Meningeal involvement in patients with AIDS-related non-Hodgkin lymphoma (ARL) is common; it confers a dismal prognosis, and therapy usually involves frequent lumbar punctures. In 137 individuals with ARL in the era of highly active antiretroviral therapy (HAART), 22 had meningeal involvement at presentation. We compared the use of standard alternating intrathecal methotrexate and cytarabine with a sustained-release formulation of intrathecal cytarabine (DepoCyt) that maintains concentrations in the cerebrospinal fluid (CSF). There were no significant changes in overall survival, the rate of fall of CSF protein, and remission rates defined as absence of lymphomatous cells in the CSF and a CSF protein level less than 0.4 mg/L. DepoCyt appears safe and effective in patients with ARL and meningeal disease and reduces the number of intrathecal administrations required.

Despite the progress that has been made in controlling cancer at most sites in the body, the outcome of individuals affected by meningeal infiltration by cancer remains poor. As few patients with this condition survive for more than several months, the management of individuals with meningeal disease remains a great challenge.1-3  The direct intrathecal instillation of anticancer drugs is one approach that has successfully been used by oncologists, particularly in the treatment and prevention of leptomeningeal leukemias and lymphomas, to circumvent the pharmacologic sanctuary resulting from the blood-brain barrier. Only methotrexate and cytarabine (cytosine arabinoside [Ara-C]) are routinely administered intrathecally, and both are specific to the cell cycle's S phase. Therefore, both agents would appear most effective when cytotoxic concentrations are maintained. Achieving this has necessitated prolonged and frequent course of lumbar punctures, which are both painful and labor intensive.

An encapsulated microvesicular liposome preparation named DepoCyt (Sykepharma, London, United Kingdom) drastically changes the pharmacokinetics of the free cytarabine released4,5  such that the mean elimination t1/2 of the depot formulation of free cytarabine is 130 to 277 hours, versus 3.4 hours for native cytarabine.6-8  In 2 randomized clinical trials by Glantz et al that have recruited a total of 89 patients,9,10  DepoCyt produced a high response rate, comparable with either methotrexate or free cytarabine, and delayed neurologic progression. The DepoCyt regimen also produced a higher clearance rate of lymphoma from the CSF and prolonged time to neurologic progression compared with conventional intrathecal chemotherapy in a randomized controlled trial.11 

Figure 1.

Survival and change in CSF protein with DepoCyt versus standard alternating methotrexate and cytarabine. (A) A Kaplan-Meier curve demonstrating the overall survival of individuals with ARL and meningeal disease, treated with either DepoCyt or alternating intrathecal installations of methotrexate and cytarabine. (B) A comparison of the rate of fall of CSF protein from the first intrathecal installation to 1 month. The median with the standard error of the mean is shown.

Figure 1.

Survival and change in CSF protein with DepoCyt versus standard alternating methotrexate and cytarabine. (A) A Kaplan-Meier curve demonstrating the overall survival of individuals with ARL and meningeal disease, treated with either DepoCyt or alternating intrathecal installations of methotrexate and cytarabine. (B) A comparison of the rate of fall of CSF protein from the first intrathecal installation to 1 month. The median with the standard error of the mean is shown.

DepoCyt has not been evaluated in HIV-1-seropositive individuals. Because patients with ARL have frequent meningeal involvement (a situation complicated by frequent poor compliance in this vulnerable patient group12,13 ), we compared the efficacy of DepoCyt with that of alternating intrathecal methotrexate and cytarabine.

Since 1996, the start of the HAART era, 137 individuals at The Chelsea and Westminster Hospital have been diagnosed with biopsy-confirmed ARL, including 22 (16%) with meningeal involvement at presentation; these comprised 0.4% of all HIV-1-seropositive individuals with whom follow up was conducted during this time. Meningeal involvement was defined as abnormal enhancement on a brain computerized tomography or magnetic resonance scan and/or the presence of lymphoma cells in the CSF.

In addition to their systemic chemotherapy, they received intrathecal chemotherapy. Up until 2004, this comprised alternating intrathecal methotrexate (12.5 mg) and intrathecal cytarabine (50 mg), given twice a week for 4 weeks, then once a week for 4 weeks, then once a fortnight for 8 weeks, and then monthly until systemic chemotherapy was completed, approximately 18 intrathecal procedures in total.14  Since that time, DepoCyt, a slow-release formulation of cytarabine, has been used alone, comprising a 50-mg intrathecal injection alone every 2 weeks for 2 months followed by monthly injections for 6 months, for a total of 10 intrathecal installations. Each DepoCyt injection was accompanied by 4 mg dexamethasone given orally or intravenously twice a day for 5 days.

There were no significant differences in overall survival between individuals who received either intrathecal alternating methotrexate and cytarabine, or intrathecal DepoCyt (Figure 1A; log-rank, P = .26). Table 1 demonstrates the characteristics of 17 HIV-1-infected individuals with meningeal involvement at ARL presentation who received alternating intrathecal methotrexate and cytarabine compared with 5 patients who received DepoCyt since 2004. There were no differences that approached significance at baseline between the 2 groups, including no difference in the initial CSF protein (Mann-Whitney U test, P = .42) or in the rate of fall in CSF protein during the first month of therapy (Mann-Whitney U test, P = .55), or thereafter (Figure 1B). Ten (45%) individuals of the 22 achieved a CSF remission, as defined by the absence of lymphomatous cells in the CSF and CSF protein levels of less than 0.4 mg/L. These comprised seven (41%) of 17 on intrathecal methotrexate and cytarabine and 3 (60%) of 5 on DepoCyt (Mann-Whitney U test, P = .46). Out of these 10 individuals who achieved a CSF remission, 6 relapsed with CSF disease; all these patients died. CSF relapse occurred a median of 4 months after diagnosis (range, 0.7 to 5.8 months), and no late relapses have been observed. Thus, the 2-year survival for patients who achieved a CSF remission is 34% (95% confidence interval, 2%-66%).

Table 1.

The clinicopathologic features of 22 ARL patients with meningeal disease treated with different intrathecal regimens




All

Methorexate/cytarabine

DepoCyte

P
No.   22*  17   5   NA  
Male, no. (%)   19 (86)   15 (88)   4 (80)   χ2 .64  
Mean age, y (range)   43 (29-60)   42 (29-60)   37 (29-47)   MW .05  
Median CD4/mm3 (IQR)  173 (150)   173 (156)   173 (136)   MW .81  
CD4 < 100/mm3, no. (%)   4 (18)   3 (1)   1 (20)   χ2 .90  
Prior ADI, no. (%)   2 (9)   2 (12)   0 (0)   χ2 .42  
On HAART at NHL diagnosis, no. (%)   15 (68)   12 (71)   3 (60)   χ2 .65  
Viral load less than 50 copies/mL, no. (%)   3/21 (14)   3/16 (19)   0/5 (0)   χ2 .29  
Bone marrow involved by NHL, no. (%)   11 (50)   9 (53)   2 (40)   χ2 .26  
Burkitt histology, no. (%)   8 (36)   7 (41)   1 (20)   χ2 .39  
ECOG PS, no. (%)     χ2 .77  
   1   6 (27)   5 (29)   1 (20)   
   2   8 (36)   6 (35)   2 (40)   
   3   2 (9)   2 (12)   0 (0)   
   4   6 (27)   4 (23)   2 (40)   
IPI group, no. (%)     χ2 .85  
   LI   3 (14)   2 (12)   1 (20)   
   HI   6 (27)   5 (29)   1 (20)   
   H   13 (59)   10 (59)   3 (60)   
Median CSF protein, mg/L (IQR)
 
0.70 (1.5)
 
0.74 (1.5)
 
0.58 (1.4)
 
MW .59
 



All

Methorexate/cytarabine

DepoCyte

P
No.   22*  17   5   NA  
Male, no. (%)   19 (86)   15 (88)   4 (80)   χ2 .64  
Mean age, y (range)   43 (29-60)   42 (29-60)   37 (29-47)   MW .05  
Median CD4/mm3 (IQR)  173 (150)   173 (156)   173 (136)   MW .81  
CD4 < 100/mm3, no. (%)   4 (18)   3 (1)   1 (20)   χ2 .90  
Prior ADI, no. (%)   2 (9)   2 (12)   0 (0)   χ2 .42  
On HAART at NHL diagnosis, no. (%)   15 (68)   12 (71)   3 (60)   χ2 .65  
Viral load less than 50 copies/mL, no. (%)   3/21 (14)   3/16 (19)   0/5 (0)   χ2 .29  
Bone marrow involved by NHL, no. (%)   11 (50)   9 (53)   2 (40)   χ2 .26  
Burkitt histology, no. (%)   8 (36)   7 (41)   1 (20)   χ2 .39  
ECOG PS, no. (%)     χ2 .77  
   1   6 (27)   5 (29)   1 (20)   
   2   8 (36)   6 (35)   2 (40)   
   3   2 (9)   2 (12)   0 (0)   
   4   6 (27)   4 (23)   2 (40)   
IPI group, no. (%)     χ2 .85  
   LI   3 (14)   2 (12)   1 (20)   
   HI   6 (27)   5 (29)   1 (20)   
   H   13 (59)   10 (59)   3 (60)   
Median CSF protein, mg/L (IQR)
 
0.70 (1.5)
 
0.74 (1.5)
 
0.58 (1.4)
 
MW .59
 

NA indicates not applicable. MW, Mann-Whitney test; IQR, interquartile range; ADI, AIDS-defining illness; ECOG PS, Eastern Cooperative Oncology Group performance status; and IPI, International Prognostic Index (low-intermediate [LI], high- intermediate [HI], and high [H]).

*

These 22 patients received systemic chemotherapy with alternating weekly BEMOP/CA (n = 4), monthly CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (n = 1), or infusional CDE (cyclophosphamide, doxorubicin, and etoposide) (n = 17) as previously described15-17 

CD4 subset analysis (cells/mm3) was performed using whole blood stained with murine antihuman monoclonal antibodies to CD4 (TetraOne; Beckman Coulter, High Wycombe, United Kingdom) and plasma viral loads (Quantiplex HIV RNA 3.0; Chiron, Halstead, United Kingdom) were recorded since 1998 with a lower limit of detection of 50 copies/mL. CSF protein was measured using the PRM assay (Sigma Aldrich, Poole, United Kingdom) with an upper limit of normal of 450 mg/L; cytospins were undertaken using standard light microscopy to detect cells. Comparison of variables between groups was by χ2 test for nominal variables and MW U test for nonparametric variables; all P values presented are 2-sided

Overall, DepoCyt is safe and effective in HIV-1-positive individuals with lymphomatous meningeal infiltration and has significant obvious advantages in its frequency of administration (18 vs 10 installations). It offers a significant alternative to the limited armamentarium of intrathecal agents in a group of individuals with well-documented issues with compliance18  and adherence.13,19 

The leptomeninges and CSF pose a specific cytokinetic problem for oncologists because CSF concentrations of drugs need to be higher than any plasma-based administration can achieve (in either the plasma or CSF), and malignant cells within the CSF tend to proliferate slowly.2,20,21  The repeated intra-CSF administrations necessary to accomplish this obviously pose difficulties and Ommaya reservoirs have been implanted to permit repeated intra-CSF installations.22  This in turn requires anesthesia and surgery, though their use has not been reported in the setting of ARL.

Standard treatment for meningeal disease is time consuming, painful, labor intensive, and the subject of much adverse media and journal coverage when errors occur.23,24  As the prognosis of patients with meningeal disease has not changed for 3 decades,2  any therapy that reduces pain, time, and labor for both patients and treating physicians without a deleterious effect on outcome should be considered as standard therapy. As improved systemic therapy has ironically resulted in greater numbers of patients with leptomeningeal disease, DepoCyt should also be considered in a trial of CNS prophylaxis in patients with ARL and others at high risk of meningeal relapse.

J.S. and D.M. contributed equally to this letter.

All authors contributed substantially to manuscript writing, data collection and interpretation, and study design and methodology, and approved the final manuscript.

1
Bleyer WA, Byrne TN. Leptomeningeal cancer in leukemia and solid tumors.
Curr Probl Cancer
.
1988
;
12
:
181
-238.
2
Bleyer WA. Intrathecal depot cytarabine therapy: a welcome addition to a limited armamentarium.
Clin Cancer Res
.
1999
;
5
:
3349
-3351.
3
Montoto S, Lister TA. Secondary central nervous system lymphoma: risk factors and prophylaxis.
Hematol Oncol Clin North Am
.
2005
;
19
:
751
-763.
4
Kim S, Kim DJ, Geyer MA, Howell SB. Multivesicular liposomes containing 1-beta-D-arabinofuranosylcytosine for slow-release intrathecal therapy.
Cancer Res
.
1987
;
47
:
3935
-3937.
5
Murry DJ, Blaney SM. Clinical pharmacology of encapsulated sustained-release cytarabine.
Ann Pharmacother
.
2000
;
34
:
1173
-1178.
6
Zimm S, Collins JM, Miser J, Chatterji D, Poplack DG. Cytosine arabinoside cerebrospinal fluid kinetics.
Clin Pharmacol Ther
.
1984
;
35
:
826
-830.
7
Kim S, Khatibi S, Howell SB, McCully C, Balis FM, Poplack DG. Prolongation of drug exposure in cerebrospinal fluid by encapsulation into DepoFoam.
Cancer Res
.
1993
;
53
:
1596
-1598.
8
Chamberlain MC, Kormanik P, Howell SB, Kim S. Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases.
Arch Neurol
.
1995
;
52
:
912
-917.
9
Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.
J Clin Oncol
.
1999
;
17
:
3110
-3116.
10
Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.
Clin Cancer Res
.
1999
;
5
:
3394
-3402.
11
Cole BF, Glantz MJ, Jaeckle KA, Chamberlain MC, Mackowiak JI. Quality-of-life-adjusted survival comparison of sustained-release cytosine arabinoside versus intrathecal methotrexate for treatment of solid tumor neoplastic meningitis.
Cancer
.
2003
;
97
:
3053
-3060.
12
Nieuwkerk PT, Sprangers MA, Burger DM, et al. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study.
Arch Intern Med
.
2001
;
161
:
1962
-1968.
13
Osterberg L, Blaschke T. Adherence to medication.
N Engl J Med
.
2005
;
353
:
487
-497.
14
Sarker D, Thirlwell C, Nelson M, Gazzard B, Bower M. Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma.
AIDS
.
2003
;
17
:
861
-865.
15
Bower M, Brock C, Gulliford T, O'Reilly SM, Smith DB, Newlands ES. A weekly alternating chemotherapy regimen with low toxicity for the treatment of aggressive lymphoma.
Cancer Chemother Pharmacol
.
1996
;
38
:
106
-109.
16
Bower M, Stern S, Fife K, Nelson M, Gazzard BG. Weekly alternating combination chemotherapy for good prognosis AIDS-related lymphoma.
Eur J Cancer
.
2000
;
36
:
363
-367.
17
Bower M, McCall-Peat N, Ryan N, et al. Protease inhibitors potentiate chemotherapy-induced neutropenia.
Blood
.
2004
;
104
:
2943
-2946.
18
Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel.
JAMA
.
2002
;
288
:
222
-235.
19
Ickovics JR, Meade CS. Adherence to HAART among patients with HIV: breakthroughs and barriers.
AIDS Care
.
2002
;
14
:
309
-318.
20
Kuo AH, Yataganas X, Galicich JH, Fried J, Clarkson BD. Proliferative kinetics of central nervous system (CNS) leukemia.
Cancer
.
1975
;
36
:
232
-239.
21
Oshiro EM, Viola JJ, Oldfield EH, et al. Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells.
Cancer Gene Ther
.
1995
;
2
:
87
-95.
22
Greenfield JP, Bilsky MH. Neurosurgical interventions for leptomeningeal tumor.
Cancer Treat Res
.
2005
;
125
:
107
-119.
23
Seale JR. Not again! Erroneous intrathecal injection results from a problem with protocols.
BMJ
.
2001
;
322
:
548
.
24
Dyer C. Doctor's manslaughter trial halted owing to defendant's health.
BMJ
.
2003
;
327
:
123
.