Subspecialty Clinics: Hematology A Clinical Update on Chronic Lymphocytic Leukemia. I. Diagnosis and Prognosis
AYALEW TEFFERI, M.D., ROBERT L. PHYLIKY, M.D., Division ofHematology and Internal Medicine
B-cell chronic lymphocytic leukemia (B-CLL)is a relatively indolent hematologic malignant disease that, despite a good response to nonaggressive orally administered chemotherapy, currently remains incurable. The overall median duration of survival is more than 5 years, and the presence of anemia or thrombocytopenia adversely affects prognosis. B-CLL is readily diagnosed because ofthe characteristic and specific phenotypic expressions of the neoplastic cells. Clinical staging continues to be the best prognostic indicator in B-CLL. In addition, cytogenetic status, pattern of leukemic infiltration in the bone marrow, and lymphocyte doubling time are now considered to have additional prognostic value. In this article, the diagnostic evaluation of lymphocytosis is discussed, and an updated analysis on the prognostic determinants of B-CLL is provided. The second part of this clinical update, which reviews current chemotherapeutic modalities;will be published in the subsequent issue of this journal.
A clonal expansion of lymphocytes may occur either at an early stage of lymphopoiesis that involves lymphoblasts and that results in acute lymphocytic leukemia or at a more differentiated late stage that results in the chronic lymphoproliferative disorders. The chronic lymphoproliferative disorders may operationally be subdivided into two categories: lymphomas or chronic lymphoid leukemias (B cell and T cell). The diagnosis of chronic lymphoid leukemias necessitates involvement of the peripheral blood. Several stages of differentiation and transformation occur in lymphocyte ontogeny and result in immunologically and morphologically different types oflymphocytes. Accordingly, several types of chronic lymphoid leukemias exist. In the Western Hemisphere, the most frequent is B-cell chronic lymphocytic leukemia (B-CLL) (more than 90% of all cases). It is character-
Address reprint requests to Dr. Ayalew Tefferi, Division of Hematology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:349-353, 1992
ized by the proliferation of small and "mature" appearing B lymphocytes. Other types of chronic lymphoid leukemias include T-CLL, hairy-cell leukemia, prolymphocytic leukemia, small cleaved cell leukemia, Sezary syndrome, adult Tcell lymphoma-leukemia, and large granular lymphocytic leukemia. This article will address B-CLL exclusively. DIAGNOSIS B-CLL is the commonest leukemia in the United States; the approximate annual incidence is 2.7 cases per 100,000 persons.' The median age at diagnosis is 55 to 60 years, and the male-to-female ratio is 2: I.' Currently, most cases are diagnosed incidentally during routine studies of the blood. Previously, the criteria for the diagnosis of B-CLL necessitated a peripheral blood absolute lymphocyte count of more than 15,000/~l,2 At present, however, the laboratory demonstration of B-cell monoclonality, in the proper clinical context, confirms the diagnosis regardless of the absolute lymphocyte count. For protocol study purposes, the National Cancer 349
350
CHRONIC LYMPHOCYTIC LEUKEMIA
Mayo Clin Proe, April 1992, Vol 67
Institute-sponsored working group on CLL recommends an immunotyping for CD5 and B-cell-specific antigens is also absolute lymphocyte count threshold value of more than recommended. In 10 to 20% of the cases, expression of 5,OOO//-lP Nonetheless, only a few patients with a newly surface immunoglobulin may be undetectable," and monoclodetected lymphocyte count of more than 5,OOO//-l1 will have B- nality may be demonstrated by B-cell immunoglobulin gene CLL; most will have reactive Tvcell Iymphocytosis." There- rearrangement studies. fore, what is the appropriate diagnostic workup of persistent lymphocytosis? PROGNOSIS The availability of numerous monoclonal antibodies with The major prognostic factor in B-CLL is the clinical stage of specific antigen targets has allowed phenotypic surface char- the disease at the time of diagnosis. Recently, three laboratory acterization of normal and neoplastic lymphocytes. For factors-e-cytogenetics, histologic pattern ofthe bone marrow, example, the clonal lymphocytes in B-CLL differ from most and lymphocyte doubling time-have been considered to normal B lymphocytes and other B leukemic cells by their have additional prognostic value. Several other phenotypic expression of low-density light chain restriction, the CD5 T- and kinetic characteristics of the leukemic cells are under cell antigen, receptors for mouse erythrocytes, and the com- current investigation for their role in prognostication. Curmon CLL-associated antigen (cCLLa).5 In addition, they rently, we are studying the cytokinetic and phenotypic charexpress several B-cell-specific surface antigens and the class acteristics of the neoplastic lymphocytes in untreated patients II human leukocyte antigen, HLA-DR. with B-CLL and their correlation with clinical stage and The extent of surface immunophenotyping performed in prognosis. the general evaluation of lymphocytosis, including the diagIn consideration of the prognostic relevance of age, a nosis of B-CLL, should be based on several factors: cost, recent report on the natural history ofCLL in patients younger expertise, practicality, and research value. In a nonprotocol than 50 years old concluded that the disease in such patients and nonstudy setting, a reasonable starting point is a periph- has the same prognostic factors and clinical features as in eral blood smear examination coupled with immunopheno- patients 50 years of age or older. 8 Although the median typing for B-cell (HLA-DR) and T-cell (CD3) surface mark- duration of survival of the young patients was longer than that ers. B-celllymphocytosis is characterized by positive HLA- of the older patients (more than 12 years versus less than 4 DR and negative CD3 expression, T-cell lymphocytosis is years), the relative median duration of survival did not differ characterized by positive CD3 expression, and natural killer significantly and therefore the influence of CLL on survival cell lymphocytosis is characterized by negative CD3 and was similar, regardless of the age of the patient. Although positive or negative HLA-DR expression. The last-men- response to treatment is a major independent prognostic tioned cell type is further confirmed by demonstrating CD16 indicator," it has limited utility because most patients with Bpositivity. CLL do not require therapy, either at diagnosis or for a Once the particular lymphocyte cell type has been identi- substantial period after diagnosis. fied, monoclonality may be determined by the demonstration Clinical Staging.-Currently, two similar clinical staging of light chain restriction in B-cell lymphocytosis and rear- systems (Rai and Binet) are used, 2,10 both of which necessitate ranged T-cell receptor genes in T-cell lymphocytosis. Be- peripheral blood and bone marrow lymphocytosis. The Rai cause natural killer cells do not rearrange the T-cell receptor staging system, which is widely used in the United States, is genes, determination of monoclonality in chronic natural outlined in Table 1. It may be condensed into three (rather killer cell lymphocytosis may necessitate X-linked DNA than five) stages that differ with respect to survival: good analysis" or cytogenetic studies, which are rarely useful. prognosis (equivalent to Rai stage 0), intermediate prognosis B-celllymphocytosis, even without clonal studies, is highly (Rai stage I or II), and poor prognosis (Rai stage III or IV).11 suggestive of a B-cell malignant growth because polyclonal The Binet system has three disease stages that are similar to B-cell lymphocytosis in the peripheral blood is an unusual the condensed Rai classification, and it considers the number phenomenon." Therefore, a peripheral smear that shows an of clinically involved lymph node sites. In the Binet system, increased number of small "mature" appearing lymphocytes five potential disease sites are defined: (l) liver, (2) spleen, (3) that express HLA-DR antigen and stain negative for CD3 is cervical, (4) axillary, and (5) inguinal lymph nodes. The consistent with a clinical diagnosis ofB-CLL. With this cost- specific lymph node area of involvement counts as one site saving approach, further immunotyping may be unnecessary whether the involvement is unilateral or bilateral. Stage C of for the nonstudy patient who does not require therapy. the Binet system corresponds to stages III or IV of the Rai For protocol studies and when chemotherapy is contem- system, except that anemia is defined as a hemoglobin level of plated, a more definitive diagnosis is necessary and is achieved 10 gldl or less rather than less than 11 g/dl. In the Binet system, through immunophenotyping for kappa and lambda light the number of disease sites involved are two or fewer in stage chains and demonstrating light chain restriction. In addition, A and more than two in stage B.
CHRONIC LYMPHOCYTIC LEUKEMIA
Mayo Clin Proc, April 1992, Vol 67
Table I.-Rai Staging System for Diagnosis of Chronic Lymphocytic Leukemia Stage Finding
0
Absolute lymphocytosis* Lymphadenopathy Palpable liver or spleen
+
II
+ +
Anemia]
Thrombocytopenia:j:
+
± +
ill
+
± ± +
IV
+
± ± ± +
*Currently, the consensus absolute lymphocyte count threshold level is >5,OOOIIl1; bone marrow lymphocytosis must also be >30%. t Anemia is defined as a hemoglobin level of
AYALEW TEFFERI, M.D., ROBERT L. PHYLIKY, M.D., Division ofHematology and Internal Medicine
B-cell chronic lymphocytic leukemia (B-CLL)is a relatively indolent hematologic malignant disease that, despite a good response to nonaggressive orally administered chemotherapy, currently remains incurable. The overall median duration of survival is more than 5 years, and the presence of anemia or thrombocytopenia adversely affects prognosis. B-CLL is readily diagnosed because ofthe characteristic and specific phenotypic expressions of the neoplastic cells. Clinical staging continues to be the best prognostic indicator in B-CLL. In addition, cytogenetic status, pattern of leukemic infiltration in the bone marrow, and lymphocyte doubling time are now considered to have additional prognostic value. In this article, the diagnostic evaluation of lymphocytosis is discussed, and an updated analysis on the prognostic determinants of B-CLL is provided. The second part of this clinical update, which reviews current chemotherapeutic modalities;will be published in the subsequent issue of this journal.
A clonal expansion of lymphocytes may occur either at an early stage of lymphopoiesis that involves lymphoblasts and that results in acute lymphocytic leukemia or at a more differentiated late stage that results in the chronic lymphoproliferative disorders. The chronic lymphoproliferative disorders may operationally be subdivided into two categories: lymphomas or chronic lymphoid leukemias (B cell and T cell). The diagnosis of chronic lymphoid leukemias necessitates involvement of the peripheral blood. Several stages of differentiation and transformation occur in lymphocyte ontogeny and result in immunologically and morphologically different types oflymphocytes. Accordingly, several types of chronic lymphoid leukemias exist. In the Western Hemisphere, the most frequent is B-cell chronic lymphocytic leukemia (B-CLL) (more than 90% of all cases). It is character-
Address reprint requests to Dr. Ayalew Tefferi, Division of Hematology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:349-353, 1992
ized by the proliferation of small and "mature" appearing B lymphocytes. Other types of chronic lymphoid leukemias include T-CLL, hairy-cell leukemia, prolymphocytic leukemia, small cleaved cell leukemia, Sezary syndrome, adult Tcell lymphoma-leukemia, and large granular lymphocytic leukemia. This article will address B-CLL exclusively. DIAGNOSIS B-CLL is the commonest leukemia in the United States; the approximate annual incidence is 2.7 cases per 100,000 persons.' The median age at diagnosis is 55 to 60 years, and the male-to-female ratio is 2: I.' Currently, most cases are diagnosed incidentally during routine studies of the blood. Previously, the criteria for the diagnosis of B-CLL necessitated a peripheral blood absolute lymphocyte count of more than 15,000/~l,2 At present, however, the laboratory demonstration of B-cell monoclonality, in the proper clinical context, confirms the diagnosis regardless of the absolute lymphocyte count. For protocol study purposes, the National Cancer 349
350
CHRONIC LYMPHOCYTIC LEUKEMIA
Mayo Clin Proe, April 1992, Vol 67
Institute-sponsored working group on CLL recommends an immunotyping for CD5 and B-cell-specific antigens is also absolute lymphocyte count threshold value of more than recommended. In 10 to 20% of the cases, expression of 5,OOO//-lP Nonetheless, only a few patients with a newly surface immunoglobulin may be undetectable," and monoclodetected lymphocyte count of more than 5,OOO//-l1 will have B- nality may be demonstrated by B-cell immunoglobulin gene CLL; most will have reactive Tvcell Iymphocytosis." There- rearrangement studies. fore, what is the appropriate diagnostic workup of persistent lymphocytosis? PROGNOSIS The availability of numerous monoclonal antibodies with The major prognostic factor in B-CLL is the clinical stage of specific antigen targets has allowed phenotypic surface char- the disease at the time of diagnosis. Recently, three laboratory acterization of normal and neoplastic lymphocytes. For factors-e-cytogenetics, histologic pattern ofthe bone marrow, example, the clonal lymphocytes in B-CLL differ from most and lymphocyte doubling time-have been considered to normal B lymphocytes and other B leukemic cells by their have additional prognostic value. Several other phenotypic expression of low-density light chain restriction, the CD5 T- and kinetic characteristics of the leukemic cells are under cell antigen, receptors for mouse erythrocytes, and the com- current investigation for their role in prognostication. Curmon CLL-associated antigen (cCLLa).5 In addition, they rently, we are studying the cytokinetic and phenotypic charexpress several B-cell-specific surface antigens and the class acteristics of the neoplastic lymphocytes in untreated patients II human leukocyte antigen, HLA-DR. with B-CLL and their correlation with clinical stage and The extent of surface immunophenotyping performed in prognosis. the general evaluation of lymphocytosis, including the diagIn consideration of the prognostic relevance of age, a nosis of B-CLL, should be based on several factors: cost, recent report on the natural history ofCLL in patients younger expertise, practicality, and research value. In a nonprotocol than 50 years old concluded that the disease in such patients and nonstudy setting, a reasonable starting point is a periph- has the same prognostic factors and clinical features as in eral blood smear examination coupled with immunopheno- patients 50 years of age or older. 8 Although the median typing for B-cell (HLA-DR) and T-cell (CD3) surface mark- duration of survival of the young patients was longer than that ers. B-celllymphocytosis is characterized by positive HLA- of the older patients (more than 12 years versus less than 4 DR and negative CD3 expression, T-cell lymphocytosis is years), the relative median duration of survival did not differ characterized by positive CD3 expression, and natural killer significantly and therefore the influence of CLL on survival cell lymphocytosis is characterized by negative CD3 and was similar, regardless of the age of the patient. Although positive or negative HLA-DR expression. The last-men- response to treatment is a major independent prognostic tioned cell type is further confirmed by demonstrating CD16 indicator," it has limited utility because most patients with Bpositivity. CLL do not require therapy, either at diagnosis or for a Once the particular lymphocyte cell type has been identi- substantial period after diagnosis. fied, monoclonality may be determined by the demonstration Clinical Staging.-Currently, two similar clinical staging of light chain restriction in B-cell lymphocytosis and rear- systems (Rai and Binet) are used, 2,10 both of which necessitate ranged T-cell receptor genes in T-cell lymphocytosis. Be- peripheral blood and bone marrow lymphocytosis. The Rai cause natural killer cells do not rearrange the T-cell receptor staging system, which is widely used in the United States, is genes, determination of monoclonality in chronic natural outlined in Table 1. It may be condensed into three (rather killer cell lymphocytosis may necessitate X-linked DNA than five) stages that differ with respect to survival: good analysis" or cytogenetic studies, which are rarely useful. prognosis (equivalent to Rai stage 0), intermediate prognosis B-celllymphocytosis, even without clonal studies, is highly (Rai stage I or II), and poor prognosis (Rai stage III or IV).11 suggestive of a B-cell malignant growth because polyclonal The Binet system has three disease stages that are similar to B-cell lymphocytosis in the peripheral blood is an unusual the condensed Rai classification, and it considers the number phenomenon." Therefore, a peripheral smear that shows an of clinically involved lymph node sites. In the Binet system, increased number of small "mature" appearing lymphocytes five potential disease sites are defined: (l) liver, (2) spleen, (3) that express HLA-DR antigen and stain negative for CD3 is cervical, (4) axillary, and (5) inguinal lymph nodes. The consistent with a clinical diagnosis ofB-CLL. With this cost- specific lymph node area of involvement counts as one site saving approach, further immunotyping may be unnecessary whether the involvement is unilateral or bilateral. Stage C of for the nonstudy patient who does not require therapy. the Binet system corresponds to stages III or IV of the Rai For protocol studies and when chemotherapy is contem- system, except that anemia is defined as a hemoglobin level of plated, a more definitive diagnosis is necessary and is achieved 10 gldl or less rather than less than 11 g/dl. In the Binet system, through immunophenotyping for kappa and lambda light the number of disease sites involved are two or fewer in stage chains and demonstrating light chain restriction. In addition, A and more than two in stage B.
CHRONIC LYMPHOCYTIC LEUKEMIA
Mayo Clin Proc, April 1992, Vol 67
Table I.-Rai Staging System for Diagnosis of Chronic Lymphocytic Leukemia Stage Finding
0
Absolute lymphocytosis* Lymphadenopathy Palpable liver or spleen
+
II
+ +
Anemia]
Thrombocytopenia:j:
+
± +
ill
+
± ± +
IV
+
± ± ± +
*Currently, the consensus absolute lymphocyte count threshold level is >5,OOOIIl1; bone marrow lymphocytosis must also be >30%. t Anemia is defined as a hemoglobin level of
