Clinical Cancer Research Holland Stand Up to Cancer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rodriguez, J.
Right arrow Articles by Kantarjian, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rodriguez, J.
Right arrow Articles by Kantarjian, H.
Clinical Cancer Research Vol. 6, 147-152, January 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Serum ß-2 Microglobulin Levels Are a Significant Prognostic Factor in Philadelphia Chromosome-positive Chronic Myelogenous Leukemia

Jose Rodriguez, Jorge Cortes, Moshe Talpaz, Susan O’Brien, Terry L. Smith, Mary Beth Rios and Hagop Kantarjian1

Departments of Leukemia [J. R., J. C., S. O., M. B. R., H. K.], Bioimmunotherapy [M. T.], and Biomathematics [T. L. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our objective was to investigate the prognostic significance of serum ß-2 microglobulin (B2M) levels among patients with chronic myelogenous leukemia (CML).

All patients with Philadelphia chromosome-positive early chronic phase CML (i.e., within 1 year of diagnosis) treated with IFN {alpha}-based therapy at the M. D. Anderson Cancer Center between 1980 and 1997, in whom pretreatment B2M levels were available, were investigated.

Two hundred one patients were evaluable. Their median B2M was 2.2 mg/dl (range, 1.1–20 mg/dl). Serum B2M levels were associated with other variables of prognostic significance, including age, spleen size, WBC count, percentage of peripheral and marrow blasts, and percentage of marrow basophils. Patients with B2M levels >2.9 mg/dl (i.e., the upper quartile of the distribution) had a significantly lower rate of major cytogenetic response compared to those in the lower three quartiles (20 versus 52%; P < 0.01). They also had a shorter survival, with a 5-year survival rate of 48%, compared with 75% for those in the lower quartiles (P = 0.01). High B2M levels (>2.9 mg/dl) could identify a group of patients with an adverse outcome within patients in stage I disease (P = 0.02). Results for patients in stages 2–4 were inconclusive because of the small number of patients in these groups.

We conclude that serum B2M levels are an important, and probably independent, prognostic factor for patients with CML in early chronic phase treated with IFN-based therapy.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CML2 is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cells (1) It is characterized by the presence, in leukemic cells, of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), referred to as the Ph chromosome (2) . Despite the constant Ph-related molecular events, the disease is heterogeneous in presentation and course. Several characteristics have been associated with prognosis in CML, including age, spleen size, platelet count, and percentage of marrow and peripheral blasts and basophils. These factors have been incorporated into prognostic systems that categorize patients into distinct risk groups with different outcomes (3 , 4) . The availability of more effective therapy, including IFN-A and allogeneic bone marrow transplantation, has changed the natural history of CML. The applicability of risk models developed in chemotherapy-treated patients may not be well applicable to patients treated with IFN-A-based therapy (5 , 6) . Hence, there is a need to identify variables with prognostic significance for IFN-A treated patients, which might be incorporated into or even substitute for existing models.

B2M is a small, 11.5-kDa polypeptide, which is the light chain of the HLA class I surface molecule, in which endogenous peptides are presented to the CD-8(+) T-cell lymphocytes (7 , 8) . This represents a fundamental event in the immunological response of the host to the tumor (9) . Serum B2M levels are an important prognostic factor in lymphoid malignancies, including non-Hodgkin’s lymphoma, Hodgkin’s disease, acute lymphocytic leukemia, multiple myeloma, and chronic lymphocytic leukemia (10, 11, 12, 13, 14, 15) . The significance of serum B2M levels in myeloid leukemias has not been investigated.

The objective of this study was to investigate the distribution of serum B2M in patients with CML and to determine whether pretreatment serum B2M levels have prognostic significance for patients with CML treated with IFN-A-based therapy.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Group.
From 1980 through 1997, 1621 patients with CML were referred to the M. D. Anderson Cancer Center. Serum B2M levels were investigated at the time of referral in 454 patients (28%). The clinical characteristics and survival of patients in whom B2M was measured or not measured were identical (data not shown), suggesting that the study population was representative of the total CML group. The stage of the 454 patients was as follows: 369 (81%) in chronic phase, of whom 285 (63%) were in ECP (i.e., within 12 months from diagnosis) and 84 (18%) were in late chronic phase; 65 (14%) in accelerated phase; and 20 (4%) in blastic phase. Of the 285 patients in ECP, 201 (71%) received IFN-A based therapy at MDACC as described previously (16) , and constitute the basis for this study.

The records of these patients were reviewed for clinical characteristics at presentation. Patients and disease characteristics investigated included age, sex, time from diagnosis to MDACC referral, peripheral blood counts and differential, platelet counts, bone marrow studies, presence of splenomegaly, and Zubrod performance status. Serum B2M levels were measured at the time of referral, using standard methods (8) . Patients were staged according to the Synthesis Staging system (4) . This system accounts for the following high-risk variables: age, >=60 years; spleen size, >=10 cm below costal margin; platelet count, >=700 x 109/liter; blasts in marrow (>=5%) or peripheral blood (>=3%); basophils in marrow (>=3%) or peripheral blood (>=7%); and cytogenetic clonal evolution. Patients with 1 high-risk feature or none are considered stage 1, those with two are considered stage 2, and those with three or more are stage 3.

Therapy.
Patients were treated in one of several sequential studies, including human leukocyte IFN-A, recombinant human IFN-A alone, recombinant IFN-A and IFN-{gamma}, recombinant IFN-A and hydroxyurea, and recombinant IFN-A and low-dose ara-C (16) . Bone marrow aspirates with morphological and cytogenetic analysis were performed before treatment, every 3 months during the first 2 years of follow-up, and every 4–6 months thereafter. Informed consent was obtained according to institutional guidelines.

Response Criteria.
Response criteria were defined as described previously (17) . A complete hematological response was defined as normalization of peripheral blood counts and differential, including a leukocyte count less than 10 x 109/liter, a platelet count less than 450 x 109/liter, absence of peripheral immature cells, and disappearance of all signs and symptoms of the disease, including palpable splenomegaly. Patients achieving a complete hematological response were further categorized by their best cytogenetic response (lowest percentage of Ph-positive metaphases): (a) complete cytogenetic response, if Ph-positive was 0%; (b) partial cytogenetic response, if it was between 1 and 34%; and (c) minor cytogenetic response, if it was between 35 and 90%. A major cytogenetic response included complete and partial cytogenetic responses, that is, patients with the lowest Ph-positive metaphase percentage below 35%.

Statistical Methods.
Survival was computed from the date of referral. The median follow-up for the total group was 49 months (18) . Estimates of survival distributions were obtained using the Kaplan-Meier method, and survival among groups of patients was compared using the log-rank test (19) , in some cases stratified over subsets as specified in the text. B2M levels were compared for patients classified by stage of disease or other characteristics by the Wilcoxon or Kruskal-Wallis tests. The association of pretreatment B2M levels with patient outcomes was evaluated by dividing patients into four groups based on quartiles of the B2M distribution and also by considering initial B2M levels as a continuous variable. A graphical smoothing technique (20) was used to plot response rates versus B2M level. To graphically explore the association of B2M level with survival outcomes, many of which were censored, residuals from a proportional hazards model including only a baseline hazard function were paired with each patient’s B2M value and plotted in a scatterplot (21) . This is analogous to plotting residuals from an ordinary linear regression analysis to assess how well a given model fits observed data.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Group.
The median B2M level among the 454 patients studied was 2.3 mg/dl (range, 1.1 to 9.8 mg/dl). B2M levels correlated with disease phase: the median level was 2.2 mg/dl for ECP, 2.45 mg/dl for late chronic phase, 2.7 mg/dl for AP, and 2.95 mg/dl for BP (P < 0.05). Patients with a B2M <2.3 mg/dl had significantly longer survival compared to those with a B2M >=2.3 mg/dl (median, 66 versus 41 months; P = 0.002). This obviously constitutes a very heterogeneous group of patients treated with various modalities according to their stage. Therefore, we focused our analysis on patients in ECP who were treated with IFN-A-based regimens.

Analysis of B2M Levels in ECP.
Characteristics of the 201 patients in ECP treated with IFN-A-based therapy (Table 1)Citation were similar to those described in previous reports of patients with ECP CML treated with IFN-A (from which most patients in this study were taken) (16) , albeit with a trend for more patients in stage 1. Cytogenetic response could be evaluated in 191 patients (95%), with 84 (44%) achieving a major cytogenetic response. After a median follow-up of 49 months, 56 of the 201 patients had died, for an estimated 5-year survival rate of 69% (95% confidence interval, 62–77%). The clinical characteristics were similar for patients in whom B2M was available and those in whom it was not, including age >=60 years (14 versus 12%; P = 0.70), peripheral blood blasts >=3% (9 versus 11%; P = 0.55), peripheral blood basophils >=7% (18 versus 16%; P = 0.64), bone marrow blasts >=5% (4 versus 4%; P = 0.91), bone marrow basophils >=3% (25 versus 26%; P = 0.98), platelets >=700 x 109/liter (14 versus 15%; P = 0.88), and spleen >=10 cm (12 versus 9%; P = 0.38). The major cytogenetic response rate was similar for patients in whom B2M was available or not (44 versus 39%; P = 0.41), with identical median survivals (84 months; P = 0.84), suggesting that the study group is representative of the total population.


View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of patients in ECP treated with IFN-A (n = 201)

 
The median serum B2M level was 2.2 mg/dl (range, 1.1–20 mg/dl). Patients with stage 1 disease tended to have lower B2M levels compared with patients in other stages, with medians of 2.1, 3.0, and 2.5 mg/dl for stages 1, 2, and 3+4, respectively (P < 0.01, Kruskal-Wallis test). There were significant associations between B2M levels and other prognostic variables, with trends for higher B2M values in recent years and also among older patients, those with enlarged spleens, and those with higher WBC counts, percentage of peripheral and marrow blasts, and percentage of marrow basophils (Table 2)Citation . B2M levels were similar among patients treated with IFN-A with (median, 2.2 mg/dl; range, 1.2–20) or without ara-C (median, 2.2 mg/dl; range, 1.2–20 mg/dl; P = 0.24).


View this table:
[in this window]
[in a new window]

  		Table 2 Association of B2M levels with other clinical characteristics with prognostic significance

 
To explore the prognostic significance of serum levels of B2M, we first investigated the response to IFN-A. Patients were initially divided in four groups based on quartiles of distribution of B2M serum levels. As shown in Table 3Citation , patients in the upper quartile (i.e., B2M >=2.9 mg/dl) had a significantly lower rate of major cytogenetic response compared with those in the lower three quartiles (i.e., B2M <2.9 mg/dl; P < 0.01). To better define this association, major cytogenetic response rate was plotted against B2M levels, and a data smoothing technique was used to estimate the response rate across changing B2M levels (Fig. 1)Citation . These results suggest that there is a marked change in the probability of response with B2M levels between 2.4 and 2.9 mg/dl (Fig. 1)Citation . The lower cytogenetic response among patients with B2M >=2.9 mg/dl was highly statistically significant compared to that of other patients, after adjustment for differences in stage of disease (P < 0.01).


View this table:
[in this window]
[in a new window]

  		Table 3 Major cytogenetic response rate by B2M levels (n = 191)a

 


View larger version (14K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Major cytogenetic response rate by pretreatment B2M.

 
Survival was next evaluated among the four groups of patients defined by quartiles of the B2M distribution. Patients in the upper quartile had substantially worse outcomes overall, with a 5-year estimated survival rate of 48%, although there was no clear evidence of ordering of survival curves among the lower three quartile groups (P = 0.01; Fig. 2Citation ). Results of the graphical method for investigating the association between censored survival outcomes and B2M considered as a continuous covariate (not shown) suggested that for B2M levels below 2.4 mg/dl there was a reduced and fairly constant risk of death, but somewhere between 2.4 and 3.0 mg/dl, the risk increased fairly steeply and remained constant thereafter. These results are consistent with findings for response rate, and also with the survival curves plotted in Fig. 2Citation . Other clinical variables were considered for their association with survival, using standard cutpoints of continuous covariates to divide groups; results are summarized in Table 4Citation . Among variables with recognized prognostic importance, only B2M and stage (according to the Synthesis Staging system) had clear prognostic implications for survival in our patient group.



View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Survival by pretreatment B2M level.

 

View this table:
[in this window]
[in a new window]

  		Table 4 Survival by patient characteristics

 
To assess the value of B2M as an independent prognostic factor, and considering that higher B2M levels tended to be associated with poor prognostic characteristics, we investigated the contribution of pretreatment B2M values to explain survival variations after adjusting for prognostic differences. Both the Synthesis and Sokal staging systems were considered because they represent different weightings of the known important prognostic factors. The statistical significance of B2M value was preserved when results were adjusted for differences in either Synthesis or Sokal stages (P = 0.02 for stratified log-rank test for either staging system), and these differences may be observed in plots of survival curves for subsets of patients based on stage of disease. The shorter survival experienced by patients with B2M values in the highest quartile may be best appreciated for patients with stage 1 disease, as they represent the majority of the study group (Fig. 3)Citation . Similarly, within groups divided by other prognostic variables (e.g., age or spleen size), B2M could separate patients with different outcomes. Among patients younger than age 60 or patients with a spleen size <10 cm below the costal margin, there was evidence that high B2M was associated with shorter survival. As for stage, this association could not be identified for patients in the higher risk groups (older or larger spleen size), probably because of the small sample size in these groups.



View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Survival by pretreatment B2M levels among patients with stage I disease.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite the constant Ph-related molecular events in CML, the disease is heterogeneous in its presentation and course. Although transformation into the blast phase is inevitable for patients without definitive therapy, occasional patients may live many years before transformation. Therefore, identification of prognostic features for patients with CML is important, in particular when evaluating new therapeutic approaches. Several characteristics have been associated with prognosis in studies of patients with CML, including age, spleen size, platelet count, and percentage of blasts and basophils in the bone marrow or peripheral blood. These factors have been incorporated into staging models based on multivariate analyses. The most frequently used models categorize patients into groups with low, intermediate, or high risk, with median survival of 53–60 months, 39 months, and 25–32 months, respectively (3 , 4) . However, these systems were developed before the introduction of IFN-A as an effective therapy for patients with CML. Although some large studies have found these models to be predictive of response and survival after IFN-A therapy, (22 , 23) , many others have not (5 , 6) . Furthermore, such systems are based exclusively on clinical factors. Studies of biological features, including the particular BCR breakpoint site and related messages, MDR expression, methylation profile, and others, have not predicted for differences in patient prognosis. In this study, we report on the first biological marker reported with prognostic significance in CML and the first to predict for response to IFN-A-based therapy.

In this study, B2M level was a significant prognostic variable for patients with CML in ECP treated with IFN-A. High B2M values (i.e., >=2.9 mg/dl) were predictive for a low rate of major cytogenetic response and worse survival. Although limited by the small number of patients in the more advanced stages (i.e., 2–4 by the Synthesis system), the prognostic significance of serum levels of B2M could be demonstrated within patients in early stage (Stage 1), suggesting that it might be an independent prognostic factor.

B2M is a small polypeptide that constitutes the light chain of the HLA class I antigen on the surface of all nucleated cells (24) . Serum levels of B2M have significant prognostic implications in patients with lymphoproliferative disorders, including multiple myeloma (25) , Hodgkin’s disease (12) , and non-Hodgkin’s lymphomas (15 , 26) . This association has also been described in lymphoid leukemias. In acute lymphoblastic leukemia, B2M levels of 4 mg/dl or higher were found in 36 of 159 (23%) patients (14) , and high values were associated with a lower complete remission (CR) rate (61 versus 80%; P = 0.02), a higher risk for development of central nervous system leukemia, and worse overall survival. Although B2M levels correlated with other prognostic variables, B2M levels were independently associated with survival in a multivariate analysis (14) .

A similar correlation has been described in chronic lymphocytic leukemia. Patients with B2M levels of >=4 mg/dl had a 5-year survival rate of 12%, compared to 86% for those with levels <2 mg/dl, 61% for levels of 2–2.9 mg/dl, and 38% for those with B2M levels of 3.0–3.9 mg/dl (P < 0.001; Ref. 27 ). Serum levels of B2M were also the most important independent prognostic variable for response to therapy and survival among 622 patients (27) .

Although elevations of B2M have been reported in small series of patients with CML, there is very little information on the prognostic significance of B2M levels in myeloid leukemias in general, and in CML in particular. Ellegaard et al. (28) reported high B2M levels in all 11 patients with CML studied, with mean levels of 5.7 mg/dl, but no information was provided on the status and outcome of patients. A correlation between WBC counts and B2M levels, with normalization of B2M levels after successful therapy, was reported in small series of patients (29 , 30) . Interestingly, no elevation was found in the blastic phase (30 , 31) . In our study of a larger population of patients, we found a correlation of B2M with WBC counts, as well as with other clinical features. B2M levels tended to be associated with differences in survival among patients in the same stage according to the Synthesis model. Patients with stage I disease with a B2M level >=2.9 mg/dl had a significantly worse outcome than those with lower B2M levels. This suggests that B2M levels might be an independent prognostic variable.

The prognostic significance for B2M levels is similar for cytogenetic remission and survival, which is a unique feature among prognostic markers in CML. Furthermore, in this analysis at levels of B2M below 2.4 mg/dl, outcome tended to be constant and favorable, but prognosis changed significantly at values between 2.4 and 3.0 mg/dl. Patients with values >=2.9 mg/dl had significantly worse outcomes but did not show evidence of a worsening trend with higher values. It is noteworthy that the same B2M level correlations were observed for both cytogenetic response (Fig. 1)Citation and overall survival, suggesting that prognosis worsened once B2M levels increased over an initial threshold, with the worst prognosis observed for patients in the upper quartile of B2M levels (i.e., >=2.9 mg/dl).

We conclude that serum B2M levels represent the first biological marker with significant and independent prognostic significance for patients with CML in ECP treated with IFN-A-based therapy. Further prospective studies in larger, more uniformly treated populations are needed to better define the most appropriate cutpoint and the value of B2M in reference to other prognostic factors. Incorporating this variable into the evaluation of CML patients might help better define subgroups of patients with different outcomes and could potentially be used for patient selection for IFN-A therapy. The prognostic implications of pretreatment B2M levels for patients with CML treated with other modalities (e.g., bone marrow transplantation, homoharringtonine, and so forth) requires further evaluation.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Leukemia, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 61, Houston, TX 77030. Phone: (713) 792-7026; Fax: (713) 794-4297. Back

2 The abbreviations used are: CML, chronic myelogenous leukemia; B2M, ß-2 microglobulin; ECP, early chronic phase; Ph, Philadelphia chromosome. Back

Received 1/15/99; revised 10/11/99; accepted 10/12/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fialkow P. J., Jacobson R. J., Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am. J. Med., 63: 125-130, 1997.
  2. Kurzrock R., Gutterman J. U., Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N. Engl. J. Med., 319: 990-998, 1988.[Medline]
  3. Sokal J. E., Cox E. B., Baccarani M., Tura S., Gomez G. A., Robertson J. E., Tso C. Y., Braun T. J., Clarkson B. D., Cervantes F., Rozman C., the ICCSG. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood, 63: 789-799, 1984.[Abstract/Free Full Text]
  4. Kantarjian H. M., Keating M. J., Smith T. L., Talpaz M., McCredie K. B. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am. J. Med., 88: 1-8, 1990.[CrossRef][Medline]
  5. Ohnishi K., Ohno R., Tomonaga M., Kamada N., Onozawa K., Kuramoto A., Dohy H., Mizoguchi H., Miyawaki S., Tsubaki K., Miura Y., Omine M., Kobayashi T., Naoe T., Ohshima T., Hirashima K., Ohtake S., Takahashi I., Morishima Y., Naito K., Asou N., Tanimoto M., Sakuma A., Yamada K. A randomized trial comparing interferon-{alpha} with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood, 86: 906-916, 1995.[Abstract/Free Full Text]
  6. Ozer H., George S. L., Schiffer C. A., Rao K., Rao P. N., Wurster-Hill D. H., Arthur D. D., Powell B., Gottlieb A., Peterson B. A. Prolonged subcutaneous administration of recombinant {alpha} 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood, 82: 2975-2984, 1993.[Abstract/Free Full Text]
  7. Otten G. R., Bikoff E., Ribaudo R. K., Kozlowski S., Margulies D. H., Germain R. N. Peptide and ß2-microglobulin regulation of cell surface MHC class I conformation and expression. J. Immunol., 148: 3723-3732, 1992.[Abstract]
  8. Bethea M., Forman D. T. ß2-Microglobulin: its significance and clinical usefulness. Ann. Clin. Lab. Sci. (Washington DC), 20: 163-168, 1990.
  9. Germain R. N., Margulies D. H. The biochemistry and cell biology of antigen processing and presentation. Annu. Rev. Immunol., 11: 403-450, 1993.[CrossRef][Medline]
  10. Kyle R. A. Prognostic factors in multiple myeloma. Stem Cells, 13: 56-63, 1995.
  11. Rodriguez J., Pugh W. C., Romaguera J. E., Luthra R., Hagemeister F. B., McLaughlin P., Rodriguez M. A., Swan F., Cabanillas F. Primary mediastinal large cell lymphoma is characterized by an inverted pattern of large tumoral mass and low ß2 microglobulin levels in serum and frequently elevated levels of serum lactate dehydrogenase. Ann. Oncol., 5: 847-849, 1994.[Abstract/Free Full Text]
  12. Dimopoulos M. A., Cabanillas F., Lee J. J., Swan F., Fuller L., Allen P. K., Hagemeister F. B. Prognostic role of serum ß2-microglobulin in Hodgkin’s disease. J. Clin. Oncol., 11: 1108-1111, 1993.[Abstract/Free Full Text]
  13. Keating M. J., O’Brien S., Robertson L., Huh Y., Kantarjian H., Plunkett W. Chronic lymphocytic leukemia: correlation of response and survival. Leuk. Lymph., 11: 167-175, 1993.
  14. Kantarjian H. M., Smith T., Estey E., Polyzos A. S., O’Brien S., Pierce S., Beran M., Feldman E., Keating M. J. Prognostic significance of elevated serum ß2-microglobulin levels in adult acute lymphocytic leukemia. Am. J. Med., 93: 599-604, 1992.[CrossRef][Medline]
  15. Litam P., Swan F., Cabanillas F., Tucker S. L., McLaughlin P., Hagemeister F. B., Rodriguez M. A., Velasquez W. S. Prognostic value of serum ß-2 microglobulin in low-grade lymphoma. Ann. Intern. Med., 114: 855-860, 1991.
  16. Kantarjian H. M., Smith T., O’Brien S., Beran M., Pierce S., Talpaz M., The Leukemia Service. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon therapy. Ann. Intern. Med., 122: 254-261, 1995.[Abstract/Free Full Text]
  17. Talpaz M., Kantarjian H. M., McCredie K. B., Trujillo J. M., Keating M. J., Gutterman J. U. Hematologic remission and cytogenetic improvement induced by recombinant human interferon-A in chronic myelogenous leukemia. N. Engl. J. Med., 314: 1065-1069, 1986.[Abstract]
  18. Schemper M., Smith T. L. A note on quantifying follow-up in studies of failure time. Cont. Clin. Trials, 17: 343-346, 1996.
  19. Peto R., Peto J. Asymptotically efficient rank invariant procedures. J R. Stat. Soc. Ser. A, 135: 185-207, 1972.[CrossRef]
  20. Selvin, S. Modern Statistical Applied Methods Using S-Plus. New York: Oxford University Press, 1998.
  21. Therneau T. M., Grambsch P. M., Fleming T. R. Martingale-based residuals for survival models. Biometrika, 77: 147-160, 1990.[Abstract/Free Full Text]
  22. Hehlmann R., Heimpel H., Hasford J., Kolb H. J., Pralle H., Hossfeld D. K., Queisser W., Loffler H., Hochhaus A., Heinze B. Randomized comparison of interferon-{alpha} with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood, 84: 4064-4077, 1994.[Abstract/Free Full Text]
  23. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N. Engl. J. Med., 330: 820-825, 1994.
  24. Grey H. M., Kubo R. T., Colon S. M., Poulik M. D., Cresswell P., Springer T., Turner M., Strominger J. L. The small subunit of HL-A antigens is ß2-microglobulin. J. Exp. Med., 138: 1608-1612, 1973.[CrossRef][Medline]
  25. Durie B. G., Stock-Novack D., Salmon S. E., Finley P., Beckord J., Crowley J., Coltman C. A. Prognostic value of pretreatment serum ß2 microglobulin in myeloma: a Southwest Oncology Group study. Blood, 75: 823-830, 1990.[Abstract/Free Full Text]
  26. Swan F., Jr, Velasquez W. S., Tucker S., Redman J. R., Rodriguez M. A., McLaughlin P., Hagemeister F. B., Cabanillas F. A new serologic staging system for large-cell lymphomas based on initial ß2-microglobulin and lactate dehydrogenase levels. J. Clin. Oncol., 7: 1518-1527, 1989.[Abstract]
  27. Keating M. J., Lerner S., Kantarjian H., Freireich E. J., O’Brien S. The serum B2-microglobulin level is more powerful than stage in predicting response and survival in chronic lymphocytic leukemia. Blood, 86: 606a 1995.
  28. Ellegaard J., Mogensen C. E., Kragballe K. Serum ß2-microglobulin in acute and chronic leukaemia. Scand. J. Haematol., 25: 275-285, 1980.[Medline]
  29. Bjerrum O. W., Gimsing P. Serial measurements of ß-2-microglobulin in plasma correlates with white blood cell counts and haptocorrin in chronic myeloid leukemia. Leuk. Res., 11: 827-831, 1987.[CrossRef][Medline]
  30. Norfolk D. R., Child J. A., Roberts B. E., Forbes M. A., Cooper E. H. Serum ß-2-microglobulin in disorders of myeloid proliferation. Acta Haematol., 69: 361-368, 1983.[Medline]
  31. Schena F. P., Liso V., Losuriello V., Mera S., Bonomo L. The behavior of ß-2-microglobulin in acute and chronic leukaemias. Biomedicine, 33: 12-15, 1980.[Medline]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
A.-M. Tsimberidou, H. M. Kantarjian, S. Wen, S. O'Brien, J. Cortes, W. G. Wierda, C. Koller, S. Pierce, M. Brandt, E. J. Freireich, et al.
The Prognostic Significance of Serum {beta}2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Patients
Clin. Cancer Res., February 1, 2008; 14(3): 721 - 730.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Gatto, G. Ball, F. Onida, H. M. Kantarjian, E. H. Estey, and M. Beran
Contribution of {beta}-2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndrome (MDS)
Blood, September 1, 2003; 102(5): 1622 - 1625.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rodriguez, J.
Right arrow Articles by Kantarjian, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rodriguez, J.
Right arrow Articles by Kantarjian, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online