Hypersensitivity to procarbazine associated with angioedema, urticaria, and low serum complement activity M.
M.
A.
Alenty,
Glovsky,
M.D., B.S.
Los
J. Braunwald, Angeles,
M.D.,
G. Opelz,
M.D.,
and
Calif.
hypersensitivity to procarbazine associated with zlrtiearia, angioedcma, and painful joint swelling was found in a do-year-old stzldent being treated for Hodgkin’s disease. A marlced fall in complement component a&city occurred simultaneously uith the dcvclopment of symtoms. It is suggested that generation of products of complement component activation could be important in the pathogenesis of hypersensitivity to some drmgs.
Procarbazine hydrocholoride (Matulane) is a methylhpdrazine derivative used in the treatment of Hodgkin’s disease. Previous reports of allergy to this drug have emphasized urticaria,ls 2 a maculopapular rash,“-” arthralgias,l and hypersensitivity pneumonitis.l, 4 Over the past year, while being treated for recurrent Hodgkin’s disease with NOPP (nitrogen mustard, vincristine [ Oncovin] , prednisone, procarbazine) , our patient had 4 episodes of urticaria, arthralgias, and angioedema. Because of the uncertainty of the causative agent and the need for therapy, individual drugs were removed from the treatment protocol. When procarbazine was given in combination or alone, angioedema, urticaria, and arthralgias occurred. During the last symptomatic period after treatment with procarbazine (100 mglday) alone a marked fall in serum complement component activity was noted. CASE
REPORT
A 20.year-old Caucasian male (M. M.) was diagnosed as having Hodgkin’s disease of the mixed cellularity type by lymph node biopsy in 1968 when he was 15 years old. He was classified as Stage II-A on the basis of mediastinal, right hilar, and right supraclavieular adcnopathy and a normal lymphangiogram and bone marrow biopsy, and was treated with mantle cobalt irradiation. Lymphadenopathy developed above the diaphragm in 1969 and below the diaphragm in 1970 and 1972. These recurrences were treated with cobalt-60 irradiation. In August, 1972, t,he patient developed pruritus, left supraclavicular sdenopathy, and From the Departments of Allergy and Clinical Immunology and Internal Medicine, and Southern California Permanente Medical Group and from the Research Laboratory, Kaiser Foundation Hospital, and from the Department of Surgery, School of Medicine, University of California at Los Angeles. Received for publication Oct. 18, 1974. Accepted for publication Nov. 26, 1974. Reprint requests to: M. M. Glovsky, M.D., Department of Allergy and Clinical Immunology, 4900 Sunset Rlvtl., Los Angeles, Calif. 90027. Vol.
57,
No.
it’, pp.
134-140
\!OLUME NUMBER
57 2
Hypersensitivity
to
I 11I
I!
135
procarbazine
MUSTARD
and ONCOVIN
9
PROCARSAZINE
I 8
I 9
I 11
I 10
I 12
I 1
I 2
I 3
MONTH-1972
FIG. were as
1. Treatment given indicated
procarbazine and n, angioedema, were
of
intravenous
by (50 lower
vertical mg or rectangle
and
painful
I 5
I 7
, 6
I 8
MONTH-1973
schedule
by
! 4
M.
M.
for
Hodgkin’s
of
10 mg
of
prednisone
injections line;
40
100 = joint
mg) 50
mg
disease. and
was given daily; mg of procarbazine/day. swelling
occurred
Nitrogen
2 mg,
mustard
respectively,
was
given
n,
higher
as
indicated
on
daily
for
7
rectangle = When symptoms by
arrow
and or
Oncovin
1 and
days
14 days 100 mg/day of (J,],
8,
q
;
urticaria, all
drugs
stopped.
on x-ray, a radiolucency in the right ileum was found. Hc \ras staged IV-B and started on combination chemotherapy with MOPP. There was both objective and subjective improvement after the first month of therapy. On the seventh day of his second course of MOPP therapy (Fig. l), he developed hives, periorbital edema, and painful knee and ankle smelling. Because of suspected hypersensitivity to procarbazine, he was challenged with this drug for 7 days at a dose of 50 mg daily with 110 ill effects. MOPP chemotherapy was resumed with no allergic reactions until the tenth day of his fourth course, when he again developed periorbital edema and arthralgias. On the fourth day of his fifth course oi’ chemotherapy, the patient again developed painful swelling of his knees and ankles. He was again challenged with procarbazine alone at a dose of 100 mg daily, and on the fifth day developed hives and some swelling of his knees, eyes, and ankle joints (Fig. I). Chemotherapy with nitrogen mustard, Oncovin, and prednisone has continued without any allergic manifestations, and the patient remains well and free of disease in September, 1975.
laboratory
studies
Periodic complete blood counts (CBC), including hemoglobin determinations, differential counts, and white blood cell counts, revealed occasional moderate lcukocytosis with normal absolute lymphocyte counts. During the episode of urticaria on July 17, 1973, the CBC was normal and eosinophils were not increased. Delayed hypersensitivity was present to XoniZia and mumps by intradermal testing. Immunoglobulin G, A, M concentrations were normal. Prick and intradermal skin tests for immediate hypersensitivity demonstrated significant reactions to grass pollen extracts only.
METHODS Ci ,a Ci esterase inhibitor (Ci Inh),r C4,s CZ,G Serum complement activity (CH50), hemolytic and hemolytic inhibition activity were determined as described, Protein concentratioll of (14 was assayed l)y radial immunodiffusion using partigen packs obtained from Rehring Diagnostics, Somerville, N. J.; C3 protein determinations were made using immunoplates from Hyland Labs, Costa Mesa, Calif. Anticomplementary activity of M. M. serum was
136
Glovsky
J. ALLERGY
et al. 140
CLIN. IMMUNOL. FEBRUARY 1976
-
120i= E
loo-;;
-.
4 5
60-r
= !!
60-’
s 8
40-
ar 20 0 i DATE
FIG. 2. Complement component ingestion of procarbazine; bar = C4/ml; R, last bar represents average figures for toms occurred on 7/17, note
n
DETERMINED
activity of patient with angioedema and urticaria after , solid bar = CH,,/ml; I%, hatched bar = Ci/ml; 0, open = C3 mg %. Gray-speckled area (67o,O-133o/O of activity] mean + standard deviation of CHSo, Ci, C4, C3. When sympa significant fall of all component activities.
assessed by mixing equal volumes (0.2 ml) of Al. M. serum the mixture for 1 hr at 37” C, and then measuring residual and individual serum controls.
with normal serum, incubating CH, activity of the mixture
RESULTS
Although reactions to a variety of drugs are well known, the association with low complement activity has only rarely been observed. As seen in Fig. 2, CH,,, Cl, C4, and ,!3,C globulin were all significantly depleted when M. M. was symptomatic. C4 protein, determined by end point radial immunodiffusion, was undetectable as well. Both before and after the reaction, the complement component activity was normal, except for a slight depression of CH,, on *July 9, 1973 (Table I), and slightly diminished Cl levels. Cl Inh and C2 were depleted during the symptomatic period as well (Table I). Procarbazine was removed from the 50-mg capsules, dissolved in veronal buffered saline at 10m2M final concentration, and tested to seeif it would directly inhibit one out of two units of human C. The methods used were described previously.” No inhibition of two units of human C was found in this way with a final concentration of 1 mM Matulane or less. When X. M. serum was mixed with normal serum, it neither inactivated CH,, in normal serum, nor did it contain significant inhibitors of normal serum activity. DISCUSSION
It is intriguing to speculate that depression of complement component activity was associated with generation of biologically active fragments. Since all of the components studied were depleted, it is likely that activation of the
VOLUME NUMBER
TABLE
57 2
Hypersensitivity
I. Complement
Date
profile
Symptoms
3123113 l/9/13 7jl~ll3 7123113 816173 Normalst
component
1
C&o
179 106 Angioedema urticaria $
of M. e
procarbazine
to
137
M. )
i?i
Inh
1
C4
(
C2
1
c3*
20,000 20.000
42,000 29.000
22,200 21.400
424 494
128 130
11,000 ND 33,000 40,000 115,000
13,000 22,000 24,000 27,000 +15,000
1,200 ND 25,000 30,000 ~12,000
364: 342 350-650
1;;: 162 140 +20
and 73.5 152 156 120-180
ND : Not done. “C3 determined by radial diffusion tRanges of normal determinations. :Menn + standard deviation.
as mg protein/100
ml serum.
classical pathway by initial activation of the early components (CT, C4, and C2) recruited terminal component activation, as evidenced by diminished ,&C globulin. Generation of fragments of C3 and C5 (C3a and C5a) have been associated with both degenerative and destructive synovitis.l* Fragments of C3*l and C5 (C3a and C5a) have anaphylotoxin activity and conceivably could have been instrumental in the induction of angioedema and urticaria. Injection of purified C3a into human skinI has been shown to produce a wheal-and-flare reaction indistinguishable from the pathophpsiologic sequelae of histamine injection. The exact cause of the low C activity has not been determined. Tt is possible that the drug, procarbazinc, or one of its metabolites induced antibody production and then immune complexes were formed on reinstitution of treatment. The time-course of the development of symptoms (3 to 10 days) would coincide with a secondary antibody response. Alternatively, drug metabolites either themselves or by activating plasma or tissue enzymes could have caused component activation. Such activation of Cl by plasma proteolytic enzymes, plasmin, or trypsin,‘” and polpcations such as protamine sulfate and poly-r,-lysine’” have been described. Since hydrazinc is known to inactivate C-l in vitro, some credence is given to this possibility. I4 Not shown in Fig. 2 are several determinations of CH,, activity after ;SI. M. was treated with mustard and Oncovin. These values were all normal and indicated that intravenous therapy with mustard and Oncorin did not lower serum CH,, activity. Since the drop in CR,, occurred when procarbazine was given alone, any effect of prcdnisone administration that in itself can lower complement component activity’” was not operative. The fact that the drug is unavailable for parenteral administration does not allow skin-testing to be performed for immediate or delayed hgpersensitirit>-. Also, the chemical structure of procarbazine provides no reactive groups for covalent bonding to cellular membranes. Indeed, the mode of action of the drug is believed to reside in metabolic products such as the azo derivative or further degradation productxl” In vitro cultures of M. M. lymphocytes responded normally to 0.25 pg phytohemagglutinin stimulation. The lymphocyte stimulation method has been described previously. I1 Five and 0.5 pg protein of dfowilin crlbicn~~ extract (Hollister-Stier Laboratories, Burbank, Calif.) produced significant stimulation
138
Glovsky et al.
J. ALLERGY
CLIN. IMMUNOL. FEBRUARY 1976
of M. M. lymphocytes. Skin tests with ilfonilin antigen were previously noted to be positive in delayed hypersensitivity after intradermal injection. Jret when larger amounts of crystalline procarbazine were added to normal or XI. Jr. lymphocytes, no significant incorporation of tritiated thymidine occurred with 20 pg of the drug. At a dose of 200 pg, moderate suppression of Iymphocytc reactivity occurred with both normal and M. M. cells. The lack of lymphocyte stimulation by c.rgstalline procarbazine is consistent with the presumption that metabolites of the drug may be responsible for its hyperscnsitivit.y rca.ctions. It is also possible that the in vitro lymphocyte culture does not contain othel cellular or humoral ingredients needed for the in vivo response or that the response is not lymphocyte-mediated. The reason for the lack of response to procarbazinc after the initial reaction is unclear (Fig. 1). Procarbazine (50 mg/dap) was given alone 17 days after the first reaction with no adverse effects. Nine days later a third course of MOPT’ therapy was not complicated by adverse reactions. This could indicate t,hat a refractory period is required between adverse reactions. Alternatively, the patient may have been rendered unable to respond to procarbaxinc by the disease process itself. Subsequent treatment, which contained procarbazinc either alone or in combination with the other drugs, produced urticaria and angioedema on three successive occasions (Fig. 1 j. Following the last episode when pro carbazine was given alone and symptoms recurred after 6 days of treatment, the drug has been stopped. There have been no further episodes of angioedema and urticaria in spite of continuing monthly mustard, Oncovin, and prcdnisonc therapy for over 27 months. It is possible that the angioedema reaction to procarbazinc was not due to the drug, but to the additive ingredients used as fillers or yellow dye (tartrazine) employed in the capsule production. When M. M. ingested other medications containing tartrazine, no reaction occurred. The patient was given gelatin capsules containing mixtures of equal amounts of each of the fillers (talc, cornstarch, and mannitol) used in the procarbazine capsule. After taking one capsule twice a day for 14 days, no episodes of angioedema or urticaria occurred. Further, monthly injections of mustard, Oncovin, and oral ingestion of prednisone for the past 27 months have not been associated with untoward reactions. Thus, the reaction to procarbazine, rather than the capsule fillers, capsule itself, or other simultaneous drugs, is established. Lowering of CH,, activity secondary to serum sickness in experimental animals has been well substantiated using protein antigens such as bovine serum albumin.18s In One of us (M. CT.) had demonstrated that transfusion of gamma A containing plasma into a patient whose serum was completely deficient in gamma A and contained antibodies to IgA was associated with an acute drop of CH,, activity,20 as well as urticaria and systemic anaphplaxis. When purified immunoglobulins CT, A, and M were injected intraclermally into the skin of this patient (several weeks after the transfusion reaction), immediate hypcrsensitivity was demonstrated to IgA alone. More reccntlp lidocaine injection was associated with systemic anaphylaxis and a precipitous drop in Ciq, C4, and C3
VOLUME NUMBEK
57 2
Hypersensitivity
to procarbazine
139
protein levels.z1 These observations implicate complement and complement component activity in the vascular permeability effects that arc associated with drug-or immune complex-induced anaphylaxis, angioedema, and urticaria. Further documentation of complement activity in adverse drug reactions ma.v provide clues to the mechanism of such reactions. It is also possible that a gamma E-mediated mechanism might be involved in the procarbazine-induced angioedema and urticaria. Such a possibility, however, cannot at present be evaluated due to a lack of suitable drugs or metabolites that could be used for in vivo and in vitro testing. We thank Dr. Donald Reed, Oregon State University, for fruitful discussions on the metabolism of Maimlane, Dr. H. Hugh Fudenberg and G. Vyas for allowing us to refer to previously unreported skin tests performed on their IgA-deficient patient with systemic anaphylaxis due to anti-IgA, and the Professional Service Department, Roche Laboratories, Nutley, N. J., for the generous supply of crystalline procarbazinc and the fillers used in the drug capsule (mannitol, talc, and cornstarch). REFERENCES
1 Jones, 8. E., Moore, M., Blank, N., and Castellino, R. A.: Hypersensitivity to procarbazine (Matulane) manifested by fever and pleuropulmonary reaction, Cancer 29: 498, 1972. Preliminary clinical results 2 Martz, G., D’Allessandri, B., Keel, H. J., and Bollag, W.: with a new antitumor agent RO-4-6467 (NSC 77213), Cancer Chemother. Rep. 33: 5, 1963. 3 Stolinsky, D. C., Solomon, J., Rugh, R. P., Stevens, J. L., and Bateman, J. R.: Clinical reticulum cell sarcoma and lymphoexperience with procarbazine in Hodgkin’s disease, sarcoma, Cancer 26: 984, 1970. 4 Lokich, J. J., and Moloney, W. C.: Allergic reaction to procarbazine, Clin. Pharmacol. Ther. 13: 573, 1972. 5 Todd, I. D. H., Natulan in management of late Hodgkin’s disease, other lymphoreticular neoplasms and malignant melanoma, Br. Med. J. 1: 628, 1965. 6 Glovsky, M. M., and Fudenberg, H. H.; Reduced complement activity in sera of patients with Waldenstriim’s macroglobulinemia, J. Immunol. 104: 1672, 1970. 7 Gigli, T., Ruddy, S., and Austen, K. F.: The stoichiometric measurement of the serum inhibitor of the first component of complement by the inhibition of immune hemolysis, J. Immunol. 100: 1154, 1968. 8 Ruddy, S., and Austen, K. F.: A stoichiometric assay for the fourth component of complement in the whole human serum using EACla gp and functionally pure human second component, J. Immunol. 99: 1162, 1967. 9 Glovsky, M. M., Becker, E. L., and Halbrook, W. J.: Inhibition of guinea pig complement by maleoprimaric acid and other derivatives of fumaropimarie acid, J. Immunol. 100: 979, 1968. 10 Ward, P. A., and Zvaifler, N. J.: Complement-derived leukotactie factors in infiammatory synovial fluids of humans, J. Clin. Invest. 50: 606, 1971. 11 Lepow, I. H., Willms-Kretschmer, K., Patrick, R. A., and Rosen, F. S.: Gross and ultrast,ructural observations on lesions produced by intradermal injection of human G3a in man, Am. J. Pathol. 61: 13, 1970. 12 Ratnoff, 0. D., and Naff, G. B.: The conversion of C’ls to C’l esterase by plasmin and trypsin, J. Exp. Med. 125: 337, 1967. 13 Siegel, J., Rent, R., and Gewurz, H.: Interactions of C-reaction protein with the complement system. I. Protamine induced consumption of complement in acute phase sera, J. Exp. Med. 140: 631, 1974. 14 Pillemer, L., Seiffer, J., and Ecker, E. E.: The effect of amino compounds on the fourth component of complement, J. Immunol. 40: 89, 1941. 15 Atkinson, J. P., and Frank, M. M.: Effect of cortisone therapy on serum complement components, Fed. Proe. 32: 992, 1973. (Abst.) 16 Reed, D. J., in SantorelIi, A., and Jones, D., editors: Handbook of experimental phnrmacology, Berlin, Springer-Verlag, chap. 70, pp. 747.765, 1975.
140
Glovsky
et al.
J. ALLERGY
CLIN. IMMUNOL. FEBRUARY 1976
mixed lymphocytic culture test, 17 Sengar, D. P. S., and Terasaki, P. I.: A semi micro Transplantation 11: 260, 1971 18 Dixon, F. J., Vazquez, J. J., Weigle, W. O., and Cochrane, C. G.: Pathogenesis of serum sickness, Arch. Pathol. 65: 18, 1958. 19 Cochrane, C. G., and Koffler, D.: Immune complex disease in experimental animals and man, in Advances in immunology, New York, 1973, Academic Press, Inc., pp. 16, 185. 20 Vyas, G. N., Perkins, H. A., and Fundenberg, H. H.: Anaphylactoid transfusion reactions associated with anti-IgA, Lancet 2: 312, 1968. 21 Tannenbaum, H., and Schur, P.: Association of lidocaine-induced anaphylaxis with serum complement utilization, J. Allergy Clin. Immunol. 53: 96, 1974. (Abst.)