American Journal of Hematology 22:213-218 (1986)

Leukapheresis for Control of Chronic Myelogenous Leukemia During Pregnancy Denis Fitzgerald, Jacob M. Rowe, and Joanna Heal

Hematology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry (D.F., J. M. R., J. H.), and Rochester Region, the American Red Cross (J. H.), Rochester, New York

Leukapheresis was used as the sole modality of treatment of a patient with chronic myelogenous leukemia (CML) during her pregnancy. The specific requirements for safe leukapheresis during pregnancy are discussed, and the literature describing the management of CML during pregnancy is reviewed. Leukapheresis may be the treatment of choice in selected pregnancy patients with CML since it avoids the potential teratogenic effects of chemotherapy or radiation therapy.

Key words: pregnancy and chronic myelogenous leukemia, leukapheresis

INTRODUCTION

The management of pregnant patients with leukemia is difficult because of a conflict between the need to treat the mother as intensively as possible with chemo- therapy and the desire to avoid harmful fetal exposure to cytotoxic drugs or ionizing radiation, especially during the early months of the pregnancy. In chronic myeloge- neous leukemia (CML), therapeutic hemapheresis is a modality that can be used in patients to decrease leukocyte and platelet count, prevent progressive splenic enlarge- ment, and sometimes improve anemia. In the pregnant patient with CML, it offers the added advantage of a lack of teratogenic effects. In this report, we describe the successful management of a patient with CML throughout her pregnancy using leukapheresis as the sole modality of treatment.

CASE REPORT

The patient is a 29-year-old white woman (gravida 2, para 1). A routine blood count taken during her 11th week of pregnancy showed a significant leukocytosis. She was otherwise asymptomatic except for mild fatigue, which she had attributed to her pregnancy. On initial examination, she was found to have an intrauterine preg- nancy of 11 weeks gestation and a spleen palapable 4 cm below the left costal margin. The initial white blood cell count (WBC) was 252,OOo/pl with 35% neutrophils, 23% bands, 13% metamyelocytes, 15% myelocytes, 1 % myeloblasts, 1 % basophils, 1 % eosinophils, 4% lymphocytes, and 1 % monocytes. The hemoglobin was 11.6 gm/dl, and the platelet count 6OO,OOO/pl. A bone marrow specimen demonstrated marked

Received for publication August 13, 1985; accepted November 21, 1985.

Address reprint requests to Dr. Jacob M. Rowe, P.O. Box Med., University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642.

0 1986 Alan R. Liss, Inc.

214 Case Report: Fitzgerald, Rowe, and Heal

myeloid hyperplasia, and marrow cells contained the Philadelphia (Ph) chromosome. The leukocyte alkaline phosphatase score was 16 (normal: 30-100). The patient was admitted to the hospital, and consent was obtained for a trial of therapeutic leukapheresis.

Figure 1 summarizes the patient’s course. Leukapheresis was begun during the 11th week of the patient’s pregnancy, and four procedures were carried out over the ensuing 2 weeks. The WBC was reduced to 123,OOO/pl and remained stable at this level until the 19th gestational week. Between the 20th and 23rd week, a progressive rise in the WBC occurred. Leukapheresis was reinstituted during the 24th week and subsequently performed on a weekly out-patient basis until the time of delivery. The platelet count and spleen size were not decreased by the hemapheresis procedures. During the 29th week. the patient complained of two episodes of headache and blurred vision lasting 30 min and associated with lightheadedness. She was admitted to the hospital and had an unremarkable neurologic and ophthalmologic evaluation. Her symptoms were attributed to a variant of migraine, and there was no recurrence. The WBC at this time was 9S,OOO/pl, and the whole blood viscosity was normal.

Because the patient lived in a rural area 100 miles from the hospital and had an expected date of confinement in the middle of the winter, she underwent elective induction of labor at the end of the 37th week. She had a vaginal delivery of a normal 3,050 g boy who had a WBC of 9.500/pI with a hemoglobin of 17.2 g/dl and a platelet count of 232,OOO/p1. There were no perinatal complications. One week after delivery, hydroxyurea was given for control of the leukocytosis. Here WBC promptly fell to lS,OOO/pI but despite maintenance therapy with hydroxyurea, she presented three weeks later with symptoms of hyperviscosity, including papilledema and a WBC of 26O.OOO/pl. These symptoms responded rapidly to leukapheresis, and therapy with

1 1 1 1 Leuhapherem 1 1 1 1 1 I 1 1 1 1 1 1 1

i g 120

40jjk 0 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

GESTATIONAL WEEK

Fig. I . Summary of patient‘s course from diagnosis at 11th week of gestation until delivery. The arrows indicate leukapheresis procedures. The solid line is the white blood cell count. with the vertical bar line indicating the post-leukapheresis white blood cell count. The dashed line is the hematocrit.

Case Report: Leukapheresis for CML During Pregnancy 215

busulfan was then instituted. She currently is in the final phase of evaluation for bone marrow transplantation from her HLA-compatible sister.

LEUKAPHERESIS

The combined platelet and leukapheresis was carried out using the Haemonetics Model 30 S Cell Separator (Haemonetics Corporation, Braintree, MA) and a standard protocol [l]. Venous access was obtained for all procedures via 16 gauge needles placed in the patient's antecubital veins. An average of 6.8 L of whole blood was processed during ten passes with anticoagulant citrate dextrose (ACD), formula B, added to the whole blood in a 1:8 ratio using a 225 ml centrifuge bowl. Each procedure took approximately 3 hr. During the harvesting in each pass, the egress flow rate was reduced to 20 ml/min and the collection begun with the platelet layer and continued for 5 min into the red cell layer. An additional 300 ml of physiological saline was given before starting each procedure so that the ex vivo volume was less than 15 % of the patient's total blood volume. All processed blood was reinfused into the patient before starting the next pass.

During each procedure, an average of 1.5 X 10" white blood cells, 2.3 x 10" platelets, and 120 ml of red blood cells were removed. The average efficiency of white blood cell removal was 20 were harvested during the 17 procedures.

4%. A total of 2.3 kg of cells (2.3 x

DISCUSSION

This report describes the management of a patient with CML by leukapheresis, which was initiated in the first trimester and continued throughout her pregnancy. When she presented at 11 weeks gestation, she had significant hyperleukocytosis, although the number of myeloblasts was small. Because of concern for potential microvascular complications in such a hyperleukocytic state [2] and the consequent effects on the mother and developing fetus, it was decided to institute leukapheresis. This was well tolerated. The episode of blurred vision and headache in the 29th week of gestation remains unexplained but is unlikely to be due to microcirculatory leuko- stasis because of the relatively low leukocyte count at that time.

Leukapheresis has been successfully used in both acute and chronic leukemia for the rapid reduction of high WBC counts in patients with impending vascular occlusion [3]. Since chronic mechanical cytoreduction does not prolong survival in these patients, and because it is inconvenient, costly, and time-consuming, leukapher- esis is not currently recommended as maintenance therapy for these diseases [4]. However, this form of treatment does offer an attractive short-term alternative to chemotherapy for the pregnant patient, since exposure to potentially teratogenic agents can be avoided.

In this patient, our standard leukapheresis procedure was modified in an attempt to minimize the cardiovascular effects of the procedure on the patient and placental circulation. A standard rather than a pediatric bowl was used so that the dwell time in the centrifuge would be sufficient to allow delineation of the buffy coat in absence of hydroxyethyl starch. Because of the bowl size and the patient's low hematocrit, the estimated ex vivo blood volume during a single pass would have been more than 15 % of the patient's total blood volume at the time of presentation. Therefore, to prevent hypotensive episodes, the patient was given an infusion of physiological saline before

216 Case Report: Fitzgerald, Rowe, and Heal

each procedure, and all processed blood was returned to the patient before starting the next pass. The cells removed were replaced with an equal volume of 5 % serum albumin. Use of a sedimenting agent such as hydroxyethyl starch has been shown to improve the yields of granulocytes obtained during leukapheresis of normal donors [5] and patients with CML. It has been suggested that leukapheresis for CML is ineffective in the absence of such a sedimenting agent [6,7]. In this case, hydroxyethyl starch was not used because of the unknown effects on the human fetus [8] and the tendency to cause a progressive increase in plasma volume with repeated administra- tion [9]. The efficiency of each leukapheresis procedure was certainly reduced and the red cell loss in the buffy coat increased, compared to a standard procedure utilizing hydroxyethyl starch. However, adequate control of the white blood cell count was still achieved. With the above precautions, the patient underwent a total of 17 procedures without complications.

Chronic leukapheresis may be followed by an anemia that is disproportionately severe compared to the number of red blood cells lost in the hemapheresis product [ 101. This may be caused by the selective removal of buoyant reticulocytes within the buffy coat layer. Such patients may require red blood cell transfusions. In this case, the standard iron and folic acid antenatal replacement therapy appeared to be sufficient to counteract the cumulative loss of red blood cells and young erythrocytes. In fact, as the white blood cell count came under control, the hematocrit rose, suggesting that a decrease in white cell mass by leukapheresis can improve hemoglobin concentration also [2].

The consequences of pregnancy and CML have been reviewed [11,12]. Preg- nancy itself appears to have no effect on the course of CML. Sheehy [ 111 found equal survival when he compared a group of pregnant and nonpregnant women with this disease. In his entire group of 89 patients, the fetal mortality was 16.2% and the maternal mortality was 6 % . In 75 % of his patients, the leukemia was diagnosed prior to the pregnancy, and some had very advanced disease. This was a collected series of patients reported from a literature survey in 1958, and treatment was not reviewed.

Until recently, the accepted treatment of pregnant patients generally involved the use of busulfan or ionizing radiation [ 131. There are many reports of patients receiving busulfan [ 12- 181 without apparent fetal effects, although adequate long- term data on a large number of patients are not available. The one report [19] of a possible teratogenic effect of busulfan was complicated by the antecedent administra- tion of radiation therapy and 6-mercaptopurine during the first trimester of the pregnancy. Similarly, ionizing radiation [20] to the spleen with shielding of the uterus has been employed without obvious teratogenic effects; however, there are potential leukemogenic effects of in utero radiation exposure [2 1,221,

There have been a few reports during the past several years on the use of leukapheresis during pregnancy. Myer et a1 [23] described the successful management of a pregnant patient with acute myelomonocytic leukemia from the 26th through the 38th week of pregnancy with the use of intensive leukapheresis alone. Caplan et al [24] reported on a patient with CML who was managed for the initial half of her pregnancy with leukapheresis but who, during the mid-portion of the second trimes- ter, required splenic radiotherapy and busulfan. Three other case reports [25-271 have described the successful use of leukapheresis in pregnant patients with CML; however, in each of these, the procedure was not initiated until the latter half of pregnancy. The successful experience in our patient would suggest that leukapheresis

Case Report: Leukapheresis for CML During Pregnancy 217

can be considered for treatment of CML as early as the first trimester of pregnancy and that it can be successfully continued throughout the pregnancy. Leukapheresis does not have an adverse impact on the course of CML and can result in symptomatic improvement. Finally, because of its lack of teratogenic effect, it may be the optimal treatment for pregnancy patients with CML who tolerate and respond to the procedure.

ACKNOWLEDGMENTS

We wish to thank the nursing staff of the Hemapheresis Center of the Rochester Red Cross for their assistance and Ms. Linda Dowdle for preparation of the manuscript.

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