The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 799-801
Copyright © 1999 by The Endocrine Society
From the Clinical Research Centers |
Inability of Short-Term, Low-Dose Hydroxychloroquine to Resolve Vitamin D-Mediated Hypercalcemia in Patients with B-Cell Lymphoma1
John S. Adams and
Vitaly Kantorovich
The Burns and Allen Research Institute and Division of
Endocrinology and Metabolism, Cedars-Sinai Medical Center, University
of California Los Angeles, Los Angeles, California 90048
Address correspondence and requests for reprints to: John S. Adams, M.D., B131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.
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Abstract
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The 4-aminoquinolines, including chloroquine and hydroxychloroquine,
have been successfully employed to treat patients with
granuloma-forming disease-associated, vitamin D metabolite-mediated
hypercalcemia. The calcium-lowering efficacy of these drugs has not
been prospectively evaluated in patients with lymphoma and elevated
1,25-(OH)2D levels. Four such hypercalcemic patients with
stage IV B-cell lymphoma were treated, two each, with either 400 mg
daily oral hydroxychloroquine or a single course of
prednisone-containing antitumor chemotherapy (CHOP). Antitumor therapy
normalized the serum calcium and 1,25-(OH)2D concentration
within 5 days. Over a 15-day period, hydroxychloroquine failed to
reduce either the serum calcium or 1,25-(OH)2D level in
lymphoma patients. In contrast, within 5 days 400 mg of
hydroxychloroquine daily lowered elevated levels of calcium and
1,25-(OH)2D by 37% and 72%, respectively, in a
hypercalcemic patient with sarcoidosis. These data suggest that
regulation of the vitamin D-1-hydroxylase in lymphoma cells, the
putative source of hormone in lymphoma patients, is refractory to the
inhibitory actions of the aminoquinolines and that
glucocorticoid-containing antitumor regimens are the antihypercalcemic
therapies of choice in lymphoma patients with high
1,25-(OH)2D levels.
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Introduction
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HYPERCALCEMIA complicates the clinical
course of a substantial number of patients with widespread
lymphoproliferative disorders, including lymphomas and the
granuloma-forming diseases like sarcoidosis (1, 2, 3, 4, 5). In many instances,
the underlying cause of hypercalcemia is the endogenous overproduction
of the active vitamin D metabolite, 1,25-dihydroxyvitamin D
(1,25-(OH)2D). Successful management of hypercalcemia in
patients with sarcoidosis can be achieved with oral administration of
the 4-aminoquinoline agents, chloroquine (6) and hydroxychloroquine
(7). We previously demonstrated that low dose, twice-daily chloroquine
treatment could restore calcium balance to normal in the matter of only
a few days (8). Because this therapeutic regimen was simple, well
tolerated and rapid, we proposed to undertake a similar trial in
patients with lymphoma-associated, 1,25-(OH)2D-mediated
hypercalcemia. Compared with antitumor chemotherapy, a preliminary
trial of this regimen in two hypercalcemic lymphoma patients failed to
resolve hypercalcemia and to reduce inappropriately elevated serum
concentrations of 1,25-(OH)2D.
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Experimental Subjects
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The sex, age, classification of lymphoma by type and
state, and mode of antihypercalcemic therapy of four patients with
stage IV small noncleaved B-cell lymphoma is presented in Table 1
. Two patients refused chemotherapy and
were treated with hydroxychloroquine 200 mg orally twice daily for 15
days. Two other patients were evaluated over the same period following
a single course of antitumor chemotherapy with cyclophosphamide,
hydroxydaunorubicin, oncovin (vincristine), and prednisone (CHOP).
Informed consent was obtained from all subjects before initiation of
the protocol. The protocol was approved by both the Institutional
Review Board and Scientific Advisory Committee of Cedars-Sinai General
Clinical Research Center (GCRC). All subjects were monitored on an
outpatient basis in the GCRC before and after initiation of
hydroxychloroquine or CHOP. Patient 2 (Table 1) expired on day 15 of
hydroxychloroquine treatment. A 36-yr-old hypercalcemic patient with
biopsy-proven, active sarcoidosis was also studied via the same
protocol for confirmation of the efficacy of the calcium- and
1,25-(OH)2D-lowering potential of the hydroxychloroquine
regimen. Serial serum calcium, albumin, and creatinine as well as urine
(on both 2-h fasting and 24-h samples) calcium and creatinine were
measured by automated technologies. The serum 25-hydroxyvitamin D
(25-OHD) and 1,25-(OH)2D concentration was determined by
competitive protein binding assay and radioreceptor assay, respectively
(Nichols Institute Diagnostics, San Juan Capistrano, CA).
PTH and PTH-related peptide (PTHrP) were measured by two-site
chemiluminescent (Endocrine Sciences, Inc., Calabasas
Hills, CA).
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Results
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Before therapy, suppressed serum concentrations of PTH (< 10
pg/mL, normal 10–65 pg/mL), nonelevated levels of PTHrP (< 1.0
pg/mL; normal < 1.3 pg/mL) and nonelevated levels of 25-OHD (<
36 ng/mL; normal 10–55 ng/mL) were confirmed in all subjects. The
serum creatinine was maintained 
2.5 gm/dL (normal < 1.5
gm/dL) at all times in all patients. Serum samples were stored at
-70° C before assay. All samples from an individual subject were
analyzed in the same assay to obviate interassay variation. The serum
calcium (corrected for serum albumin) and 1,25-(OH)2D
levels in four hypercalcemic patients with lymphoma was followed for up
to 20 days following administration of hydroxychloroquine or antitumor
chemotherapy with CHOP (Fig. 1). The two
patients who were initiated on twice daily oral administration of 200
mg hydroxychloroquine failed to normalize either the corrected serum
calcium or the serum 1,25-(OH)2D concentration over a 2- to
3-week observation period. By comparison, successful antitumor
chemotherapy was effective in restoring normal calcium homeostasis in
the two other patients with neoplasms of similar type and extent.
Restoration of the serum calcium and 1,25-(OH)2D levels to
the normal range (Fig. 1) and return of the urinary calcium:creatinine
excretion ratio to 0.10 occurred within 5 days of initiation of
chemotherapy in both patients. A similar time frame for correction of
the parameters was observed in a hypercalcemic patient with active
sarcoidosis (Fig. 1); this patient’s response confirms the efficacy of
the hydroxychloroquine regimen to rapidly correct deregulated
extrarenal vitamin D synthesis in a granuloma-forming disease.
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Figure 1. Serum calcium (left panel)
and 1,25-dihydroxyvitamin D levels (right panel) in four
lymphoma patients with hypercalcemia; the numbers correspond to
patients identified in Table 1 . Patients were treated with
hydroxychloroquine 200 mg twice daily (HCQ, dark
squares) or the chemotherapeutic regimen CHOP (CT,
shaded squares). For comparison are similar data from a
hypercalcemic patient with sarcoidosis treated with hydroxychloroquine
200 mg twice daily (HCQ, open squares). The total serum
calcium concentration was corrected for the serum albumin concentration
according to the formula, measured serum calcium + 0.8 (4.0 -
measured serum albumin). Shaded regions represent the
range of normal values.
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Discussion
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Hypercalcemia is a complication of lymphoma, particularly
wide-spread B-cell neoplasms (9). In the largest prospectively analyzed
cohort of hypercalcemic lymphoma patients (10), the incidence of
1,25-(OH)2D-mediated hypercalcemia was 55%. In patients
with granuloma-forming diseases like sarcoidosis as well as in patients
with malignant lymphoproliferative disorders, like the B-cell lymphoma
patients examined here, the source of the vitamin D hormone is believed
to be extrarenal (11). This supposition is based on three central
observations. First, hypercalcemia persists in the presence of
suppressed PTH and elevated 1,25-(OH)2D concentrations; PTH
and 1,25-(OH)2D are the major stimulator and inhibitor of
the renal vitamin D-1 hydroxylase, respectively (12). Second,
functionally anephric patients with these disorders can develop
1,25-(OH)2D-mediated hypercalcemia (13). Third,
administration of an antiinflammatory dose of glucocorticoid is the
most effective means of reducing the serum calcium and
1,25-(OH)2D levels in lymphoma patients (9) as well as in
patients with granuloma-forming diseases (5).
Because inflammatory cells were the presumed source of hormone in both
granuloma-forming and malignant lymphoproliferative diseases, we
hypothesized that the 4-amino-quinoline derivatives would be as
efficacious in lowering 1,25-(OH)2D and calcium levels in
B-cell lymphoma patients as they are in patients with granuloma-forming
diseases. This hypothesis appears to be incorrect, as the vitamin
D-1-hydroxylase activity in lymphoma cells, the putative source of
hormone in lymphoma patients, is refractory to the inhibitory actions
of the aminoquinolines (Fig. 1). It is possible that failure to achieve
normocalcemia in lymphoma patients with this regimen is due to 1) an
inadequate dose of the drug; 2) inadequate duration of therapy; and/or
3) a relatively greater burden of the 1-hydroxylase compared with
patients with granuloma-forming diseases like sarcoidosis.
Alternatively, insensitivity of the hypercalcemic lymphoma patient to
hydroxychloroquine may be principally due to a difference in the cell
in which the hydroxylase gene is expressed. In macrophages, the
1,25-(OH)2D synthetic site in human granuloma-forming
disease (14), the chloroquine-sensitive phospholipase C (PLC) pathway
(15) and inducible nitric oxide synthase (iNOS) pathway (16, 17) are
considered to be key regulators of the enzyme. These same signal
transduction pathways may not be as highly expressed or involved in
1-hydroxylase regulation in the lymphoma cell as they are in the
macrophage.
In conclusion, we have shown that, compared with a patient with active
sarcoidosis, short-term (2 weeks), low-dose hydroxychloroquine
administration at well tolerated doses is an ineffective calcium
lowering regimen in patients with non-Hodgkins B-cell lymphoma and
1,25-(OH)2D-mediated hypercalcemia. In such patients,
glucocorticoid-containing antitumor regimens should be considered the
antihypercalcemic therapy of choice.
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Footnotes
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1 This work was supported in part by General Clinical Research Center
Grant 00425–28 and AI-40403 from the National Institutes of
Health. 
Received July 7, 1998.
Revised October 26, 1998.
Accepted October 29, 1998.
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Abstract
Introduction
