A Case of Leukemic Reticuloendotheliosis Responding to Oxymetholone

STEPHEN E. FEFFER, MD,’ DAVID W. WESTRING, MD,t ANTONIO C. LEE, MD, AND JEN H. LIN, MD*

A 63-year-old man presented with fever, easy bruisability, splenomegaly and pancytopenia. Bone marrow aspiration was unsuccessful, and marrow biopsy revealed crowding by sheets of mononuclear cells; a diagnosis of leukemic reticuloendotheliosis (LRE) was made and the patient underwent splenectomy. There was no hematologic improvement, and the patient continued to have a significant requirement for erythrocytes and platelet transfusions. Within two months of beginning oxymetholone therapy (50 mg orally three times a day) the patient’s platelet count had normalized, followed by improved erythrocyte and leukocyte counts. When the drug was discontinued, the peripheral blood counts deteriorated dras- tically; he again demonstrated hematologic improvement when oxymetholone therapy was reinstated. We feel that by demonstrating a hematologic response to oxymetholone, relapse when it was withdrawn, and another remission upon readministration, that we have provided stronger evidence than previously reported for the efficacy of this drug in LRE.

Cancer 50:396-400, 1982.

EUKEMIC RETICULOENDOTHELIOSIS (LRE; Hairy L cell leukemia) is a distinct neoplastic disorder of the hematopoietic system characterized by a chronic course, splenomegaly without substantial lymphade- nopathy, and by several laboratory features which usu- ally provide the diagnosis. These include pancytopenia, abnormal circulating mononuclear cells with cytoplas- mic projections (hairy cells) and tartrate-resistant acid phosphatase staining, and typical histopathologic ap- pearance of the bone marrow and spleen.

LRE has a chronic and variable course.‘.’ Treatment sometimes is not necessary for months or years. Bou- runcle’ has documented spontaneous remission in one patient. When treatment is required, splenectomy is considered the most beneficial form of therapy, espe- cially in those patients with massive splenomegaly and hypersplenism. Chemotherapy has achieved little suc- cess,’ 3*6 although Davis et reported prolonged re-

From the Departments of Medicine and Pathology, Nassau County Medical Center, East Meadow, New York.

Assistant Professor of Medicine, State University of New York, Stony Brook, New York.

t Associate Professor of Medicine, State University of New York, Stony Brook, New York.

$ Clinical Assistant Professor of Pathology, State University of New York, Stony Brook, New York.

Address for reprints: Stephen E. Fefier, MD, Division of Hema- tology and Medical Oncology, Nassau County Medical Center, 2201 Hempstead Turnpike, East Meadow, N Y 11554.

The authors thank Ethel Ford for her assistance in preparing this manuscript.

Accepted for publication May 26, 198 I .

mission in a patient treated with cyclophosphamide and cytosine arabinoside.

Isolated reports of androgen therapy for this dis- ease9 ” prompted us to give oyxmetholone to a patient who had not responded to all other measures. In this report we describe the apparent response of this patient to androgen therapy, on two separate occasions, after failure of splenectomy and chemotherapy to raise the peripheral blood counts.

Case Reports

A 63-year-old man experienced easy fatigability and mild exertional dyspnea in I977 but did not seek medical attention until January 1978 when he developed fever, chills, easy bruis- ability, and increasing weakness and dyspnea. He was admit- ted to another hospital where petechiae, retinal hemorrhages and mild splenomegaly were found. No hepatomegaly or ad- enopathy were noted. The hemoglobin was 6.0 g/dl, hema- tocrit was 18%, and the leukocyte 1.2 X 106/1, with 12% seg- mented cells, 2% monocytes and 84% lymphocytes. Ten to 20% of the lymphocytes were reported as “atypical.” The platelet count was 10.0 X 109/l. Three attempts a t bone mar- row aspiration were unsuccessful. A biopsy revealed scanty hematopoietic precursors crowded by sheets of mononuclear cells expanding the bone marrow stroma. These cells showed moderately scanty cytoplasm with indistinct cellular borders (Fig. 1 ) . A diagnosis of LRE was entertained and a two-week trial of vincristine 2 mg intravenously ( IV) weekly, with pred- nisone 30 mg orally daily was started. The patient was sup- ported with antibiotics and erythrocytes and platelet trans- fusions but the counts did not improve.

0008-543X/82/080l/0396 $0.75 0 American Cancer Society

396

No. 3 LRE RESPONDING TO OXYMErHOLONt * Fefler et a/. 397

FIG. 1 . The hypercellular marrow (90-100% cellularity) is diffusely infiltrated by leukemic cells and is practically devoid of hematopoietic cells (PAS, original magnification X 1600).

The patient was transferred to Nassau County Medical Center on February 12, 1978 for splenectomy. His course is shown in Figure 2. Examination at that time revealed extensive petechiae and ecchymoses. The temperature was 38.3"C and the spleen was palpable four cm below the rib margin. The hematocrit was 27%. the leukocytes 1.9 X 106/1, with 81% lymphocytes and 15% granulocytes. Platelet count was 29 X 109/1 and the reticulocyte count was 0.2%. Splenectomy was performed on February 16, 1978. Spleen weight was 640 g . Sections revealed dilated sinuses and red pulp architecture obliteration by mononuclear cell infiltrates resulting in a marked widening of the pulp cords. Splenic imprints revealed mononuclear cells which stained with tartrate-resistant acid phosphatase. Electron microscopy showed syncytial mononu- clear cells, diffusely infiltrating pulp cords, and frequently seen in the sinuses. The relatively rich cytoplasm contained mod- erate amounts of cytoplasmic organelles-mitochondria, rough endoplasmic reticulum, free ribosomes and Golgi complexes, with occasional lyosomes. No ribosomal lamellar complexes were seen. The cells were mostly tightly arranged and showed complex interdigitations in some areas. Occasional loose, short cytoplasmic extensions were seen in subsinusal regions. Ke- covery from splencctomy was complicated by pneumonia. Pan-

cytopenia persisted for three weeks after surgery when a splenic scan revealed no excessory spleen. A course of v in- cristine, 2 mg IV weekly with bleomycin 20 mg intramuscu- larly ( IM) two times weekly and prednisone 60 mg orally daily for five days every three weeks, was initiated but discontinued after two cycles when the patient demonstrated no objective evidence of improvement.

In March 1978, the patient was found to have fever of 38.9"C accompanied by severe low back pain. Neurologic ex- amination revealed significant paresis of both lower extremi- ties without any sensory level. X-rays of the region, bone scan and myelogram all failed to reveal any abnormality consistent with the clinical findings. A neurologist considered peripheral nruropathy as the best explanation for his disability.

From March 1978 to July 1978 he was admitted at three to four week intervals for blood transfusion. I n late May, ox- ymetholone 50 mg three times a day was started. Transfusion requirements fell i n June and his last blood transfusion was given in July. The last platelet transfusion was administered in June; by mid-July his platelet count was 233 X 109/l. At that time hemoglobin was 8.9 g/dl, hernatocrit 25.2%, leu- kocyte count 2.3 X 106/1 with 72% lymphocytes (890 atypical) and 15% granulocytes. A bone marrow biopsy performed in

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OXYMETHOLONE -1 FIG. 2. Hematologic values of patient prior to and during oxymetholone therapy.

FIG. 3. At six months after splenectomy, and two months after beginning oxymetholone therapy, bone marrow biopsy reveals 80% cellularity. More than two-thirds of the marrow is infiltrated by leukemic cells. However, there are clusters of normoblasts. granulocytic precursors and scattered megakaryocytes (Giemsa, original magnification X2500).

No. 3 LRE RESPONDING TO OXYMETHOLONE * Fefleer et al. 399

TABLE 1. Summary of Therapy in LRE Patients Given Androgens _____

Prior chemotherapy Androgens Cases Prior

reported - Age Sex splenectomy Response Drugs Response Drugs Response

Lusch er a / , ' ' 42 M Yes Yes 1. CTX + VCR Yes I . FM I . No

2. Bleomycin Yes 2. OM 2. Yes

I . EtP 1. Yes 2. ND 2. Yes

None reported 1. FM 1. Yes - 2. MT 2. Yes

+ Prednisone

Besa er a/."' 48 M Yes ? None reported -

Gardner' 80 M N o -

69 M No None reported 1. MT Erythroid only -

- 2. TCPP

FeKer el al. 63 M Yes N o I . VCR + Prednisone 1. No OM Yes (current 2. Bleomycin + Prednisone 2. No study) + VCR

TCPP: testosterone cycle pentyl propionate; MT: methyl testoster- one; FM: fluoxyniesterone; OM: oxymetholone; EtP: etiocholanolone

and prednisone; ND: nandrolone decanoate; CTX: cyclophosphamide; VCR: vincristine.

July was similar to those of the previous winter, with sheets of mononuclear cells constituting 80-90% of the marrow ele- ments; however, this specimen revealed isolated islands of he- matopoietic h u e not seen in the previous sample (Fig. 3). By November 18, 1978 the hemoglobin had risen 11.9 g/dl, hematocrit 32.8% with a leukocyte of 5.1 X 106/1. At this point oxymetholone was withdrawn in spite of continued abnormal mononuclear cells i n the blood and marrow to determine if spontaneous remission had occurred. The patient was noted in late December, 1978 to have numerous petechiae; CBC revealed hematocrit 24, polys 700, platelets 16,000. At this point oxymetholone was resumed and hematologic values again rose until the platelet count was normal on April 3, 1979, although modest anemia and granulocytopenia per- sisted. On a physical therapy program, the strength i n his lower extremities improved to the point where he was able to ambulate unassisted.

In mid-July, 1979, (6% months after the reinstitution of oxymetholone therapy) the patient had again developed severe anemia and granulocytopenia, although his platelet count re- mained within normal limits. Approximately two months later, the patient was admitted because of temperature of 40.0"C and rapidly succumbed to overwhelming infection.

Discussion

Isolated reports of androgen therapy of LRE suggest it is effective. These are summarized with our case in Table 1. Gardner and Pringle' reported improved eryth- rocyte counts and disappearance of abnormal cells from the blood smear in a patient treated with fluoroxymes- terone. Besa et ~ 1 . ' ' described a dramatic improvement in peripheral blood counts in a patient with prior sple- nectomy treated with etiocholanolone (a nonvirilizing metabolite of testosterone) and prednisone acetate. More recently, Lusch et al. ' I observed peripheral he- matologic recovery in a patient treated for four months with oxymetholone, although bone marrow studies re-

vealed persistent mononuclear cell infiltration. The drug was stopped because of the appearance of abnormal liver function tests. Our patient responded to oxymeth- olone in the peripheral blood, relapsed when oxymeth- olone was discontinued, and responded again to the rein- stitution of oxymetholone. Bone marrow did not normalize at any time.

Recent identification of this disorder, its relative in- frequency and its chronic course have impaired our understanding of its natural history. There are no con- trolled studies to demonstrate that any therapy has a real effect on outcome. Median survival has not been accurately determined.

Certain patterns have emerged as experience with the disease increases. There is wide agreement that sple- nectomy has a favorable influence on the course when leukopenia is present. There is also agreement that che- motherapy is not the treatment of choice, but may offer benefit when the disease is refractory, as was demon- strated in a paper by Golomb et a1.,'* describing four patients achieving lengthy remission after low dose long-term therapy with chlorambucil.

We review here the very limited reported experience with androgen therapy and suggest a pattern is evident. It includes the following measures: ( 1 ) responses to an- drogen therapy are apparent in the peripheral blood, but do not induce bone marrow remission; (2) trans- fusion requirements, susceptibility to infection and thrombocytopenia may be favorably affected by andro- gen therapy. A relationship between prior splenectomy and response to androgens is not apparent. There is, at the present time, no adequate evidence to suggest that androgens offer any effect on survival.

We believe that our patient, by demonstrating he- matologic response to androgen therapy, relapse upon its withdrawal, and another remission upon its read-

400 CANCER August I 1982 Vol. 50

ministration, has provided evidence for the efficacy of androgens in this disorder that was lacking in previous anecdotal reports.

In a recent editorial, Bertino13 has called for coop- erative studies to determine the effects of chemotherapy on patients with LRE. We believe that androgen ther- apy merits inclusion in those studies.

References

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2. Burke JS. Byrne GE Jr. Rappaport H. Hairy cell leukemia (leu- kemic reticuloendotheliosis). I : A clinical pathologic study of 21 pa- tients. Cancer 1974; 33:1399-1410.

3. Catovsky D, Pettit JE, Galton D, Spiers A, Harrison C. Leu- kemic reticuloendotheliosis (hairy cell leukemia): A distinct clinico- pathological entity. Br J Haematology 1974: 26:9-27.

4. Catovsky D. Hairy-cell leukemia and prolymphocytic leukemia. Clin Haematol 1977: 6:245-268.

5. Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia. Annals Inr Med 1978; 89:677-683.

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