Cladribine

We report a case of primary pulmonary hypertension in an adult man with CD8/T-cell large granulocyte leukemia. Successful treatment of his leukemia with cladribine resulted in dramatic and sustained improvement of his pulmonary hypertension.

Key words: CD8/T-cell granulocyte leukemia; chronic granulocyte leukemia; cladribine; primary pulmonary hypertension

Abbreviations: Hct=hematocrit; PPH = primary pulmonary hypertension; RV = right ventricle

Primary pulmonary hypertension (PPH) is a progressive and usually lethal disease of unknown etiology. It is characterized by pulmonary hypertension (mean pulmonary artery pressure at rest [is greater than] 25 mm Hg and [is greater than] 30 mm Hg with exercise) secondary to the narrowing or obliteration of resistance pulmonary arteries.[1-3]

We report a unique case of an adult man with a rare CD8/T-cell large granulocyte leukemia who developed PPH. He had no evidence of any other disease recognized as a secondary cause of pulmonary hypertension.[3-9] Successful treatment of his leukemia coincided with a dramatic improvement of his PPH.

CASE REPORT

A 39-year-old white man presented with complaints of palpitations and near syncope. He was well until age 22 years when he was found to have a right lower lobe pneumonia with a purified protein derivative of 20 mm induration. The biopsy specimen of a single enlarged cervical lymph node demonstrated caseating granulomas. Acid-fast smear and culture were negative. He received 14 months of isoniazid and ethambutol therapy that was discontinued when his hematocrit (Hct) fell to 26% (baseline, 41%). Results of a bone marrow examination and liver biopsy at that time were reportedly normal. He remained asymptomatic for 4 years when his anemia worsened (Hct, 17%) and he developed splenomegaly. The pathology report following splenectomy was interpreted as showing lymphoid hyperplasia. A biopsy specimen of the liver was normal and results of the bone marrow examination were consistent with dyserythropoiesis.

Fifteen years later, his Hct was 24%, leukocyte count was 12,500/[mm.sup.3] with 82% lymphocytes, and platelet count was 242,000/[mm.sup.3]. The peripheral blood had a predominance of large granular lymphocytes with the phenotype CD2, CD3, CD5, CD8, and CD57. Rearrangement of the T-cell [beta]-chain receptor gene, however, was not demonstrated. A bone marrow biopsy specimen revealed an infiltration of small lymphocytes which were marked as T cells. A diagnosis of CD8/T-cell large granulocyte leukemia was made. He denied all risk factors for and tested negative for HIV on multiple occasions. Tests for HTLV-1 and HTLV-2 were also negative.

Two years later, the patient developed near-syncope and was found on an ECG to have right axis deviation and the pattern of right ventricular (RV) strain. An initi-al two-dimensional, Doppler echocardiogram revealed severe right atrial and RV dilation with significant paradoxical septal motion and tricuspid regurgitation (Table 1). The pulmonary artery pressure was estimated at 110 mm Hg. On catheterization, the pulmonary systolic pressure was approximately 90 mm Hg with a pulmonary vascular resistance of 369 dyne.s.[cm.sup.-5] (Table 2). A ventilation-perfusion scan was interpreted as low probability for a pulmonary embolism with multiple bilateral subpleural shallow perfusion defects.[10] A wedge biopsy specimen of the right middle lobe revealed severe pulmonary arteriopathy characteristic of PPH. Extensive vascular medial smooth muscle hypertrophy, duplication of the elastic lamina, and plexogenic changes with intimal lesions predominantly of the acellular eccentric and nonlaminar concentric type were demonstrated. A few,vessels also contained the concentric laminar intimal fibrosis.[4] Right heart catheterization repeated to evaluate the response to sublingual nifedipine demonstrated a 35% reduction in pulmonary vascular resistance with a 40-mg cumulative dose (Table 2). He was discharged from the hospital on a dose of 120 mg long-acting nifedipine per day and subsequently started on a regimen of warfarin sodium (Coumadin).

Chemotherapy was initiated with 2-chlorodeoxyadine (cladribine), 0.12 mg/kg infused over 2 h daily for 5 days every 5 weeks for a total of six cycles. Following completion of therapy, the bone marrow was somewhat hypocellular, but the patient had no evidence of lymphoproliferative disease confirmed by flow cytometry and DNA analysis. The CBC count and differential count became normal. His exercise tolerance improved dramatically nifedipine therapy was tapered and discontinued. Warfarin therapy had been discontinued just prior to cladribine therapy. Three years following therapy echocardiography (Table 1), cardiopulmonary incremental exercise testing, and hemodynamic variables (Table 2) showed dramatic improvement. The pulmonary vascular resistance fell to 240 dyne.s.[cm.sup.-5] without nifedipine (65% of baseline).

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Discussion

PPH is, by definition, a disorder without identifiable etiology. The associated pulmonary arteriopathy involves the muscular arteries and arterioles with three subtypes identified on the basis of the predominating vascular lesion.[11,12] Pulmonary artery medial hypertrophy is found in all forms of pulmonary hypertension, rarely alone, usually associated with other vascular lesions.[3,4,11] Plexogenic pulmonary arteriopathy is recognized to occur in both the primary and secondary forms of PPH and is the most frequent type of arteriopathy.[4,7,13] It is characterized by medial hypertrophy and destructive lesions of the intima and entire wall of the artery.[5,14] Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis in the presence of medial hypertrophy of the small arteries and arterioles. This patient's biopsy specimen revealed an arteriopathy with destructive elements of all these patterns.

Recent case reports suggest an increased incidence of PPH in HIV-positive patients.[7,15] Many of these, but not all, had risk factors for secondary pulmonary hypertension such as TV drugs or long-term factor VIII use. Most patients had low CD4 counts and inverted CD4/CD8 ratios. In those with normal CD4 counts, the CD4/CD8 ratio was reduced in the only case in which it was reported.[16] This reflects a relative or absolute excess of CD8 cells.

The pathophysiologic state of PPH is unclear, but the invariable involvement of the intima has suggested a role for the pulmonary vascular endothelium.[17] Recently, speculation has encompassed the role of prostacyclin, endothelium-derived nitric oxide and hyperpolarizing factor, endothelin, and platelets, but the mechanism remains unknown.[18] In HIV-infected patients, there has been speculation of primary infection of the vascular endothelium; however, a recent study failed to demonstrate HIV particles in the pulmonary endothelium of these patients.[7] A growth factor has been identified, elaborated by retrovirus-infected T cells, that stimulates and supports the growth of human vascular endothelial cells in cell culture.[19] Endothelial cells have been shown to elicit proliferative and cytotoxic responses by lymphocytes and secrete soluble antigens and other factors with immunoregulatory activity.[20] CD8 celis also express functional interleukin-2 receptors on recognition of endothelial cell-specific antigens.[21] It is thus conceivable that a modification of the endothelial cell-CD8/T-cell interaction in this rare leukemia and in HIV infection might directly or indirectly result in the endothelial dysfunction and the development of PPH. The mechanisms of this interaction remain unclear.

Our patient demonstrated severe pulmonary hypertension with all diagnostic studies highly characteristic of PPH. The finding of both an absolute and relative excess of CD8 to CD4 cells, similar to that seen in patients infected with HIV, was intriguing in this individual who remains without any evidence of retroviral infection or any secondary cause of pulmonary hypertension. This may be coincidental or suggest a pathophysiologic role of the CD8/T-cell in the development of PPH. The dramatic improvement with treatment Suggests that the process can be reversed to a great extent. The patient is now 3 years into remission of and has shown marked regression of his PPH without the need for vasodilator therapy. This is all the more dramatic as spontaneous regression of PPH has never been clearly documented and the median overall survival in PPH is only 2.8 years from time of diagnosis (National Institutes of Health Registry). The expected median survival is only 6 months in a functional class IV patient such as ours.[22] Also unusual is the sustained complete (marrow) remission with six cycles of cladribine. A variety of regimens in this leukemia have had variable success but this patient remains disease free in excess of 2 years without any treatment.[23] Cladribine has rarely been used for more than three or four cycles. This patient tolerated six widely spaced (5 weeks) cycles without significant complications or need for hospitalization. Finally, the coincidence of hematologic and hemodynamic improvement suggests a relationship between the CD8/ T-cell and pulmonary vascular endothelium and smooth muscle. The failure to reverse the pulmonary vascular resistance to normal is likely a result of permanent loss of pulmonary vascular cross-sectional area.

References

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[19] Nakamura S, Salahuddin SZ, Biberfeld P, et al. Kaposi's sarcoma cells: long-term culture with growth factor from retrovirus-infected CD4+ T cells. Science 1988; 242: 426-30

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[21] Mizuochi T, McKean DJ, Singer A. IL-1 as a cofactor for lymphokine-secreting CD8+ murine T cells. J Immunol 1988; 141:1571-77

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[23] Langhan JP, Kidd PG, Starkenbaum G. Treatment of large granular lymphoete leukemia with oral low-dose methotrexate. Blood 1994; 84:2164-70.

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