Development of Polycythemia Vera and Chronic Lymphocytic Leukemia During the Course of Refractory Idiopathic

Thrombocytopenic Purpura

GRACE WANG, MD,' YEON S. AHN, MD,t CLARENCE C. WHITCOMB, MD.* AND WILLIAM J. HARRINGTON, MDS

A case in which polycythemia Vera and chronic lymphocytic leukemia (CLL) developed during the course of idiopathic thrombocytopenic purpura (ITP) is described. Observations in this case suggest that ITP was a premonitor of the clinical development of CLL and preceded the manifestation of polycythemia Vera. The polycythemia was mild, requiring infrequent phlebotomies, and, as the CLL progressed, the requirement for phlebotomy diminished. Evidence of both CLL and myeloid proliferation, as well as severe immune thrombocytopenia, persisted throughout her course. Studies on lymphocytes revealed characteristics of those of CLL. Excellent therapeutic response of the CLL was observed with the use of vinblastine and steroids.

Cancer 531770-1776, 1984.

HE ASSOCIATION OF POLYCYTHEMIA VERA and lym- T phocytic neoplasms has been described,'-' but it is rare. Although the association of these disorders may rep- resent mere coincidence, it may also be explained as a proliferative disorder including pluripotent stem cells.

The association of idiopathic thrombocytopenia with lymphocytic neoplasms is also well recognized,'-' but the association of this disorder with polycythemia has not been described previously.

We report here a patient who developed both poly- cythemia Vera and chronic lymphocytic leukemia during the course of long-standing idiopathic thrombocytopenic purpura (ITP).

From the Center for Blood Disease. Departments of Oncology. Med- icine. and Pathology, Medical and Research Service. Veterans Admin- istration Hospital, University of Miami. Miami. Florida.

Supported by grants NIH 1 ROI AM25485 and 5 M01 RR00262 and a Veterans Administration Merit Review Award 02 15-0 1, by the Wom- en's Cancer Association. and by research funds given in memory of Mary Beth Weiss and Kenneth Chasen.

* Assistant Professor of Oncology. t Associate Professor of Medicine. $ Adjunct Assistant Professor of Pathology. 5 Distinguished University Professor. Address for reprints: Grace Wang, MD. Department of Oncology,

University of Miami School of Medicine. PO Box 016960 (D 8-4) Miami, FL 33101.

The authors thank Dr. Adel Yunis and his laboratory for their assistance in performing PHA Stimulation studies and arranging erythropoietin assay.

Accepted for publication January 21, 1983.

Materials and Methods

Blood counts were performed at the special Hematology Laboratory, University of Miami Hospital and Clinics. All platelet counts, leukocyte counts, and differentials were performed manually.

Platelet antibody assay was performed by the method previously described by Dr. William J. Harrington."

Erythropoietin level measurements w'ere performed by bioassay at the laboratory of Dr. A. S. Gordon at New York University.

PHA stimulation was performed at the laboratory of Dr. Adel Yunis at University of Miami.''

Determination of erythrocyte mass was performed by tagging erythrocytes with sodium radiochromate (C?'), and volume determination by an isotope dilution tech- nique utilizing radioiodinated serum albumin

Case Report

A 66-year-old white woman experienced easy bruisability and epistaxis in October 1968. and was found to be thrombocyto- penic. She gave no prior history of upper respiratory infection or use of medications. Her past medical history was unre- markable. Examination revealed only scattered petechiae and ecchymoses. There was no adenopathy or hepatosplenomegaly. Her platelet count was 6000/mm'. Clotting studies were normal, and the ANA test was negative. Bone marrow aspiration revealed increased megakaryocytes, but was otherwise normal. A diagnosis of idiopathic thrombocytopenic purpura was made.

1770

No. 8 P VERA, CLL, A N D ITP IN ONE PATIENT - U'ung et al

Following treatment with prednisone 60 mg daily her platelet count rose to h0,000/nirn3, but then rapidly fell to 8000/mm3. In December 1968. a splenectomy was performed. Histologic examination revealed only fibrocongestive changes without any evidence of lymphoma. Following the splenectomy the platelet count increased only transiently.

In March 1969. she suffered a gastrointestinal hemorrhage complicated by sepsis. Following her recovery, a trial of aza- thioprine 150 mg daily was attempted, but there was no im- provement in the thrombocytopenia. She received no further therapy.

When seen at the University of Miami Hospital and Clinics 1.5 years later, her examination was unremarkable except for multiple ecchymoses and petechiae. Her hemoglobin was 13.5 g/dl. hematocrit 42'10. leukocyte count 19,300/mm3 with a dif- ferential count of 7S% neutrophils, 22% mature lymphocytes. 3'2, monocytes. Platelet count was 8000/mm3. An indirect platelet antibody assay by agglutination method demonstrated 4+ antibodies."' Therapy with cyclophosphamide 50 mg twice daily for 4 months failed to produce any increase in her platelet count. In 1972. intermittent intravenous injections of 2 mg Oncovin (vincristine) were administered, with a transient im- provement of the platelet count. Her clinical and hematologic courses are illustrated in Figures 1A and IB.

In 1974. she presented with lethargy. headache, plethora and severe leg swelling with diffuse ecchymoses on both lower ex- tremities. At this time her hemoglobin was 20. I g/dl, hematocrit 70C;,. leukocyte count 36,200/mm3, with 75% segmented nzu- trophils and 21% lymphocytes. Her platelet count was 37,000/ mm3. Her total blood volume was 5048 ml(96.6 ml/kg), plasma volume. 1630 ml (31.2 ml/kg) and erythrocyte volume was 3418 ml (65.4 ml/kg). Arterial blood gas p02 was 70 mm Hg with a saturation of9270. Serum vitamin BIZ level was elevated at I274 pg/ml and the leukocyte alkaline phosphatase score was 160 (normal, 10-90). The erythropoietin level was 0.03 U/ml in the serum, and was undetectable in the urine. A bone marrow biopsy in April 1975 revealed a hypercellular marrow due to panmyeloid hyperplasia, and a paratrabecular aggregate of lym- phocytes was present ((Fig. 2A). No abnormality was observed in the chromosome study from bone marrow.

A diagnosis of polycythemia Vera was made. Phlebotomy resulted in clinical improvement (Fig. 1A). A repeat bone marrow biopsy in 1977 again demonstrated panmyeloid hyperplasia in juxtaposition to an infiltrate of lymphocytes. In addition reticulin has increased.

The patient's leukocyte count gradually increased to a peak of 350.000/mm3 with 80% lymphocytes (Fig. IB), and gener- alized lymphadenopathy developed. In December 1978. a lymph node and a bone marrow biopsy (Fig. 2B) contained a diffuse infiltrate of mature lymphocytes consistent with chronic lym- phocytic leukemia. However, numerous megakaryocytes were still evident in the marrow biopsy.

Serum immunoglobulin levels were IgG 752 (710-1540), IgA 50 (60-400). IgM 83 (37-204) mg/dl. There was no monoclonal spike on the serum protein electrophoresis. The lymphocytes in the peripheral blood and bone marrow (Fig. 3) were small cells characteristic of chronic lymphocytic leukemia. Phyto-

61 l o [ z

1771

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FIGS. IA A N D IB. (A, bottom) Clinical course and (B, top) hematologic parameters are illustrated. AIHA: autoimmune hemolytic anemia: P: phlebotomy.

hemagglutination stimulation of these lymphocytes" showed suboptimal. delayed response, consistent with chronic lympho- cytic leukemia.

In January 1979. because of severe fatigue. rising leukocyte count. and increasing peripheral lymphadenopathy, chemo- therapy with monthly vinblastine and prednisone (300 mg daily for I week) was begun. Clinical improvement was followed by regression of the lymphadenopathy.

In April 1979, she developed an acute hemolytic episode. Her hematocrit was 20%. reticulocyte count 50.8%). and un- conjugated hyperbilirubinemia was present (Figs. IA and I B). The direct Coombs test was positive. Treatment with prednisone 60 mg daily resulted in resolution of the hemolysis, but her thrombocytopenia was not improved. Throughout her illness, her blood smears revealed many nucleated erythrocytes and Howell Jolly bodies. In August 1980, she developed recurrent gastrointestinal bleeding with sepsis and died. Autopsy revealed pne u mo n ia due t o A spergillus. Di ffu se 1 y m p hade n o pa t h y , chronic lymphocytic leukemia, two accessory spleens with ev- idence of both extramedullary hematopoiesis and lymphocytic infiltration. (Fig. 4), and bone marrow findings similar to those observed in December 1978 were present.

Discussion and Review of Literature

Data on seven patients (four men and three women) with polycythemia Vera and lymphatic neoplasms re- ported in the literature are summarized in Table 1 . The

1772 CANCER April 15 1984 Vol. 53

No. 8 P VERA, CLL, A N D ITP IN ONE PATIENT . Wung et a/. 1773

FIGS. 2A AND ZB. (A, top) Bone marrow biopsy, 1975. Notice the paratrabecular aggregate of lymphocytes ( H & E, original magnification X250). (B. bottom) Bone marrow biopsy, 1978. A diffuse infiltrate of lymphocytes is present. but numerous megakaryocytes, often in clusters, remain ( H & E. onginal magnification X400).

ages of these patierits range from 61 to 83 years of age (mean, 75 years of age). In five of the seven cases, poly- cythemia and chroinic lymphocytic leukemia were both evident at the time of presentation. In two patients, chronic lymphocytic leukemia preceded polycythemia Vera by 3 to 7 years.

In one cast: (Case 5), polycythemia Vera was present initially. but a bone marrow examination 1 year later revealed a lymphocytic infiltrate consistent with early lymphocytic leukernia.

Because chronic lymphocytic leukemia is a more in- dolent, slowly progressive disorder than polycythemia Vera, it is possible that both disorders may have been present early in the course of this case also.

In most reported cases, follow-up of patients was lim-

ited, and there is little information on the natural course of this interesting syndrome. It appears, however, that polycythemia Vera developed during the course of lym- phoproliferative disorders in most instances. The poly- cythemia was relatively mild, requiring infrequent phle- botomies, and in one case seems to have suppressed the activity of the chronic lymphocytic l e ~ k e m i a . ~

There are no data in the literature to give any insight into the mechanism involved in the development of poly- cythemia Vera in chronic lymphocytic leukemia. One possibility is that neoplastic lymphoid cells may produce excessive erythropoietin. This possibility can be excluded in our patient because her erythropoietin level was not elevated. Alternatively immunologic abberations asso- ciated with chronic leukemia or the use of mutagenic

FIG. 3. Peripheral blood smear during phase of chronic lymphocytic leukemia (Wright-Giemsa, X 1000).

1774 CANCER April 15 1984 Vol. 53

FIG. 4. Accessory spleen, autopsy material. Megakaryocytes and myeloid precursors can be found within a diffuse infiltrate of lymphocytes (H & E, X400).

agents such as azathioprine and cyclophosphamide could predispose for the development of a second neoplasm, such as polycythemia Vera.

Data on our patient were available over a period of fifteen years. Her disease began with idiopathic throm- bocytopenic purpura (ITP) refractory to steroids, sple- nectomy, and immunosuppressive agents such as aza- thioprine and cyclophosphamide. Only a fair response followed the use of vinca alkaloids. The development of lymphoproliferative disorders during the course of ITP has been well documented.'-' Indeed, in our case a mild lymphocytosis, suggesting the emergence of chronic lym- phocytic leukemia, was observed in the later phase of her ITP, even though several bone marrow examinations failed to demonstrate marrow lymphocytosis. It is possible that the prednisone therapy masked any evidence of CLL in the spleen in 1968. Treatment with cyclophosphamide and vincristine also may have hidden earlier evidence of CLL in the marrow.

In general, CLL is indolent, less responsive to vinca alkaloids. Excellent clinical response to vinblastine and

prednisone is noteworthy in this patient. It remains to be clarified whether such a response to vinblastine and prednisone is unique to CLL associated with polycythemia Vera or to a certain subtype of CLL to which this case belongs.

Autoimmune hemolytic anemia ensued 4 months after the initiation of chemotherapy, which resembles the ob- servation of Lewis and associates who described the au- toimmune complications following irradiation and che- motherapy in patients with lymphoproliferative disor- ders. ' Hemolysis responded well to glucocorticoids.

An autoimmune ITP-like syndrome was first described in 195 1. '" The data in the literature and in our case favor the sequence of ITP, CLL, and then the emergence of polycythemia Vera. As the CLL progressed to an advanced stage, the polycythemia is suppressed. Histologic evidence of myeloid proliferation coexisted with features of CLL throughout the course of our patient. Although her thrombocytopenia remained refractory, an excellent re- sponse of the CLL was observed with the use of vinblastine and steroids.

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1776 CANCER April 15 1984 VOl. 53

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