|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4648-4656 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4508 Assessment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by Absolute Lymphocyte Counts in 2,126 Patients: 20 Years of Experience at The University of Texas M.D. Anderson Cancer Center
From the Departments of Leukemia, Biostatistics and Applied Mathematics, Lymphoma/Myeloma, and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Apostolia M. Tsimberidou, MD, PhD, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: atsimber{at}mdanderson.org
Purpose Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are currently considered the same entity, but controversy remains over whether CLL and SLL should be treated similarly. We assessed whether characteristics of patients with CLL and SLL differ in ways other than the absolute lymphocyte count (ALC) and evaluated treatment outcomes and prognostic factors. Methods We searched the electronic database for patients with CLL or SLL who presented to The University of Texas M.D. Anderson Cancer Center (Houston, TX) between 1985 and 2005. We reviewed patient records to determine presenting characteristics, treatment, and clinical outcomes. Cox models using training and validation sets of patients and resampling methods were used to develop a model predicting survival. Results Among 2,126 consecutive CLL/SLL patients, 312 (15%) had ALC less than 5 x 109/L. Patients with ALC less than 5 x 109/L had lower rates of cytogenetic abnormalities (P = .0002) and higher rates of CD38-positive results (P = .0002) and had mutated immunoglobulin heavy-chain variable region gene status (P = .034). Rates of response, survival, and failure-free survival (FFS) were not different among ALC groups. Regimens that included rituximab and a nucleoside analog were associated with superior rates of response and FFS compared with other therapies, irrespective of ALC. Deletion 17p or 6q with or without other cytogenetic abnormalities, age at least 60 years, β2-microglobulin at least 2 mg/L, albumin less than 3.5 g/dL, and creatinine at least 1.6 mg/dL were each found to independently predict shorter survival and formed the basis of a scoring system. Conclusion Patients with CLL or SLL can be treated similarly. A new prognostic score is proposed.
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are viewed as similar entities by the WHO.1 Histologically and immunophenotypically, CLL and SLL are identical, but patients with CLL, by definition, have more marked peripheral blood involvement.2-4 An absolute lymphocyte count (ALC) of 5 x 109/L has been used to distinguish SLL from CLL (with SLL defined by an ALC < 5 x 109/L). This cutoff is somewhat arbitrary, however, and has never been evaluated definitively. Homing receptors may explain the clinical differences between CLL and SLL. SLL tissue samples are reported to be positive for L-selectin, CD44, and CD11c/CD18, but they lack lymphocyte function–associated antigen-3 (LFA-3) and intercellular adhesion molecule-1.2 LFA-1 is expressed by SLL, but not by CLL cells.3,5 The clinical course of CLL/SLL varies widely. The indolent clinical behavior of SLL has often led to the approach of deferring treatment in asymptomatic patients until progressive disease becomes evident.6 Patients with SLL are eventually offered therapies developed for other indolent lymphomas, the most common being follicular lymphoma, even though the biology of SLL differs from that of follicular lymphomas. Treatment of CLL is also deferred until indications for therapeutic intervention are present. In recent years, combination therapies with nucleoside analogs and rituximab have led to improved outcomes in SLL and CLL, but there is still no consensus as to the optimal treatments for these diseases. To assess whether the presenting characteristics of patients with CLL/SLL differ in ways other than the ALC and to address which therapy is best for CLL and SLL patients, we retrospectively analyzed data from the largest series of CLL/SLL patients to date. The secondary end point was to identify prognostic factors predicting clinical outcomes.
We searched an electronic database of 2,359 consecutive, previously untreated patients designated as having either CLL or SLL who presented to The University of Texas M.D. Anderson Cancer Center Department of Leukemia or Department of Lymphoma/Myeloma (Houston, TX) between 1985 and 2005. All patient records were reviewed to determine presenting features, treatment, and clinical outcomes. A waiver of informed consent and a waiver of authorization were granted by the institutional review board.
Diagnosis
Therapy
End Points and Statistical Methods
The
Patient Characteristics A total of 2,126 patients were included in the analysis; 233 patients were excluded because, on subsequent assessment, the disease was better characterized as mantle-cell lymphoma, marginal zone lymphoma, or hairy cell leukemia; data were incomplete; or the patient was lost to follow-up. The median age was 58 years (range, 17 to 90 years). There was a male preponderance (61%). A total of 312 patients (15%) had an ALC less than 5 x 109/L, along with lower rates of organomegaly and lymph node involvement and less extensive bone marrow infiltration than patients with ALC at least 5 x 109/L. Patients with ALC less than 5 x 109/L also had lower rates of genomic aberrations by cytogenetic analysis (13% v 27%; P = .0002) and fluorescence in situ hybridization (FISH) analysis (55% v 71%; P = .037) and higher rates of CD38 expression (36% v 22%; P = .0002) and Ig heavy chain variable region gene (IgVH) mutations (76% v 55%; P = .034) compared with patients with higher ALCs.
Time to Treatment
Survival
The correlations between the presenting characteristics and survival are shown in Table 1. All of the listed characteristics, except for bone marrow involvement, CD38 and zeta-associated protein-70 (ZAP-70) expression, and FISH analysis, were significantly associated with survival.
Independent Prognostic Factors and the Prognostic Factor Model Factors independently prognostic of survival in all patients with CLL/SLL are shown in Table 2. Two thirds of the patients were randomly chosen to develop a model, and the remaining one third were used to validate the model. Cytogenetics, age, and β2-microglobulin, albumin, and creatinine levels each independently affected survival both in the training and the validation sets (Tables A1 and A2), whereas hepatomegaly, hemoglobin, sex, and ALC were prognostic in the training but not in the validation set. When the 2,126 patients were resampled to obtain 1,000 separate 1,417-patient data sets in each of which we fit a Cox model, cytogenetics, age, and β2-microglobulin were each independently significant in 100% of the samples, albumin in 93%, and creatinine in 79%. The respective proportions for hepatomegaly, hemoglobin, sex, and ALC were 18%, 8%, 2%, and 1%.
On the basis of the results of both analyses, 17p del or 6q del with or without other cytogenetic abnormalities, age at least 60 years, β2-microglobulin at least 2 mg/L, albumin less than 3.5 g/dL, and creatinine at least 1.6 mg/dL were used to develop a scoring system. Patient scores can range from 0 to 5. The Kaplan-Meier survival curves using the scores calculated from these five risk factors were similar using the training (Fig A2A, online only) and validation (Fig 2A) data sets. Application of this scoring system is shown in Figure A2B. At 5 years, 98%, 83%, 69%, and 21% of patients with 0, 1, 2, and 3 to 5 risk factors, respectively, are expected to be alive (Fig A2B). When the Rai and Binet staging systems were added to the model, they were also significant, but were associated with lower relative risks (RRs) than the top five factors (RR = 1.24 and 1.35, respectively). Survival by the Rai and Binet staging systems is shown in Figures 2B and 2C, respectively.
Therapy and Response Overall, 1,041 patients were treated, and 965 patients were analyzed. Seventy-six patients who were treated with regimens other than those specified in the Methods section were excluded from the analysis. To control for differences in clinical features, the 965 patients were analyzed according to their pretreatment characteristics (Table 3). There were differences between the treatment groups by sex; ALC; levels of hemoglobin, lactate dehydrogenase, and β2-microglobulin; number of nodal sites; RAI stage; cytogenetics; IgVH mutational status; and CD38 positivity.
In univariate analysis, factors predicting overall response were hemoglobin levels higher than 11 g/dL (P < .0001), age less than 60 years (P = .001), absence of 17p deletion or 6q deletion (P = .01), and albumin levels at least 3.5 g/dL (P = .05). There was no difference in response rates between patients with ALC less than 5 x 109/L and those with higher ALCs (P = .73). In multivariate analysis, hemoglobin levels higher than 11 g/dL (P = .0007), age less than 60 years (P = .003), and absence of 17p deletion or 6q deletion (P = .025) were independent factors predicting response. When treatment was included in the multivariate analysis, therapy with FCR, R-FCM, or R-FND was associated with higher response rates (P = .0001).
FFS
In univariate analysis, age less than 60 years (P < .0001), absence of 17p del with or without other abnormalities (P = .0008), hemoglobin levels more higher 11 g/dL (P = .009), RAI stage 0 to 2 (P = .01), lower IgG levels (P = .06), higher IgA levels (P = .03), and absence of lymphadenopathy (P = .03) predicted longer FFS. There was no significant difference in FFS between patients with ALC less than 5 x 109/L and those with higher ALCs (P = .59). In multivariate analysis, pretreatment parameters that remained independently significant for longer FFS were age less than 60 years (P < .0001), absence of 17p del with or without other abnormalities (P = .0037), and hemoglobin levels higher than 11 g/dL (P = .03). When treatment was added to the model, therapy with FCR, R-FCM, or R-FND was also independently correlated with longer FFS (P < .0001).
Survival According to Treatment Regimen Complete data on ZAP-70, IgVH gene mutational status, and FISH analysis were available in 219 patients (10.3%). However, the short follow-up period and the few events (seven deaths) preclude a valid analysis of these patients at the present time.
This report demonstrates that CLL and SLL are clinically similar diseases, with a few notable exceptions. A key finding of the current study is that therapy with FCR, R-FCM, or R-FND resulted in superior response and FFS rates compared with other regimens in both CLL and SLL. The current analysis also demonstrates that the prognostic relevance of the Rai and Binet staging systems may be enhanced by the incorporation of additional data, including the presence of cytogenetic abnormalities and levels of serum β2-microglobulin and albumin. According to the WHO classification, lymphocytosis in CLL/SLL is defined as an ALC at least 10 x 109/L, but the diagnosis of CLL/SLL can still be made with a lower ALC if morphologic and immunophenotypic features are typical of CLL/SLL.1 Several other definitions of lymphocytosis have also been used. In 1975, Rai et al19 proposed a staging system in CLL defining lymphocytosis as an ALC at least 15 x 109/L. In a multivariate analysis, we identified ALC at least 30 x 109/L as an independent factor predicting shorter survival. This is consistent with results of other investigators who defined "smoldering CLL" as an ALC of less than 30 x 109/L.20,21 The higher rate of CD38 expression (36%) in patients in the low-ALC group (ALC < 5 x 109/L) in our study is consistent with a previous report22 and with a higher expression of CD38 in the lymph nodes compared with bone marrow or peripheral blood in patients with CLL/SLL in another report.23
The strongest independent predictor of poor survival was the presence of a 17p or 6q deletion, with or without other cytogenetic abnormalities. These findings confirm those of earlier studies showing that 17p deletion24 and 6q deletion25 are associated with adverse prognosis in CLL/SLL. It has been suggested that 6q deletion may be an initial event in leukemogenesis, caused by the absence of an unidentified recessive tumor suppressor gene. As expected, older age was also an independent predictor of shorter survival (Table 2). Older age has been associated with shorter survival in most studies,26,27 with the exception of one study demonstrating that younger and older patients with CLL had a similar probability of survival.28 The disparity could be explained by the low death rate in both age groups in that study (26% for patients On the basis of the five most statistically significant independent factors (ie, 17p or 6q deletion with or without other cytogenetic abnormalities; age; and levels of β2-microglobulin, albumin, and creatinine), a prognostic score was developed. Our proposed CLL/SLL prognostic score may supplement the well-established Rai and Binet staging systems,19,33 keeping in mind that more effective treatment strategies have become available over time, as well as the use of risk-adapted therapies. Several other prognostic factors have been identified in CLL/SLL, and new markers are being validated in clinical trials.34-39 Until these results become available, treatment decisions outside of clinical trials should conform to the NCI-sponsored Working Group criteria.40 In the treatment of CLL/SLL, regimens containing rituximab and a nucleoside analog, such as FCR, R-FCM, or R-FND, were highly effective and were associated with superior rates of response and FFS. It is likely that these results will also translate into superior survival, although longer follow-up is needed. This speculation is supported by a Cox regression analysis in which, when treatment was added to the model (Table 2), therapy other than FCR, R-FCM, or R-FND was an independent predictor of shorter survival (P < .0001). Rates of response, survival, and FFS did not differ by ALC group, suggesting that patients with CLL/SLL and ALCs less than 5 x 109/L should be treated similarly to those with higher ALCs. The results of this report should be interpreted with caution because of (1) the retrospective nature of the analysis, (2) the long time interval during which different therapies were offered, and (3) the variation in selection criteria for the different regimens, which naturally resulted in strong interactions between various therapies and other characteristics (Table 3). Another limitation is the difference in response criteria for CLL and SLL. Computed tomography scans were required for assessment of response in SLL, but they have not been uniformly utilized in CLL. This study emphasizes the need for standardized, common response criteria for CLL/SLL. Patients with untreated CLL/SLL should be assessed using standard and new markers, including FISH analysis, IgVH, and ZAP-70. Future research should focus on using prognostic factors to assign risk-adapted therapies and prolonging FFS by optimizing maintenance therapy and developing strategies to eradicate minimal residual disease.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Michael J. Keating, Berlex Labs (C), Genentech (C) Stock Ownership: None Honoraria: Peter Mclaughlin, Co-Med Communications, Health Science Communications; William Wierda, Celgene; Michael J. Keating, Berlex Labs, Genentech Research Funding: Apostolia M. Tsimberidou, Sanofi-Synthelabo; Susan O'Brien, Genentech, Berlex; Peter Mclaughlin, Berlex, Biogen IDEC Pharmaceuticals, Genentech, Schering-Plough, Integrated Therapeutics, OSI Pharmaceuticals, Millenium Pharmaceuticals; William Wierda, Berlex, Sanofi, Memgen, Genitope, Genmab; Alessandra Ferrajoli, Celgene, Bayer Healthcare; Stefan Faderl, Genzyme, Genentech, Bayer Healthcare; Alma M. Rodriguez, Amgen, Ortho Biotech (Tibotec), IDEC; Hagop Kantarjian, Novartis Pharmaceuticals, MGI Pharmaceuticals, Bristol-Myers Squibb; Michael J. Keating, Berlex Labs, Genentech Expert Testimony: None Other Remuneration: None
Conception and design: Apostolia M. Tsimberidou, Michael J. Keating Financial support: Michael J. Keating Administrative support: Emil J. Freireich, Michael J. Keating Provision of study materials or patients: Susan O'Brien, Peter Mclaughlin, William G. Wierda, Alessandra Ferrajoli, Stefan Faderl, John Manning, Alma M. Rodriguez, Hagop Kantarjian, L. Jeffrey Medeiros, Michael J. Keating Collection and assembly of data: Apostolia M. Tsimberidou, Peter Mclaughlin, Susan Lerner, Chinh Mai, Mark Hess, L. Jeffrey Medeiros, Michael J. Keating Data analysis and interpretation: Apostolia M. Tsimberidou, Sijin Wen, Peter Mclaughlin, Kim-Anh Do, Emil J. Freireich, L. Jeffrey Medeiros Manuscript writing: Apostolia M. Tsimberidou, Susan O'Brien, Peter Mclaughlin, John Manning Final approval of manuscript: Apostolia M. Tsimberidou, Sijin Wen, Susan O'Brien, Peter Mclaughlin, William G. Wierda, Alessandra Ferrajoli, Stefan Faderl, John Manning, Susan Lerner, Chinh Mai, Alma M. Rodriguez, Mark Hess, Kim-Anh Do, Emil J. Freireich, Hagop Kantarjian, L. Jeffrey Medeiros, Michael J. Keating
PATIENTS AND METHODS Methods Studies for ZAP-70 expression and IgVH mutational analysis were performed as previously published (Muller-Hermelink HK, Catovsky D, Montserrat E, et al: Chronic lymphocytic leukemia/small lymphocytic lymphoma, in Jaffe ES HN, Stein H, Wardiman JW [eds]: Tumors of Haematopoietic and Lymphoid Tissues: World Health Organization Classification of Tumors. Lyon, France, IARC Press, 2001, pp 127-130; Freedman AS, Nadler LM: Non-Hodgkin's lymphomas, in Kufe DW, Pollock RE, Weichselbaum RR, et al [eds]: Cancer Medicine [ed 6], Hamilton, Ontario, Canada, BC Decker Inc, 2003, pp 2189-2210).These assays were performed in patients who presented in recent years. Therapy The criteria for initiating treatment were the standard criteria from 1989 to 1996 and the modified National Cancer Institute (NCI) 1996 criteria from 1996 to present. Briefly, the modified NCI criteria were disease-related progressive symptoms; progressively worsening anemia or thrombocytopenia; autoimmune hemolytic anemia or thrombocytopenia; progressive bulky lymphadenopathy pressuring underlying tissues; worsening massive splenomegaly or hypersplenism; progressive hyperlymphocytosis with a doubling time less than 12 months; and increased susceptibility to bacterial infections. The decision to initiate treatment—and regarding the type of treatment—was made at M.D. Anderson Cancer Center. If the treatment protocol allowed, patients could receive the recommended therapy from their primary hematologist/oncologist and return to M.D. Anderson for response assessment. Patients with ALC less than 5 x 109/L presented to the Lymphoma Department according to the departmental/institutional policy. These patients were usually Ann Arbor stage IV and were offered protocol therapy (Spertini O, Freedman AS, Belvin MP, et al. Leukemia 5:300-308, 1991). Off-protocol watchful waiting was sometimes used. Patients with higher ALCs typically presented to the Leukemia Department. In general, patients who were untreated at the time of presentation to M.D. Anderson were included in the analysis. ALCs used for classification into the two ALC groups (eg, higher than 5.0 or lower than 5.0 x 109/L), as well as other baseline characteristics, were recorded at the time of initial evaluation at M.D. Anderson. Progressive or relapsed disease was treated with salvage regimens, which were followed by stem-cell transplantation in selected patients. End Points and Statistical Methods Depending on clinical relevance and data availability, the following parameters were included in the multivariate analyses: age; sex; performance status; ALC; hemoglobin level; platelet count; levels of lactate dehydrogenase, β2-microglobulin, albumin, creatinine, and alkaline phosphatase; quantitative IG; hepatomegaly, with or without splenomegaly; presence of palpable lymphadenopathy (assessed by physical examination of three individual nodal sites [head and neck, axillary, and inguinal]); proportion of bone marrow lymphocytes; cellularity; bone marrow CD38 expression; ZAP-70 expression; cytogenetic features; and Ig heavy chain variable region gene (IgVH) mutational status. Patients with missing data were excluded from the multivariate analyses. Statistical analyses were carried out using SAS 8.2 (SAS Institute, Cary, NC) and S-Plus, version 2000 (Insightful Corp, Seattle, WA).
RESULTS Treatment Indications Indications to treat were as follows: 941 patients were treated in the Leukemia Department, 13% with progressive symptoms, 20% with worsening anemia or thrombocytopenia, 0.6% with hemolytic anemia, 8% with worsening bulky lymphadenopathy, 8% with massive organomegaly, 25% with progressive hyperlymphocytosis, 0.4% with increased susceptibility to infections, 7% with progressive disease, 9% with physician's choice, and 9% for reasons that cannot be identified in this retrospective analysis. One hundred patients were treated in the Lymphoma Department, 22% with bulky lymphadenopathy, 6% with progressive disease, 4% with worsening anemia or thrombocytopenia, 64% with Ann Arbor stage 4 disease (19 patients with international prognostic index [IPI]-1, 42 with IPI-2, and 3 with IPI-3), and 4% for unknown reasons.
Independent Prognostic Factors and the Prognostic Factor Model
Results of a multivariate analysis in the training and validation samples of patients are shown in Tables A1 and A2, respectively.
When the Rai and Binet stage were added to the multivariate analysis for survival (fitted Cox model), cytogenetic abnormalities, age, β2 microglobulin, albumin, and creatinine remained independent factors, and Rai or Binet stage were also significant (Tables A4 and A5).  However, the relative risk of Rai or Binet stage was 1.24 and 1.35, respectively (< 2 for each) and, therefore, stage was not included in the proposed model. Survival by Rai and Binet stage are shown in Figure 2D-2E. Factors such as IgVH mutational status and CD38 or ZAP-70 expression did not significantly correlate with survival, perhaps because of missing data in several patients.
Because the results of cytogenetic analysis are not often available, we also performed a multivariate analysis for survival without including cytogenetics. Independent factors predicting shorter survival were age at least 60 years, β2M levels at least 2 mg/dL, albumin levels less than 3.5g/dL, creatinine levels at least 1.6 mg/dL, hepatomegaly, hemoglobin less than 11g/dL, male sex, and ALC at least 30 x 109/L. (Table 6).
Survival in Treated Patients With CLL/SLL by Absolute Lymphocyte Counts
In univariate survival analysis in 965 treated patients (Table 4), there was no statistically significant difference (P = .19) between patients with lower ALC (< 5 x 109/L) and higher ALC (
Supported in part by the Wolf Creek Charitable Foundation and the American Society of Clinical Oncology Development Award (A.M.T.). Presented in part at the 9th International Conference on Malignant Lymphoma, June 9-11, 2005, Lugano, Switzerland; at the 47th Annual Meeting of the American Society of Hematology, December 10-13, 2005, Atlanta, GA; and at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Muller-Hermelink HK, Catovsky D, Montserrat E, et al: Chronic lymphocytic leukemia/small lymphocytic lymphoma, in Jaffe ES HN, Stein H, Wardiman JW (eds): Tumors of Haematopoietic and Lymphoid Tissues: World Health Organization Classification of Tumors. Lyon, France, IARC Press, 2001, pp 127-130 2. Freedman AS, Nadler LM: Non-Hodgkin's lymphomas, in Kufe DW, Pollock RE, Weichselbaum RR, et al (eds): Cancer Medicine (ed 6), Hamilton, Ontario, Canada, BC Decker Inc, 2003, pp 2189-2210 3. Spertini O, Freedman AS, Belvin MP, et al: Regulation of leukocyte adhesion molecule-1 (TQ1, Leu-8) expression and shedding by normal and malignant cells. Leukemia 5:300-308, 1991[Medline] 4. Hubbard SM, Chabner BA, DeVita VT Jr, et al: Histologic progression in non-Hodgkin's lymphoma. Blood 59:258-264, 1982 5. Christiansen I, Gidlof C, Kalkner KM, et al: Elevated serum levels of soluble ICAM-1 in non-Hodgkin's lymphomas correlate with tumour burden, disease activity and other prognostic markers. Br J Haematol 92:639-646, 1996[CrossRef][Medline] 6. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med 311:1471-1475, 1984[Abstract] 7. Rai K, Patel DV: Chronic lymphocytic leukemia, in Hoffman R, Benz EJ, Shaffil SJ, et al (eds): Hematology: Basic Principles and Practice (ed 3). Philadelphia, PA, Churchill Livingstone, 2000, pp 1350-1363 8. Keating MJ, Kantarjian H, O'Brien S, et al: Fludarabine: A new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 9:44-49, 1991 9. Keating MJ, O'Brien S, Kantarjian H, et al: Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood 81:2878-2884, 1993 10. O'Brien S, Kantarjian H, Beran M, et al: Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82:1695-1700, 1993 11. O'Brien SM, Kantarjian HM, Cortes J, et al: Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 19:1414-1420, 2001 12. Tsimberidou AM, Keating MJ, Giles FJ, et al: Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia. Cancer 100:2583-2591, 2004[CrossRef][Medline] 13. Keating MJ, O'Brien S, Albitar M, et al: Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23:4079-4088, 2005 14. McLaughlin P, Hagemeister FB, Rodriguez MA, et al: Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 27:37-41, 2000[Medline] 15. Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064-3071, 2004 16. McLaughlin P, Liu N, Poindexter N, et al: Rituximab plus GM-CSF for indolent lymphoma. Ann Oncol 16:104, 2005 (suppl; abstr) 17. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 18. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244-1253, 1999 19. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234, 1975 20. Montserrat E, Vinolas N, Reverter JC, et al: Natural history of chronic lymphocytic leukemia: On the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol 30:359-361, 1988[Medline] 21. Dighiero G. Guidelines for clinical management of chronic lymphocytic leukemia, in Faguet GB (ed): Contemporary Hematology: Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis and Management. Totowa, NJ, Humana Press, 2004, pp 219-240 22. Hamblin TJ, Orchard JA, Gardiner A, et al: Immunoglobulin V genes and CD38 expression in CLL. Blood 95:2455-2457, 2000 23. Jaksic O, Paro MM, Kardum Skelin I, et al: CD38 on B-cell chronic lymphocytic leukemia cells has higher expression in lymph nodes than in peripheral blood or bone marrow. Blood 103:1968-1969, 2004 24. Döhner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000 25. Cuneo A, Rigolin GM, Bigoni R, et al: Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis. Leukemia 18:476-483, 2004[CrossRef][Medline] 26. Montserrat E, Gomis F, Vallespi T, et al: Presenting features and prognosis of chronic lymphocytic leukemia in younger adults. Blood 78:1545-1551, 1991 27. Molica S, Brugiatelli M, Callea V, et al: Comparison of younger versus older B-cell chronic lymphocytic leukemia patients for clinical presentation and prognosis: A retrospective study of 53 cases. Eur J Haematol 52:216-221, 1994[Medline] 28. Mauro FR, Foa R, Giannarelli D, et al: Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: A single institution study of 204 cases. Blood 94:448-454, 1999 29. Keating MJ, Lerner S, Kantarjian H, et al: The serum b2-microglobulin level is more powerful than stage in predicting response and survival in chronic lymphocytic leukemia. Blood 86:2412, 1998 (abstr) 30. Hallek M, Wanders L, Ostwald M, et al: Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma 22:439-447, 1996[Medline] 31. Oscier DG, Gardiner AC, Mould SJ, et al: Multivariate analysis of prognostic factors in CLL: Clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 100:1177-1184, 2002 32. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003 33. Binet JL, Auquier A, Dighiero G, et al: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198-206, 1981[CrossRef][Medline] 34. Reinisch W, Willheim M, Hilgarth M, et al: Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J Clin Oncol 12:2146-2152, 1994 35. Hallek M, Langenmayer I, Nerl C, et al: Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 93:1732-1737, 1999 36. Austen B, Powell JE, Alvi A, et al: Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 106:3175-3182, 2005 37. el Rouby S, Thomas A, Costin D, et al: p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452-3459, 1993 38. Hamblin TJ, Orchard JA, Ibbotson RE, et al: CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 99:1023-1029, 2002 39. Calin GA, Ferracin M, Cimmino A, et al: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793-1801, 2005 40. Binet JL, Caligaris-Cappio F, Catovsky D, et al: Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 107:859-861, 2006 Submitted October 6, 2006; accepted July 16, 2007.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test and t test were used in univariate analyses of categoric and continuous variables, respectively. Survival curves were estimated using the Kaplan-Meier method, and survival between groups was compared using the two-sided log-rank test. The multivariate Cox proportional hazards regression model was used to examine risk factors related to survival or FFS after adjusting for other factors. A randomly selected training set and a validation set of patients were used to perform multivariate analyses for survival. We also used a "bootstrapping" method in which we repeatedly (1,000 times) randomly selected 67% of the total population and assessed in what proportion of the 1,000 samples the Cox model identified a covariate as having independent prognostic significance. Those covariates found to be significant in the training and validation sets and noted to be independently significant in at least 75% of the randomly selected 1,000 bootstrapping sets were used to design a model to predict an individual patient's risk of death: the CLL/SLL score. P < .05 was considered to be statistically significant. 
5 x 109/L) ALCs. 
55 years and 19% for those > 55 years),
