Prolonged survival in chronic lymphocytic leukemia: A case report

Medical and Pediatric Oncology 6:47-50 ( 1 9 7 9 )

Prolonged Survival in Chronic Lymphocytic Leukemia: A Case Report Colonel Ralph D. Reynolds, USAF, MC, Major McDonald K. Horne I I I,USAF, MC, Bernard R. Greenberg, MD, Malcolm R. MacKenzie, MD, Henry J. Binder, MD, R. Shihman Chang, MD, and John H. Lawrence, MD Hematology Oncology Service, David Grant Medical Center, Travis Air Force Base, California (R.D. R., M. K.H.); School of Medicine, University of California at Davis (R.D. R., B.R.G., M.R.M., R.S.C.); Yale University Schoolof Medicine, New Haven (H.J.B.), and Donner Laboratory of Medical Physics, University of California at Berkeley (J.H. L.)

A patient with long-standing chronic lymphocytic leukemia with both humoral and cellular immunodeficiency had lymph node receptor evidence of a B lymphocyte disorder. He was also found to secrete the Epstein-Barr virus.and, late in his illness, developed a markedly positive antinuclear antibody. Interrelationship of these findings may be important in the ultimate determination of the etiology and functional mechanisms in lymphocyte malignancies. Key words: chronic lymphocytic leukemia, cancer, virus, immunity, second tumors, complications

INTRODUCTION

Chronic lymphocytic leukemia is usually characterized by a progressive accumulation of immunologically incompetent lymphocytes, but the presentation and clinical course may be quite variable [l-111 . Herein is reported a patient with a lymphoproliferative disease of 38 years duration whose clinical course was associated with a decreasing marrow and circulating lymphocyte tumor load, immunologic incompetence involving both the humoral and cellular systems, progressive neurologic deterioration, a predominance of lymphocytes with Fc receptors, severe diarrhea, multiple skin cancers, positive antinuclear antibody, and secretion of the Epstein-Barr virus.

Dr. Horne is now at the Department of Medicine, Wadley Institutes of Molecular Medicine, 9000 Harry Hines Boulevard, Dallas, Texas. Address reprints requests to Colonel Ralph D. Reynolds, Chief, Hematology Oncology Service, (SGHMCO), David Grant Medical Center, Travis AFB, CA 94535.

0098-1532/79/0601-0047$01.10 0 1979 Alan R. Liss, Inc.

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CASE HISTORY

The patient, a 35-year-old white male seaman, was diagnosed as having chronic lymphocytic leukemia in October 1936. The diagnosis was based on minimal cervical adenopathy, peripheral white blood count 22,7OO/cu mm with 95% lymphocytes and marrow lymphocytosis (Table I). The white blood count rose to 52,OOO/cu mm four years later and the hemoglobin fell to 50% (approximately 8 gm/100 ml). He received 10 mCi 32Pin 1942. Later that year his w h t e count was 7,85O/cu mm with 54%lymphocytes and hemoglobin 7 1% (10 gm/100 ml). The white blood count gradually increased to 25 ,OOO/ cu mm in 1959, at which time the differential consisted of 90% lymphocytes, hemoglobin 13.5 gm/100 ml, platelets 360,OOO/cu mm, and 84% lymphocytes on stained smears of the marrow aspirate. The total white blood count became normal in 1967 and remained normal thereafter. The number of marrow lymphocytes was also noted to be decreased. Mild to moderate thrombocytopenia, first detected in 1942, continued to be documented but bleeding never became a problem. The cervical adenopathy, noted at the time of diagnosis in 1936, remained minimal and unchanged until 1946, when enlarged epitrochlear nodes developed. These remained small and received no specific therapy. In 1959, the patient developed 3-cm submental and anterior cervical nodes which were treated with 600 rads local external radiation (250 kV). The nodes disappeared until 1963, when the patient developed cervical and axillary adenopathy. He was given 4 mCi ’*P with incomplete resolution of the nodes and therefore was given an additional 5 mCi 32Pin 1966 which was associated with disappearance of the adenopathy. While the peripheral blood, bone marrow, and lymph node manifestations remained under control, he began to have problems with other aspects of his disease.

TABLE I. Representative Blood Counts

WBC Date

(1o3/cu mm)

Lymphocytes

(%I

Marrowb Hemoglobin” Platelets lymphocytes (em/lOo ml) ( 1 03/cu mm) (%I

Oct 1936

22.7

95

10.0

-

Nov 1936 Mar 1937

42.0 21 .o

95 92

7.5 8.5

-

Sep 1940 Oct 1942 Oct 1946 May 1952 Oct 1959 Apr 1963 Jan 1966 Aug 1967 Jan 1969 Jul 1970 Sep 1974 May 1975

52.0 7.9 10.6 13.4 25.0 10.7 11.2 6.6 9.0 7.0 7.6 5.4

93 54 82 92 90 63 50 43 48 49 35 39

9.0 10.6 13.0 11.3 13.5 15.0 15.3 14.3 14.6 15.2 13.2 13.6

-

-

124 193 214 36 0 93 96 310 60 118 84 142

aVaIues in percentage transposed to approximate value in gm/lOO ml. bPercentage of total nucleated cells. ‘RT) Radiation therapy

80

Therapy Fowler’s solution -

~

Liver extract

~

-

45 68 82 84 74 -

-

10 mCi 3

2 ~

~

Local R T ~ 4 mCi ’ZP 5 mcij2P

60

-

-

Local R T ~

35 20

~

-

Chronic Lymphocytic Leukemia

49

Between 1960 and 1966 he was hospitalized 23 times for bacterial pneumonia, sepsis, or sinusitis. A submucous resection in 1963 showed infiltration of small lymphocytes. In 1966, he developed watery diarrhea, with 14 stools daily. He was found to have hypogammaglobulinemia (0.10 gm/100 ml), absent serum IgM, and a low serum IgA (10 mg/ 100 ml). He was successfully managed with monthly infusions of fresh frozen plasma as reported elsewhere [ 121 . Diffuse skin infiltrations over his entire body first appeared in 1967 and persisted throughout the remainder of his life. Because of hoarseness, laryngoscopy was performed in 1967 and leukemic infiltrations were found in the laryngeal biopsy specimen. Examination of the specimen obtained from transurethral resection of the prostate in 1973 showed benign glandular hyperplasia and nodular lymphocytic infiltration. Four squamous and two basal cell skin cancers were excised between 1961 and 1974. Skin testing of delayed hypersensitivity antigens prior to 1968 had shown reactivity to mumps, trichophyton, first-strength PPD, and coccidioidin. The coccidioidin, intermediate PPD, and second-strength PPD became negative in 1968, and the mumps and trichophyton skin tests became negative in 1972. Immunization with BCG, typhoid, rubella, influenza and polio failed to result in either conversion of the PPD or in serum titer elevations of the other antigens. In spite of repeated streptococcal infections, including facial erysipelas, there was no elevation in the AS0 or CRP titers. The SK-SD skin test also remained negative. In 1974, antinuclear antibody (ANA) test showed a 4+ nucleolar pattern and the LE prep was positive. Throat washings collected in May 1973 were found to contain the leukocyte transforming agent which is believed to be identical to or closely associated with the EpsteinBarr virus [13, 141. In April 1974, the patient had a grand ma1 seizure, and subsequent evaluation revealed weakness of lower extremities, anisocoria, dysequilibrium with changes in posture and bilateral hypesthesia of the first division of the fifth cranial nerve. In 1968, he developed dysphagia and aspirated during a barium swallow. Severe neurosensory hearing loss appeared suddenly in 1972. The weakness became progressive until the patient was unable to walk. In 1973, he was reported to have bizarre behavior, including mental confusion, inappropriate activities, insomnia, blurred vision, slurred speech, progressive memory loss, irritability, and lethargy. Examination in 1974 revealed muscle weakness in the lower extremities and diplopia. Multifocal leukoencephalopathy was considered to be a possible etiology for his progressive neurologic deterioration. In 1975, he was found to have bulbar palsy, disorientation, left hemiparesis, and further weakening of the lower extremities. A feeding tube was inserted but the patient died in a nursing home at the age of 74, several days after his discharge from the hospital. His death was attributed to aspiration pneumonia. No autopsy was obtained.

DISCUSSION

This patient had chronic lymphocytic leukemia established at the relatively young age of 35. The bone marrow showed a large percentage of small mature lymphocytes for several years, but eventually became less involved. He received a total of 19 mCi 32Pand two courses of local radiotherapy to enlarged cervical nodes as the only specific therapy for his illness. In spite of the frequently indolent nature of this disease, very few survivors exceeding 25 years have been reported. Marlow et a1 [15] reported a patient who lived 28 years.

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Reynoldset al

Rai et a1 [ l l ] included one that lived 32 years and Pisciotta et a1 [ 161 described a patient who lived for 35 years. Our patient lived nearly 39 years. During the last ten years of his illness, the patient developed progressive neurologic deterioration that eventually led to his death. Multifocal leukoencephalopathy remains a possible explanation for this aspect of his course, but is is unusual for such a problem to exist for longer than one year [4, 171. The etiology of the thrombocytopenia remains speculative. Concomitant idiopathic thrombocytopenic purpura has been found to be associated with chronic lymphocytic leukemia [ 181 . This patient lived longer than any previously reported person with chronic lymphocytic leukemia. His disease was characterized by decreasing blood and marrow manifestations while other tissue involvement increased. The transition from chronic lymphocytic leukemia to welldifferentiated lymphocytic lymphoma is less often encountered than is the opposite transition. Other manifestations such as hypogammaglobulinemia, increased susceptibility to infections, decreased cellular immune response, and the development of multiple skin carcinomas continued to appear. ACKNOWLEDGMENTS

The authors wish to acknowledge the assistance of Dr. Jack English, MSgt. Jack Krause, Mr. Ken Snyder, Mrs. Millie Pricer, and Mrs. Alethea McClain for technical assistance. REFERENCES 1. Boggs DR, Sofferman SA, Wintrobe MM, Cdrtwright GE: Factors influencing the duration of survival of patients with chronic lymphocytic leukemia. Am J Med 40:243-254,1966. 2. Green RA, Divon H: Expectancy for life in chronic lymphatic leukemia. Blood 25:23-30, 1965, 3. Aisenberg AC, Long JC: Lymphocytic surface characteristics in malignant lymphoma. Am J Med 58:300-306,1975, 4. Castleman B, Scully RE, McNeely BU: Case records of the Massachusetts General Hospital. N Engl J Med 286:1047-1054,1972. 5. Manusow D, Weinerman BH: Subsequent neoplasia in chronic lymphocytic leukemia. JAMA

232~267-269,1975. 6. Marchalonis JJ: Lymphocyte surface immunoglobulins. Science 190:20-29,1975. 7. Preud’homme JL, Seligmann M: Surface bound immunoglobulins as a cell marker in human lymphoproliferative diseases. Blood 40:777-792, 1972. 8. Rowlande DT, Daniels RP, Nowell PC, Wurzel HA: Characterization of subpopulations in chronic lymphocytic leukemia. Cancer 34:1962-1970,1974. 9. Gray JL, Jacobs A, Block M: Bone marrow and peripheral blood lymphocytosis in the prognosis of chronic lymphocytic leukemia. Cancer 33:1169-1178, 1974. 10. Peterson LC, Bloomfield CD, Sunberg RD, Gajl-Peczalska KJ, Brunning RD: Morphology of chronic lymphocytic leukemia and its relationship to survival. Am J Med 59:316-324, 1975. 11. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234,1975. 12. Binder HJ, Reynolds RD: Control of diarrhea in secondary hypogammaglobulinemia by fresh plasma infusions. N Engl J Med 277:802-$03, 1967. 13. Chang RS, Lewis JP, Abildgaard CF: Prevalence of oropharyngeal excreters of leukocytetransforming agents among a human population. N Engl J Med 289:1325-1329, 1973. 14. Miller G, Niederman JC, Andrews LL: Prolonged oropharyngeal excretion of Epstein-Barr virus after infectious mononucleosis. N Engl J Med 288:229-232, 1973. 15. Marlow GR, Bartlett CR: Survival for twenty-nine years in chronic lymphocytic leukemia. JAMA 152~1033-1035,1953. 16. Pisciotta AV, Hirshboeck JS: Therapeutic considerations in chronic lymphocytic leukemia. Arch Intern Med 99:334-345, 1957. 17. Rubinstein LJ, Hermen MM, Long TF, Wilbur JH: Disseminated necrotizing leukoencephalopathy: Complication of treated central nervous system leukemia and lymphoma. Cancer 35:291-305, 1975. 18. Carey RW, McGinnis A, Jacobson BM, Carvalho A: Idiopathic thrombocytopenia purpura complicating chronic lymphocytic leukemia. Arch Intern Med 136:62-66, 1976.