Uncommon leukemias: Implications for clinical practice

Uncommon Leukemias: Implications for Clinical Practice Carol A. Sheridan

CUTE nonlymphocytic leukemia (ANLL) is a group of diseases that originate in a disordered multipotent stem cell, resulting in the overproduction of immature myeloid cells and the decreased production of platelets and erythrocytes; eventually the host succumbs to signs and symptoms of bone marrow failure. Subcategories of ANLL are recognized by clinicians and labeled as "rare" leukemias. This review will focus on three uncommon leukemias; acute monocytie leukemia (Ms), erythroleukemia (M6), and acute megakaryoblastic leukemia (MT) (see Table I). In addition, an unusual chronic leukemia, hairy cell leukemia, will be discussed. In an effort to standardize terminology, in 1976, the French-American-British cooperative group proposed and accepted diagnostic criteria for establishing and categorizing various forms of ANLL. The treatment for the various forms of ANLL is the same; however, the complications and prognosis associated with each form are different. ACUTE MONOCYTIC LEUKEMIA

In order to make the diagnosis of acute monocytic leukemia (Ms), 80% or more of the nonerythroid cells in the bone marrow must be monoblasts, promonocytes, or monocytes.2 Acute monocytic leukemia (AMoL) can be further subdivided based on differentiation of the cells. The MSA subcategory is acute monoblastic leukemia representing poorly differentiated cells. The bone marrow demonstrates early monoblasts with less than 3% mature promonocytes or monocytes. The MsB category is AMoL, representing partial differentiation. 3 The bone marrow reflects a mixture of monoblasts and promonocytes. To assist in the diagnosis, histochemical stains, From the Departments of Medicine and Nursing, Memorial Sloan-Kettering Cancer Center, New York, NY. Carol A. Sheridan, RN, MSN, OCN: Clinical Nurse Specialist--Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Carol A. Sheridan, RN, MSN, OCN, Department of Nursing, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. © 1990 W.B. Saunders Company. 0749-2081190/0601-0007505.00/0 44

nonspecific monoclonal antibodies, and cytogenetic tests for abnormalities may be helpful in further differentiating between these two subcategoties. The M 5 subcategory represents about 8% to 10% of all acute non-lymphocytic leukemias.4"7 The diagnosis of acute monoblastic leukemia (MsA) is usually made in children and young adults. Despite leukemic transformation, the monocytes retain their ability to migrate, and they infiltrate tissue. As a result, a significant amount of extramedullary disease is seen in the liver, spleen, lymph nodes, skin, and gingiva. Infiltration of the central nervous system (CNS) can be seen in 5% to 20% of these Patients. 4'6 Patients with acute monocytic leukemia generally have higher leukocyte (>100,000/ttL) and platelet counts than other forms of ANLL. Monoblasts are the largest white blood cells (WBC) and, as such, hyperleuk0cytosis is considered an oncologic emergency. The potential for leukostasis in the capillary beds of either the lungs or brain presents the potential for life-threatening complications. Pulmonary leukostasis can exhibit a range of clinical signs from transient pulmonary infiltrates to severe hypoxia requiring intubation and respiratory support. As capillary endothelial damage progresses, hemorrhage into the alveolar space may occur, further compromising gas exchange, and contributing to the hypoxic state, s Intensive leukapheresis has been used to rapidly reduce the WBC count, followed by treatment with antileukemic medication. One third to one half of all M 5 patients have thrombocytopenia (<50,000/I.tL) at the time of initial presentation. Laboratory evidence consistent with a diagnosis of disseminated intravascular coagulation (DIC) may be present and is second only to acute promyelocytic leukemia (M3) in its incidence of DIC in ANLL. 9 The blast cells that occur in monocytic leukemia contain muramidase (lysozyme). As monoblasts lyse spontaneously or secondary to antileukemic treatment, muramidase is released and excreted through the kidneys. The serum concentration of lysozyme is elevated in 67% to 100% of patients. 4 Lysozyme is a known renal tubule toxin and, as a result, hypokalemia and renal tubule acidosis occur. These patients require intensive monitoring Seminars in Oncology Nursing, Vol 6, No 1 (February), 1990: pp 44-49

UNCOMMON LEUKEMIAS

45 Table 1. Characteristics of Uncommon Leukemias

Type of Leukemia Acute monocytic leukemia Ms MSA Msa Erythroleukemia Ms Megakaryoblastic M7 Hairy cell

Bone Marrow Cellularity

Incidence (%)

80% monoblasts

8-10

Promonocytes or monocytes Poorly differentiated Partially differentiated

Age Groups Childhood

Extramedullary infiltration

Early adulthood

Leukostasis DIC CNS involvement Renal failure Pain

50% erythroblasts

4-5

Age >50 yr

30% megakaryoblasts

3-12

Adults

Hairy cells

2

Adults

and support of their fluid and electrolyte balance to prevent irreversible renal failure.4'9'1° Central nervous system involvement in monocytic leukemia is common. Clinical features at the time of diagnosis that are predictive for subsequent CNS leukemia are high leukocyte counts, elevated levels of lysozyme, and evidence of extramedullary infiltrates. In adult ANLL, CNS prophylaxis has not demonstrated an improvement in response rate, but should be considered to prevent recurrence in AMoL. 9'it Recent improvements in antileukemic therapy such as high-dose cytosine arabinoside may be effective in these patients because this therapy has the benefit of crossing the bloodbrain barrier, thereby obviating the need for local CNS treatment with either cranial irradiation or intrathecal medication. 12-15 ERYTHROLEUKEMIA

Erythroleukemia (M6) is truly an uncommon leukemia, representing 4% to 5% of all acute nonlymphocytic leukemia. 3-12'x6 The disease has a somewhat contradictory history, with many terms being used over the past century to describe various phases of the same disease. Copelli in 1912 used the term erythromatosis. In 1917, DiGuglielmo described a malignant process in the erythroid series with little involvement of the myeloid line, thus giving rise to the term DiGuglielmo's syndrome. Finally, in 1940, Moeschlin coined the term erythroleukemia. 17 As recently as 1985, the French-AmericanBritish cooperative group revised their criteria for the diagnosis of acute erythroleukemia. There

Common Complications

Bleeding, anemia; osteosclerotlc and osteolytic lesions Splenomegaly; myelosuppression

must be 30% or more type I or type II blast cells in the nonerythroid nucleated cells, but at least 50% of the total number of the nucleated cells must be erythroblasts? Due to the diagnostic criteria changes over the past decade, and earlier historical reports describing this syndrome, the literature is replete with case reports that would otherwise now be classified as erythroleukemia. The disease erythroleukemia has been described as having three phases. 17:8 The first is the primary erythroid phase, sometimes called erythemic myelosis or DiGuglielmo's syndrome. The bone marrow reflects an erythroid hyperplasia, and the patient may show a megaloblastoid anemia. The second phase, sometimes described as the transitional phase, is erythroleukemia. Here both. ei'ythroblastic and myeloblastic proliferationis evident. Finally, in the purely myeloblasti'c i~hase, the myeloblast is the predominant Cell. Frequently this marrow is indistinguishable from an M l or M 2 type of ANLL. Clinically these patients present with a similar picture to other ANLL patients. Most patients are over the age of 50, and there is a male predominance. Common presenting signs and symptoms include pallor, weakness, and lethargy. One third of all patients may present with non-lifethreatening bleeding (petechiae and/or hematomas). Signs of distant 6rgan involvement, hepatosplenomegaly and lymphadenopathy, may be present in approximately 25% of all patients. 4 w e infrequently think of pain as a problem for leukemia patients. Hertzel and Gee described 46 cases of erythroleukemia in which one third of their patients experienced joint, abdominal, back, and

46

CAROL A. SHERIDAN

chest pain. 17 In all patients, they were able to associate this pain with increased levels of immunoglobulins (IgG, IgA, IgM), the presence of rheumatoid factor, or a positive antinuclear antibody. Unfortunately, the etiology of these immunologic findings remains unclear in the clinical course of erythroleukemia. The treatment of erythroleukemia is similar to other subtypes of ANLL involving induction remission regimens. Some authors make the case that the advanced age of many patients favors supportive care, such as transfusions, in lieu of more aggressive antileukemic therapy. Clearly, the patient's underlying condition, preexisting medical problems, and the presence of infection and bleeding will influence that patient's choice as to whether or not to begin antileukemic therapy. Two points must be made: age is not a reason to withhold therapy, and the patient has a fight to make an informed choice. 19 The nursing staff can play a pivotal role in assisting patients and their families in making these choices. MEGAKARYOBLASTIC LEUKEMIA

Acute megakaryoblastic leukemia (MT) has been described over the past 50 years. Terms such as "acute myelofibrosis" and "malignant myelosclerosis" have been used in the literature. 4 In 1985, megakaryoblastie leukemia was added to the revised French-American-British cooperative group's accepted diagnostic criteria. 2 Before 1985 the literature had multiple reports describing a heterogeneous group of hematopoietic disorders. Megakaryoblastic leukemia is a rare variant, representing 3% to 12% of all adult cases of ANLL. 4'16 The standardization of diagnostic criteria since 1985 will promote accurate description of the clinical course of this disease. The diagnosis of acute megakaryoblastic leukemia (MT) can be made when 30% or more of the blast cells are of the megakaryocyte line. This must be substantiated by either a positive platelet peroxidase reaction or by reactivity with a specific platelet antibody. Frequently, attempts to make the diagnosis via bone marrow aspiration result in what clinicians describe as "dry taps." These patients may have a significant amount of myelofibrosis, and bone marrow biopsy is necessary in these cases. Clinically the patient presents with early symptoms of bone marrow failure: anemia, fatigue,

weakness, fever, and bleeding. These symptoms precede the patient reporting for medical attention by 1 to 3 months. Although rare, lymphadenopathy and splenomegaly may be present at initial diagnosis. Profound thrombocytopenia is present in over 60% of all patients, contributing to the bleeding and anemia that are seen initially.4 Osteosclerotic and osteolytic lesions have been described in acute megakaryoblastie leukemia. Patients are at risk for pathological fractures as a result of these lesions, and nursing measures should be initiated to protect patients from this complication. As in all variants of ANLL, if untreated, the accelerating malignant process results in death in a few months. Induction chemotherapy including cytosine arabinoside and daunorubicin should be promptly initiated. HAIRY CELL LEUKEMIA

Hairy cell leukemia represents approximately 2% of all adult leukemias diagnosed annually in the United States. Unlike the other rare leukemias, effective therapy leading to long-term disease control is possible. First coined "hairy cell" leukemia by Boumocle in 1958, 20 the disease has also been called leukemic reticuloendotheliosis. 17'21 This is a chronic disease that involves a lymphoproliferative process. Most investigators agree that the malignant cell is of the B-lymphocyte origin, although rare reports of T-cell hairy cell leukemia exist. 22'23 Two components contribute to the development of symptoms in these patients. First, there is an overproduction of hairy cells which infiltrate the bone marrow and spleen. This may result in a decreased production of normal cell lines (erythrocytes, granulocytes, and megakaryocytes). Second, the spleen may sequester increasing numbers of normal hematopoietie cells. The cause of the diverse cytopenias, (granulocytopenia, thrombocytopenia, anemia) that hairy cell leukemia patients experience may be totally related to the disease process, before the initiation of any treatment. The oncology nursing and medical literature is laden with references describing the adverse effects of granulocytopenia. There is, in fact, an inverse relationship between the degree and duration of neutropenia and the risk of life-threatening infection.24 In addition to granulocytopenia, hairy cell leukemia patients also have other changes in their immune system that place them at increased

UNCOMMON LEUKEMIAS

risk for infection. Mackowiak and colleagues25 have proposed a defect of cellular immunity in hairy cell leukemia patients. Yam et a126 were able to demonstrate that leukocytes from hairy cell leukemia patients also had mobilization and migration problems. This represents a qualitative defect in granulocytes. Finally, in 1984, Golomb and colleagues completed an 8-year retrospective review of 127 hairy cell leukemia patients to determine incidence of infection and the effect of infection on patient outcome. 27 They found that 47 (37%) had documented, culture-positive infections, and that 40 (31.5%) had clinical/nondocumented infections. These patients had clinical infections, and culture results were either negative or not available. In addition, 40 (31.5%) patients had no significant infection. The total incidence of clinical infection from this series was 68.5%. The two most frequently occurring types of infections were bacteremia and pneumonia. They also found that patients without infections lived longer. There has been an explosion of treatment modalities available for hairy cell leukemia patients over the past 5 years. Treatment options now include splenectomy, radiation, chemotherapy, a n d biologic response modifiers.

Treatment Options Splenectomy. If splenomegaly develops and causes clinical symptoms such as abdominal pain, fullness, and difficulty eating, and if the patient's cytopenias become significant, requiring transfusions with red blood cells and/or platelets, a splenectomy may be recommended. The rationale for splenectomy in hairy cell leukemia is an attempt to remove the organ responsible for the increased destruction of peripheral blood cells. It is also an attempt to decrease the production of hairy cells by removing the spleen, the presumed source of growth factors in hairy cell leukemia. 23 The complete response rate is between 40% and 70%, the partial response rate is between 12% and 58%, and approximately 0 to 14% of patients may have no response at all in their hairy cell leukemia. Two factors preclude surgery as an early intervention: there is an increased risk of bacterial and viral infection, and approximately 35% to 45% of patients will have progressive disease within 5 years, requiring further medical treatments. Radiation therapy. Before 1984, splenic irradiation was used in patients whose underlying con-

47

dition (advanced age, chronic respiratory or cardiac disease) placed them at considerable risk for splenectomy. Low doses of radiation were used (250 to 600 cGy) and delivered at a slow rate (5 cGy/min). With the introduction of a-interferon, and its relatively minor side effects, radiation therapy is infrequently used. Along with the pancytopenia, hairy cell leukemia patients have evidence of bone involvement. Hairy cell infiltration into the matrix of long bones, or the axial skeleton, is responsible for the lytic lesions seen on radiographic examination.28 The time from initial diagnosis to the time of bone involvement averages 20 months. 29 The treatment for osteolytic lesions caused by hairy cell leukemia is local external beam radiotherapy to control pain and to prevent possible p a t h o l o g i c fractures. 21'28"29 Also, the systemic therapy may be changed to treat what is considered an advancing disease. Although skeletal involvement occurs in fewer than 3% of hairy cell patients, the morbidity associated with lytic lesions, chronic pain, and possible pathologic fracture is of concem to medical and nursing clinicians alike. Early recognition of patients developing bone involvement will assist the nurse in planning ways to prevent pathologic fractures. Chemotherapy. Spiers and colleagues in 1984 reported complete remissions in two patients using a new antimicrobial agent pentostatin (2 ldeoxycoformycin).3° This agent has been available since 1974, and was identified from the Streptomyces fungus. Although an effective agent, it is not without toxicities. 3°r31 Nausea and vomiting were noted within 12 to 24 hours of drug administration, and mild, asymptomatic increases in liver function levels were also observed. In addition, an initial decrease in hemoglobin, platelets, and granulocytes was noted within the first month of therapy. Increases in these cell lines began to occur after 4 weeks of treatment. Additional antineoplastic chemotherapy (zobrubicin, cytosine arabinoside, cyclophosphamide, low-dose chlorambucil, andhigh-dose methotrexate with leucovorin) has been u s e d . 32"34 Unfortunately, in hairy cell leukemia, the patients' bone marrow reserve is limited, and treatment with these agents is limited bybone marrow toxicity. Biologic response modifiers. Only within the past 5 years have clinicians been able to demonstrate the effectiveness of a-interferon in the treat-

48

CAROL A. SHERIDAN

ment of hairy cell leukemia. 3s Since then, a number of studies have been conducted to determine effective dosing, administration schedules, and management of side effects. Although its exact mechanism of action in hairy cell leukemia is unclear, a-interferon may have a direct antigrowth effect and may also promote stimulation of the immune system. 23"36 In treating patients with a-ii/terferon it is imPortant to remember that the first indication of a response is a decrease in the peripheral hairy cell count. Following peripheral complete blood counts is critical because 50% of all patients may have a decrease in their granulocyte and/or platelet count within the first month of treatment. 2a'37 Early signs of bleeding and either elevations or decreases in temperature should be promptly reported and assessed. Side effects described as minimal in the literature may actually cause significant distress for patients, as An influenza like syndrome, involving fatigue anorexia, malaise, fever, and chills, has been reported early in the course of treatment, but resolves as the patient continues therapy. Later toxicites, including the elevation of hepatic transaminase levels, depression, subtle memory loss, and peripheral sensory neuropathy have also been described. It is important for nurses to recognize that minor responses to et-interferrn may be functionally meaningful to patients and be associated with prolonged survival. Potential therapeutics for HCL. One of the potential drawbacks to antineoplastic chemotherapy in this group of patients is bone marrow suppression. Within the next decade we will see the initiation of clinical trials combining chemotherapeutic agents and colony-stimulating growth factors (CSFs). 23 In addition, cooperative multicenter studies should be initiated to determine the superior treatment regimen, in the initial treatment of hairy cell leukemia (splenectomy V et-interferon). 39

ethical activities. Specific nursing interventions aimed at supporting bone marrow suppressed patients have been addressed in the literature and other reports in this issue. 4°'4f The potential for oncologic emergencies in these rare leukemias is great. These include disseminated intravascular coagulation (DIC), cerebral and pulmonary leukostasis, sepsis, and acute renal failure. Recognition that patients are at risk for these acute events prepares nurses for their assessment, diagnosis, and plans of care. Eleven high-incidence problems for cancer patients have been described, and all can be applied to these patients. 42 Emotionally, patients and their families rely on nurses to assist them in coping with a new diagnosis of cancer, and/or dealing with the chronic nature of their disease. Open communication, firmly based on a thorough knowledge of the particular disease and treatment; will promote trust and a sense of comfort as the patient begins treatment. Finally, it is important for all nurses caring for cancer patients to identify their personal feelings and biases. In the current environment where clinical investigation is a part of everyday care, the nurse must be comfortable with the research process and the participation of human subjects in clinical trials. Nurses play a role in the development of clinical trials and the process of informed consent, and in the management of patients involved in clinical trials. Over the last 5 years, we have witnessed a dramatic increase in the number of therapies available for one particular rare leukemia (hairy cell leukemia). This has resulted in significant improvements in patient outcomes. In the next decade, our ability to combine and refine therapies will further enlarge our options for treatment of other forms of cancer, hopefully resulting in longer periods of disease-free survival for patients.

SUMMARY

The author wishes to thank the expert nursing staff on the oncologyunit at MontefioreMedical Center, Bronx,NY, who taught her much about the care of leukemiapatients and their families; and to DarleneShannonfor her secretarialassistance.

The nursing management of patients with rare leukemias involves physiologic, psychologic, and

ACKNOWLEDGMENT

REFERENCES

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UNCOMMON LEUKEMIAS

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in hairy cell leukemia with pentostatin (21-deoxycoformycin). N Eugl J Med 361:825-830, 1987 23. Steis RG, Longo DL: Update on the treatment of hairy cell leukemia, in Devita V, Hellman S, Rosenberg SA, (eds): Cancer Principles and Practice of Oncology, vol 2. Philadelphia, PA, Lippincott, 1988, pp 1-12 24. Newman KA: The leukemias. Nurse Clin North Am 20:227-234, 1985 25. Mackowiak PA, Demian SE, Sutker WL, et al: Infections in hairy cell leukemia. Am J Med 68:718-724, 1980 26. Yam LT, Chaudry AA, Janckila AJ: Impaired marrow granulocyte reserve and leukocyte mobilization in leukemic reticuloendotheliosis. Ann Intern Med 87:444-446, 1977 27. Golomb HM, Hadad LJ: Infectious complications in 127 patients with hairy cell leukemia. Am J Hematol 16:393-401, 1984 28. Quesada JR, Keating MJ, Libshitz HI, et al: Bone involvement in hair cell leukemia. Am J Med 74:228-231, 1983 29. Lembersky BC, Ratain MJ, Golomb HM: Skeletal complications in hairy cell leukemia: Diagnosis and therapy. J Clin Oncol 6:1280-1284, 1988 30. Spiers ASD, Parekh S J, Biship MB: Hairy cell leukemia: Induction of complete remission with pentostatin (2 Ideoxycoformycin). J Clin Oncol 2:1336-1342, 1984 31. Spiels ASD, Moore D, Cassileth PA, et al: Remission in hairy cell leukemia .with pentostatin (2Ldeoxycoformycin). N Engl J Med 316:825-830, 1987 32. Golomb HM, Schmidt K, Vardiman JW: Chlorambucil: Therapy of twenty-four postsplenectomy patients with progressive hairy cell leukemia. Semin Oncol 11:502-506, 1984 (suppl 2) 33. Joosten P, Hagenbeck A, Lowenberg B, et al: High-dose methotrexate with leueovorin rescue: Effectiveness in relapsed hairy cell leukemia. Blood 66:241-242, 1985 34. Portlock CS: Therapeutic approaches to the treatment of hairy cell leukemia. Semin Oncol 13:55-59, 1986 (suppl 5) 35. Quesada JR, Rueban JR, Manning J r , et al: Alpha interferon for induction of remission in hairy cell leukemia. N Engl J Med 310:15-18, 1984 36. Gutterman JU: The role of interferons in the treatment of hematologic malignancies. Semin Hematol 25:3-8 1988 (suppl 3) 37. Golomb HM, Jaeobs A, Fefer A: Alpha-2 interferon of hairy cell leukemia: A multicenter study of 64 patients. J Clin Oncol 4:900-905, 1986 38. Hahn MB, Jassak PF: Nursing management of patients receiving interferons. Semin Oncol Nurs 4:95-101, 1988 39. Steis RG, Smith JW, Urba WJ: Resistance to recombinant interferon alfa-2a in hairy cell leukemia associated with neutralizing anti-interferon antibodies. N Engl J Med 318:14091413, 1988 40. Campbell JB, Preston R, Smith KY: The leukemias: Definition, treatment, nursing care. Nurse Clin North Am 18:523-541, 1983 41. Johnson BL: Leukemias, in Groenwald SL, (ed): Cancer, Nursing Principles and Practice. Boston, MA, Jones & Bartlett, 1987, pp 654-670 42. American Nurses' Association and Oncology Nursing Society: Standards of Oncology Nursing Practice. Kansas City, MO, American Nurses' Association, 1987