Stage II

19.4%

% Stage III

15.3%

% Stage IV

23.6%

a

Average only of cases were patient course was followed until death. Cases wherein patient was still alive at time of publication (25 in total) were excluded as the follow-up times varied in these studies from several years to as short as several weeks

b

Average only of cases where outcome was reported

T cell markers. MRI with gadolinium was again unremarkable. An abdominal CT revealed extensive retroperitoneal and periaortic adenopathy and splenomegaly. A second lumbar puncture was again consistent with a lymphocytic pleocytosis. Flow cytometry of the CSF cells revealed small kappa light-chain-restricted B-cell lymphocytes corresponding to the systemic findings and consistent with CLL involvement of leptomeninges. Given this evidence of CNS involvement, he was started on high-dose IV steroids, to which his encephalopathy had partial improvement but no chemotherapy offered due to uncertainty of pathological role or CLL in CSF. On August 8th, his steroid course was completed and he was deemed appropriate for transfer to a rehabilitation hospital. His condition steadily worsened after discontinuation of his steroid therapy. On August 21st, he was observed to have acute-onset motor hyperactivity with intermittent, disorganized myoclonic movements. He was again admitted to the hospital. His white count was 27,000 9 1012/l, hemoglobin 11.9 g/l, and platelets 109,000 9 109/l. A repeat CT showed extensive progression of his disease burden systemically. An MRI with contrast of his brain revealed subtle leptomeningeal enhancement throughout the meninges, which is non-specific (Fig. 1b). No diffusion or FLAIR abnormalities were noted. His CSF remained persistently abnormal with a WBC of 54 with elevated protein and normal glucose levels. The patient remained at this baseline neurologically, but soon developed pleural effusions and ascites. He passed away in December 2007 from Richter’s transformation of his CLL systemically. A postmortem was not performed.

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Fig. 1 FLAIR (a) section of patient in Case 1 showing subtle left medullary lesion and contrast T1-weighted (b) axial MRI of Case 2 showing the subtle leptomeningeal enhancement

Discussion CNS involvement of CLL remains a poorly studied phenomenon in the literature. Given the scarcity of this complication, large-scale investigations are difficult to perform, and it is therefore difficult to gain insight into the appropriate diagnosis and management of this disease. We report our two cases of CNS involvement were difficult to diagnose given the rarity of this presentation. It highlights the need to think of this possibility early on and to do a thorough work-up to rule out CLL as the cause of neurological symptoms. We also provide a comprehensive review of the literature involving 80 reported cases. Although viral encephalitis and other toxic-metabolic causes are commonly thought of in this setting, clinicians should also be aware of the possibility of direct involvement of CLL. Imaging and standard CSF studies are not specific and so a more careful assessment of CSF with quantitative flow and PCR studies need to be done in comparison to blood. The incidence of CNS involvement has been reported to range from 0.8 to 2% in antemortem studies [26]. Bower et al. reported that within a cohort of 962 CLL patients with neurologic symptoms, only eight were attributable to leptomeningeal involvement [9]. Interestingly, autopsy studies have shown leukemic invasion ranging from 8 to 71% [4, 6, 54, 68]. This suggests the complication either remains subclinical or is severely under-diagnosed. Our Case 1 also suggests that post-mortem evidence of CNS involvement may not be remarkable in patients having undergone treatment. The mechanisms allowing for leukemic infiltration remains unknown. Access could be gained via one of three routes (a) transmigration across perforating cerebral vessels into the subarachnoid space, (b) direct extension from seeded meninges into the CSF (especially via the ependymal lining and the choroid plexus) or (c) via perineural sheaths on cranial and spinal nerve roots [15]. This

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infiltration can either be a result of an elevated leukemic burden, or as part of a process that permits aberrant leukemic transmigration across the blood–brain-barrier. From their analysis of autopsy studies, Cramer et al. [15] suggest that CLL patients with CNS involvement have a higher number of organ system failures compared to nonCNS involved patients. Additionally, they report four extraneural sites unique to CNS-involved patients only: parathyroid, prostate, heart, and larynx. It is unclear whether this occurs as a result of a more aggressive form of CLL or from a higher tumor burden.

Does CNS involvement suggest malignant transformation? CNS symptoms could signal the first manifestation of a more malignant variant arising from a dedifferentiation of the underlying CLL. Prolymphocytic transformation, Richter’s syndrome, and blastic transformation may all represent manifestations of this malignant progression. The non-Hodgkin lymphoma (NHL) component of Richter’s syndrome may well behave like primary, high-grade NHLs, which have been shown to have an elevated propensity for meningeal invasion. Our review of literature (summarized in Tables 1, 2) demonstrates that the incidence of highgrade lymphomas and more aggressive CLL variants generally corresponds with the incidence of these variants within the overall general CLL population. If more aggressive variants inferred a higher risk of CNS infiltration, one would expect these variants to be represented more frequently within the CNS-involved population; our data does not reflect this. The incidence of Prolymphocytic Leukemia (PLL) for instance, a more aggressive form of CLL, has been shown to be 10% in CLL cases overall; we demonstrate 13.8% (11/80) of those having CNS

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involvement. Similarly, it has been shown that Richter’s transformation occurs in approximately 5–10% of the CLL population; we found 9 (11.3%) reported cases of Richter’s transformation with intracranial involvement, i.e., there is no clear association of higher grade disease with higher risk of CNS involvement in this limited cases series. It has been previously suggested that T-cells are better able to transmigrate the blood–brain-barrier and therefore T-cell CLL is more likely to cause CNS involvement [17]. Po´ltorak et al. [51] report a case wherein the lymphocyte population in the CSF had a higher proportion of T-cells than B-cells compared to the peripheral leukemic pool, suggesting a greater migratory preference of T-cells. Gobbi et al. [24] suggest a similar mechanism in their PLL case. Our review of the literature suggests that this may not be the case. T-cell variants occur in only 5% of all CLL cases; we show 5% (4/80) of cases with CNS involvement or 6.5% (4/61) of cases with a known lymphocyte phenotype being attributed to T-cell CLL. Miller et al. [41] report a case wherein CD11c, a cell marker involved with cellular adhesion, was aberrantly over-expressed in the B-cell population, suggesting that perhaps CNS infiltration is a result of specific malignant transformations. This is again suggested in the Knop et al. [31] case series. However, both of the cases we present involve CD11c-negative lymphocyte infiltration. Early identification of CNS involvement Studies attempting to identify risks factors in patients who develop CNS infiltration have failed to identify common characteristics [10, 15]. Our literature review corroborates this, as we fail to identify any clear correlation with age, sex, presenting neurologic symptoms, or Rai stage at time of onset. Although it has previously been mentioned that CNS infiltration occurs more frequently in late-stage disease, our analysis of the literature does not reflect this view. One fourth (18/80) of all the cases published have been during Rai stage 0 of CLL. We also report that in earlier CLL stages, neurologic symptoms are more likely to present as the first manifestations of CLL. 48.8% (21/43) of patients with Stage 0 through II disease had neurologic symptoms upon presentation, while only 10.7% (3/28) of those with Stage III and IV disease had neurologic symptoms upon presentation. Radiographic manifestations of CNS involvement have been described as diffuse coating of the leptomeninges by a thin layer of leukemic cells, nodular growths, plaque-like deposits, and intraparenchymal infiltration. However, cranial imaging has consistently proven insensitive to the presence of intracranial CLL. Our data reaffirms this; less than one third (32/80) of reported cases had demonstrable imaging findings.

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Tumor markers specific for leukemic CNS invasion have also remained elusive. Soluble CD27 (sCD27), believed to be a marker for leptomeningeal involvement, was studied by van den Bent et al.; their results showed the marker reliable in ruling out presence of the disease with a negative predictive value of 92%, however due to its presence in various non-malignant inflammatory conditions, it remained highly non-specific to CNS involvement (positive predictive value: 54%) [67]. In addition, CSF cytology is also considered a poor modality for diagnosis: CLL cells cannot be easily distinguished from reactive lymphocytes in the CSF by morphology alone. This is compounded by the fact that CLL patients are more prone to opportunistic infections given their immune compromise. Several studies have shown that flow cytometry increases the detection rate of malignant cells in the CSF considerably [12, 26]. Another advantage to this technique is that it can differentiate a polyclonal reactive B-cell population from a monoclonal malignant population [12]; the former would preclude intrathecal chemotherapy, while the latter would indicate it. The sensitivity of this technique can be enhanced by cytocentrifuge methods as described by Akintola et al. [1]. PCR amplification of immunoglobulin heavy chain (IgH) has also been reported as a method [21]. This technique takes advantage of the highly conserved CDR III rearrangements in B-cell clones of CLL. The PCR protocol, in theory, offers a much more sensitive test for presence of monoclonal B-cells within the polyclonal milieu. False negatives can be expected in cases where the CDR III rearrangement varies substantially from the primers used for annealment. Treatment and outcome of CNS involvement In light of its neurologic complications, timely diagnosis and treatment of CNS involvement is crucial. Once invaded, leukemic cells have been reported to induce a variety of neurologic injuries; these include parenchymal ischemia by way of blood supply occlusion, competing for oxygen and metabolites, and also hydrocephalus of the communicating and non-communicating types. Neurologic symptoms can appear insidiously, and can be easily misinterpreted as symptoms caused by advanced age or CLL itself. Although subtle, the earliest manifestations should be identified quickly and treatment should be begun, even in the setting of early stage disease. Given the non-specific presentation of this complication, any persistent, abnormal neurologic finding on exam in the setting of someone with CLL should warrant consideration for CNS disease. We recommend a low threshold of suspicion and careful flow and PCR studies on CSF compared to peripheral blood studies in addition to ruling out viral and other etiologies.

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Overall survival of patients who manifest with CNS disease is difficult to extrapolate given the available data. Of the 36 cases that reported a death, the average latency from onset of CNS symptoms to mortality was 12.06 months. This average, however, excludes a significant proportion of cases wherein patients remained in remission at time of publication—a follow up time that varied significantly. It is unclear how many would have relapsed given appropriate long term follow up. Nevertheless, of those 36 cases, the average survival was 3.79 years from time of CLL diagnosis to death. This survival is shorter than the average survival of CLL patients without CNS involvement; 6 years [59]. Treatment for CNS involvement has been variously described. The majority of cases have shown improvement only in the presence of either intrathecal chemotherapy or whole-brain radiation. The vast majority of these cases used methotrexate. Schmidt-Hieber et al. [59], Oshimi et al. [46], and Thiruvengadam and Bernstein [66], all report cases of non-responders to intrathecal therapy; in the first case the post-therapy course was prematurely terminated by death due to pulmonary embolism; in the second only intrathecal hydrocortisone was used. Eight cases [15, 25, 30, 31, 35, 47, 64] show initial response to therapy with subsequent relapse of symptoms. It appears that some cases are refractory to the initial chemotherapeutic agent chosen, and others soon develop resistance. Hoffman et al. [27] report a case in which neurologic remission was achieved with intrathecal thiotepa, and Hagberg et al. [25] report a case were durable remission was achieved only with the addition of intrathecal cladribine. Given the experiences described in the literature, it seems reasonable that in such cases secondary agents should promptly be started, as there have been no reports published of CNS involvement exhibiting cross-resistance to multiple agents. Of the seven cases we found that were treated with systemic chemotherapy alone, only two had a sustained resolution of neurologic symptoms without relapse. In the Elliott et al. [19] case, fludarabine was used. Other reports did not reproduce this outcome with fludarabine treatment alone [18, 31]. In the Poplawska et al. [7] case, CCNU and procarbazine were used; both agents known to cross the blood brain barrier. Of the patients who received intrathecal chemotherapy and/or cranial radiation in the absence of systemic chemotherapy, 83% (10/12) showed improved neurologic symptoms. This may imply that neurologic disease burden is entirely unrelated to overall systemic disease. When outcomes are stratified based on whether intrathecal chemotherapy and brain radiation were used in combination or alone, there did not seem to be a marked variation between the groups; durable remission was achieved in 69% (9/13) when radiation alone was used, 76% with intrathecal chemotherapy alone, and 85.7% with

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both (these outcomes include cases with and without systemic chemotherapy usage). In cases of isolated SIADH, intrathecal chemotherapy has been shown to be very effective in resolving complications. Hagberg et al. [25] present two cases and Stagg and Gumbart [61] a third, wherein SIADH was effectively treated with intrathecal methotrexate. Hagberg et al. further suggest that the addition of XRT in their second case was likely not required to achieve good outcome. Conversely, Rye et al. [58] present a case of SIADH treated with systemic chemotherapy alone, with minimal resolution of symptoms. Cases involving direct cerebral infiltration have shown favorable response to radiation therapy. Of the six described cases that received irradiation, five showed resolution of intraparenchymal CLL infiltrations. In the Getaz and Miller [23] case, response to radiation was supervened by a seemingly unrelated cardiovascular event. Fain et al. [20] report a case treated with pituitary surgical resection; although symptoms were resolved, long-term survival was not reported. In addition, Currie et al. [16] and Cash et al. [12] describe four cases, and our Case 1, a likely fifth CNS involvement manifesting as optic neuropathy, all treated with cranial radiation. All cases demonstrated partial resolution. Mowatt et al. [43] present as case wherein complete resolution of optic neuropathy was achieved with intrathecal therapy alone. They suggest that this therapy may in fact be superior to radiation alone, given the fact that only partial resolution was achieved in the previous cases. This option may afford patients the possibility of avoiding side effects of radiation therapy as well. Lastly, the correlation between symptom relief and CSF clearance has also been studied. Our analysis reveals that of those who were treated and achieved CSF clearance, 87.5% (21/24) enjoyed sustained resolution of neurologic symptoms without relapse. In those who did not clear CSF, 58.3% (7/12) had resolution. Twenty-seven cases did not report post-treatment CSF levels. Although not statistically significant, this data suggests neurologic resolution can be achieved in the setting of persistently positive CSF, albeit at lower rates. Our review highlights the challenges of diagnosis and treatment of CNS invasion of CLL. Our patients’ outcomes correlate with previously published case reports. CNS involvement should be promptly diagnosed and aggressively treated if good patient outcomes are to be achieved. Further studies should look into the causes of intracranial invasion; whether it is leukemic burden or aberrant lymphocyte physiology that allows for intracranial seeding. Elucidation of this key issue will be the single most important factor in identifying patients who will require prompt, early, and aggressive CNS directed treatments.

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Acknowledgment This work was supported in part by grants from NIH 3P30CA023100-25S8 to S. Kesari. 20. Conflict of interest

None. 21.

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