Chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder arising from neoplastic transformation of pluripotent stem cells and is characterized clinically by excessive growth of myeloid cells and their progenitors.1 CML results from an acquired injury to the DNA of a stem cell in the marrow. The injury is not present at birth. Currently researches do not understand what produces this change in the DNA in patients with CML.

This change in the stem cell confers a growth and survival advantage on the malignant stem cell. The result of this change in the DNA of the stem cell is the uncontrolled growth of white cells, which can cause the number of white blood cells in the bone marrow to be 20 to 40 times higher than normal. If unchecked, this may lead to a massive increase in a person's concentration of WBC in the blood.

The cause of CML and the mechanisms that determine its progression are unknown at present. It is an acquired disease, but there are no clues to its etiology other than an increased risk in individuals exposed to ionizing radiation.2

Most cases of CML affect adults and occur very rarely in children (4% of childhood cases). CML is about half as common as chronic lymphocytic leukemia (CLL). CML is diagnosed most commonly is people who are middle-aged following referral from primary care physicians.3 Men and women are affected equally. Many patients are symptomatic at a time of diagnosis, and are diagnosed because of abnormalities detected on blood counts obtained for unrelated reasons. Acceptable criteria for diagnosis include monocytosis with less than 5% circulating blasts. In bone marrow biopsies, hypercellularity is evident in most cases. Bone marrow aspirate reveals myeloid and monocytic predominance, with blast forms variably increased up to 20%, and a decrease in other hematopoietic elements.4 Dysplasia in maturing hematopoietic elements may be present.

Clinical onset of CML is frequently insidious with weakness, infections, or bleeding. Splenomegaly and hepatomegaly are present in about 40% of patients. A patient may also present with abdominal fullness or easy satiety secondary to an enlarged spleen. Hematological findings include moderate anemia, moderate thrombocytosis, and a marked granulocytic leukocytosis with a specific differential count.5

On a cytogenic and molecular level, most patients with CML demonstrate BCR-ABL fusion genes in hematopoietic progenitor cells, which result form a reciprocal translocation between chromosomes 9 and 22. This translocation leads to a shortened chromosome 22, called the Philadelphia chromosome.6 The DNA removed from chromosome 9 contains most of the proto-oncogene designated ABL (for Abelson). The break in chromosome 22 occurs in the middle of a gene designated BCR (for breakpoint cluster region). The resulting Philadelphia chromosome has the Section of BCR fused with most of ABL. The Philadelphia chromosome was the first specific karyotype marker found to characterize a particular human neoplastic disease, namely CML. Research shows that near 99% of CML patients are Philadelphia chromosome positive.2 Chromosome binding techniques identified the Philadelphia chromosome as a deleted chromosome 22, and revealed that the deleted part was translocated to the distal long arm of chromosome 9. Translation of the fusion products yields chimeric proteins of variable size that have increased tyrosine kinase activity of the BCR-ABL protein, which blocks the cell death (apoptosis) pathway.6 Currently, curative treatment aimed at eliminating the Philadelphia positive cells to decrease tyrosine kinase activity is being studied.

Philadelphia chromosome positive cells appear to lose their capacity to differentiate and the accumulation of undifferentiated blast cells is directly or indirectly responsible for the invariably fatal outcome of this leukemia. The prognosis for Philadelphia chromosome negative cells is similar to that for Philadelphia positive CML.7

The course of CML4 can be divided into 3 clinical periods: stable or chronic phase, accelerated phase, and an acute phase also known as blast crisis. Early in the disease, symptoms are mild and nonspecific: fatigue, fever, malaise, decreased exercise tolerance, weight loss, and night sweats. In the chronic phase, the bone marrow is predominantly myeloid and hypercellular, myeloblasts are less than 5% of all cells, and maturing granulocytes are readily identified. In addition, eosinophils and mast cells may be increased.

Within an average of 3 or 4 years after diagnosis of chronic phase CML, metamorphosis through periods of accelerated growth and blast crisis occurs. The accelerated phase, which typically lasts 3 to 6 months, refers to a period of clinical and hematological deterioration without a marked increase in the blast percentage. During this period, the bone marrow myeloblast count increases to 5% to 30%. Progressive splenomegaly, anemia, and thrombocytosis invariably accompany this metamorphosis; and additionally, fever and resistance to therapy often manifest.

In blast crisis, which typically lasts 2 to 4 months, CML becomes acute with blasts exceeding 30% of the marrow cellularity or peripheral blood. Morphological and immunological features of blasts in blast crisis may be discordant. Blast crisis is often heralded by a prodrome of fever, bone pain, weight loss, and increasingly splenomegaly. During this blast crisis phase, white cell counts become erratic and demonstrate increased basophils and immature forms. Blast crisis represents evolution to overt acute leukemia and occurs in about 85% of patients.

The type of treatment used for CML is dependent upon the phase of disease. Treatment given during the chronic phase responds very well to simple, nonintensive therapy. The majority of patients live at least 5 years when the disease is diagnosed and treated in the chronic phase.3 Treatment in chronic phase is palliative, directed simply at control of white blood cells and platelet counts via single agent chemotherapy. Survival is clearly prolonged by therapy including alpha interferon, hydroxyurea, and allogenic bone marrow transplantation (BMT). To date, allogenic BMT affords the only potential cure for CML. It is most successful when performed in the chronic phase, where long-term disease free survival approaches 50% to 60%.3 Once CML undergoes metamorphosis to an accelerated and then acute phase, it responds poorly or sometimes not at all to therapy, even when it is intensive.' Therefore, treatment options during the accelerated phase are to increase hydroxyurea and try combination chemotherapy. Once the CML has reached the acute phase, it is clinically identical to "de novo" as acute myelogenous or acute lymphocytic leukemia except that it is entirely refractory to treatment. In the acute phase, life expectancy is optimistically less than 1 year.

Current studies in treatment of CML offer promise of a new, biologically targeted therapy. ST1571 is an inhibitor of protein tryosine kinases, which blocks the cell death (apoptosis) pathway. ST1571 seems to mediate its inhibitory effects by occupying the kinase pocket of the tyrosine kinase, thus preventing successful binding of ATP to the kinase enzyme.8 Having generated a relatively selective tyrosine kinase inhibitor for the BCR-ABL protein, investigators demonstrated that ST 1571 could inhibit the growth of the BCR-ABL positive cells in vitro.9

Physical therapy interventions for patients with CML will vary depending on the phase of the disease and the course of treatment. In the chronic phase, where chemotherapy, alpha interferon, hydroxyurea, or allogenic BMT may be used as treatment, these patients are often hospitalized for an extended time period. As a result, they will be at risk for a generalized loss of strength and endurance.

It is important to determine the patient's prior level of function in order to develop an appropriate plan of physical therapy care. The therapist should develop an active exercise program that will maintain strength, range of motion, and endurance. However, with the various side effects of treatment and the symptoms of CML, it is important for the therapist to monitor hemoglobin, platelet, and fatigue levels. Each chemotherapy agent may result in drug specific side effects that might include neuropathies, orthostatic hypotension, impaired balance, respiratory disease, and pulmonary fibrosis." Therefore, physical therapy interventions should be altered to compensate for and to minimize the impact these side effects will have on the patient's functional mobility and ability to complete their activities of daily living.

Patients who receive BMT in the chronic phase of CML have further physical therapy considerations. Typically, these patients are placed on high doses of steroids to prevent graft verus host disease therefore increasing the opportunity for development of osteoporosis, aseptic necrosis, and myopathics.10 Additionally,

BMT patients may require prolonged bed rest, dialysis, and intubation. At this time, prevention of deconditioning should be done via positioning, range of motion, and active exercises. Furtherance of therapy should include progressive ambulation and therapeutic exercises to improve and maintain strength, range of motion, balance, coordination, and endurance.

For those patients in the acute phase, who are very debilitated and have a relatively short life expectancy, the goal of therapy should be to maximize or maintain the patient's quality of life and enable them to remain in their home environment. This may be accomplished by maximizing the patient's functional ability and providing family and patient education regarding daily care routines, positioning, and transfers.

REFERENCES

1. Murphy GP, Lawrence W, et al. American Cancer Society Textbook of Clinical Oncology. 2nd ed. Atlanta, Ga: American Cancer Society; 1995:490-493.

2. Deisseroth AB, Arlinghaus RB. Chronic Myelogenous Leukemia: Molecular Approaches to Research and Therapy. Houston, Tex: Marcel Dekker, Inc.; 1991.

3. Hill JM, Meehan KR. Chronic myelogenous leukemia: curable with early diagnosis and treatment. Postgrad Med. 1999;106(3):149-152.

4. Rector JT, Veillon DM, Schumacher HR, et al. Chronic leukemias of myeloid origin. Med Lab Obs. 1998;30(12):28-31.

5. Spiers AS. Clinical manifestation of chronic granulocytic leukemia. Semin Oncol. 1995;22(4):380-395.

6. Faderl S, Talpaz M, Estrov Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207-219.

7. Wujcik D. Update on the diagnosis of and therapy for acute promyelocytic leukemia and chronic myelogenous leukemia. Onc Nurs Soc Online. 1996;23(3):1-16.

Goldman JM, Melo JV. iargeting the bcr-abl tyrosine Kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1084-1086.

9. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the abl tyrosine kinase on the growth of bcr-abl positive cells. Nat Med. 1996;2:561-566.

10. Zoerink-Baker M. Adult leukemias and physical therapy considerations. Rehab Oncol. 1998;16(1):19-21.

Michelle B. Lucero, SPT

Cancer Rehabilitation

Medical College of Virginia/ VCU

Richmond, Virginia

Copyright Rehabilitation in Oncology 2001
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