The BCR gene and philadelphia chromosome-positive leukemogenesis.
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Animals↗
Biomedical subjects
M Talpaz
Publications and source records attributed to M Talpaz.
Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.
PURPOSE: We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer. PATIENTS AND METHODS: Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72. RESULTS: Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study. CONCLUSION: rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
Adult↗
Expression of a truncated first exon BCR sequence in chronic myelogenous leukemia cells blocks cell growth and induces cell death.
We have shown that a deletion mutant form of Bcr [Bcr(64-413)] is a strong inhibitor of the tyrosine kinase of Bcr-Abl in vitro and also inhibits its oncogenic growth effects (Liu et al., Cancer Res., 56: 5120-5124, 1996). To determine the effects of this Bcr-Abl kinase inhibitor on chronic myelogenous leukemia (CML) cells, we cloned BCR(64-413) into a recombinant, replication-defective adenovirus to express useful quantities of Bcr(64-413) in a wide variety of cells in culture. Infection of Cos1 cells with plaque-purified virus at a multiplicity of infection of 20-40 induced high expression of Bcr(64-413) as detected by Western blotting. Infection of hematopoietic cells at modest multiplicities of infection (20-40) required special conditions involving shifting cycling cells to a nongrowing condition involving serum starvation and cell crowding. Under these conditions, both Bcr-Abl-positive and -negative hematopoietic cells can be efficiently infected by adenovirus, as demonstrated by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining of cells infected by beta-galactosidase (beta-GAL) adenovirus. We found that expression of Bcr(64-413) in Bcr-Abl-positive K562 and BV-173 cells, but not Bcr-Abl-negative SMS-SB cells, increased cell-cell clumping and inhibited cell growth. In contrast to the effects of the Bcr(64-413) adenovirus, the beta-GAL adenovirus, despite infecting both types of cells, did not block growth or increase cell-cell clumping of Bcr-Abl-positive and -negative hematopoietic cells. Expression of Bcr(64-413) protein in primary cultures of cells from CML patients with active disease interfered with cell growth, induced apoptosis (as measured by annexin staining), and increased cell-cell clumping, whereas the beta-GAL adenovirus and mock-infected cells lacked these effects. In contrast, normal marrow cells did not exhibit these effects on infection with Bcr(64-413) adenovirus. We conclude from these findings that Bcr(64-413) interferes with the oncogenic effects of Bcr-Abl and therefore has the potential for use in therapy of CML.
Adenoviridae↗
Chronic myelogenous leukemia in chronic phase.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by genomic instability leading to its inevitable clinical evolution from an easily controlled chronic phase to a terminal blastic phase. The molecular abnormality responsible for this disease--BCR-ABL--and the critical biochemical aberrations resulting from it have been studied in depth. These discoveries have led to the development of a molecule, STI571, that specifically inhibits the abnormal kinase enzymatic activity exhibited by BCR-ABL. Early results of clinical trials using STI571 have shown responses even in blast crisis. There has also been striking hematologic and cytogenetic remission rates in patients with advanced chronic phase disease, with very little toxicity. It is our opinion that this molecule will revolutionize the treatment of CML. Furthermore, the path leading to its discovery will become a paradigm for cancer therapeutics. At the time of this writing, STI571 remains investigational (although it is widely believed that it will be approved for clinical use in the United States this year ). Although suggested therapy for a disease does not generally incorporate medications that are still investigational, in this case, the impact of a still investigational agent cannot be ignored. The current data suggest that STI571 will be the treatment of choice for patients with advanced or resistant chronic phase. To date, STI571 has not been studied adequately in untreated CML patients. Even so, it is our feeling that, based on its compelling success in patients with interferon-refractory and advanced disease and on its benign side effect profile, it will quickly become the front-line therapy for CML once it becomes available. Despite the ease of administration of STI571, patients should continue to be encouraged to participate in clinical studies so that several vital issues can be resolved: 1) the percentage of untreated CML patients who will eventually develop molecular remissions; 2) the proportion of patients in whom resistance to STI571 will emerge; 3) the optimum length of treatment; and 4) the impact on survival. Because interferon-alfa can also result in cytogenetic remissions, albeit in a small percent (less than 20%) of early chronic phase patients, it seems reasonable to suggest that patients who do not attain cytogenetic/molecular remissions with STI571 alone be treated with a combination of STI571 and interferon-alfa. Patients who are resistant to STI571 with or without interferon-alfa should undergo allogeneic hematopoietic cell transplant. Salvage therapy after transplant may include donor lymphocyte infusions, interferon-alfa, additional transplant, and perhaps STI571. Medications such as hydroxyurea appear destined to play a very limited role in CML. They may be used in the palliative treatment of older STI571-resistant patients or those without a transplant donor, although these patients may be best served by being considered for clinical trials of molecules, such as polyethylene glycol-interferon-alfa, on other novel agents.
Antineoplastic Agents↗
Interferon-alfa-based treatment of chronic myeloid leukemia and implications of signal transduction inhibition.
The cytokine interferon-alfa (IFN-alpha) has substantial activity in chronic myeloid leukemia (CML) and is the nontransplant standard of care for chronic-phase disease. When used as front-line therapy, IFN-alpha induces a state of tumor dormancy and delays progression to advanced phase. Unfortunately, IFN-alpha is associated with substantial toxicity at therapeutic doses. The introduction of pegylated IFN-alpha (PEG-IFN-alpha), a modified form of the protein that permits weekly administration, may alleviate some of the problems observed with IFN-alpha. Combination regimens of IFN-alpha with other drugs such as cytarabine (Ara-C) appear to enhance efficacy and are currently under investigation. The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) also is efficacious in chronic-phase CML, with a low toxicity profile. However, its potential to cure CML remains unknown even though it achieves frequent cytogenetic responses. To enhance treatment outcome, a combination of IFN-alpha and imatinib mesylate therapies is proposed. Low-dose IFN-alpha may be given after imatinib mesylate-induced remission as a specific immune stimulant to consolidate the remission. Recent data showing a possible additive effect of imatinib mesylate and IFN-alpha suggest that concurrent use of these agents may also be more effective than single use, particularly in advanced stages of CML where imatinib mesylate has activity but resistance develops.
Antineoplastic Combined Chemotherapy Protocols↗
Long-Term follow-up of recipients of CD8-depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation.
Donor lymphocyte infusions (DLIs) are an effective treatment for relapsed Chronic myeloid leukemia (CML) after allogeneic transplantation but are limited by the occurrence of GVHD. CD8+ T lymphocytes are involved in the pathogenesis of GVHD but may not be essential for the graft-versus-leukemia (GVL) effect in CML. We have treated 26 CML patients with posttransplantation relapse with CD8-depleted DLI. Thirteen of 15 patients (87%) who relapsed in early-phase CML achieved complete cytogenetic response, but only 1 of 11 who relapsed in advanced-phase disease achieved complete response. Acute GVHD occurred in 2 patients (8%), and extensive chronic GVHD occurred in 2 patients (11%). Treatment-related mortality was 11.5%. Responses were durable; with a median follow-up of 4.2 years (1-7.5 years), only 1 responding patient relapsed (7%). CD8-depleted DLI was equally effective and safe after unrelated donor transplants and sibling transplants. Cytogenetic clonal evolution at the time of DLI was not predictive of treatment failure unless associated with hematologic criteria for disease acceleration. CD8 depletion is an effective method to separate GVL from GVHD for posttransplantation relapsed CML. This strategy is associated with durable complete remissions and a low rate of complications and therefore merits further investigation in larger-scale comparative trials.
Adult↗
Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase.
The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an adequate cytogenetic response on an IFN-alpha-based regimen.
Actuarial Analysis↗
Imatinib mesylate: clinical results in Philadelphia chromosome-positive leukemias.
Targeted cancer therapy has long been sought by the oncology community as a potentially better approach than currently available therapies. One targeted therapy that has shown great success is the tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) which was recently approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Basic scientific investigation into the molecular causes and pathogenesis of CML and encouraging preclinical investigations on the mechanism of action of imatinib mesylate led to the initiation of phase I clinical trials. Clinical development of imatinib mesylate continued with three large, multicenter, phase II trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses. Results from ongoing studies will determine the durability of these responses and will evaluate ways to optimize treatment in advanced-stage patients using imatinib mesylate in combination with other therapies. Additional trials are planned to investigate the efficacy of imatinib mesylate to treat a variety of solid tumors whose pathogenesis is driven by the other tyrosine kinase targets, c-Kit and platelet-derived growth factor receptor.
Antineoplastic Agents↗
Therapeutic choices in younger patients with chronic myelogenous leukemia.
BACKGROUND: Allogeneic stem cell transplantation (SCT) and interferon (IFN)-alpha therapy have significantly improved the prognosis of patients with Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML). Both therapies may be suitable for younger patients. The authors reviewed current data to assist in prioritizing these modalities in an individual patient. METHODS: The authors reviewed and summarized current data on outcomes of SCT and IFN-alpha therapy in patients with early chronic phase CML. RESULTS: Several disease-, patient-, and physician-related factors affect outcomes with both modalities. Interferon-alpha does not induce myelofibrosis. The course of CML is predictable in most patients; sudden emergence of blastic phase; disease is unusual. There is no significant adverse impact of delaying SCT for the 12 months usually necessary to assess cytogenetic response to an IFN-alpha-based regimen. Interferon-alpha may be discontinued some months before SCT and is not associated with an adverse impact on post-SCT outcomes. CONCLUSIONS: An individualized risk assessment-based approach is of value in prioritizing SCT and IFN-alpha in younger patients with chronic phase CML. The authors recommend a risk-based therapy algorithm based on the expected SCT associated 1-year mortality for an individual patient.
Adult↗
Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia.
PURPOSE: : To evaluate the efficacy and toxicity profiles of a combination regimen of homoharringtonine (HHT) and low-dose cytarabine (ara-C) in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who had experienced treatment failure with interferon alfa (IFNalpha) therapy. PATIENTS AND METHODS: One hundred five patients were treated: 100 in chronic phase (15 with cytogenetic clonal evolution) and five in accelerated phase. Their median age was 52 years; all had been treated unsuccessfully with IFNalpha; 94% were in late chronic phase; 43% had been exposed to ara-C and 11% had been exposed to HHT. Patients received HHT 2.5 mg/m(2) by continuous infusion daily for 5 days and ara-C 15mg/m(2) daily in two subcutaneous injections for 5 days every 4 weeks. The outcome of the 100 patients in chronic phase was compared with a previous study group of 73 patients treated with HHT alone. RESULTS: Overall, the complete hematologic response (CHR) rate in chronic phase was 72%; the cytogenetic response rate was 32% (major response, 15%; complete response, 5%). Toxicities were acceptable, mostly related to moderate diarrhea (3%), headaches (3%), cardiovascular events (3%),and myelosuppression-associated complications (3% to 14%). With a median follow-up period of 25 months, the estimated 4-year survival rate was 55%. Response rates were identical with HHT plus ara-C versus HHT alone, but the survival was significantly longer with the combination after accounting for differences in the study groups and by multivariate analysis. CONCLUSION: The combination regimen of HHT and ara-C is effective and safe in patients with CML who have experienced treatment failure with IFNalpha and needs to be investigated together with IFNalpha as part of front-line CML therapy. The addition of ara-C did not improve the response rates but may have improved survival, perhaps through suppression of clones related to disease transformation.
Antineoplastic Combined Chemotherapy Protocols↗
Avascular necrosis of the femoral head in chronic myeloid leukemia patients treated with interferon-alpha: a synergistic correlation?
BACKGROUND: The objectives of this study were to describe cases of avascular necrosis of the femoral head (ANFH) observed in chronic myeloid leukemia (CML) patients who were treated with interferon-alpha and to review the literature. METHODS: The authors undertook a case review of the M. D. Anderson experience with ANFH occurring in CML patients who were managed with interferon-alpha-based therapy. MEDLINE (from 1966 to November 1999) and CancerLit (from 1983 to November 1999) searches were conducted to identify cases of avascular necrosis (AVN) associated with either CML or interferon-alpha. RESULTS: Three patients with ANFH were identified from the authors' experience. No common features related to the disease or therapy were seen among them, except for the presence of thrombocytosis and loss of response. A literature review revealed seven cases of ANFH associated with CML with or without interferon-alpha-based therapy. ANFH was not reported in association with interferon-alpha use for indications other than the treatment of patients with CML. CONCLUSIONS: ANFH may be the result of an interaction between CML and interferon-alpha therapy. ANFH that occurs in patients with CML who are treated with interferon-alpha should be recognized for treatment implications. Thrombocytosis with consequent microvascular thrombi and avascular necrosis manifesting in susceptible vascular or weight-bearing areas (e.g., the femoral head) may be an associated finding along with loss of response to interferon-alpha therapy.
Adult↗
Expression of thrombopoietin and its receptor (c-mpl) in chronic myelogenous leukemia: correlation with disease progression and response to therapy.
BACKGROUND: Chronic myelogenous leukemia (CML) represents a paradigm of the stepwise increment in disease aggressiveness, resistance to therapy, and transformation. Thrombopoietin (TPO) and its receptor, c-mpl, support the proliferation of multiple types of immature hematopoietic progenitor cells, and induce clonal growth of leukemic cells. The authors investigated whether TPO or c-mpl overexpression might correlate with progression of CML, disease aggressiveness, or response to therapy. METHODS: Expression of c-mpl and TPO was measured in bone marrow samples from 208 patients with CML by Western blot analysis and solid-phase plate radioimmunoassay (used for quantification). Samples obtained from individuals without evidence of hematologic abnormalities were used as controls. RESULTS: There were no significant differences in TPO or c-mpl expression among patients in different phases of CML or between patients with Philadelphia chromosome positive and negative CML. When TPO and c-mpl levels were analyzed in relation to prognostically important host and disease characteristics in early chronic phase CML, platelet and white blood cell counts demonstrated significant differences in both TPO and c-mpl expression, but age and spleen size demonstrated significant differences in TPO expression only. Responses to interferon (INF)-alpha-based therapy and survival were not influenced by TPO or c-mpl levels. CONCLUSIONS: TPO or c-mpl overexpression did not correlate with different CML phases, suggesting that they were not involved in CML progression from early to advanced phase. Neither TPO nor c-mpl overexpression was particularly evident in any risk group, suggesting lack of correlation between their expression and disease aggressiveness. This was supported by the finding of similar response to IFN-alpha-based therapy and survival regardless of the level of TPO or c-mpl expression.
Adolescent↗
Autoantibodies to Abl and Bcr proteins.
Formation of an aberrant, chimeric Bcr-Abl protein is the hallmark of Philadelphia (Ph) chromosome-positive leukemias. The Bcr-Abl protein, as well as its normal cellular counterparts--Abl and Bcr--are intracellular molecules with postulated roles in a variety of critical biologic functions. In this study, we demonstrate the existence of autoantibodies against these proteins. Plasma from 18 of 31 individuals (58%), including 14 of 20 Ph-positive CML patients (70%), two of four normal volunteers (50%), and two of seven patients with Ph-negative leukemia (29%) recognized p210Bcr-Abl when used in immunoprecipitation followed by immunoblotting experiments. In all 18 patients, plasma was able to recognize baculovirus-expressed Abl protein; in four patients, recognition of baculovirus-expressed Bcr protein was also demonstrated. These observations suggest that a humoral immune response to p210Bcr-Abl is discernible in both Ph-positive and -negative leukemias and in healthy individuals, and is most likely due to autoantibodies which recognize normal Abl and, to a lesser extent, normal Bcr proteins.
Adult↗
Cytoplasmic and nuclear localization of the 130 and 160 kDa Bcr proteins.
Formation of the Bcr-Abl chimeric protein is the molecular hallmark of Philadelphia-positive leukemia. Normal Bcr is a complex protein which has been found in the cytoplasm, has serine kinase activity, and has been implicated in cellular signal transduction. However, we have recently demonstrated that Bcr can also associate with condensed chromatin. Since two major Bcr proteins have been characterized (p160Bcr and p130Bcr), we sought to determine if different forms of Bcr localized to the nucleus vs the cytoplasm. Metabolic labeling and Western blotting experiments were performed using nuclear and cytoplasmic extracts of three human Philadelphia-negative leukemia/lymphoma cell lines (KG-1, HL-60, and Jurkat). Both methodologies showed that p160Bcr and p130Bcr localized to the cytoplasm, but the p130 form predominated in the nucleus. These results suggest that Bcr serves both nuclear and cytoplasmic functions, and that different forms of Bcr may be preferentially involved in these distinct activities.
Acute Disease↗
Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients.
Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr-Abl-CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr-Abl-positive patients. Activation-specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr-Abl-CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down-regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.
Adaptor Proteins, Signal Transducing↗
Acute pancreatitis associated with interferon alpha therapy for chronic myelogenous leukemia.
Acute pancreatitis related to interferon alpha therapy is very rare. We report two patients with chronic myelogenous leukemia (CML) who developed acute pancreatitis following treatment with interferon alpha. A review of the literature on the association of pancreatitis and interferon alpha is provided. Possible pathophysiologic mechanisms are also discussed.
Acute Disease↗
Clinical significance of minimal residual disease in leukemia.
Considerable progress has been made in the treatment of acute and chronic leukemias. Remission rates are generally high and cure rates of up to 80% can be achieved in children with acute lymphoblastic leukemia (ALL). However, in many patients the disease will ultimately recur. In most if not all of these patients, relapse is thought to result from subclinical levels of residual leukemia, termed minimal residual disease (MRD). Therefore, the study of MRD holds a significant potential to understand the biology of relapse and remission and to design new therapies to improve the cure rate of patients. A major goal of these studies is to be able and identify patients at a defined risk of relapse which can lead to risk-adapted therapy approaches. Laboratory assays such as polymerase chain reaction (PCR) and multicolor flow cytometry are sensitive enough to detect one leukemic cell in up to 104-105 normal cells and have become ideal tools to monitor MRD. Especially PCR has been used extensively. Although a wealth of data has been generated, some questions remain as to the impact of monitoring MRD on clinical outcome and are the object of this review.
Acute Disease↗
Serum beta-2 microglobulin levels are a significant prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia.
Our objective was to investigate the prognostic significance of serum beta-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 (ie., 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.
Aged↗