- Email: [email protected]
Long-term outcome of adult acute lymphoblastic leukemia in Lebanon
original research report Long-term outcome of adult acute lymphoblastic leukemia in Lebanon: a single institution experience from the American University of Beirut Khalil M. Charafeddine,a Hassan A. Hatoum,b Zaher K. Otrock,a Rami A. Mahfouz,a Ziad M. Salem,b Ali I. Shamseddine,b Ali T. Taher,b Nagi S. El-Saghir,b Ali Bazarbachib From the aDepartment of Pathology and Laboratory Medicine and the bDepartment of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. Correspondence: Ali Bazarbachi, MD, PhD · Department of Internal Medicine, American University of Beirut Medical Center, P.O. Box 1136044, Beirut, Lebanon · T: +961-3612434 F: +961-1345325 · [email protected] · Accepted for publication June 2009 Hematol Oncol Stem Cel Ther 2009; 2(2): 333-339
BACKGROUND AND OBJECTIVES: The most important studies about outcome of acute leukemia come from developed countries, whereas most of the patients with this disease are in developing countries. We report preddictive and prognostic factors in patients with acute lymphoblastic leukemia (ALL) in a tertiary care center in a developing country. PATIENTS AND METHODS: We retrospectively reviewed the records of adult patients with acute leukemia who were referred to the American University of Beirut Medical Center between 1996 and early 2006. Results: Of 105 patients, 36 (34%) patients were diagnosed with ALL, and included 19 (53%) males and 17 (47%) females with a median age of 34 years (range, 14-79 years). Induction chemotherapy with curative intent was administered to 34 (94%) patients. Twenty-seven patients received intrathecal chemotherapy as prophylaxis (n=24) or as treatment for CNS disease (n=3). Twenty-eight patients (82%) achieved complete remission (CR) after induction chemotherapy. The median overall survival (OS) time was 22 months and the five-year OS for ALL patients was 38%. The median disease-free survival (DFS) time was 12 months, while the five-year DFS was 38%. Multivariate analysis showed that age <40 years, WBC <30×109/L, achievement of CR after first induction, and CNS prophylaxis were predictive factors for OS and DFS. Conclusion: Despite limitations and the relatively low socioeconomic status of the Lebanese population, OS (38%) and DFS (38%) are quite similar to international data. Trends toward a higher CR and DFS in adults are due to intensified consolidation chemotherapy, the use of stem cell transplantation, and improvements in supportive care.
T
he incidence of acute leukemia is increasing worldwide.1-3 As the population ages, it is antticipated that an even greater number of patients will be diagnosed with this malignancy.4,5 The overall inciddence of acute lymphoblastic leukemia (ALL) is 1 to 1.5 per 100 000 persons,6 with a bimodal distribution at ages 4 to 5 years (with an incidence as high as 4 to 5 per 100 000 persons) and at age 50 years (with an incidence 2 per 100 000 persons).6 There are no reports clearly describing the incidence of ALL in developing countries. The most important studies about outcome of acute leukemias come from developed countries, whereas most of the patients with this disease are in developing countries
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based on the distribution of the would be world’s popullation.7,8 In ALL, the most important prognostic factor for overall survival is age,9 while the most important facttor for disease-free survival (DFS) is karyotype.10 The 5-year overall survival (OS) of adult patients with ALL is 20% to 40%.11-15 For those less than 30 years of age, the OS is 34% to 57%, compared to 15% to 17% for patients older than 50 years of age.16-20 Moreover, although most cases of ALL are found in developing countries, there is scarcity of data in the liteerature reflecting the condition of these patients includiing clinical features, description of prognostic factors and predictors as well as the outcome. In this manuscript, we
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original research report Table 1. Patient’s characteristics at presentation. Patient characteristics
Patients (n=36)
Male/female
19/17
Median age (range) (years) Clinical findings
8 (22%)
Hepatomegaly
0 (0%)
Splenomegaly
6 (17%)
Testicular involvement
0 (0%)
Mediastinal enlargement
0 (0%)
Fever
16 (44%)
Bleeding
0 (0%)
Fatigue
21 (58%)
Laboratory findings (normal range)
Median (range)
LDH, IU/L (normal range, 110-265 IU/L)
2023.9 (101-8948)
WBC, ×109/L (normal range, 4.0-11.0×109/L)
64.8 (1-484)
Hemoglobin, g/dL (Male: normal range, 13-18 g/dL) (Female: normal range, 12-16 g/dL)
9.5 (5.4-14.3)
Blasts, %
40 (0-94)
Platelets, ×10 /L (normal range, 150-400×109/L) 9
104 (8-368)
LDH: lactate dehydrogenase; WBC: white blood cell count
ALL n=36 patients
Supportive treatment n=2 patients (6%)
Complete remission n=26 patients (76%)
Induction chemottherapy n=34 patients (94%) Death during induction n=5 patients (15%)
Induction failure n=3 patients (9%)
Reinduction
Complete Complete remission remission n=2 n=2 patients patients
Death Death n=1 n=1patients patient
Total complete complete Total remission remission n=28 patients patients (78%) (78%) n=28
Figure 1. Disposition of 36 patients with acute lymphoblastic leukemia (ALL).
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report predictive and prognostic factors in patients with ALL in a tertiary care center in a developing country.
PATIENTS AND METHODS
34 (14-79)
Lymphadenopathy
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We retrospectively reviewed the records of consecuttive patients with newly diagnosed and previously unttreated acute leukemia who were referred to the adult hematology service of the American University of Beirut Medical Center (AUB-MC) between 1996 and early 2006. The number of patients reviewed was 131. These patients were studied for family and personal history, medical history, disease presentation, and management and outcome of leukemia. The biological characteristics of the leukemia including morphologiccal, immunophenotypic, cytogenetic and molecular data were also analyzed. A morphological review of all cases was performed by one hematopathologist (RM). Twenty-six patients were excluded from this study; 14 of these were diagnosed but not treated at AUB-MC, 6 patients were rediagnosed as having hematologic malignancies other than acute leukkemia, and the remaining 6 patients did not have suffficient data to be included in the analysis. Therefore, a total of 105 patients were included in the data collected. Of these 105 patients, 69 (66%) had acute myelogenous leukemia (AML) and 36 patients (34%) had ALL. This study was approved by the Institutional Review Board at AUB-Faculty of Medicine. Hospital records of the patients were reviewed in the Department of Medical Records and the private clinics. Phone calls were also done for the most recent follow up of patients. The diagnosis of ALL was made according to the French-American-British (FAB) morphologiccal and cytochemical criteria.21 Cytogenetic analysis was performed routinely using standard methods. Immunophenotyping was also performed using flow cyttometry. Bone marrow aspirate and/or biopsy were anallyzed for cellularity and blast count. Blood chemistry, complete blood count (CBC), coagulation profile, and left ventricular ejection fraction data were collected. For assessment of response, bone marrow aspirrate was performed at the end of the induction phase. Complete hematological remission (CR) was defined as less than 5% marrow blasts with normal peripheral blood counts and differential, with no evidence of exttramedullary leukemia. Partial remission (PR) required similar criteria except for the presence of 5% to 20% marrow blasts. Resistance was defined as persistent leukkemia in blood and/or bone marrow in patients surviviing more than 1 month after start of induction treatmment. Death during induction was defined as death that occurred while the patient was receiving induction
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therapy. Disease-free survival (DFS) was defined as the time from the first day of CR to relapse, death, or last visit, and overall survival (OS) as the time from the day of diagnosis to death or last visit. Hematological relapse was considered when more than 5% blasts were seen in bone marrow aspirates as confirmed by flow cytomeetry. We describe numerical variables by their median and range, whereas categorical variables are described by their relative frequencies and counts. Survival curves were calculated according to the methods of Kaplan and Meier and compared between groups with the log-rank test.22 Differences were considered statistically significant when the P value was less than .05. Potential prognostic factors tested for the univariate analysis comprised age, sex, WBC count, hemoglobin, platelet count, percentage of blasts in the bone marrow, cytogenetic abnormalities, CNS involvement, type of chemotherapy and response to first induction chemotherapy. Univariate and multivvariate analysis were done for all factors assessed. The analyses were performed using SPSS software version 15.0 (SPSS, Chicago, IL, USA).
1.0 Overall survival (median, 22 months) Disease-free survival (median, 12 months)
0.9 0.8 Disease-free survival
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0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0
12
24
36 48 60 72 Follow up (months)
84
96
108
120
Figure 2. Overall and disease-free survival for 36 patients with acute lymphoblastic leukemia.
RESULTS
Response to induction chemotherapy Induction chemotherapy with curative intent was administered to 34 patients (94%), and the remainiing 2 patients (6%) received palliative chemotherapy due to old age, poor performance status, or severe
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1.0
Overall survival
Initial Presentation Of the 105 patients analyzed, 36 (34%) patients were diagnosed with ALL (Table 1) and 69 (66%) patients were diagnosed with AML. There were 19 (53%) males and 17 (47%) females with a median age of 34 years (range 14-79 years). Five patients were <18 years and 2 patients were ≥60 years old at diagnosis. The symptoms at presentation of these patients were fatigue (58%), weakness (47%), fever (44%), pallor (31%), weight loss (28%) and anorexia (25%). Of the 36 ALL patients, only 3 had CNS involvement at pressentation. The patients had a median WBC count of 64.8×109/L (1-48.4), a median hemoglobin count of 9.5 g/dL (5.4-14.3), and a median platelet count of 104×109/L (8-36.8). Seventeen patients (53%) had a blast count of < 30% on peripheral blood. Thirty-one patients (86.1%) had B-ALL and 5 patients (13.9%) had T-ALL. Twelve patients (33%) had abnormal karyotype including 5 patients with Philadelphia posiitive ALL, 17 patients (47%) had normal karyotype, and 7 patients (20%) had failed or missing karyotype testing result.
0.9
Age <40 years (n=23, median 56 months)
0.8
Age ≥40 years (n=13, median 14 months)
0.7
P=.013
0.6 0.5 0.4 0.3 0.2 0.1 0 0
12
24
36
48 60 72 84 Follow-up (months)
96
108
120
Figure 3a. Overall survival by age.
concomitant diseases. Induction chemotherapy conssisted of BFM 90-like regimen (21 patients, 58%),23 HyperCVAD protocol24 (7 patients, 20%) and various other regimens (6 patients, 17%). At the discretion of the attending physicians, 27 patients received intratthecal chemotherapy as prophylaxis (n=24) or treatmment of CNS disease (n=3). Of the 34 patients who received induction chemotherapy with curative intent,
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original research report
ther consolidation and maintenance chemotherapy. Of the patients who achieved a first CR, 13 patients relapsed and were treated with chemotherapy. Four patients underwent stem cell transplantation.
1.0 Age <40 years (n=23, median 19 months) Age ≥40 years (n=13, median 3 months)
0.9 0.8
P=.079
Disease-free survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36 48 60 Follow-up (months)
72
84
96
Figure 3b. Disease-free survival by age.
1.0
WBC <30×109 (n=21, median 42 months)
0.9
WBC ≥30×109 (n=12, median 11 months)
0.8
P=.024
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0
12
24
36
48
60
72
84
96
108
120
Follow-up (months)
Figure 4a. Overall survival by WBC count.
26 (72%) patients achieved CR after first induction, 5 (15%) patients died during induction and 3 (9%) patients had persistent blasts at day 21-28 (Figure 1). These 3 patients received a second induction; two of them achieved CR and one died. The two patients who received palliative chemotherapy died of septic shock at day 43 and 171. Overall 28 patients achieved CR after induction chemotherapy and received furt-
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Survival and prognostic factors The median follow-up of the patients was 18.5 months. The median OS time was 22 months and the 5-year OS of ALL patients was 38% (Figure 2). The median DFS was 12 months, while the 5-year DFS was 38%. Multivariate analysis showed that age <40 years, WBC <30×109/L, and achievement of CR after first inducttion were predictive factors for OS and DFS. Twentythree patients with age less than 40 years had a median OS of 56 months and a 5-year OS of 46% compared with 13 patients 40 years of age or older who had a meddian OS of 14 months (P=.013) (Figure 3a). Median DFS time was 19 months and 5-year DFS was 43% for patients less than 40 years old compared with 3 months for patients 40 years of age or older (P=.079) (Figure 3b). No patient in the latter group had 5 years of DFS. Twenty-two patients with WBC <30×109/L had a meddian OS time of 42 months compared with 14 patients with WBC ≥30×109/L with median OS time of 11 months (P=.024) (Figure 4a). There was no significant difference in DFS between these two groups, probably because of the small sample size (Figure 4b). Twentysix patients who achieved CR after first induction had a median OS of 56 months compared with 6 months for the 10 patients who did not achieve CR (P<.0001) (Figure 5). There was no significant difference in survvival according to immunophenotype (B or T cell lineeage). Median OS for B lineage (n=31) and T lineage (n=5) cells were 44.2 and 59.2 months, respectively) (P=.287). Karyotype results were available for 29 pattients at presentation. They were classified into three groups according to karyotype: the good karyotype group (n=14) included patients with normal karyottype, and patients with 9p deletions; the “standard-risk” karyotype group (n=6) included patients with del(6q), hyperdiploidy, and miscellaneous translocations; and the high-risk karyotype group (n=9) included t(9;22), t(4;11), and t(1;19).25 According to this classification, the difference in OS or DFS was not statistically significcant between the three groups (data not shown). The median OS time for good karyotype, “standard-risk” karyotype, and bad karyotype groups were 56, 16, and 12 months, respectively (P=.182), and the median DFS for the good and bad karyotype groups were 24 and 17 months, respectively, and the median DFS for “standdard-risk” karyotype was not reached (P=.814). Three patients of 36 (8.3%) had initial CNS involvement. The
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median OS time for patients receiving CNS prophylaxis (n=24) or treatment (n=3) with intrathecal methotrexaate was 42 months compared with 11 months for those who did not receive intrathecal prophylaxis or treatment (n=9) (P=.001) (Figure 6a), while the median DFS for patients receiving CNS prophylaxis or treatment with intrathecal methotrexate was 19 months compared to 0 months in those who did not receive intrathecal propphylaxis or treatment (P=.004) (Figure 6b). There was no significant difference in OS and DFS among differeent treatment regimens (data not shown).
Disease-free survival
1.0 0.9
WBC <30×109 (n=21, median 19 months)
0.8
WBC ≥30×109 (n=12, median 9 months)
0.6 0.5 0.4
DISCUSSION
0.3
This report describes the results of 36 ALL patients from a tertiary care center in a developing country. There is limiteed access of patients to such centers mainly due to financial reasons, since many third party payers do not cover centers such as AUB-MC. The average worldwide incidence of adult ALL is 1 per 100 000. Therefore, we expect to have 40 patients diagnosed with adult ALL per year in country like Lebanon where the population is around 4 000 000. Since our center accommodates almost 10% of the patients in Lebanon, four patients with ALL are to be admitted to the center yearly. This explains the limited number of adult patients with ALL in our center. The prognosis of adults with ALL remains poor with a reported 5-year survival of 20% to 40%.14,26,27 Overall, our patients had 5-year OS and DFS rates of 38%, quite comparable to the results from developed countries. However, treatment-related mortality rate was 15% (5 patients out of 34), which is more than that reported in the literature (5-10%).28 As expected, patients who achieved CR after first induction showed a better OS than those who did not (median of 56 vs 6 months, respectively) (P<.0001). In our population of 36 consecutive ALL patients, the most common clinical symptoms at presentation were non-specific, consisting mainly of fatigue, weaknness, fever, pallor, weight loss and anorexia. This is in keeping with the classical presentations described in the medical literature.29-31 However, the median age (34 years) was significantly lower than in developed counttries (median, 37 years),19 reflecting both the younger age of the Lebanese population and a potential bias of referral to AUB-MC. Age has been described as a well known prognostic factor in ALL,32 and even as the most important prognostic factor for survival.33 In ALL, as age increases, OS continuously decreases.16-19 Different working groups defined different cut-off points for age as prognostic factors. Almost two-thirds of our patients were younger than 40 years of age and they had a better survival than patients older 40 years of age (56 versus
0.2
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P=.147
0.7
0.1 0.0 0
12
24
36
48
60
72
84
96
Follow-up (months)
Figure 4b. Disease-free survival by WBC count.
1.0 CR achieved (n=26, median 56 months) CR not achieved (n=10, median 6 months)
0.9 0.8
P<.0001
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48
60
72
84
96
108
120
Follow-up (months)
Figure 5. Overall survival by complete remission after first induction.
16 months, P=.013). There was no significant differeence in survival according to gender. Previous reports consistently showed that high white blood count is associated with higher risk of relapse and poorer OS.16,19,20,34 This is mostly true with ALL of Bcell origin.9 Most of our patients have ALL of B-cell
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original research report 1.0 0.9
Intrathecal treatment (n=27, median 42 months)
0.8
No intrathecal treatment (n=9, median 11 months)
P=.001
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48 60 72 Follow-up (months)
84
96
108
120
Figure 6a. Overall survival by intrathecal chemotherapy.
Disease-free survival
1.0 0.9
Intrathecal treatment (n=27, median 19 months)
0.8
No intrathecal treatment (n=9, no median)
0.7
P=.004
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48
60
72
84
96
Follow-up (months)
Figure 6b. Disease-free survival by intrathecal chemotherapy.
origin and accordingly, in our group, patients with WBC <30×109/L had an OS of 42 months compared with 14 months for those with a WBC >30×109/L (P=.024).
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However, there was no significant difference in survival among patients with different subtypes of ALL (B and T cell lineage). This could be due to the insufficient number of patients that are needed for such a comparison. Traditionally cytogenetics are described as the most important prognostic factor for DFS10,35,36 with t (9,22) having the worst prognosis in adult ALL before the era of imatinib mesylate.13 However, our population did not show any significant difference in CR rate or survvival according to cytogenetic risk groups. This could be due to the small number of patients we have compared with the huge diversity of cytogenetic abnormalities desscribed in the literature so far. Different induction chemotherapy protocols were used, mostly BFM-like or MD Anderson HyperCVAD regimen. Indeed, until June 2008, there were no unified treatment protocols for adult ALL patients at AUBMC. Different attending physicians used different regimen based on their previous experience, a situation frequently encountered in developing countries. An absence of a difference in OS when comparing differeent treatment regimens is in accordance with the fact that in the literature, until now, there is no advantage of one regimen over the other in ALL. Nevertheless, our results confirmed that patients who received intatheccal chemotherapy had a better OS than those who did not (42 versus 11 months, P=.001). Recently, following the establishment of a sister institution status between AUB-MC and the MD Anderson Cancer Center, uniffied protocols have been established for the treatment of adult acute leukemia. Later on, outcomes of patients prospectively included in the unified protocols will be presented to show the potential benefit of unified prottocols in a tertiary care center in a developing country. We have reported predictive and prognostic facttors in patients with ALL in a tertiary care center in a developing country. Significant prognostic factors in our treated group were age, WBC count more than 30×109/L, achievement of CR after the first induction, and CNS prophylaxis, while the type of chemotherapy regimen did not show any effect on survival. Factors desscribed earlier in the literature to affect survival such as cytogenetic abnormalities, and cell lineage were not signnificant in our study, probably due to the relatively few patients. Despite all the above limitations and the relattively low socioeconomic status of the Lebanese populattion (Lebanon is still considered a developing country with a gross domestic product of 4500 US dollars per capita), the OS of our patients (38%) and DFS (38%) were quite similar to the international data.14,26,27
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adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547-561. 25. Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, et al. A comprehensive genetic classification of adult acute lymphoblastic leukemmia (ALL): analysis of the GIMEMA 0496 protocol. Blood 2005;105:3434-3441 26. Eden OB, Harrison G, Richards S, Lilleyman JS, Bailey CC, Chessells JM, et al. Long-term folllow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblasttic leukaemia, 1980-1997. Medical Research Counccil Childhood Leukaemia Working Party. Leukemia 2000;14:2307-2320. 27. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia 2000;14:22052222. 28. Horowitz MM, Messerer D, Hoelzer D, Gale RP, Neiss A, Atkinson K, et al. Chemotherapy comppared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remisssion. Ann Intern Med 1991;115:13-18. 29. Hoelzer D, Thiel E, Loffler H, Buchner T, Ganser A, Heil G, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemmia in adults. Blood 1988;71:123-131. 30. Beutler E. Platelet transfusions: the 20,000/miccroL trigger. Blood 1993;81:1411-1413. 31. Hoelzer D, Gokbuget N, Digel W, Faak T, Kneba M, Reutzel R, et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002;99:4379-4385. 32. Degos L, Linch D, Lowenberg B. Textbook of Malignant Hematology 2nd edition ed. London: Infforma HealthCare; 1 edition (July 1, 2003), 2004. 33. Pui CH, Evans WE. Treatment of acute lymphobblastic leukemia. N Engl J Med 2006;354:166-178. 34. Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, et al. Adult acute lymphoccytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am 2000;14:1353-1366, x. 35. Cytogenetic abnormalities in adult acute lympphoblastic leukemia: correlations with hematologiic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique. Blood 1996;87:3135-3142. 36. Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalitties in adult acute lymphoblastic leukemia. Blood 1998;91:3995-4019.
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BACKGROUND AND OBJECTIVES: The most important studies about outcome of acute leukemia come from developed countries, whereas most of the patients with this disease are in developing countries. We report preddictive and prognostic factors in patients with acute lymphoblastic leukemia (ALL) in a tertiary care center in a developing country. PATIENTS AND METHODS: We retrospectively reviewed the records of adult patients with acute leukemia who were referred to the American University of Beirut Medical Center between 1996 and early 2006. Results: Of 105 patients, 36 (34%) patients were diagnosed with ALL, and included 19 (53%) males and 17 (47%) females with a median age of 34 years (range, 14-79 years). Induction chemotherapy with curative intent was administered to 34 (94%) patients. Twenty-seven patients received intrathecal chemotherapy as prophylaxis (n=24) or as treatment for CNS disease (n=3). Twenty-eight patients (82%) achieved complete remission (CR) after induction chemotherapy. The median overall survival (OS) time was 22 months and the five-year OS for ALL patients was 38%. The median disease-free survival (DFS) time was 12 months, while the five-year DFS was 38%. Multivariate analysis showed that age <40 years, WBC <30×109/L, achievement of CR after first induction, and CNS prophylaxis were predictive factors for OS and DFS. Conclusion: Despite limitations and the relatively low socioeconomic status of the Lebanese population, OS (38%) and DFS (38%) are quite similar to international data. Trends toward a higher CR and DFS in adults are due to intensified consolidation chemotherapy, the use of stem cell transplantation, and improvements in supportive care.
T
he incidence of acute leukemia is increasing worldwide.1-3 As the population ages, it is antticipated that an even greater number of patients will be diagnosed with this malignancy.4,5 The overall inciddence of acute lymphoblastic leukemia (ALL) is 1 to 1.5 per 100 000 persons,6 with a bimodal distribution at ages 4 to 5 years (with an incidence as high as 4 to 5 per 100 000 persons) and at age 50 years (with an incidence 2 per 100 000 persons).6 There are no reports clearly describing the incidence of ALL in developing countries. The most important studies about outcome of acute leukemias come from developed countries, whereas most of the patients with this disease are in developing countries
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based on the distribution of the would be world’s popullation.7,8 In ALL, the most important prognostic factor for overall survival is age,9 while the most important facttor for disease-free survival (DFS) is karyotype.10 The 5-year overall survival (OS) of adult patients with ALL is 20% to 40%.11-15 For those less than 30 years of age, the OS is 34% to 57%, compared to 15% to 17% for patients older than 50 years of age.16-20 Moreover, although most cases of ALL are found in developing countries, there is scarcity of data in the liteerature reflecting the condition of these patients includiing clinical features, description of prognostic factors and predictors as well as the outcome. In this manuscript, we
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original research report Table 1. Patient’s characteristics at presentation. Patient characteristics
Patients (n=36)
Male/female
19/17
Median age (range) (years) Clinical findings
8 (22%)
Hepatomegaly
0 (0%)
Splenomegaly
6 (17%)
Testicular involvement
0 (0%)
Mediastinal enlargement
0 (0%)
Fever
16 (44%)
Bleeding
0 (0%)
Fatigue
21 (58%)
Laboratory findings (normal range)
Median (range)
LDH, IU/L (normal range, 110-265 IU/L)
2023.9 (101-8948)
WBC, ×109/L (normal range, 4.0-11.0×109/L)
64.8 (1-484)
Hemoglobin, g/dL (Male: normal range, 13-18 g/dL) (Female: normal range, 12-16 g/dL)
9.5 (5.4-14.3)
Blasts, %
40 (0-94)
Platelets, ×10 /L (normal range, 150-400×109/L) 9
104 (8-368)
LDH: lactate dehydrogenase; WBC: white blood cell count
ALL n=36 patients
Supportive treatment n=2 patients (6%)
Complete remission n=26 patients (76%)
Induction chemottherapy n=34 patients (94%) Death during induction n=5 patients (15%)
Induction failure n=3 patients (9%)
Reinduction
Complete Complete remission remission n=2 n=2 patients patients
Death Death n=1 n=1patients patient
Total complete complete Total remission remission n=28 patients patients (78%) (78%) n=28
Figure 1. Disposition of 36 patients with acute lymphoblastic leukemia (ALL).
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report predictive and prognostic factors in patients with ALL in a tertiary care center in a developing country.
PATIENTS AND METHODS
34 (14-79)
Lymphadenopathy
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We retrospectively reviewed the records of consecuttive patients with newly diagnosed and previously unttreated acute leukemia who were referred to the adult hematology service of the American University of Beirut Medical Center (AUB-MC) between 1996 and early 2006. The number of patients reviewed was 131. These patients were studied for family and personal history, medical history, disease presentation, and management and outcome of leukemia. The biological characteristics of the leukemia including morphologiccal, immunophenotypic, cytogenetic and molecular data were also analyzed. A morphological review of all cases was performed by one hematopathologist (RM). Twenty-six patients were excluded from this study; 14 of these were diagnosed but not treated at AUB-MC, 6 patients were rediagnosed as having hematologic malignancies other than acute leukkemia, and the remaining 6 patients did not have suffficient data to be included in the analysis. Therefore, a total of 105 patients were included in the data collected. Of these 105 patients, 69 (66%) had acute myelogenous leukemia (AML) and 36 patients (34%) had ALL. This study was approved by the Institutional Review Board at AUB-Faculty of Medicine. Hospital records of the patients were reviewed in the Department of Medical Records and the private clinics. Phone calls were also done for the most recent follow up of patients. The diagnosis of ALL was made according to the French-American-British (FAB) morphologiccal and cytochemical criteria.21 Cytogenetic analysis was performed routinely using standard methods. Immunophenotyping was also performed using flow cyttometry. Bone marrow aspirate and/or biopsy were anallyzed for cellularity and blast count. Blood chemistry, complete blood count (CBC), coagulation profile, and left ventricular ejection fraction data were collected. For assessment of response, bone marrow aspirrate was performed at the end of the induction phase. Complete hematological remission (CR) was defined as less than 5% marrow blasts with normal peripheral blood counts and differential, with no evidence of exttramedullary leukemia. Partial remission (PR) required similar criteria except for the presence of 5% to 20% marrow blasts. Resistance was defined as persistent leukkemia in blood and/or bone marrow in patients surviviing more than 1 month after start of induction treatmment. Death during induction was defined as death that occurred while the patient was receiving induction
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therapy. Disease-free survival (DFS) was defined as the time from the first day of CR to relapse, death, or last visit, and overall survival (OS) as the time from the day of diagnosis to death or last visit. Hematological relapse was considered when more than 5% blasts were seen in bone marrow aspirates as confirmed by flow cytomeetry. We describe numerical variables by their median and range, whereas categorical variables are described by their relative frequencies and counts. Survival curves were calculated according to the methods of Kaplan and Meier and compared between groups with the log-rank test.22 Differences were considered statistically significant when the P value was less than .05. Potential prognostic factors tested for the univariate analysis comprised age, sex, WBC count, hemoglobin, platelet count, percentage of blasts in the bone marrow, cytogenetic abnormalities, CNS involvement, type of chemotherapy and response to first induction chemotherapy. Univariate and multivvariate analysis were done for all factors assessed. The analyses were performed using SPSS software version 15.0 (SPSS, Chicago, IL, USA).
1.0 Overall survival (median, 22 months) Disease-free survival (median, 12 months)
0.9 0.8 Disease-free survival
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0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0
12
24
36 48 60 72 Follow up (months)
84
96
108
120
Figure 2. Overall and disease-free survival for 36 patients with acute lymphoblastic leukemia.
RESULTS
Response to induction chemotherapy Induction chemotherapy with curative intent was administered to 34 patients (94%), and the remainiing 2 patients (6%) received palliative chemotherapy due to old age, poor performance status, or severe
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1.0
Overall survival
Initial Presentation Of the 105 patients analyzed, 36 (34%) patients were diagnosed with ALL (Table 1) and 69 (66%) patients were diagnosed with AML. There were 19 (53%) males and 17 (47%) females with a median age of 34 years (range 14-79 years). Five patients were <18 years and 2 patients were ≥60 years old at diagnosis. The symptoms at presentation of these patients were fatigue (58%), weakness (47%), fever (44%), pallor (31%), weight loss (28%) and anorexia (25%). Of the 36 ALL patients, only 3 had CNS involvement at pressentation. The patients had a median WBC count of 64.8×109/L (1-48.4), a median hemoglobin count of 9.5 g/dL (5.4-14.3), and a median platelet count of 104×109/L (8-36.8). Seventeen patients (53%) had a blast count of < 30% on peripheral blood. Thirty-one patients (86.1%) had B-ALL and 5 patients (13.9%) had T-ALL. Twelve patients (33%) had abnormal karyotype including 5 patients with Philadelphia posiitive ALL, 17 patients (47%) had normal karyotype, and 7 patients (20%) had failed or missing karyotype testing result.
0.9
Age <40 years (n=23, median 56 months)
0.8
Age ≥40 years (n=13, median 14 months)
0.7
P=.013
0.6 0.5 0.4 0.3 0.2 0.1 0 0
12
24
36
48 60 72 84 Follow-up (months)
96
108
120
Figure 3a. Overall survival by age.
concomitant diseases. Induction chemotherapy conssisted of BFM 90-like regimen (21 patients, 58%),23 HyperCVAD protocol24 (7 patients, 20%) and various other regimens (6 patients, 17%). At the discretion of the attending physicians, 27 patients received intratthecal chemotherapy as prophylaxis (n=24) or treatmment of CNS disease (n=3). Of the 34 patients who received induction chemotherapy with curative intent,
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original research report
ther consolidation and maintenance chemotherapy. Of the patients who achieved a first CR, 13 patients relapsed and were treated with chemotherapy. Four patients underwent stem cell transplantation.
1.0 Age <40 years (n=23, median 19 months) Age ≥40 years (n=13, median 3 months)
0.9 0.8
P=.079
Disease-free survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36 48 60 Follow-up (months)
72
84
96
Figure 3b. Disease-free survival by age.
1.0
WBC <30×109 (n=21, median 42 months)
0.9
WBC ≥30×109 (n=12, median 11 months)
0.8
P=.024
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0
12
24
36
48
60
72
84
96
108
120
Follow-up (months)
Figure 4a. Overall survival by WBC count.
26 (72%) patients achieved CR after first induction, 5 (15%) patients died during induction and 3 (9%) patients had persistent blasts at day 21-28 (Figure 1). These 3 patients received a second induction; two of them achieved CR and one died. The two patients who received palliative chemotherapy died of septic shock at day 43 and 171. Overall 28 patients achieved CR after induction chemotherapy and received furt-
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Survival and prognostic factors The median follow-up of the patients was 18.5 months. The median OS time was 22 months and the 5-year OS of ALL patients was 38% (Figure 2). The median DFS was 12 months, while the 5-year DFS was 38%. Multivariate analysis showed that age <40 years, WBC <30×109/L, and achievement of CR after first inducttion were predictive factors for OS and DFS. Twentythree patients with age less than 40 years had a median OS of 56 months and a 5-year OS of 46% compared with 13 patients 40 years of age or older who had a meddian OS of 14 months (P=.013) (Figure 3a). Median DFS time was 19 months and 5-year DFS was 43% for patients less than 40 years old compared with 3 months for patients 40 years of age or older (P=.079) (Figure 3b). No patient in the latter group had 5 years of DFS. Twenty-two patients with WBC <30×109/L had a meddian OS time of 42 months compared with 14 patients with WBC ≥30×109/L with median OS time of 11 months (P=.024) (Figure 4a). There was no significant difference in DFS between these two groups, probably because of the small sample size (Figure 4b). Twentysix patients who achieved CR after first induction had a median OS of 56 months compared with 6 months for the 10 patients who did not achieve CR (P<.0001) (Figure 5). There was no significant difference in survvival according to immunophenotype (B or T cell lineeage). Median OS for B lineage (n=31) and T lineage (n=5) cells were 44.2 and 59.2 months, respectively) (P=.287). Karyotype results were available for 29 pattients at presentation. They were classified into three groups according to karyotype: the good karyotype group (n=14) included patients with normal karyottype, and patients with 9p deletions; the “standard-risk” karyotype group (n=6) included patients with del(6q), hyperdiploidy, and miscellaneous translocations; and the high-risk karyotype group (n=9) included t(9;22), t(4;11), and t(1;19).25 According to this classification, the difference in OS or DFS was not statistically significcant between the three groups (data not shown). The median OS time for good karyotype, “standard-risk” karyotype, and bad karyotype groups were 56, 16, and 12 months, respectively (P=.182), and the median DFS for the good and bad karyotype groups were 24 and 17 months, respectively, and the median DFS for “standdard-risk” karyotype was not reached (P=.814). Three patients of 36 (8.3%) had initial CNS involvement. The
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median OS time for patients receiving CNS prophylaxis (n=24) or treatment (n=3) with intrathecal methotrexaate was 42 months compared with 11 months for those who did not receive intrathecal prophylaxis or treatment (n=9) (P=.001) (Figure 6a), while the median DFS for patients receiving CNS prophylaxis or treatment with intrathecal methotrexate was 19 months compared to 0 months in those who did not receive intrathecal propphylaxis or treatment (P=.004) (Figure 6b). There was no significant difference in OS and DFS among differeent treatment regimens (data not shown).
Disease-free survival
1.0 0.9
WBC <30×109 (n=21, median 19 months)
0.8
WBC ≥30×109 (n=12, median 9 months)
0.6 0.5 0.4
DISCUSSION
0.3
This report describes the results of 36 ALL patients from a tertiary care center in a developing country. There is limiteed access of patients to such centers mainly due to financial reasons, since many third party payers do not cover centers such as AUB-MC. The average worldwide incidence of adult ALL is 1 per 100 000. Therefore, we expect to have 40 patients diagnosed with adult ALL per year in country like Lebanon where the population is around 4 000 000. Since our center accommodates almost 10% of the patients in Lebanon, four patients with ALL are to be admitted to the center yearly. This explains the limited number of adult patients with ALL in our center. The prognosis of adults with ALL remains poor with a reported 5-year survival of 20% to 40%.14,26,27 Overall, our patients had 5-year OS and DFS rates of 38%, quite comparable to the results from developed countries. However, treatment-related mortality rate was 15% (5 patients out of 34), which is more than that reported in the literature (5-10%).28 As expected, patients who achieved CR after first induction showed a better OS than those who did not (median of 56 vs 6 months, respectively) (P<.0001). In our population of 36 consecutive ALL patients, the most common clinical symptoms at presentation were non-specific, consisting mainly of fatigue, weaknness, fever, pallor, weight loss and anorexia. This is in keeping with the classical presentations described in the medical literature.29-31 However, the median age (34 years) was significantly lower than in developed counttries (median, 37 years),19 reflecting both the younger age of the Lebanese population and a potential bias of referral to AUB-MC. Age has been described as a well known prognostic factor in ALL,32 and even as the most important prognostic factor for survival.33 In ALL, as age increases, OS continuously decreases.16-19 Different working groups defined different cut-off points for age as prognostic factors. Almost two-thirds of our patients were younger than 40 years of age and they had a better survival than patients older 40 years of age (56 versus
0.2
Hematol Oncol Stem Cell Ther 2(2)
P=.147
0.7
0.1 0.0 0
12
24
36
48
60
72
84
96
Follow-up (months)
Figure 4b. Disease-free survival by WBC count.
1.0 CR achieved (n=26, median 56 months) CR not achieved (n=10, median 6 months)
0.9 0.8
P<.0001
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48
60
72
84
96
108
120
Follow-up (months)
Figure 5. Overall survival by complete remission after first induction.
16 months, P=.013). There was no significant differeence in survival according to gender. Previous reports consistently showed that high white blood count is associated with higher risk of relapse and poorer OS.16,19,20,34 This is mostly true with ALL of Bcell origin.9 Most of our patients have ALL of B-cell
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original research report 1.0 0.9
Intrathecal treatment (n=27, median 42 months)
0.8
No intrathecal treatment (n=9, median 11 months)
P=.001
Overall survival
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48 60 72 Follow-up (months)
84
96
108
120
Figure 6a. Overall survival by intrathecal chemotherapy.
Disease-free survival
1.0 0.9
Intrathecal treatment (n=27, median 19 months)
0.8
No intrathecal treatment (n=9, no median)
0.7
P=.004
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
12
24
36
48
60
72
84
96
Follow-up (months)
Figure 6b. Disease-free survival by intrathecal chemotherapy.
origin and accordingly, in our group, patients with WBC <30×109/L had an OS of 42 months compared with 14 months for those with a WBC >30×109/L (P=.024).
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However, there was no significant difference in survival among patients with different subtypes of ALL (B and T cell lineage). This could be due to the insufficient number of patients that are needed for such a comparison. Traditionally cytogenetics are described as the most important prognostic factor for DFS10,35,36 with t (9,22) having the worst prognosis in adult ALL before the era of imatinib mesylate.13 However, our population did not show any significant difference in CR rate or survvival according to cytogenetic risk groups. This could be due to the small number of patients we have compared with the huge diversity of cytogenetic abnormalities desscribed in the literature so far. Different induction chemotherapy protocols were used, mostly BFM-like or MD Anderson HyperCVAD regimen. Indeed, until June 2008, there were no unified treatment protocols for adult ALL patients at AUBMC. Different attending physicians used different regimen based on their previous experience, a situation frequently encountered in developing countries. An absence of a difference in OS when comparing differeent treatment regimens is in accordance with the fact that in the literature, until now, there is no advantage of one regimen over the other in ALL. Nevertheless, our results confirmed that patients who received intatheccal chemotherapy had a better OS than those who did not (42 versus 11 months, P=.001). Recently, following the establishment of a sister institution status between AUB-MC and the MD Anderson Cancer Center, uniffied protocols have been established for the treatment of adult acute leukemia. Later on, outcomes of patients prospectively included in the unified protocols will be presented to show the potential benefit of unified prottocols in a tertiary care center in a developing country. We have reported predictive and prognostic facttors in patients with ALL in a tertiary care center in a developing country. Significant prognostic factors in our treated group were age, WBC count more than 30×109/L, achievement of CR after the first induction, and CNS prophylaxis, while the type of chemotherapy regimen did not show any effect on survival. Factors desscribed earlier in the literature to affect survival such as cytogenetic abnormalities, and cell lineage were not signnificant in our study, probably due to the relatively few patients. Despite all the above limitations and the relattively low socioeconomic status of the Lebanese populattion (Lebanon is still considered a developing country with a gross domestic product of 4500 US dollars per capita), the OS of our patients (38%) and DFS (38%) were quite similar to the international data.14,26,27
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