Vol. 15, #1

Reversal Of Chemotherapy-Induced
Myelosuppression With Electroacupuncture
Gerald W. Grass, MD

ABSTRACT
Background     Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western Hemisphere. Although chlorambucil has been widely used in the treatment of malignant lymphoproliferative disease, several reports of irreversible bone marrow failure and death have been attributed to its use. Electroacupuncture may be a treatment modality to reverse chlorambucil-induced myelosuppression.
Objective     To illustrate the use of electroacupuncture in the treatment of chemotherapy-induced myelosuppression.
Design, Setting, and Patient     A case report of a 61-year-old man with myelosuppression following chlorambucil administration for Rai stage III CLL.
Intervention     The patient was treated with electroacupuncture at BL 11, BL 17, LR 3, and SP 6.
Main Outcome Measure     Resolution of chemotherapy-induced myelosuppression following treatment; specifically, measurement of hemoglobin, leukocytes, and platelets, and need for blood transfusions.
Results     Following 8 treatment sessions, the patient's hematological measurements increased and stabilized. The patient did not report any adverse effects following acupuncture. Follow-up at 1 year revealed hemoglobin, leukocyte, and platelet counts within normal ranges. He had not required any additional blood transfusions.
Conclusion     The case reported herein suggests that electroacupuncture may be a promising therapeutic modality for the treatment of myelosuppression secondary to chemotherapeutic regimens.
KEY WORDS
 Acupuncture, Electroacupuncture, Myelosuppression, Anemia, Chemotherapy, Chronic Lymphocytic Leukemia, Chlorambucil

INTRODUCTION
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western Hemisphere, with an annual incidence of 1.8-3 per 100,000 in the United States. Affecting twice as many men as women, CLL accounts for approximately 25%-30% of all leukemias. Chronic lymphocytic leukemia occurs more frequently in older individuals; 90% of cases are found in people older than 50 years, but it is increasingly seen in younger patients as well.1

The approach to the management of CLL differs from that taken to treat most malignant diseases because many patients with CLL live for long periods without therapeutic intervention. Treatment decisions and stratification are frequently based on the Rai classification: patients with a Rai stage 0 at diagnosis have approximately a 60% or greater chance of survival for 20 years or longer without treatment, while those with a Rai stage III or IV have mean survival times of 1.5-4 years.2

Currently, patients with a Rai stage III or higher classification are treated with myelosuppressive therapy. The most commonly used chemotherapy drugs in the treatment of CLL are fludarabine and chlorambucil. Chlorambucil has been used in the treatment of malignant lymphoproliferative disease since the mid-1950s and is generally well tolerated.3 Although there are few reports in the scientific literature of significant hematopoietic adverse effects,4,5 Rudd et al6 reported the deaths of 2 patients who experienced irreversible bone marrow failure following chlorambucil treatment for connective tissue diseases.

Although acupuncture is gaining greater recognition in the scientific literature for its ability to treat a wide range of disorders, there are few published studies concerning the effects of electroacupuncture on hematological parameters.7-10 A search of MEDLINE failed to identify any published studies or case reports concerning the treatment of pancytopenia with acupuncture. Published studies examining the role of acupuncture in the treatment of leukopenia offer conflicting results. Bensoussan, for example, reported on the experimental work of Mu; in 1985, he treated 25 patients with leukopenia resulting from radiotherapy or chemotherapy. In that report, the average white blood cell count was raised by 5128/mm3 following treatment,11 while other investigators report that electroacupuncture was not beneficial in raising leukocyte counts in leukopenic patients.12

It is possible that electroacupuncture may enhance bone marrow recovery and be beneficial in the treatment of myelosuppression secondary to chemotherapy for lymphoproliferative diseases.

CASE REPORT
A 61-year-old man was referred from his primary care physician for treatment of restless leg syndrome. He began to develop mild symptoms in his youth that gradually increased in severity into adulthood. Acupuncture treatment sessions for the restless leg syndrome began in late March 2000 (but were hampered by frequent cancellations of his scheduled appointments).

Upon inquiry of this situation, the patient reported that he had to undergo frequent blood transfusions for a profound anemia that was the result of chemotherapy for CLL. He was discovered to have Rai stage III CLL during a routine physical examination in August 1999. The next month, he subsequently began weekly treatments with chlorambucil and prednisone for 8 weeks. Following the conclusion of the treatment regimen, he was found to be free of CLL but as a consequence of the therapy, developed chronic pancytopenia. He reported the requirement to undergo transfusions of 2 units of packed red blood cells every 10-14 days to maintain a hematocrit above 7%, and injections of 3 mg of oprelvekin (Neumega, Genetics Institute Inc, St Davids, Pa; recombinant human interleukin 11 [rhIL-11]) every 10 days for thrombocytopenia for the past 7 months.

I suggested the possibility that acupuncture might be of some benefit for the myelosuppression, and the patient was anxious to try. We then discussed the possibility of using acupuncture to help correct the anemia and thrombocytopenia with his primary care physician and oncologist. Although skeptical, they agreed to suspend the transfusions and oprelvekin therapy for a brief period to see if acupuncture would be of any benefit. Provisions were made that the patient would continue to have weekly complete blood cell count determinations. It was agreed that if at any time during the treatment sessions he developed any apparent infectious complications, his hematocrit fell below 7%, or if his platelet count did not increase to above 20 x 103/mL, he would immediately resume the transfusions and oprelvekin. Acupuncture therapy for restless leg syndrome was discontinued during these treatment sessions.

His hemoglobin, leukocyte, and platelet counts for 2 months prior to beginning electroacupuncture treatment are illustrated in Figures 1-3. Physical examination revealed a 61-year-old white man who appeared chronically fatigued, pale, and occasionally short of breath. His affect was somewhat depressed, but he denied symptoms of depression. Initial vital signs were remarkable for symptoms of orthostatic intolerance13,14 manifested by a progressive elevation in resting heart rate from 72/min to 128/min while standing for 15 minutes,
without significant changes in blood pressure (110/78 mm Hg).

HEENT examination findings were unremarkable. Chest examination revealed bibasilar rales to auscultation without rubs, rhonchi, or wheezing. Cardiovascular examination revealed a soft S2 gallop, but no other rubs or murmurs were detected. Results of the abdominal examination were unremarkable. The patient's extremities were significant for mild pitting edema and a well-healed surgical incision in the left lower leg secondary to a gunshot wound. Neurological examination revealed normal muscle mass, tone, and strength. Deep tendon reflexes were present, 2+ and bilaterally symmetrical. The patient had a mild reduction in vibratory sensation in both lower extremities, left greater than right, as well as diminished proprioception sense of both lower extremities, also greater on the left than the right.

At the time of presentation, his medications included oprelvekin, 3 mg every 10 days; allopurinol, 300 mg/d; furosemide, 20 mg/d; amitriptyline, 25 mg at bedtime; and acetaminophen with codeine, 1 tablet every 6 hours. His medical history included restless leg syndrome and CLL. In addition to the surgical incision mentioned above, he had a tonsillectomy early in life. He reported no allergies. The patient was a pack-a-day smoker for 40 years and occasionally consumed alcohol.

METHODS
The following acupuncture points (Table 1) were chosen based on their classical descriptions suggesting the ability to influence the hematopoietic system, as well as their known anatomical relationship to the sympathetic and parasympathetic nervous systems.

Table 1. Points Used in Electroacupuncture

Point

Name

Function

Peripheral Nerve

Segment

BL11

Dashu

Point of the Sea of Blood

Primary ramus

T1

BL 17

Geshu

Hui-Meeting point of Blood

Primary ramus

T7

LR 3

Tai Chong 

Nourishment of Liver Blood 

Deep peroneal nerve

L5, S1

SP 6

San Yin Jiao 

Three Yin Intersection 

Tibial nerve

S1, S23


Consent was obtained and the patient was initially placed in a supine position on the treatment table and 4, 32-gauge, 60-mm Seirin "L" type (Seirin Kasei Co, Shimizu City, Japan) acupuncture needles were inserted bilaterally to a depth necessary to elicit the traditional De Qi sensation at points LR 3 and SP 6. The patient was then turned to a prone position and 4, 32-gauge, 60-mm Seirin "L" type acupuncture needles were inserted bilaterally to a depth necessary to elicit the traditional De Qi sensation at points BL 11 and BL 17. The needles were subsequently manipulated by twirling in a clockwise direction to enhance the De Qi sensation and produce a "tonifying" stimulation. Following insertion and manipulation of the needles, an AWQ-104 Series (OMS Medical Supplies, Braintree, Mass) microcurrent generator with an asymmetrical biphasic waveform pattern, a pulse width of 400 ms, and a continuous duty cycle was used to stimulate the needles.

Bladder points were connected to the microcurrent stimulator in a montage similar to those used in Craig-PENS (percutaneous electrical nerve stimulation) therapy. The negative terminal was connected to BL 17 on the patient's left side, with the positive terminal connected to BL 11 on the left; BL 11 on the patient's right side was connected to the positive terminal,l and the negative terminal connected to BL 17 on the patient's right side. These points were electrically stimulated with an alternating frequency of 5 and 100 Hz with a current setting of 20 mA.

Distal points were also electrically stimulated bilaterally. The negative terminal of the microcurrent stimulator was connected to LR 3, and the positive terminal to SP 6 on the ipsilateral side. This same pattern was duplicated on the patient's opposite side. These points were electrically stimulated with a constant frequency of 5 Hz and a current setting of 20 mA.

Prior to each treatment session, the microcurrent generator was calibrated using a Kaito MY66 digital multimeter (Kaito Electronics, Walnut, Calif) and then connected to the needle electrodes for 30 minutes at each treatment session.The patient received 8 consecutive treatments over a 2-month period. The point selection and electroacupuncture current settings remained constant for all treatment sessions. 

RESULTS
The patient's overall hematological indices stabilized following the initiation of treatment and he did not require any further blood transfusions. All hematological parameters began to show progressive improvement following the 5th treatment session. The overall results of the treatment sessions are summarized in Figures 4-6.

There were no adverse effects attributable to the acupuncture therapy noted at any time during or after the treatment sessions. The patient did report a slight worsening of his restless leg syndrome that was episodic in nature, but he was consoled by the fact that he did not require ongoing blood transfusions and also noted an improved sense of general wellbeing and increased energy. He was also tested for orthostatic intolerance, a marker of autonomic dysregulation, at the conclusion of his therapy. His blood pressure and heart rate were monitored every 5 minutes during a 30-minute period standing motionless. The results showed no significant change in heart rate or blood pressure.

Patient follow-up was conducted at 6 months and 1 year. Hemoglobin, leukocyte, and platelet counts were within normal ranges and the patient had not required any additional blood transfusions or oprelvekin administration.

DISCUSSION
Cytotoxic chemotherapy kills neoplastic cells as well as rapidly growing normal cells. Hematopoietic cells are particularly vulnerable to cytotoxic drugs because of their high renewal rate. Anemia, granulocytopenia, and thrombocytopenia are common toxicities, but these can be existing conditions as a manifestation of the underlying disease and may be exacerbated by the therapy.15,16 Generally, these conditions resolve spontaneously following the cessation of therapy, and can be enhanced by the administration of erythrocyte-, granulocyte-, or platelet-stimulation factors in most non-myeloid cancers.17,18 In this case, the patient had a myeloid line-derived cancer and could be treated only with blood transfusions and oprelvekin, an rhIL-11 platelet-stimulating factor.

Figure 1. Pretreatment Hemoglobin Measurements

Figure 2. Pretreatment Leukocyte Counts

Figure 3. Pretreatment Platelet Counts


Oprelvekin is an effective therapy for the treatment of thrombocytopenia in many patients. The likelihood of requiring a platelet transfusion in rhIL-11-treated patients receiving chemotherapy is approximately 40% lower than the risk for untreated patients, and responses are normally noted by the 9th day following administration.17

However, in this case, the patient had received a prolonged course of oprelvekin therapy without clinical response. In addition, despite the cessation of chemotherapy, the patient did not experience any resolution of his anemia and required blood transfusions every 10 days to maintain a hemoglobin concentration between 7-8 g/dL.

It is entirely possible that the patient's condition began to improve spontaneously, and that the improvements noted were coincidental with his electroacupuncture treatments. However, given the fact that spontaneous recovery of bone marrow function following chlorambucil therapy is usually seen within several weeks following the cessation of therapy, and until this patient's electroacupuncture treatments began, he had sustained pancytopenia for at least 7 months following the cessation of chemotherapy, this would seem an unlikely explanation.

The regulation of the hematopoietic system is influenced by multiple factors, and the role of neurohumoral factors, cytokines, and the autonomic nervous system in hematopoiesis is a rapidly growing and complex area of investigation.19 Various factors have been identified as playing regulatory roles in hematopoiesis that encompass effects on the proliferation, survival, and migration of myeloid progenitor cells, including interleukins 1, 2, 6, and 10; erythropoietin; granulocyte-, macrophage-, and megakaryocyte-colony stimulating factors; and others.20-24

Although it is beyond the scope of this article to review all the possible mechanisms by which electroacupuncture may influence hematopoiesis, I have chosen to focus on the potential role of the autonomic nervous system in the regulation of hematopoiesis in this case. This hypothesis was based on several factors including the patient's initial physical findings suggestive of a mild dysautonomia, as well as research that suggests that patients with autonomic dysfunction show a blunted response to hematopoietic-stimulating factors.25

Several factors may have contributed to the findings of dysautonomia in this case. For example, while common adverse effects of chlorambucil therapy include nausea, vomiting, alopecia, and bone marrow suppression, it is also known to produce various forms of neuropathy.16,26 Also, researchers have identified various forms of autonomic nervous system dysfunction in patients with restless leg syndrome and movement disorders.27,28

Therefore, it does not seem unreasonable to consider the possibility that this patient's pre-existing restless leg syndrome, in addition to chlorambucil therapy, may have produced or contributed to the autonomic dysfunction, possibly blunting his response to oprelvekin and other endogenous hematopoietic-stimulating factors.

Autonomic Control of Erythropoiesis
Several research studies have focused on the effects of the autonomic nervous system's role in the regulation of hematopoietic processes.25,29-31 The effect of autonomic dysfunctions on anemia in various neurological disorders, such as familial amyloidotic polyneuropathy (FAP) type I, pandysautonomia, and Shy-Drager syndrome, was investigated by Ando et al.29 They found that patients with FAP and pandysautonomia had significant anemia and hypoplastic bone marrow comparable with the severity of the autonomic dysfunctions, while Shy-Drager patients exhibited mild anemia and normal bone marrow cytoarchitecture. Treatment with erythropoietin improved orthostatic hypotension as well as anemia in 4 patients with FAP, but had no effect in the Shy-Drager group. Similarly, Biaggioni et al25 investigated 84 patients with known autonomic dysfunction and orthostatic hypotension. They found that 32 of the 84 patients were severely anemic, had low plasma norepinephrine levels but normal erythropoietin levels. This suggests that in the presence of autonomic dysfunction, responses to endogenous erythrocyte-stimulation factors may be blunted, leading to anemia, and that autonomic dysfunction may be connected with erythropoiesis.  This concept has been further supported by findings demonstrating that lymphocytes bear cholinergic receptors, while granulocytes bear adrenergic receptors on the cell surfaces that may be involved in the proliferation, survival, and migration of the cell lines.32

While acupuncture stimulation has long been known to modulate various autonomic functions such as vasodilatation, heart rate, and gastrointestinal motility,33 Mori et al34 were able to demonstrate that electroacupuncture may produce immunomodulation of both granulocyte and lymphocyte levels through stimulation of the autonomic nervous system. In their experimental studies, Mori and colleagues identified 3 groups of healthy young volunteers: group 1 showed pretreatment patterns of granulocytosis and lymphocytopenia; group 2 showed pretreatment patterns of granulocytopenia and lymphocytosis; and group 3 had a normal pretreatment pattern. Each patient was treated with electroacupuncture at LI 4 and LU 6 bilaterally at 1 Hz for 20 minutes. Blood samples were collected 10 minutes prior to treatment, 10 minutes after the start of stimulation, and 20 minutes following the start of stimulation. In addition, the heart rate was monitored in all patients both before and during the treatment sessions as a measure of parasympathetic activity. Results of the study showed a generalized normalization across all groups, and those individuals with granulocytosis and lymphocytopenia experienced an elevation of the lymphocyte count and a decrease in the granulocyte count. A similar reversal in pattern was noted in group 2 with granulocytopenia and lymphocytosis. Those with normal patterns of granulocytes and lymphocytes showed no significant changes in absolute numbers. All patients had a decrease in heart rate during electroacupuncture, confirming parasympathetic nerve stimulation.

Figure 4. Hemoglobin Measurements During Treatment

Figure 5. Leukocyte Counts During Treatment

Figure 6. Platelet Counts During Treatment



This study demonstrated once again that acupuncture stimulation tends to correct or modulate the homeostatic balance of the individual undergoing treatment. Both those with excessive, as well as those with diminished numbers of granulocytes, were normalized when treated with identical treatment points. As an aside, Mori et al also mention unpublished experience in which electroacupuncture induced long-lasting normalization of leukocyte patterns in several patients.34

Notable is that the acupuncture points selected in this case, although they were initially chosen because of their classical descriptions to influence blood, are also potent sympathetic and parasympathetic points. Also supporting the possible role of the autonomic nervous system dysfunction in this case is the simultaneous improvement noted in both the hematological values and the resolution of the patient's orthostatic intolerance. However, it is difficult to explain the lack of improvement noted in the restless leg syndrome with this hypothesis.

Although it is difficult to ascertain the underlying mechanisms of action of electroacupuncture in regard to hematopoietic stimulation, it is reasonable to suggest that, in this case, electroacupuncture may modulate proliferation of erythrocytes, granulocytes, and megakaryocytes through autonomic nervous system stimulation.

CONCLUSION
Acupuncture appears to be a promising therapeutic modality for the treatment of myelosuppression due to cytotoxic chemotherapy for lymphoproliferative disease. Although all the mechanisms that may underlie this phenomenon are not known, this case suggests some interesting immunological responses induced by electroacupuncture. The technique is minimally invasive, requires only 30 minutes per week, and was associated with no significant adverse effects or safety issues. Perhaps this report will encourage other clinicians who are treating anemic patients to use this procedure and report their findings to help determine the overall applicability of electroacupuncture for chemotherapy-induced myelosuppression.

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AUTHOR INFORMATION
Dr Gerald W. Grass is Board-certified in Emergency Medicine, and is a Fellow of the Association of Emergency Physicians, and a Diplomat of the American Board of Medical Acupuncture and the American Academy of Pain Management. Dr Grass maintains a private practice specializing in Medical Acupuncture and Pain Management.
Gerald W. Grass, MD*
1245 Park Ave, Suite 2G
New York, NY 10128
Phone: 212-369-9173 • E-mail: gwgrass@grassmedical.com

*Correspondence and reprint requests

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