Monocytosis in chlorpromazine-associated agranulocytosis

Monocytosis

in Chlorpromazine-Associated Agranulocytosis* Termination in Acute Leukemia PETER A. CASSILETH, M.D.? New York, New York

A patient with chlorpromazine-induced agranulocytosis was found to have a marked monocytosis. Eighteen months after complete recovery, acute leukemia developed. Unlike earlier reported cases of leukopenic monocytosis appearing prior to recovery from agranulocytosis, the monocytosis was associated with leukocytosis and appeared at the onset of chlorpromazine toxicity. At the time of agranulocytosis and during the recovery period, no blast cells were seen in the marrow aspirates. Before the appearance of leukemia the patient had neither objective nor subjective evidence of a hematologic disorder. The possible relationship between marrow injury and subsequent development of acute leukemia is discussed.

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reactions,

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has

variety and

included

accomeffects.

summarized

allergic,

dermatitides

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noma of the right mandible was deferred because marked anxiety had developed. The patient was admitted to the New York State Psychiatric Institute on March 3, 1965, in a state of agitated depression ascribed to fear of further disfigurement by surgery and unhappiness because of her recent retirement. On the first day she received 100 mg. of chlorpromazine (Thorazine@) orally; three days later she was given 25 mg. intramuscularly. She also received 1 gm. of chloral hydrate each night and 65 mg. of sodium amytal orally per day for sedation. Because of continued agitation, chlorpromazine therapy was reinstituted on March 17, 100 mg. orally per day. On March 21 the dose was increased to 200 mg. per day. Cough, coryza and fever (temperatures up to 103’F.) developed on March 23, and she was given 1 gm. of tetracycline orally. Two white blood cell counts the following day were 16,500 and 24,500 per cu. mm. with 82 per cent and 89 per cent monocytes, respectively. She was transferred to the medical service. No other medication was given. Liver function studies had been normal on admission to psychiatry, and all previous white blood cell counts prior to January 25,1965, were within normal limits. Physical examination disclosed a well developed, well nourished, very anxious, trembling white woman with several papular erythematous lesions of the mons pubis, and erythematous macules in both groins. Her pulse was 120 beats per minute and regular, blood pressure 126/78 mm. Hg, respiration

these and skin

[3,4] and ocular [5] and central nervous system alterations [6]. Two of these idiosyncratic responses, hepatic damage and agranulocytosis, have resulted in fatalities [7,8 1. The case history to be cited is an example of chlorpromazine-induced agranulocytosis. Diagnosis was delayed because of the unusual and marked monocytosis found on admission. One and a half years after complete recovery from agranulocytosis acute myeloblastic leukemia developed. pigmentation,

CASE

REPORT

A sixty year old married

white woman, a retired secretary, was transferred from the New York State Psychiatric Institute to the Columbia-Presbyterian Medical Center because of one day of fever and leukocytosis. Over a period of more than forty years multiple operations had been performed to correct scoliosis, nontoxic nodular goiter and prognathism. an intraductal papilloma and a More recently, bronchial adenoma had been removed. During these admissions no hematologic abnormality was ever observed. In January 1965 excision of an adamanti-

* From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York. Manuscript received August 31, 1966. t Hematology Trainee, U. S. Public Health Service Grant No. CA-5011 from the National Cancer Institute. VOL.

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Agranulocytosis-Cassileth

TABLE I PERIPHLRAL BLOOD STUDIES

IN A PATIENT IN WHOM

White

WITH

ACUTE

CHLORPROMAZINE-ASSOCIATED

LEUKEMIA

AGRANULOCYTOSIS

DEVELOPED

Blood Cell Count (per cu. mm. 1 Differential

Total 3/24,‘65 3/27/65 3/29/a 3/31/65 4/2/65 4/4/65 4/7/65 4/9/65 4/11/65 4113165 4/19/65 4:22/65 4/26/65 4/28/65 4,30/‘65 5/11/65 6/11/65 11/23,‘65 9/8/66

‘6,360 10.960 6;840 3,880 5,600 5,800 5.700 3;200 4,720 5,850 h 880 4,800 6,300 4.840 4,760 4,600 7,050 5,700 !31,000

(

Pal\ morphonucle‘u Let1kocytes 264 0 0 0 560 0 0 1,024 2,124 3.276 4:816 3,552 2,898 1,936 1,761 1,242 2.327 3;420 0

LymphocyttX

MIXKIcytes

5,808 1,973 274 0 1,120 464 1,938 1.728 1;463 1.170 I ;789 768 1,827 1,597 1,666 2,668 4,089 1,824 0

20,064 8,987 6,566 3,880 4,020 5,336 3.762 ‘448 1,133 1,404 138 288 1,008 581 857 506 564 342 0

Eosinophils

Ba50phils

0 0 138 192 56: 726 476 184 0 114 0

264 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 70 0 0

20, and temperature 101’~. There were no ecchymoses, petechiae or fundic lesions. There was no lymphadenopathy or hepatosplenomegaly. Nontender swelling of the right mandible (due to an adamantinoma), multiple scars of previous surgery and slight dorsal kyphosis were present. Six superficial ulcerated purulent perirectal lesions (1 cm. in diameter) were seen. The erythrocyte sedimentation rate was 47 mm. per hour; hemoglobin, 10.3 gm. per cent; hematocrit. 34 per cent; platelets, 120,000 per cu. mm.; the reticulocyte count was 0.0 per cent. The white blood cell count was 26.360 per cu. mm. wit:1 a differential count of 76 per cent monocytes, 22 per cent lympho-

FIG. 1. Bone marrow aspirate taken on admission showing monoeytic predominance.

ReticulocyttS (%I 34 32 29 26 38 35 27 38 39

0.0

120,000

0.0 1.1 4.8 4.7 4.0

168,000 300,000 280,000 250,000 414,000

4.1

180,000 310,000 321,000

37

3.6 2.4 5.2 3.9

42 22

0.0

41

PlateletS

(per cu. mm.)

160,000 19.000

Comments

Chlorpromazine stopped Transfusion 2 units Became afebrile Transfusion 2 units

Blast forms 88 per cent

cytes, 1 per cent basophil and 1 per cent segmented polymorphonuclear leukocytes (Table I). Other studies were performed and yielded normal or negative findings:chest roentgenogram and skeletal and urine culture, stool guaiac, survey, urinalysis serologic test for syphilis, venous clotting time, blood urea nitrogen, uric acid, six blood cultures, electrocardiogram, and (later returned) bone marrow and gastric aspirations cultured for fungus and tuberculosis. Electrophoresis showed a depressed albumin (3.5 gm. per cent) and gamma globulin (0.5 gm. per cent). The prothrombin time was slightly elevated (fifteen seconds; control, twelve seconds). The serum bilirubin was 2.8 mg. per cent with 1.8 mg. per cent in the indirect fraction, and the serum alkaline phosphatase and serum glutamic oxaloacetic and pyruvic transaminases (SGOT and SGPT) were normal. Serum calcium was 8.4 mg. per cent, serum phosphorus 1.8 mg. per cent. In a bone marrow aspirate obtained on admission megakaryocytes were present as well as a preponderance (80 per cent) of monocytes (Fig. 1) ; erythropoiesis and granulopoiesis were virtually absent. As in the peripheral blood, despite many atypical cells, no more than 3 to 5 per cent of the monocytic cells were monoblasts. Culture of the peri-anal ulcers yielded Proteus mirabilis and Escherichia coli. Throat culture showed Candida albicans. Because of the patient’s severe agitation, she was maintained on a regimen of chlorpromazine (200 mg. per day orally) with 1 gm. of chloral hydrate as a nighttime sedative. From March 26 to 29 she was given 10 million units of penicillin and 1 gm. of tetracycline intravenously every twenty-four hours AMERICAN

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without effect on her spikes in temperature, which ranged up to 103’ to 104”~. A lumbar puncture was performed on March 30 because of increasing disorientation, stupor and weakness. Spinal fluid pressure, protein, sugar and serologic reaction was normal, there were no cells and culture was negative. Despite a negative tuberculin (purified protein derivative) skin test to the second strength, administration of isonicotinic acid hydrazide, 300 mg. per day orally, and streptomycin, 1 gm. per day intramuscularly, was begun in combination with Staphcillin@, 8 gm. per day intramuscularly, on March 31 as further empirical treatment for infection. Ten cubic centimeters of gamma globulin were given intramuscularly each week for the first three weeks. Two units of blood were given on March 31 and on April 7, when the hematocrit declined to 26 to 27 per cent. Several stool specimens were quaiacpositive. Examination of the gastrointestinal tract which included roentgenograms of the upper gastrointestinal tract and small intestine and a barium enema, revealed no abnormalities; bleeding did not recur. An oral cholecystogram showed a single radiolucent stone. On March 29 chlorpromazine therapy was discontinued, but the patient continued to receive chloral hydrate and barbiturate. On April 2 her fever diminished; she felt better and was more alert. She became afebrile on April 4 and remained so. Table I shows her white blood cell counts chronologically. Leukopenia appeared on March 31, when the bone marrow showed 50 per cent monocytic cells. By April 5 only 19 per cent monocytes were present. Large numbers of polymorphonuclear cells did not appear in the peripheral blood until April 9. The prothrombin time and serum bilirubin level returned to normal by April 9, at which time the serum alkaline phosphatase (25 King-Armstrong units) and transaminases (SGOT, 95 and SGPT, 93) were elevated. These also returned to normal values by April 19. By April 12 the hypogammaglobulinemia was replaced by a hypergammaglobulinemia of 1.6 gm. per cent. The administration of Staphcillin was discontinued on April 11 and the antituberculous therapy on April 22. The patient was discharged on April 30. A normal blood count (Table I) was noted on November 23, 1965. A complete physical examination revealed no abnormalities and the patient felt well when seen in the clinic on June 10, 1966. Hemoptysis began on August 25, 1966, and over the next two weeks the patient experienced progressive difficulty with frontal headaches, malaise, easy bruisability and bleeding gums. She took only aspirin and a single Coricidin@’ tablet, without relief. On admission to the hospital on September 8, she appeared acutely ill and was febrile. Physical examination revealed multiple ecchymoses and mucous membrane hemorrhages. No ulcerations, lymphadenopathy or hepatosplenomegaly were found. VOL.

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The erythrocyte sedimentation rate was 32 mm. per hour; hemoglobin, 7.5 gm. per cent; platelets, 19,000 per cu. mm.; the white blood cell coumiwas 231,000 per cu. mm. with a differential count of 88 per cent blast forms, 11 per cent promyelocytes and 1 per cent myelocytes on smear. Other studies performed included serum bilirubin 1.2 mg. per cent, SGOT 61 units and prothrombin time sixteen seconds (control, thirteen seconds). Urinalysis revealed 1+ proteinuria and 30 to 40 red blood cells per high power field and urine culture grew out Esch. coli. Other studies were returned with normal or negative findings, including serum calcium, phosphorus, uric acid, blood urea nitrogen, Coombs’ test, serologic reaction for syphilis, venous clotting time, SGPT, alkaline phosphatase, chest roentgenogram and electrocardiogram. A bone marrow aspirate (Fig. 2) showed 93 per cent blast forms compatible with acute myelocytic leukemia. Therapy with 6-mercaptopurine, vincristine, prednisone and whole blood transfusions was initiated on the first hospital day. The patient remained febrile. Acute pulmonary edema developed on the second hospital day and responded to the usual measures. Two days later she became comatose abruptly, with physical findings compatible with a cerebrovascular accident, thought to be an intracranial hemorrhage; she died one hour later. A blood count on the morning of her death showed no change save for a decrease in the white blood cell count to 76,000 per cu. mm. Permission for autopsy was denied.

COMMENTS Monocytic leukemia was the initial diagnostic impression because of the marked monocytosis. In favor of an acute monocytic leukemia were the fever, constitutional symptoms, skin lesions, perirectal ulcerations, and the white blood cell and the differential counts. Although the onset was acute, the patient lacked thrombocytopenia,

FIG. 2. Bone marrow aspirate showing leukemic blast cells.

takrn

on readmission

474

Monocytosis

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adenopathy, organomegaly, gum hyperplasia and the appropriate marrow picture for acute monocytic leukemia. Despite the variable morphology of the monocytic cells, no more than 5 per cent could be called “blast forms.” In addition, the marrow was hypocellular and difficult to obtain, instead of being hyperplastic. On the other hand, the recent onset and fulminant course differed from the slow progression of chronic monocytic leukemia as defined by Sinn and Dick [9]. The elevation of white blood cell count and of monocytes in the present patient occurred in their cases of chronic monocytic leukemia only after many years of more minor elevations. The patient’s white blood cell count and differential were within normal limits two months before her acute illness. Because of the uncertainty of diagnosis, other causes of monocytosis were considered. Maldonado and Hanlon [70], in a recent review of 160 patients at the Mayo Clinic with monocytosis (more than 500 monocytes per cu. mm.), found that the most commonly associated ilnesses were hematologic disorders (Hodgkin’s disease and lymphomas in 12 per cent and monocytic leukemia in 9 per cent) and connective tissue diseases (10 per cent). An infectious etiology was found in 6 per cent. The rickettsial and protozoa1 infestations noted in Wintrobe’s [ 77 ] review were absent. Except in the monocytic leukemias, monocyte elevations did not reach the absolute levels described in this case report. Many of these possibilities could be eliminated as etiologic in the present patient by the history, physical examination and initial laboratory tests and cultures. Monocytosis appearing in the recovery phase of agranulocytosis was noted in the Mayo Clinic review (one patient) and by Wintrobe. As the total white blood cell count declined during the first five hospital days, a drug-induced agranulocytosis became a major diagnostic consideration. After chlorpromazine therapy was discontinued there was a decrease in fever in two days and a rapid return of marrow function as evidenced by reticulocytosis (from 0.0 to 1.1 per cent) two days later. Subsequent evidence of mild hepatic dysfunction helped to confirm the impression of chlorpromazine toxicity. Since the first report of chlorpromazineinduced agranulocytosis recorded by Lomas [72] in 1954 more than sixty-nine cases [6] have appeared in the literature. In 1963 Best [ 731 commented that of the drugs reported to the American Medical Association registry of

Agranulocytosis-Cassileth drug-associated blood dyscrasias, chlorpromazine was the most frequent sole cause of agranulocytosis. Phenothiazines other than chlorpromazine have been implicated in agranulocytosis [ 74-771. Most of these cases of agranulocytosis occurred in elderly (over fifty years old) women (80 per cent) who received the drug from one to ten weeks [ 7,6,74,78]. Chlorpromazine, given in doses as low as 75 mg. per day [S], has been reported to cause agranulocytosis. Up to one third of the patients died [7], and the incidence increased when liver damage was evident [ 791. The mechanism of phenothiazine agranulocytosis is not clear. Long-term studies of patients receiving protracted high dosages of phenothiazine [6] showed no evidence of cumulative hematologic or hepatic toxicity even after many years of administration. A direct toxic effect on marrow in the manner of the antineoplastic agents is unlikely. Pisciotta and associates [ 78,20-Z?], using tritium-labeled thymidine incorporation by marrow, found inhibition of nucleic acid synthesis in the marrow by phenothiazine. These in vitro studies employed concentrations much in excess over therapeutic levels. In addition, the inhibitory effect was not observed in phenothiazine-sensitive patients whose marrows were studied before and after the oral administration of chlorpromazine. Nevertheless, the in vitro studies did show greater inhibition of marrow granulocyte deoxyribonucleic acid turnover in those with prior episodes of chlorpromazine agranulocytosis than in randomly selected mental patients. Consistent failure to re-induce agranulocytosis with small amounts of the drug [74] argued against an antigen-antibody type of agranulocytosis exemplified by amidopyrine sensitivity [23]. Pisciotta was unable to demonstrate leukoagglutinins in any of his patients, however, Hoffman et al. [24] found one example, but in low titer (1: 16). Pisciotta et al. [78] treated two patients with phenothiazine one year after their recovery from agranulocytosis. In one patient agranulocytosis did not recur despite one year of continuous therapy; in the other it did reappear after 5 gm. of chlorpromazine was given in twenty-one days (compared to 19 gm. over 121 days required for the initial episode of agranulocytosis). Pollack [25] and Platzer and Glaser [26] each reported that readministration of chlorpromazine more than six months after recovery from agranulocytosis resulted in the reappearance of agranulocytosis after only ten

Monocytosis

in Chlorpromazine

to thirteen days of therapy whereas the initial episode occurred after two months of therapy. The lesser amounts and briefer courses required on repeat administration suggest an anamnestic response. An immunologic mechanism for chlorpromazine agranulocytosis has not been ruled out. Phenothiazine agranulocytosis usually produces leukopenia with peripheral blood and marrow lymphocytosis [78]. In this patient, however, granulocyte and erythrocyte depletion resulted in a monocytic proliferation. The initially low gamma globulin level correlates well with the absence or depression of the usual with impaired gamma lymphoid response, globulin production. In addition, in no previous case was leukocytosis (except in recovery with an “overshoot”) reported. Monocytes increased only slightly (to 700 and 1,100 per cu. mm.) in two of sixteen cases reported by Pisciotta et al. [78]. Monocytosis usually appeared only in the recovery phase of agranulocytosis, not in the inception of the illness as in the present case. The favorable prognostic significance of a relative monocytosis was noted by Rosenthal in 1932 [27]. He separated this variety of agranulocytosis into a special category which he termed “leukopenic infectious monocytosis.” A recently reported case in a hospital radiology technician [28] was presented as an example of this entity. It is doubtful that a well defined clinical entity of this kind exists. The eight patients discussed by Rosenthal were a heterogeneous group. Two probably had hepatitis, two had arsenical toxicity and one had received prior radiotherapy. It is more likely that the response to leukopenia of differing etiologies may include (rarely) a variable degree of monocytosis. In this instance the temporal relationships strongly suggest that a chlorpromazine-induced agranulocytosis was responsible for this patient’s clinical picture. Definite proof, through readministration of the drug, was not attempted. The occurrence of acute leukemia and agranulocytosis within a year and a half in the same patient suggests an interrelationship. Three possible explanations are (I) coincidence; (2) initial occult leukemia that remitted coincidentally with drug withdrawal or infection; and (3) the agranulocytosis predisposed to the development of acute leukemia. Although none of the three alternatives can be excluded definitely, the probability of two such rare dyscrasias appearing coincidentally is small. Remission in an occult leukemia could have been in response VOL.

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to infection, to drug-induced marrow depression or to blood transfusions. Remissions in acute leukemia with exchange [29] or simple [30] blood transfusions have been reported, but they are usually incomplete and of short duration (less than six months). Spontaneous remissions have occurred in the natural history of acute leukemia, are frequently preceded by- severe infections, leukopenia and marrow hypoplasia [37], and are of short duration [32]. Against the presence of leukemia initially is the fact that several marrow examinations at the time of the acute illness and during recovery from agranulocytosis failed to show an increased number of blast cells. Analogous to the present patient was Bassen and Kohn’s [33] patient, a nineteen month old girl who presented with three separate episodes of aplastic anemia with complete remissions each time (over an eleven month period) before marrow aspiration revealed acute leukemia. An aplastic marrow with islands of leukemic cells was found postmortem. Bassen and Kohn concluded that leukemia was present initially and that the early impression of pyramidon-induced aplasia was incorrect. Dameshek and Gunz [34], speculating on the interrelationship between agranulocytosis and the later development of leukemia, favored the likelihood of a pre-existing acute leukemia. Marrow hypoplasia may appear in acute leukemia, and occult foci may elude even multiple marrow aspirations. Nevertheless, the possibility of an etiologic relationship between the occurrence of agranulocytosis of diverse causes and acute leukemia is not removed. In addition, in all the examples of the “preleukemic state” described by Block et al. [35] abnormalities of peripheral blood and of bone marrow and/or clinical symptoms were continuously present. In contrast, the present patient was entirely well, with normal blood studies for eighteen months before acute leukemia became evident. Freireich et al. [36] noted a chromosomal deletion in three patients with refractory anemia; in two of these acute leukemia developed later. Rowley et al. [37] noted a similar chromosomal defect in a patient with aplastic anemia secondary to chloramphenicol therapy and observed that a variety of hematologic disorders are now recognized as potential leukemic syndromes. It is possible that marrow injury may produce an altered genome and eventuate in acute leukemia. Acknowledgment: John E. Ultmann

I would like to thank Dr. for his helpful criticisms of

476

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this paper and Dr. John deKiewiet and Mrs. Florence Lefcourt for their help in the preparation of the manuscript. REFERENCES

1. HOLLISTER, L. E. Complications from the use of tranquilizing drugs. New England J. Med., 257: 170,1957. 2. CAIRNS, R. J., CAPOORE, H. S. and GREGORY, I. D. R. Oculocutaneous changes after years on high doses of chlorpromazine. Lancet, 1: 239, 1965. 3. HAYS, G. B., LYLE, C. B. and WHEELER, C. E., JR. Slate-grey color in patients receiving chlorpromazine. Arch. Dermat., 90: 471, 1964. 4. ZELICKSON,A. S. and ZELLER, H. C. A new and unusual reaction to chlorpromazine. J.A.M.A., 188: 394, 1964. 5. MASSEY, L. W. C. Skin pigmentation, cornea1 and lens opacities with prolonged chlorpromazine treatment. Cannd. M. A. J., 92: 186, 1965. ten years’ experi6. AYD, F. J., JR. Chlorpromazine: ence. J.A.M.A., 184: 51, 1963. 7. GRUBER, L. N., CHAPMAN, W. and PRATT-THOMAS, H. R. Fatal toxic reaction to chlorpromazine (Thorazine@). Case report and brief review of literature. J. South Carolina M. A., 59: 203, 1963. 8. TASKER, J. R. Fatal agranulocytosis during treatment with chlorpromazine. &it. M. J., 1: 950, 1955. 9. SINN, C. W. and DICK, F. W. Monocytic leukemia. Am. J. Med., 20: 588, 1956. 10. MALDONADO,J. E. and HANLON,D. G. Monocytosis: a current appraisal. Proc. Mayo Clin., 40: 248,1965. p. 262. 11. WINTROBE, M. M. Clinical Hematology, Philadelphia, 1961. Lea & Febiger. and agranulocytosis. 12. LOMAS, J. Chlorpromazine Brit. M. J., 2: 358, 1954. 13. BEST, W. R. Drug-associated blood dyscrasias: recent addition to the Registry. J.A.M.A., 185: 286, 1963. 14. KORST, D. R. Agranulocytosis caused by phenothiazine derivatives. J.A.M.A., 170: 2076, 1959. 15. MCFARLAND, R. B. Fatal drug reaction associated with prochlorperazine (Compazine). Report of a case characterized by jaundice, thrombocytopenia and agranulocytosis. Am. J. Clin. Path., 40: 284, 1963. 16. BRACHMAN,P. S., MCCREARY, T. W. and FLORENCE, R. Agranulocytosis induced by Trimeprazine. New England J. Med., 260: 378, 1959. 17. WOODWARD, D. J. and SOLOMON, J. D. Fatal agranulocytosis occurring during promazine (Sparine) therapy. J.A.M.A., 162: 1308, 1956. 18. PISCIOTTA,A. V., EBBE, S., LENNON,E. J., METZGER, G. 0. and MADISON, F. W. Agranulocytosis following administration of phenothiazine derivatives. Am. J. Med., 25: 210, 1958. 19. SCHICK,G. and VIRKS, J. Agranulocytosis associated with chlorpromazine therapy. Report of a case and review of the literature. New England J. Med., 255: 798, 1956. 20. PISCIOTTA, A. V. and KALDAHL, J. Studies on agranulocytosis. IV. Effects of chlorpromazine on nucleic acid synthesis of bone marrow cells in vitro. Blood, 20: 364, 1962.

Agranulocytosis-Cussileth 21. PISCIOT.TA,A. V., SANTOS, A. S. andjKELLER, C. Studies on agranulocytosis. v. Patterns of recovery from drug-induced bone marrow damage. J. Lab. & Clin. Med., 63: 445, 1964. 22. PISCIOTTA, A. V. Studies on agranulocytosis. VII. Limited proliferative potential of CPZ-sensitive patients. J. Lab. & Clin. Med., 65: 240, 1965. 23. DAMESHEK,W. and COLMES,A. The effect of drugs in the production of agranulocytosis with particular reference to amidopyrine hypersensitivity. J. Clin. Invest., 15: 85, 1936. 24. HOFFMAN,G. C., HEWLETT, J. S. and GARZON, F. L. A drug-specific leuco-agglutinin in a fatal case of agranulocytosis due to chlorpromazine. J. Clin. Path., 16: 232, 1963. 25. POLLACK,B. Recurrent thorazine-induced agranulocytosis. Am. J. Psych&., 113: 557, 1956. 26. PLATZER, R. F. and GLASER, G. Agranulocytosis due to chlorpromazine. New York J. Med., 57: 1424, 1957. 27. ROSENTHAL,N. Leucopenic infectious monocytosis. (A benign form of agranulocytosis). In: Libman Anniversary Volumes, vol. 3, p. 1003. New York, 1932. The International Universities Press, Inc. 28. STONE, G. E. and REDMOND,A. J. Leukopenic infectious monocytosis. Report of a case closely simulating acute monocytic leukemia. Am. J. Med., 34: 541, 1963. 29. BESSIS, M. C. and DAUSSET, J. l%tude critique des remissions au tours des leu&mies aigues trait&s par exsanguino-transfusions (comparaison avec les &missions spontanCes et celles induites par les antagonistes de l’acide folique). Rev. himat., 5: 188, 1950. 30. LEREBOULLET, J., PLUVINAGE, R. and CATHALA, H.-P. Cryptoleucose aigue traitte par des transfusions rCpttCes. R&mission clinique et htmatologique prolongte. Bull. et mim. Sot. mtd. h6p. Paris, 65: 518, 1949. 31. DIAMOND,L. K. and LUHBY, A. L. Pattern of “spontaneous” remissions in leukemia of childhood observed in 26 of 300 cases. (Abstract.) Am. J. Med., 10: 238, 1951. 32. TIVEY, H. The natural history of untreated acute leukemia. Ann. New York Acad. SC., 60: 322, 1954. 33. BASSEN,F. A. and KOHN, J. L. Multiple spontaneous remissions in a child with acute leukemia. Occurrence of agranulocytosis and aplastic anemia in acute leukemia and their relationship to remissions. Blood, 7: 37, 1952. 34. DAMESHEK,W. and GUNZ, F. Leukemia, pp. 57, 97. New York, 1964. Grune & Stratton, Inc. 35. BLOCK, M., JACOBSON,L. 0. and BETHARD, E. F. Pre-leukemic acute human leukemia. J.A.M.A., 152: 1018, 1953. 36. FREIREICH, E. J., WHANG, J., TJIO, J. H., LEVIN, R. H., BRITTIN,G. M. and FREI, E., III. Refractory anemia, granulocytic hyperplasia of bone marrow, and a missing chromosome in marrow cells. A new clinical syndrome? (Abstract.) Clin. Res., 12: 284, 1964. 37. ROWLEY, J. D., BLAISDELL, R. K. and JACOBSON, L. 0. Chromosome studies in pre-leukemia. I. Aneuploidy of group C chromosomes in three patients. Blood, 27: 782, 1966. AMERICAN

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