Periodic oscillation of blood leukocytes, platelets, and hemoglobin in a patient with chronic eosinophilic leukemia

1. Introduction 

Oscillation of the peripheral blood leukocyte occurred in healthy individuals presumably due to the alleration of a homeostatic mechanism controlling granulopoiesis [1]. Morley et al. reported for the first time a spontaneous cyclic leukocytosis in patients with chronic myelogenous leukemia (CML) in 1967 [2]. So far, a total of 17 such cases have been reported in the literature [3], [4], [5], [6], [7], [8], [9], [10]. The mechanism of the cycling of the blood cells in these CML patients has not been fully clarified. Some evidences suggested that hematopoietic stem cell abnormality and feedback control mechanisms for hematopoiesis were the cause of the cyclic oscillation [2], [10], [11].

In this report, we describe a case of chronic eosinophilic leukemia (CEL) with cyclic leukocytosis as well as cyclic variations in several other hematologic parameters.

2. Case report 

A 54-year-old Chinese man was referred to his local hospital in March 2001 because of fatigue, cough, night sweats, general malaise, and mild bone, joint and muscle pain. His peripheral blood counts at presentation were white blood cell (WBC) 148×109l−1 with a differential of 2% myelocytes, 9% metamyelocytes, 36% eosinophils, platelets 105×109l−1 and hemoglobin (Hb) 131gl−1. Bone marrow aspirate smear showed marked granulocytic hyperplasia with full maturation, and a marked increase of eosinophils. A differential count of 500 nucleated cells was as follows: myeloblasts 3.5%, promyelocytes 9%, eosinophilic myelocytes 2%, eosinophilic metamylocytes 7%, eosinophilic band forms 10%, and eosinophilic segmented form 9%. Findings on physical examination were within normal limits except for a palpable spleen 3cm below the left costal margin. A suspicious diagnosis of CEL was made. After hospitalization, his WBC count dropped spontaneously without any treatment. During the following months, serial blood cell counts revealed a cyclic oscillation in his blood cells. It was also noted that when the leukocyte count peaked, the symptoms of the patient worsened, and the spleen size enlarged, the symptoms were significantly relieved with the dropping of WBC count, and the spleen shrank to unpalpable at the leukocyte nadir. The patient was admitted to our hospital for further evaluation in October 2001. There was no allergy, parasitic diseases, collagen vascular diseases and neoplastic disorders in his past history. Repeated stool examinations for ova were negative. Serum IgE level and the results of immunological tests were normal. Chest X-ray, ECG, ultrasonic cardiogram were normal. The patient was kept under observation for another cycle without any treatment.

2.1. Cyclic leukocytosis 

Upon the retrospective survey of his documented blood routine records examined during the last 9 months period, it was revealed that there was a periodic variation of leukocyte count as well as some other blood parameters with a cycle duration of about 60 days (Fig. 1). The range of oscillations in WBC was as high as 256×109l−1 at the peak and as low as 3×109l−1 at the nadir. The platelet showed similar cyclic variations but the beginning of the cycle was about 14 days earlier than that in WBC. The cyclic variations of hemoglobin level occurred almost at the same time as the WBC’s. At the WBC peak, bone marrow aspirate and biopsy demonstrated a significant granulocytic hyperplasia, hyper-eosinophilia with a left-shifted eosinophilic cells, and the eosinophils showed remarkable dysplasia including tri-lobed and ring formed nuclei, marked cytoplasmic vacuolization, hyper- or hypo-granulation, mixed basophilic and eosinophilc granulation in a same cell and micro-eosinophils. The morphologic features of eosinophils were confirmed by the electronic-microscopy. At the WBC nadir, both the bone marrow aspirate and biopsy showed a normal cellularity.

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Fig. 1. Cycle oscillation of WBC, platelet and hemoglobin levels observed in the patient from March to December 2001.

2.3. In vitro colony assay and serum CSFs determination 

The results of bone marrow hematopoietic progenitor cells (granulocyte-macrophage colony-forming units (CFU-GM), erythroid colony-forming units (CFU-E), BFU-E) culture during the cyclic course are presented as shown in Table 1. At the peak, the number of CFU-GM exceeded normal control’s by nearly five times and decreased to around normal at the nadir. CFU-E and BFU-E decreased mildly at the peak, and markedly at the nadir. Serum IL6, TNF-α, IL-2, and Epo levels increased at the peak. IL-6, TNF-α and IL-2 decreased, while IL-1β and Epo significantly increased at the nadir (Table 1).

Table 1. Hematologic and biologic characteristics at the peak and at the nadir

	Parameter	At the peak (13 November 2001)	At the nadir (7 December 2001)	Normal contral
	WBC (×109, l−1)	186.25	3.7
	Hb (gl−1)	57	33
	Plt (×109, l−1)	36	44
	BM biopsy	Hypercellularity	Normal
	CFU-E	58/2 × 104 cells	14/2 × 104 cells	73.4 ± 11.3/2 × 104 cells
	BFU-E	14/2 × 104 cells	0/2 × 104 cells	29.6 ± 5.9/2 × 104 cells
	CFU-GM
	Cluster	287/2 × 105 cells	14/2 × 105 cells
	Colony	157/2 × 105 cells	23/2 × 105 cells	37.1 ± 7.4/1 × 105 cells
	IL-1β (ngml−1)	0.21	1.81	0.19–0.33
	IL-6 (pgml−1)	226.57	75.8	0–92.2
	TNF-α (ngml−1)	2.24	1.21	0.62–1.44
	IL-2 (ngml−1)	8.97	4.61	0–2.96
	Epo (mIUml−1)	118.48	952.6	5.8–12.3

3. Discussion 

Although it was not commonly appreciated, cyclic leukocytosis has been previously described in 17 patients with CML in English literatures [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. Those patients comprised 10 males and 7 females with a median age of 45 (12–73) years. The durations of the fluctuation varied from 30 to 70 days except one whose fluctuating durations were 100–120 days [2]. Among the 17 patients, the fluctuation involved only leukocytes in 5, both leukocytes and platelets in 10, and multiple hematologic parameters in 2. The cyclic variation in platelets started and ended 5–14 days earlier in the sequence than that in leukocyte in some reports [4], [8], and as well as time leukocyte in the others [2], [3]. To our knowledge, this patient should be the first case of CEL with periodic fluctuation in peripheral WBC counts and other hematologic parameters.

It is believed that granulopoiesis in normal person was controlled partially by a negative feedback mechanism between blood and marrow through the humoral factor colony-stimulating factor (CSF). Decreasing blood neutrophils below a critical level results in increased CSF activity, in turn, which induces proliferation and differentiation of the pluripotent hemopoietic stem cell along the neutrophilic cell line. Some researches and observations have been carried out on the mechanism for cyclic oscillation of the blood cells CML. Morley et al. [2] suggested that to CML patients with cyclic leukocytosis, the bone marrow should be either sensitive to a feedback stimulus or be affected intermittently by an abnormal strong stimulus originating at a site other than bone marrow. Inverse relationship between CSF levels and peripheral leukocyte counts was noted in some patients [6], [7], [10]. We noted a decrease in marrow cellularity at the nadir of the WBC counts in our patient, the same phenomenon as in Shadduck et al.’s case [5]. In contrast, hyperplasia of the marrow, the increased CFU-GM numbers and CSF levels occurred concomitantly with the increase of peripheral WBC count, the oscillation in peripheral WBC would appear to be the result of the alteration of granulocyte production. A direct correlation between the spleen size and the WBC count during the periodic variations observed in our patient was also observed in Rodriguez and Lutcher’s patients with CML [8], the spleen size variations should be the result of the cyclic leukocytosis. The reason for platelet and hemoglobin oscillation with WBC has not been clarified, at least, it suggests that the leukemic clone of these CML and CEL patients is originated from a bone marrow stem cell.