Pergamon Leukemia Research Vol. 21, No. 3, pp 249-253, 1997.

Copyright 0 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain

0145-2126197 S17.M) + 0.00

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CASE REPORT

FATAL HYPERLEUKOCYTIC SYNDROME IN A PATIENT WITH CHRONIC MYELOMONOCYTIC LEUKEMIA

C. Aul, N. Gattermann, U. Germing, T. Siidhoff, K. A. Hollmig and A. Hey11 Department of Internal Medicine, Hematology and Oncology Division, Heinrich Heine University,

Diisseldorf, Germany

(Received 3 September 1996. Accepted 5 October 1996)

Abstract-A 53-year-old male patient was admitted to our hospital with painful splenomegaly. He was diagnosed as having chronic myelomonocytic leukemia (CMML) with leukocytosis, monocytosis, increased lysozyme concentrations in serum und urine, and lack of the Phila- delphia chromosome. The clinical course of the disease was characterized by rapidly rising leukocyte counts, cutaneous infiltrates, respiratory insufficiency and neurological symptoms. Excessive hyperleukocytosis with a significant increase in monocytic cells led to micro- circulatory obstruction, vascular endothelial damage and organ malfunction. This complication could not be prevented by low-dose chemotherapy with cytosine arabinoside. The patient finally died from pulmonary and cerebral hyperleukocytic syndrome. cl 1997 Elsevier Science Ltd. All rights reserved.

Key words: chronic myelomonocytic leukemia, myelodysplastic syndrome, hyperleukocytic syndrome, low-dose chemotherapy, microvascular hyperviscosity, pulmonary circulation, leukocyte adhesion molecules.

Introduction

Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder in elderly patients, characterized by increased monocytic cells in the bone marrow and peripheral blood. Because of the common dysplastic changes of erythropoiesis, granulopoiesis and mega- karyopoiesis, CMML was classified as a subtype of myelodysplastic syndrome (MDS) by the FAB group [l]. Clinically and hematologically, however, CMML shares features of both myelodysplastic and chronic myeloproliferative disease [2]. On cytogenetic and molecular analysis, CMML can be separated from

Abbreviations: AML, acute myeloid leukemia; Am-C, cytosine arabinoside; BCR, breakpoint cluster region; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; FAB, French-American-British cooperative group; LDH, lactate dehydrogenase; MD& myelodysplastic syn- drome; VCAM-I, vascular adhesion molecule 1; WBC, white blood cell count.

Correspondence lo: Carlo Aul, MD, Department of Internal Medicine, Hematology and Oncology Division, Heinrich Heine University, MoorenstraRe 5, 40225 Diisseldorf, Ger- many.

chronic myeloid leukemia (CML) by a lack of the Philadelphia chromosome and BCR/ABL rearrangement [3]. Based on peripheral leukocyte counts, the FAB group recently proposed to distinguish two subtypes of CMML: a myelodysplastic (WBC < 13 x 109/1) and a myeloproliferative (WBC3 13 x 109/1) variant [4]. The heterogeneity of the disorder is reflected not only by the variety of hematological manifestations, but also by great differences in median survival, varying from 8 to 60 months in different studies [5, 61. Main causes of death are infections and hemorrhages with or without transformation into acute myeloid leukemia (AML) [7]. Here we report the rare case of a hyperleukocytic syndrome with a fatal outcome in a 53-year-old patient with CMML, a hitherto undescribed complication of the disease.

Case Report

A 53-year-old male patient was referred to our hospital with painful splenomegaly. Six months prior to admission, he complained of painful swelling of both

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basal joints of the big toes, probably reflecting gout arthritis due to excessive hyperuricemia. The further history was uneventful. On physical examination, the patient was in reduced clinical condition with a pallor of the skin and mucous membranes. There were no signs of hemorrhagic diathesis or icterus. The spleen was enlarged below the umbilicus and was of firm consis- tency. On ultrasound, marked splenomegaly was verified (24 x 12.5 cm) with several small hilar infarcts, while there was only moderate hepatomegaly. Heart and lungs were without pathological findings. The chest X-ray and electrocardiography were normal.

Laboratory investigations showed normocytic normo- chromic anemia (hemoglobin 9.9 mg/dl), thrombocyto- penia (67 x 109/1) and leukocytosis (41.9 x 109/1). The peripheral blood smear revealed 2% metamyelocytes, 4% juvenile granulocytes, 24% segmented granulocytes, 34% lymphocytes, 2% eosinophils, 8% basophils and 26% monocytes (absolute monocyte count 10.9 x 109/1). The following were also recorded: LDH 774 U/l, serum deoxythymidine kinase activity 130 U/u1 (normal value < 5 U&l), uric acid 11.9 mg/dl, serum vitamin Br2

1 LDAra-C20mgidi.v.I

Blasts(%) H 1 1 “BC

3244 pg/ml, serum folic acid 4.2 &ml, serum lysozyme 95 mg/l (normal value < 2.25 mg/l) and urine lysozyme 11.1 mg/l (normal value < 0.1 mg/l). The sucrose lysis test, Ham test and Coombs test were all negative.

Cytological bone marrow examination showed a massive hyperplasia of granulomonopoiesis with a corresponding reduction of erythro- and megakaryo- poiesis. Granulopoiesis showed a shift to the left with 5% blasts. There was an elevation of monocytic cells (promonocytes and monocytes) to 21% of all nucleated cells. The diagnosis of chronic myelomonocytic leuke- mia was confirmed by trephine biopsies showing nearly a complete lack of adipocytes, without any signs of myelofibrosis. Cytogenetic analysis of 26 metaphases showed a normal male karyotype without the Philadel- phia chromosome.

The clinical course of the disease is shown in Fig. 1. A massive increase in leukocytes (168 x lO”/l), painful splenomegaly as well as deteriorating respiratory function (dyspnea and tachypnea, small bilateral pleural effusions, arterial hypoxemia with a partial oxygene pressure of 48 mm Hg) necessitated treatment with low-

PT RBC

ml

14 300

I

250

I 1 I I 1 2 3 Months

LD Ara-C, low-dose cytosine arabinoside RBC, packed red blood cell transfusions PT. platelet transfusions

Peripheral blood cell counts, serum LDH activity as well as peripheral blood and medullary blast cell percentages in a 53- year-old patient with CMML and hyperleukocytic syndrome. Parallel evolution of respiratory and neurological symptoms and

leukocytosis.

Fatal hyperleukocytic syndrome in CMML 251

dose cytosine arabinoside (Ara-C) (20 mg/day, given by continuous intravenous infusion over 2 weeks). Because of painful splenomegaly, oral corticosteroids (predniso- lone 20-60 m&day) were administered. The patient’s condition improved, and leukocyte counts and splenic size decreased. Six weeks after admission, the patient complained again of abdominal discomfort and increas- ing dyspnea. The patient’s trunk showed multiple brownish lesions, about 15 mm in diameter, which were histologically proven to represent cutaneous manifesta- tions of CMML. Because of rapidly rising leukocyte counts (174 x 109/1) as well as increasing medullary blast cell infiltration (8%), a second cycle of low-dose Ara-C was applied, leading to the disappearance of skin infiltrates. With only a marginal decrease in leukocyte counts at the end of the second Ara-C cycle, the patient developed profound thrombocytopenia (9 x 109/1) and anemia (6.5 g/dl), requiring repeated platelet and RBC transfusions.

In the treatment-free interval, hyperleukocytosis of more than 300 x lo”/1 developed. The peripheral blood smear showed progressive monocytosis (32-39%) with- out any blasts. Ten days prior to death, the patient complained of increasing dyspnea, visual blurring, tinnitus and dizziness. On neurological examination, there were no pathological focal or meningeal signs. A spinal fluid tap excluded meningeal leukemia. Ophthal- mological evaluation revealed papillary edema and retinal vein distention. The chest X-ray showed bilateral streaky infiltrates in the pulmonary middle and upper fields that were unresponsive to antibiotic therapy with oxacillin, cephalosporins and aminoglycosides (Fig. 2). Serological tests provided no evidence of acute infection with herpes simplex virus, Epstein-Barr virus, cyto- megalovirus, Legionella pneumophila, Mycoplasma pneumoniae, Candida or Aspergillus species. In addi- tion, various samples obtained by bronchoscopy (brush abrasio, alveolar fluid, biopsy) were negative for infectious agents, including fungal organisms. Histo- logical evaluation of the transbronchial biopsy specimen showed dilation and increased leukocyte crowding of pulmonary capillaries as well as septal alveolar edema. The patient became stuporous and finally died of respiratory failure. The patient’s relatives did not give permission for an autopsy.

Discussion

The hyperleukocytic syndrome is one of the most dangerous complications of acute and chronic leukemias with high lethality if rapid reduction of leukocyte cell mass is not achieved through cytostatic drugs or leukapheresis [S]. The main manifestations are pulmon- ary or cerebral hyperleukocytic syndrome, whose frequency is often underestimated. Van Buchem et al.,

Fig. 2. Comparison of chest roentgenograms during the course of disease. Panel a shows the baseline chest radiograph when the patient was admitted. The chest radiograph taken 10 days prior to death (panel b) shows perihilar pulmonary infiltrates as well as small bilateral pleural effusions. Panel c shows the chest roentgenogram 1 day prior to death, demonstrating confluency of interstitial infiltrates in the middle and upper

zones of both lungs.

252 C. Au1 et al.

performing postmortem examinations in 52 patients with AML and myeloproliferative syndromes, found histo- pathological signs of pulmonary leukostasis in 40% of cases [9]. Neuropsychiatric symptoms or loss of con- sciousness in patients suffering from leukemia with high leukocyte counts should alert physicians not only to the possibility of meningeal leukemia or cerebral bleeding, but also to central leukostasis [lo, 111.

The appearance of the hyperleukocytic syndrome in patients with leukemia is primarily dependent on the number of leukocytes as well as the size and deform- ability of circulating leukemic cells. According to experimental investigations, microcirculatory distur- bances can be expected if the vessel diameter is less than 75% of the leukocyte diameter [12]. These correlations explain why relevant disturbances of micro- circulation occur in various forms of leukemia with different frequency. Patients with chronic myeloid leukemia and hyperleukocytic AML develop clinical signs of hyperleukocytic syndrome in up to 14% of cases [lo]. On the contrary, such complications are rare in patients with chronic lymphocytic leukemia (< l%), as even extensive elevations of leukocyte counts have no rheological effects because of the small size of tumour cells. To develop the full picture of hyperleukocytic syndrome, blood viscosity is of relatively low signifi- cance, because the increase in leukocrit is usually compensated by concomitant anemia.

An extreme increase in leukocyte counts in patients with CMML is very rare. According to a meta-analysis of Zittoun, 46% of patients with CMML showed moderate leukocytosis (lo-50 x 109/1) at diagnosis; leukocyte counts above 100 x 109/1 were found in only six (3%) out of 220 patients [13]. A similar distribution of leukocyte counts at presentation was found in our own patient population. Out of 145 CMML patients of the Diisseldorf MDS registry, only one patient showed leukocytosis above 100 x lo’/1 [14]. This explains why hyperleukocytic syndromes in CMML patients have previously not been described in the literature. In our patient who died with signs of pulmonary and cerebral leukostasis, excessive leukocyte counts with a large proportion of monocytic cells were present in the peripheral blood. As a first indication of a hyperleuko- cytic syndrome, the patient complained of respiratory symptoms (dyspnea), which could not be explained by anemia or infectious complications. These symptoms decreased temporarily under cytostatic therapy. Prior to death, the patient developed the full clinical picture of a hyperleukocytic syndrome with dyspnea, hypoxia and interstitial pulmonary infiltrates, characteristic ophthal- mological signs as well as central nervous system symptoms. These manifestations strongly correlated with rapidly rising leukocyte and monocyte counts. Pulmonary leukostasis could be verified by means of a

transbronchial lung biopsy. The histopathological changes were similar to the findings of other authors in patients suffering from leukemia with hyperleuko- cytic syndrome [9, 15, 161.

In addition to hyperleukocytosis and rigidity of mono- cytic cells, other characteristics of tumour cells must be considered to contribute to the appearance of micro- circulatory problems. These include increased adhesion of monocytic cells to the endothelial vessel wall, their ability for diapedesis and microvascular invasion as well as the unfavourable influence of circulating or locally aggregated leukemic cells on the endothelial barrier via the release of cytokines [17]. Increased adhesive con- tacts between monocytes and the endothelial wall, which may explain the cutaneous infiltrates and splenomegaly in our patient, are mediated by cytokine-induced leukocyte adhesion molecules, primarily located in the postcapillary venoles [18]. Unlike neutrophils, clonal non-transformed monocytes seem to use primarily the VCAM-1 (vascular adhesion molecule 1) receptor on the endothelial cell surface. In our own studies on patients with MDS, a highly significant correlation between soluble VCAM-1 isoforms and circulating monocyte counts could be established [19].

Acknowledgement-This work was supported by the Leuklmie-Liga e.V.

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