B.G. Kennedy, MD
Abstract
ANEMIA may occur during the course of chronic lymphatic leukemia. The study of erythrokinetics has revealed that the development of this anemia may be due to decreased erythropoiesis with normal or increased red blood cell destruction or loss. There is little understanding of the reason for the failure of leukemic marrow to provide adequate erythro-poiesis. A metabolic competition between develop-ing red blood cells and pathological white cells has been suggested.1 Because of the stimulation of erythropoiesis produced by androgenic hormones, androgens were administered to patients with lym-phatic leukemia.
In patients with advanced breast cancer, andro-genic hormones produced reticulocytosis, normo-blastic hyperplasia of the bone marrow, and an in-crease in hemoglobin even to polycythemic values (Fig l).2,3 Because of these observations, androgens were employed in the treatment of a variety of anemias.3-5 Improvements were noted in aplastic anemia, refractory anemia, myelofibrosis, and vari-ous diseases with erythroid hypoplasia. During a study of the effect of androgenic hormones in malig-nant diseases with depressed marrow function, a striking response in patients with chronic lymphatic leukemia was noted.
Materials
Androgenic hormones were administered to 12 patients with subacute or chronic lymphatic leu-kemia and anemia to improve the hematopoietic function of the bone marrow and as an adjuvant to cancer chemotherapy.
The androgenic hormones employed were fluoxy- mesterone, 20 to 50 mg orally per day, and testosterone enanthate, 400 to 1,800 mg per week intramuscularly in divided doses. A minimum period of effective therapy was regarded to be two months. Adrenal steroids were administered with the androgenic hormone because it has been observed that combined therapy appears to potentiate the stimulation of erythropoiesis.2
Table 1 . Erythropoiesis-stimulating Effect of Androgenic Hormone Therapy in Seven of 12 Patients With Lymphatic Leukemia and Anemia.
Results
Androgenic hormone was administered to nine patients with chronic lymphatic leukemia and three patients with subacute lymphatic leukemia. The major problem in all these patients was an anemia characterized by erythroid hypoplasia of the bone marrow. Hemolysis was excluded as a major cause of the anemia and adrenal steroids had not been effective in its treatment.
A striking increase in erythropoietic activity and a resultant increase in hemoglobin occurred in seven patients (Table). This increased activity resulted in reticulocytosis, an increase in hemoglobin, and a normoblastic hyperplasia of the bone marrow.
Report of a Case
A 44-year-old man had a carcinoma of the left testis removed in 1954. Surgery was followed by irradiation therapy. In 1959 a diagnosis of leukemia was established and repeated courses of irradiation therapy were administered. By January, 1962, there was marked anemia requiring repeated transfusions. In March, 1962, prednisone was begun with no effect.
The patient was first seen at the University of Minnesota Hospitals on April 2, 1962.
The patient was pale. There were enlarged nodes in the cervical, supraclavicular, axillary, and inguinal regions. There was slight hepatomegaly and splenomegaly. Roentgenograms revealed mediastinal and retroperitoneal nodes. The hemoglobin was 6.4 gm% and white blood cell (WCB) count, 10,950 cumm, with 18% neutrophils and 70% mature lymphocytes. The platelet count was 62,000/ cumm and Jess than 0.1% reticulocytes were present. A bone marrow aspiration could not obtain marrow material. A cervical lymph node biopsy and a rib biopsy revealed chronic lymphatic leukemia of the node, marrow, and muscle. The marrow count had 73.6% lymphocytes, 0.6% normoblasts, and 23.2% neutrophils. Stool urobilinogen value was 150 mg per day and the serum iron was 207 7%. During the study the hemoglobin dropped to 4.9 gm%.
The course of the patient is demonstrated in Fig 2. Blood transfusions were administered to maintain the hemoglobin above 8 gm%. Three months after prednisone therapy was begun there was no evidence of improvement. Therefore, testosterone enanthate therapy, 400 mg three times a week intramuscularly, was begun. There was an immediate reticulocytosis to a maximum level of 6.1%. The hemoglobin rapidly increased to a maximum level of 18.2 gm%. The WBC count slowly rose to 92,000/ cu mm. A successful bone marrow aspiration revealed 10.8% normoblasts and 70% lymphocytes. After 4% months of androgen therapy the patient developed a severe epistaxis. The hemoglobin level fell to 14.0 gm%. Because this complication was apparently due to the polycythemia, the androgen and steroid therapy were discontinued. Because of the elevated WBC count, 20 mg of uracil mustard was administered orally for two days. A decrease in the leukocyte count occurred. A second course of uracil mustard three months later produced a further decrease of WBC’s to a low of 13,400/cu mm. The hemoglobin level remained normal for six months after androgen therapy was discontinued. At that time the anemia recurred. Retreatment with testosterone enanthate, prednisone, and cyclophosphamide resulted in a second remission. The patient has continued to receive a maintenance dose of testosterone enanthate, 400 mg every three weeks, and prednisone, 10 mg daily. Two years after initiating androgen therapy the patient is well, with a normal WBC count and hemoglobin level. A bone marrow aspiration revealed 27.5% normoblasts and 65% lymphocytes.
Figure 1. Stimulation of erythropoiesis by testosterone propionate in woman with advanced breast cancer.
The duration of androgen therapy was less than two months in five patients with chronic lymphatic leukemia and in one with subacute lymphatic leu-kemia. Of these, only one patient with chronic lymphatic leukemia had an improvement. In the other five patients, therapy was interrupted because of death due to intercurrent infection. In general, these patients had advanced leukemia.
Figure 2. Effect of testosterone enanthate in 44*year-old patient with chronic lymphatic leukemia and erythroid hypoplasia of bone marrow.
Four patients with chronic lymphatic leukemia and two with subacute lymphatic leukemia were treated more than six months with androgenic hor-mone; all had a significant increase in erythroid ac-tivity (Table). The mean pretreatment level of hemoglobin was 6.9 gm% for the seven patients that improved. The mean of the maximum hemoglobin value was 15.6 gm%, or a mean increase of 8.7 gm%.
Four of the seven patients are still receiving an-drogen therapy, three for more than 24 months. Three patients who had increased erythroid activity died of intercurrent infection.
In all the patients, the initial platelet count was reduced, in some instances limiting the use of spe-cific anti-leukemic therapy. During androgenic hor-mone administration, significant increases of the platelet count occurred in three patients also dem-onstrating an erythroid response (patients 2, 4, and 7), but in one of these the count did not approach normal levels (patient 2). There was no increase in platelet count in the five patients that failed to demonstrate an erythropoietic response.
Four patients with chronic lymphatic leukemia developed leucocytosis or lymphadenopathy after stimulation of erythropoiesis had been demon-strated. The administration of uracil mustard or cyclophosphamide resulted in an objective improvement in all these patients.
Comment
Androgenic hormone therapy was administered to 12 patients with subacute or chronic lymphatic leukemia characterized by erythroid hypoplasia of the bone marrow. In seven patients, a significant increase in erythroid activity occurred, and in four of these, the hemoglobin levels exceeded 16 gm%. It was apparent that a minimum period of at least two months was required to provoke this effect.
Adrenal steroid therapy was administered to some of these patients prior to the use of androgenic hormone. The adrenal steroid alone was ineffective. Whether the adrenal steroid was necessary to evoke the effect in those patients receiving both hormones is not clear, though earlier studies in metastatic breast cancer have suggested that the rate of increase in erythropoiesis and the maximum values attained are greater with combined therapy.2
The improvement in the erythropoietic state of the patients with lymphatic leukemia was associated with increases in WBC counts. That this increase is directly related to the androgenic hormone is not clear, but other observations have suggested that the androgenic hormone may have a stimulating effect on WBC metabolism.6 The increase in the WBC count to abnormally high levels required the administration of anti-leukemic chemotherapy in four patients which was effectively carried out. In three patients an increase of the platelet count towards normal was observed. It could not be ascertained whether this was the result of direct stimulation of the platelets or whether the platelet count rose along with the generalized increased cellularity of the stimulated bone marrow. Since the administration of cytotoxic agents was frequently contraindicated in the presence of an initially hypoplastic marrow, the response to the androgenic hormone was a demonstration of the usefulness of this hormone as an adjuvant to cancer chemotherapy.
It would appear that once the erythropoietic re-sponse from androgen therapy was obtained, the maintenance of therapy at lower doses or less fre-quent intervals is necessary. Three patients have now been treated for more than two years. The slow discontinuance of the adrenal steroid therapy may be possible.
In lymphatic leukemia characterized by erythroid hypoplasia of the bone marrow and anemia, the ad-ministration of androgenic hormone appears to be indicated and it is effective when employed at a massive dose for a prolonged period.
Summary
Twelve patients with subacute or chronic lym-phatic leukemia characterized by erythroid hypo-plasia and anemia were treated with massive doses of androgenic hormone. Increases in erythropoiesis to normal or above normal levels of hemoglobin occurred in seven patients. Maintenance therapy is recommended.
The hematological studies were performed by Miss Kay Newton.
The testosterone enanthate was supplied by the Squibb Institute for Medical Research, Brunswick, New Jersey.
This investigation was supported by Public Health Service research grant CY3143 from the National Cancer Institute, National Institutes of Health, and a grant from the Minnesota Division of the American Cancer Society.
Generic and Trade Names of Drugs
Fluoxymesterone—Halotestin, Ultandren.
Testosterone enanthate—Delatestryl.
Prednisone—Deltrasone, Delta, Meticorten, Paracort.
Chlorambucil—Leukeran.
Cyclophosphamide—Cytoxan.
References
Wintrobe, M.M.: Clinical Hematology, Philadelphia: Lea & Febiger, 1962, p 944.
Kennedy, B.J., and Gilbertsen, S.: Increased Erythropoiesis Induced by Androgenic Hormone Therapy, New Èng J Med 256:719-726, 1957.
Kennedy, B.J.: Stimulation of Erythropoiesis by Androgenic Hormones, Ann Int Med 57:917-936,1962.
Shahidi, N.T., and Diamond, L.K.: Testosterone-Induced Remission in Aplastic Anemia, Amer J Dis Child 98:293-302,1959.
Gardner, F.H., and Pringle, J.C.: Androgens and Erythropoiesis, Arch Intern Med 107:846-862,1961.
Kennedy, B.J.: Unpublished data.