Chronic lymphocytic leukemia in Turkey: experience of a single center in Istanbul.

Background: In this study, the clinical characteristics, survival, and prognostic factors of 200 patients diagnosed as having chronic lymphocytic leukemia (CLL) were analyzed.

Methods: The medical charts of 200 CLL patients registered to our center between 1984 and 2000 were retrospectively evaluated.

Results: Of all patients, 129 were men and 71 were women (male/female ratio, 1.82). The median age at the time of initial diagnosis was 63 years (range, 38-90 years). Sixty patients were classified as Binet's Stage A, 49 as Stage B, and 91 as Stage C. Sixty-two cases were diagnosed during routine laboratory examinations when they were asymptomatic. Forty-three patients were lost to follow-up, and 157 patients have been followed regularly until the end of the study period. Hemolytic anemia developed in nine (5.7%) patients, second primary cancer in six (3.8%), and Richter's syndrome in two (1.2%). Forty-eight percent of CLL patients were treated immediately after initial diagnosis. The overall response (complete or partial) to first-line and second-line therapies was 61.6% and 54.4%, respectively. The median time of follow-up for patients followed up regularly was 47 months (range, 1-195 months). Sixty-three patients died during the follow-up: the deaths of 39 (62%) of these were attributable to CLL-related causes. The median survival time was 48 months. The 5-year survival rate was 36.5% and the 10-year survival rate was 8%. Stage according to Rai's classification, lymphocyte count, and age showed a significant prognostic effect on survival by univariate analysis. On multivariate analysis, advanced age and lymphocyte count were independent prognostic parameters.

Conclusion: In our study, more asymptomatic CLL patients have been diagnosed in recent years. The survival, especially of our early-stage patients, was shorter than that in other CLL series of Western origin. Rai's staging system was seen to determine prognosis better than Binet's staging system.

Key Words: chronic lymphocytic leukemia, survival, prognosis, Rai's classification, Binet's classification

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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a disease characterized by the clonal proliferation and accumulation of neoplastic B cells in peripheral blood, bone marrow, lymph nodes, and the spleen. (1,2) In recent years, because of performing a whole blood count more frequently as part of the routine physical examination and for preoperative evaluation before surgery, CLL has been diagnosed more frequently and at earlier stages of disease. (3) During the 1970s, 30 to 40% of CLL patients were diagnosed while asymptomatic; however, this ratio has been reported to be approximately 60% in the 1990s. (1) The prognosis of CLL is highly variable: most patients have a slow clinical course with few symptoms, whereas some patients have a rapidly downhill course unresponsive to therapy. (1,4,5) Recently published articles about CLL have been attempting to determine factors that would help to define the clinical course of the disease at the time of the initial diagnosis (6-8) so that patients with a benign course will not be administered unnecessary aggressive therapies and alternative treatment modalities will be advised to patients with a malignant course. In this study, we evaluated the general clinical features, the treatment modalities, and the survivals of patients who were diagnosed with CLL at our center. Our aim was to determine the survival and factors affecting prognosis in our series of CLL patients.

Patients and Methods

In this study, the medical charts of 200 patients diagnosed as having CLL at the Cerrahpasa Medical Faculty, Department of Internal Medicine, Division of Hematology between 1984 and 2000 were retrospectively evaluated. All patients were diagnosed according to the criteria recommended by the International Workshop on CLL. (9) Bone marrow biopsy and/or aspiration was performed in 67% of the cases. The diagnosis of CLL was confirmed by analysis of cell surface markers in only 35 of the patients. The effect of immunophenotyping on prognosis was not evaluated because the number of patients was not high and because different methods were used at different times.

For clinical staging of the patients, the staging systems proposed by Rai et al (4) and Binet et al (10) were used. The bone marrow involvement pattern was assessed by the criteria suggested by Rozman et al, (11) and the lymphocyte doubling time was assessed by the criteria suggested by Montserrat et al. (12)

Patients in late stages (Rai Stages III and IV or Binet Stage C), those with lymphadenopathy and/or splenomegaly producing mass effect, and patients with systemic symptoms were treated at once. In others, treatment was delayed until the disease showed progression. Prednisone associated with chlorambucil was used as first-line therapy in 75% of the patients and as second-line therapy in 71% of the patients. In the rest of the cases, either fludarabine associated with prednisone or different combination chemotherapy regimens (eg, COP, CHOP) were administered.

In survival analyses, active leukemia, disease-associated infections, Richter syndrome, bone marrow failure, and second primary malignancies were considered as causes for CLL-related deaths. Of 200 CLL patients, 43 were lost to follow-up because of various reasons. Thus, all 200 CLL patients were included while assessing the general clinical features at initial diagnosis but, when evaluating survival and prognostic factors, only 157 patients followed up regularly were considered.

Statistical Analysis

The [chi square] test was used to compare the clinical features of the patients. Survival curves were drawn according to Kaplan-Meier, and the log-rank test was used to compare these curves. While estimating survival, the period of time starting from diagnosis until the end of the follow-up period or the time of death was calculated. The multiple regression model of Cox was applied to estimate the importance of prognostic factors. The prognostic factors included were age (<70 versus [greater than or equal to]70 yr), sex, Rai's Stage (0 + I + II versus III + IV), Binet's Stage (A + B versus C), signs of disease progression (lymphocyte doubling time [greater than or equal to]12 versus <12 mo), bone marrow involvement pattern (diffuse versus nondiffuse), and lymphocyte number (<100,000/[mm.sup.3] versus [greater than or equal to]100,000/[mm.sup.3]). Lymphocyte doubling time could be calculated in only 43 patients, whereas the bone marrow histology was present in 65.

Results

General Clinical Features

Of 200 patients diagnosed as having CLL, 129 (64.5%) were men and 71 (35.5%) were women (male/female ratio, 1.82). The mean age of the women (65.5 [+ or -] 9 years) was higher than that of the men (61 [+ or -] 9 years) (P = 0.001). Seventeen patients (8.6%) were less than 50 years of age and 44 (22.3%) were more than 70 years of age. The distribution of the patients into Binet's Stages and the laboratory results are shown in Table 1.

Sixty-two patients (31%) had no complaint at initial diagnosis. During the last 2 years of the study, 50% of the patients were diagnosed while asymptomatic; however, this ratio was 14% during the first 2 years of the study. The distribution of patients diagnosed while asymptomatic into stages is listed in Table 1. The symptoms of the subjects at initial admission are listed in Table 2.

Of 65 patients whose bone marrow involvement patterns were available, 34 (52.3%) had diffuse involvement. Diffuse bone marrow involvement was more common in late stages (Binet's C) when compared with early stages (Binet's A and B) (Table 1) (P < 0.001).

During the study period, 180 episodes of infection were diagnosed in 100 (64.5%) patients followed up regularly. Infections were significantly more frequent in late stages (67.2%) when compared with early stages (32.8%) (P < 0.05). The organs most frequently affected by infection were the lungs (pneumonia, 59 episodes; acute bronchitis, 23 episodes; tuberculosis, 12 episodes).

Hemolytic anemia was diagnosed in 5.7% (9 of 157) of the patients. During the follow-up period, a second primary cancer developed in six patients (3.8%) and Richter's syndrome developed in two (1.2%). The second malignancies were prostate and bladder carcinoma (two cases each) and skin basal cell and colon carcinoma (one case each).

Treatment

Of 157 CLL patients, there was urgent indication for treatment in 76 (48.4%) after initial diagnosis. The distribution of patients who were immediately treated into stages is shown in Table 1. Seven patients in Stage A and 11 patients in Stage B were treated because of constitutional complaints, lymphadenopathy, and/or splenomegaly causing symptoms; also, two patients in Stage B were treated because of hemolytic anemia. An indication for treatment occurred in 32 patients after a median of 12.5 months (range, 1-138 months), and 49 patients have not received any treatment for CLL.

A response to treatment (complete, 25.3%; partial, 36.3%) was obtained in 61.6% of patients initially administered therapies. For second-line therapies, the overall response rate was 54.4% (complete, 8.8%; partial, 45.6%). Third- and fourth-line therapies administered after relapse and in patients unresponsive to treatment yielded an overall response rate of only 2.4%.

Assessment of Survival

The median time of follow-up for 157 patients followed up regularly was 47 months (range, 1-195 months). Sixty-three of these died during the follow-up period. The percentage of deaths in men (38%) was higher than that in women (20%) (P = 0.008). Forty patients (69.8%) died in Stage IV, 15 (23.8) in Stage III, 3 in Stage II, and 1 in Stage I (P < 0.05).

Thirty-nine deaths (62%) were CLL-related and 24 deaths (38%) were CLL-unrelated; 66.6% of deaths in late stages (Binet's C) and 55.6% of deaths in early stages (Binet's A and B) were considered to be CLL-related (P < 0.05). Most of the CLL-related deaths (77%) were because of infections and most of the CLL-unrelated deaths (54.2%) were secondary to cardiovascular causes.

The median survival of patients was 48 months (range, 1-138 months). In both staging systems, the survival of patients in early stages was significantly longer than the survival of patients in late stages (Table 3) (P < 0.05). The 5- and 10-year survival rates of the patients were 36.5% and 8%, respectively. The 5- and 10-year survival rates of patients in different stages are shown in Table 3.

During the follow-up period, disease in 36 (41%) of the 88 patients who were in early Rai's stages on initial diagnosis progressed to late stages, whereas disease in 52 (59%) patients remained stable. The progression of disease in patients in early stages to late stages occurred during a median period of 22.5 months. The median survival of patients diagnosed in early stages but whose disease progressed to late stages (30 months) was significantly shorter than that of patients who remained stable in early stages (67 months) (P = 0.002).

The Kaplan-Meier survival curves of early- and late-stage patients according to Rai's staging system are shown in Figure 1 (when all deaths are considered) and Figure 2 (when CLL-related deaths are considered). According to Rai's stages, there were significant differences between early- and late-stage survival curves in both conditions (P < 0.05). However, according to Binet's stages, when all deaths and only CLL-related deaths were considered, the difference between early- and late-stage survival curves was not significant (P > 0.05).

Univariate analysis revealed that Rai's stage, lymphocyte count, and age had a prognostically significant role on survival (Table 4). Parameters such as sex, Binet's stage, lymphocyte doubling time, and bone marrow involvement pattern had no significant effect on survival. When multivariate analysis with the regression model of Cox was performed, only advanced age and lymphocyte count were seen to be independent prognostic factors (Table 4).

Discussion

In our retrospective study, there were more male CLL patients than female patients (male/female ratio, 1.82). In CLL series similar to our study, the predominance of male patients is noteworthy. (1,13-15)

Approximately one-third of our cases had no symptoms at initial diagnosis. One of the important results of our study is that more asymptomatic CLL patients have been diagnosed in recent years. This result might be explained by performing whole blood counts more frequently and by referring patients with lymphocytosis--even if they have no symptoms--to hematology centers. Studies published in recent years also report that CLL has been being diagnosed mostly at the asymptomatic stage. (1,3)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

The clinical course in CLL is very heterogenous, and the median survival varies from several months to 20 years, depending on the stage of the disease. (8) The uncertainty about the clinical course of CLL made it obligatory for hematologists to search for new parameters that would have predictive value in determining survival and prognosis. Rai's and Binet's staging systems, which were developed because of this purpose, are commonly used (especially when making treatment decisions) because of their easy applicability. (4,10,16) However, both staging systems are insufficient in detecting patients in early stages who are at risk of progressive disease. (8) Therefore, some studies evaluated the effects of various clinical and laboratory parameters--in addition to the role of classic staging systems--on prognosis. (11,12,16,17) Recent studies about CLL suggest that four parameters especially are associated with a poor prognosis (1,8): diffuse involvement of the bone marrow, lymphocyte count greater than 50,000/[mm.sup.3], lymphocyte doubling time less than 12 months, and multiple or complex karyotype anomalies. Of all the prognostic parameters evaluated in our study, univariate analysis revealed that Rai's stage, lymphocyte count, and age were independent prognostic parameters, and multivariate analysis showed that lymphocyte count and advanced age were independent prognostic parameters.

Diffuse bone marrow involvement, which is accepted as a negative prognostic parameter in some CLL series, was diagnosed more frequently in our late-stage patients. Although the number of patients assessed was low, we observed that diffuse bone marrow involvement had no independent role on survival. One recently performed study reported that this type of involvement should be interpreted as a negative prognostic factor, because it is commonly seen in late stages. (18) In addition, in one recently reported CLL series consisting of 177 patients, multivariate analysis showed that [[beta].sub.2]-microglobulin was the most important prognostic factor. (19) Because our study was retrospective, [[beta].sub.2]-microglobulin was available in a few patients diagnosed in recent years; therefore, we were unable to assess its role on survival.

Infections are common complications during the course of CLL. (20) In our study, the most common location of infection was the lungs. The development of a second primary malignancy in CLL is well known. In such cases, it is thought that, independent of the treatment modality and age, a disease-related immunodeficient state is responsible for this complication. (21) We diagnosed a second malignancy in 3.8% of our patients: this was consistent with the ratio in the literature.

The median survival of our patients was 48 months. In our patients who had early-stage disease according to the Rai and Binet systems, the median survival was significantly longer. Although the 5-year survival rates of our patients were significantly higher in early stages than in late stages, the 10-year survival rates in early and late stages were similar (Table 3). Our 5-year survival rates were in accordance with the results in most CLL series of Western origin; however, the 10-year survival rate in our series was shorter. For example, the 10-year survivals in the series of Rozman et al (22) were 76% in Stage 0, 45% in Stages I and II, and 24% in Stages III and IV; and in the series of Moura et al, (21) the 10-year survivals in CLL patients less than 55 years of age and greater than or equal to 55 years of age were 45.3% and 54.8%, respectively.

In our cases with long follow-up periods, the survival rates--especially in early-stage patients--were lower than in series of Western origin. This might possibly be explained by the lack of health care facilities in our country. Other contributing factors might be the mean life expectancy in Turkey being shorter than in Western countries and patients' failure to attend their regular follow-up visits because of socioeconomic problems and seeking our help only when disease progression has occurred. In addition, nearly half of our patients lost to follow-up had early-stage CLL, and they did not regularly attend their follow-up visits because they probably had no complaints. This fact might have increased the number of our problematic patients on regular follow-up, thereby having a negative effect on survival.

Most of the patients who died were men. Although the cause is not known, it is reported that male CLL patients generally have a poorer prognosis than female patients. (8) We evaluated age as an independent prognostic parameter. However, as was expected, CLL-unrelated deaths were more common in our older patients.

Because of the variable course of the disease, it is difficult to make a decision regarding therapy, especially in early-stage patients. In spite of some of their limitations, CLL staging systems are helpful in planning therapy and in making an estimation of survival. (1,23) There is no curative treatment for CLL, and therapeutic applications are mainly palliative. Fludarabine seems to be a promising agent in uncontrolled trials as initial therapy for CLL. (24) However, in one large, controlled study by Rai et al, (25) it was concluded that although fludarabine yielded higher response rates and a longer duration of remission than chlorambucil, it did not increase overall survival. We used fludarabine as a first- and second-line therapy in only a small number of our patients. Therefore, we could not compare the overall survival rates achieved with fludarabine and chlorambucil. In our study, the overall response rates to first- and second-line therapies were similar; however, the complete response rate to first-line therapies was significantly higher. The response rates to further therapies were much lower.

As a result, we observed that the long-term survivals, especially of our early-stage CLL patients, were shorter than in Western CLL series. Staging systems (mainly that proposed by Rai), lymphocyte count, and age were seen to be the factors reflective of survival.

Table 1. The general clinical and laboratory features of the patients
according to Binet's stages at initial diagnosis (a)

                             Stage A              Stage B

No. (%)                       60 (30)              49 (24.5)
Age (yr)
  Median                      62                   62
  Range                       38-80                40-86
Sex-age
  Male (%)                    31 (24.0)            36 (27.9)
    Median (range)            62.5 (38-73)         60.5 (40-75)
  Female (%)                  29 (40.8)            13 (18.3)
    Median (range)            62 (49-80)           64 (47-86)
Splenomegaly (%)              20                   69.4
Asymptomatic case (%)         48.3                 30.6
Diffuse BM involvement (%)    20                   46.7
Initial therapy (%)           15                   34.2
Hemoglobin (g/dl,
  mean [+ or -] SD)           13.2 [+ or -] 1.5    12.6 [+ or -] 1.5
Lymphocyte (X [10.sup.9]/L,
  mean [+ or -] SD)           76.5 [+ or -] 16.4   82.9 [+ or -] 13.3
Platelet (X [10.sup.9]/L,
  mean [+ or -] SD)          212.8 [+ or -] 77.7  178.1 [+ or -] 64.4

                             Stage C             Total

No. (%)                       91 (45.5)           200
Age (yr)
  Median                      64                   63
  Range                       41-90                38-90
Sex-age
  Male (%)                    62 (48)
    Median (range)            62.5 (41-82)         62 (38-82)
  Female (%)                  29 (40.8)
    Median (range)            67.5 (53-90)         65 (47-90)
Splenomegaly (%)              71.4                 55.5
Asymptomatic case (%)         19.8                 31
Diffuse BM involvement (%)    76.7                 52.3
Initial therapy (%)           83.6                 48.4
Hemoglobin (g/dl,
  mean [+ or -] SD)            8.5 [+ or -] 1.6    11.0 [+ or -] 2.7
Lymphocyte (X [10.sup.9]/L,
  mean [+ or -] SD)           84.9 [+ or -] 12.9   82.0 [+ or -] 14
Platelet (X [10.sup.9]/L,
  mean [+ or -] SD)          137.8 [+ or -] 92.2  170.3 [+ or -] 87

(a) BM, bone marrow.

Table 2. The symptoms defined by the chronic lymphocytic leukemia
patients at initial admission

Symptoms                  %

Weakness, fatigue         33
Effort dyspnea            16.5
Abdominal fullness, pain  15
Fever, night sweating     17
Weight loss               12
Skin lesions, pruritus     3.5
Bleeding symptoms          2

Table 3. The median survival and the rates of 5- and 10-yr survivals
according to Binet's and Rai's Stages

                Median         5-yr         10-yr
Stage        survival (mo)  survival (%)  survival (%)

Binet A         82.5
Binet B         52             48.1          11.1
Binet C         31             27.8           5.6
Rai 0        Not reached
Rai I, II       64.5           52            12
Rai III, IV     30             26             5.2

Table 4. Significance of prognostic variables in chronic lymphocytic
leukemia patients (a)

                                              P value at univariate and
                                                multivariate analysis
Prognostic variables                          Univariate   Multivariate

Rai's stage (0, I, and II versus III and IV)      0.03       NS

Lymphocyte count (<100 versus                     0.04       0.03
  [greater than or equal to]100 X
  [10.sup.9]/L)
Age                                              <0.001      NS
Age ([greater than or equal to]70 versus
  <70 yr)                                        <0.001      0.04

(a) NS, not significant.

Accepted July 29, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0240

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RELATED ARTICLE: Key Points

* In recent years, more asymptomatic chronic lymphocytic leukemia (CLL) patients have been being diagnosed.

* In our CLL series, the 5-year survival rate was similar to that in Western series; however, the 10-year survival rate was significantly lower.

* The 5-year survival rate in our early-stage CLL patients was significantly longer when compared with late-stage patients; however, the 10-year survival rates in both stages were almost similar.

* Independent prognostic parameters were age and lymphocyte count on both univariate and multivariate analyses, and Rai's stage on univariate analysis.

Omer Nuri Pamuk, MD, Gulsum Emel Pamuk, MD, Teoman Soysal, MD, Seniz Ongoren, MD, Zafer Baslar, MD, Burhan Ferhanoglu, MD, Yildiz Aydin, MD, Birsen Ulku, MD, Gulten Aktuglu, MD, and Nuran Akman, MD

From the Division of Hematology, Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.

Reprint requests to Omer Nuri Pamuk, MD, Koca Sinan Mah., Sadik Ahmet Cad., Ikinci Aralik, Varli Apt. 25, Daire 2, Kutlutas, Edirne, Turkey. Email: [e-mail]