GM-CSF can improve the cytogenetic response obtained with interferon-alpha therapy in patients with chronic myelogenous leukemia

Patients with chronic myelogenous leukemia (CML) who achieve a major cytogenetic remission when treated with interferon-alpha (IFN-A) have a survival advantage when compared to patients with no cytogenetic response. We investigated the effect of combining granulocyte-macrophage colony-stimulating factor (GM-CSF) with IFN-A in the cytogenetic response of patients with minor responses to IFN-A alone. CML patients were eligible if they had shown sensitivity to IFN-A as determined by achievement of a hematologic or cytogenetic response, but failed to achieve or lost a major cytogenetic response after a minimum of 12 months of therapy with IFN-A alone. Patients received GM-CSF 30 microg/m2 daily, subcutaneously and the dose was escalated to 60 microg/m2 if tolerated. IFN-A was continued at the same dose being received by the patient and escalated when possible. Fourteen evaluable patients were included, 13 in chronic phase and one in accelerated phase. The best response prior to GM-CSF was a transient major cytogenetic response in two patients (14%), minor cytogenetic response in nine (64%), and complete hematologic response in three (22%). The median time on IFN-A prior to the start of GM-CSF was 39 months (range 12-72 months). Four patients achieved a significant cytogenetic response, including two complete (14%) and two partial (14%) cytogenetic remissions during therapy. One partial cytogenetic remission converted to complete shortly after therapy was discontinued. Two other patients had a significant reduction in the percentage of Philadelphia chromosome-positive metaphases. The dose of IFN-A could be escalated in half of the patients treated. No toxicity could be attributed to the addition of GM-CSF. We conclude that the addition of GM-CSF to the treatment with IFN-A in CML patients who are sensitive to IFN-A alone but fail to achieve a major cytogenetic response may be beneficial in some patients and should be further investigated.     

Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia

The aim of this analysis was to evaluate the efficacy of alpha-interferon (alpha-IFN) regimens in late chronic phase (diagnosis >12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The alpha-IFN programs were sequential studies with human leukocyte alpha-IFN (seven patients), recombinant alpha-IFN alone (15 patients) or with IFN-gamma (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive <35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that alpha-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.     

Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis

BACKGROUND: Chronic myelogenous leukemia (CML) is an indolent but ultimately fatal disease. Because the natural history of CML varies and quality of life with CML may be excellent until shortly before death, deciding whether and when to pursue unrelated donor bone marrow transplantation is often difficult. OBJECTIVE: To compare early transplantation, delayed transplantation, and no transplantation for patients with chronic-phase CML on the basis of discounted, quality-adjusted life expectancy. DESIGN: A markov model comparing different strategies was constructed. This model considers patient age, quality of life, risk aversion, and the competing risks for CML progression and transplant toxicity. SETTING: Therapeutic decision at the time of diagnosis of CML. PATIENTS: The base case is a 35-year-old patient with intermediate-prognosis CML. Younger and older patients with better and worse prognoses are also evaluated. INTERVENTION: Early transplantation, delayed transplantation, and no transplantation. MEASUREMENTS: Quality-adjusted, discounted life expectancy. RESULTS: For patients with newly diagnosed CML, transplantation within the first year provides the greatest quality-adjusted expected survival, although this benefit decreases with increasing patient age. For a 35-year-old patient with intermediate-prognosis CML, transplantation within the first year results in 53 more discounted, quality-adjusted years of life expectancy than does no transplantation. This finding is robust even with varying baseline assumptions. CONCLUSIONS: These results support the use of early unrelated donor bone marrow transplantation for most patients with CML.     

Prognostic value of P-glycoprotein and leukocyte differentiation antigens in chronic myeloid leukemia

P-glycoprotein (Pgp) mediated multidrug resistance is often the cause of therapy failure in some tumors. Pgp expression was shown to have prognostic value in several hematological malignancies, especially in acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). In chronic myeloid leukemia (CML) Pgp is expressed by peripheral blood (PB) cells more often in the terminal disease stages (20-50% of patients have Pgp+ phenotype). Sequential studies show that Pgp+ cells often disappear from the PB during the course of therapy. Nevertheless Pgp expression has some prognostic value in blast crisis (BC) predicting shorter BC, while CD13 has the same predictive value in BC. 10% of patients formed a distinct group with large numbers of Pgp+CD34+ blasts in the PB and also had shorter BC. Cases with inactive Pgp were found in chronic and accelerated phases of CML but not in BC.     

The infradome graft: a new technique to improve dome reshaping in rhinoplasty

PURPOSE: The impact of treatment options on survival and late neurologic toxicity was investigated in a series of patients with primary cerebral lymphoma (PCL) and no known cause of immunosuppression. PATIENTS AND METHODS: Prognostic factors for survival and treatment-induced late neurotoxicity were investigated in a retrospective series of 226 patients with PCL. RESULTS: With a median follow-up of 76 months, the median overall survival was 16 months and 5-year survival was 19%. In a univariate analysis, age greater than 60 years, performance status, CSF protein level greater than 0.6 g/L, involvement of corpus callosum or subcortical grey structures, detectable lymphoma cells in CSF, increased serum lactate dehydrogenase (LDH), but not histological subtype, were significantly correlated with a poor survival. Treatment with chemotherapy versus radiotherapy alone (P = .05), high-dose methotrexate (HDMTX; P = .0007), and cytarabine (P = .04) correlated with a better survival in univariate analysis. Using the Cox model, age, performance status, and CSF protein were independently correlated with survival. After adjustment of these factors, treatment with an HDMTX-containing regimen remained the only treatment-related factor independently correlated with survival (P = .01). The projected incidence of treatment-induced late neurotoxicity was 26% at 6 years in this series, with a median survival from the diagnosis of late neurotoxicity of 12 months. Treatment with radiotherapy followed by chemotherapy was the only parameter correlated with late neurotoxicity in multivariate analysis (relative risk, 11.5; P = .0007). CONCLUSION: Patients with PCL treated with regimens that included HDMTX followed by radiotherapy have an improved survival, but not a higher risk of late neurotoxicity as compared with other treatment modalities in this series.     

An evaluation of the prognostic significance of antigen CD95(Fas/APO-1) expression on the cells of patients with a myelodysplastic syndrome, acute myeloid leukemia and chronic myeloleukemia

AIM: The expression of CD95(Fas/APO-1) antigen was studied on bone marrow cells of 19 MDS patients, peripheral blood blast cells of 15 acute myeloid leukemia (AML) patients, blast cells and granulocytes of 68 patients with chronic myeloid leukemia (CML)--24 in chronic, 9 in accelerated phase and 35 in blastic crisis (BC)--by indirect surface immunofluorescence assay using flow cytometry (FACScan, Becton Dickinson, USA). RESULTS: CD95(Fas/APO-1) antigen was revealed on bone marrow cells of 8 out of 19 (36.8%) MDS patients; the percentage of antigen-positive cells was 38.1 +/- 19.2%; on 45.5 +/- 22.8% of cells in 6(45%) of 15 AML patients. Fas/APO-1 antigen was totally absent in CML chronic stage; its expression was found in 34% (12 of 35) of our patients with CML BC on peripheral blood blasts and in 56% (5 of 9) on peripheral blast cells of CML patients in acceleration phase. CONCLUSION: The data on overall survival of CD95-positive MDS patients suggest that the presence of Fas antigen is a favorable prognostic sign for patients with MDS. The patients from CD95-negative group represent a risk group both for survival and AML transformation. In CML BC group the survival does not depend upon Fas-antigen expression.     

Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity

OBJECTIVES: To determine factors influencing survival and need for hospitalisation in patients needing dialysis, and to define the potential basis for rationing access to renal replacement therapy. DESIGN: Hospital based cohort study of all patients starting dialysis over a 4 year recruitment period (follow up 15-63 months). Groups were defined on the basis of age, comorbidity, functional status, and whether dialysis initiation was planned or unplanned. SETTING: Renal unit in a district general hospital, which acts as the main renal referral centre for four other such hospitals and serves a population of about 1.15 million people. SUBJECTS: 292 patients, mean age 61.3 years (18-92 years, SD 15.8), of whom 193 (66%) were male, and 59 (20%) were patients with diabetes. Dialysis initiation was planned in 163 (56%) patients and unplanned in 129 (44%). MAIN OUTCOME MEASURES: Overall survival, 1 year survival, and hospitalisation rate. RESULTS: Factors affecting survival in the Cox's proportional hazard model were Karnofsky performance score at presentation (hazard ratio 0.979, 95% confidence interval 0.972 to 0. 986), comorbidity severity score (1.240, 1.131 to 1.340), age (1.036, 1.018 to 1.054), and myeloma (2.15, 1.140 to 4.042). The Karnofsky performance score used 3 months before presentation was significant (0.970, 0.956 to 0.981), as was unplanned presentation in this model (1.796, 1.233 to 2.617). Using these factors, a high risk group of 26 patients was defined, with 19.2% 1 year survival. Denying dialysis to this group would save 3.2% of the total cost of the chronic programme but would sacrifice five long term survivors. Less rigorous definition of the high risk group would save more money but lose more long term survivors. CONCLUSIONS: Severity of comorbid conditions and functional capacity are more important than age in predicting survival and morbidity of patients on dialysis. Late referral for dialysis affects survival adversely. Denial of dialysis to patients in an extremely high risk group, defined by a new stratification based on logistic regression, would be of debatable benefit.     

Inadequate measurement of urinary chloride

Fifteen years ago Talpaz and colleagues were the first to determine that natural interferon alpha (INF-alpha) induces hematologic remission in chronic phase patients with chronic myeloid leukemia (CML). Further research revealed that this agent, contrarily to conventional chemotherapy with busulfan or hydroxyurea, eliminates leukemic hematopoietic cells having Philadelphia chromosome (Ph1-positive) in about 20% of patients, leading to the phase of cytogenetic remission. Comparison of the efficiency of IFN-alpha with conventional chemotherapy was carried out in several randomized clinical trials. It was found, that IFN-alpha delays the occurrence of blastic phase of CML and prolongs patients life span. It does not create, however, a likely chance of full recovery. The results of the randomized trails, carried out in France, showed that the combination of IFN-alpha and cytarabine as compared with INF-alpha alone, increases the rate of major cytogenetic response and prolongs survival in the chronic phase of CML. IFN-alpha efficiency in acceleration and blastic transformation phases of CML has not been proven so far, although this drug may be of certain value in combination with hydroxyurea or other cytostatic agents. At present, it is more often considered that IFN-alpha should be a first line therapy in newly diagnosed CML in its chronic phase, if due to absence of appropriate donors or advanced age, allogenic bone marrow transplantation cannot be performed.     

Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-alpha (IFN-alpha), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-alpha results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-alpha on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-alpha therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-alpha, whereas 22, 23, and 25 patients received IFN-alpha for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-alpha therapy administered for > or = 6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2. 1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-alpha therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight > or = 110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-alpha for less than 6 months before transplant, who were < or = 50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% +/- 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-alpha when the patient is < or = 50 years of age and has an HLA-compatible unrelated volunteer donor.     

Experimental rat model representing both acute and chronic heart failure related to autoimmune myocarditis

The most important clinical manifestation of myocarditis is congestive heart failure. The precise mechanisms of heart failure during myocarditis have not been elucidated because no animal model that would permit in vivo study of hemodynamics in severe active myocarditis has been available. We monitored hemodynamics and left ventricular function in a rat model of experimental autoimmune myocarditis to determine if this model could be useful for the study of in vivo hemodynamics in severe active myocarditis. Lewis rats were immunized with human cardiac myosin suspended in complete Freund's adjuvant. Baseline hemodynamics were measured using an ultraminiature catheter pressure transducer via the right internal carotid artery, 4 weeks after immunization in one group of rats (acute phase) and 3 months after immunization in another group (chronic phase). Untreated rats served as the control group. Hemodynamic measurements were also obtained after infusion of dobutamine in the acute-phase and chronic-phase groups. The heart weight-to-body weight ratios were significantly higher in both the acute-phase group and the chronic-phase group compared with normal control rats. The baseline left ventricular systolic pressure was significantly lower in the chronic phase group than in the control group. Peak dP/dt and peak -dP/dt were significantly lower in both the acute-phase group and the chronic-phase group compared with the control group. Dobutamine significantly increased left ventricular systolic pressure, peak dP/dt, and peak -dP/dt in the chronic-phase group but caused only minor changes in hemodynamic variables in the acute-phase group. In vivo measurements of hemodynamic variables indicated the presence of left ventricular dysfunction in rats with experimental autoimmune myocarditis. This animal model may be useful for the study of both acute heart failure related to acute myocarditis and chronic heart failure due to diffuse myocardial fibrosis.     

A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers

The different therapeutic options available for the treatment of chronic leukemias and myelofibrosis are discussed. In reference to chronic myeloid leukemia (CML), the choice of the most appropriate treatment must take into account not only the clinical condition but also the age of the patient. While subjects under 50 might benefit from the options offered by alpha-interferon, bone marrow and peripheral stem cell transplant, in older age groups treatment of the chronic phase must still rely on standard treatment. Chronic lymphocytic leukemia (CLL) and its variants is a disease of mostly middle and late life, with a variable clinical course. Patients show wide differences in morbidity and mortality. Many features have been shown to influence the prognosis, and the most important ones are incorporated into the staging systems currently in use. The results obtained from the study of large trials support the concept that treatment of patients with stable stage A CLL should be postponed until progression of disease. Treatment relies principally on alkylating agents, corticosteroids and radiation therapy; the new nucleoside analogues, such as fludarabine and 2-chlorodeoxyadenosine, have recently acquired established value in improving overall survival. With regard to myelofibrosis, the histological and biological features that influence the natural course of the disease are described, as well as the choice of the most appropriate treatment, which ranges from the use of alkylating agents and androgens, to splenectomy and splenic irradiation.     

Importance of mixed chimerism to predict relapse in persistently BCR/ABL positive long survivors after allogeneic bone marrow transplantation for chronic myeloid leukemia

Determination of hematological chimerism could be helpful in understanding the biology of leukemic relapse after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML), because the detection of malignant residual cells carrying the bcr/abl message by qualitative RT-PCR is of limited value in predicting disease progression for individual patients. We have studied the chimerism pattern and the bcr/abl status by Southern-blot in 15 CML patients (M/F:6/9) transplanted with unmanipulated BM from HLA identical sibling donors, persistently bcr/abl positive by RT-PCR. The median age of the series was 31 years (18-49) and disease status at BMT was: chronic phase: 11, accelerated phase: 3 and blast crisis: 1 patient. Of the 15 patients, 9 are alive and in complete remission (CR), 4 have died in CR and 2 are alive but suffered relapse at + 19 and +26 months post-BMT. The median follow-up is 81 months (13,7-168). Rearrangement of the BCR gene was performed by Southern-blot using P32-labeled transprobe-1. PCR analysis of chimerism was assessed using primers for the following VNTR loci: D1S80, D1S111, 33.1, APO-B, YNZ-22, lambdag3 and DXS52. Seventy-nine samples were analyzed (median per patient 5 (range 2-9)). Thirteen patients showed complete chimerism and lacked BCR rearrangement over time by Southern-blot. The 2 patients who relapsed showed mixed chimera status from +9 and +5 months respectively until the end of the study. Persistent BCR rearrangement was observed in these 2 patients from +12 and +11 months respectively. Our data suggest that mixed chimerism may predict hematologic or cytogenetic relapse by several months in those patients who are persistently PCR-positive post-BMT.     

Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators

PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.     

Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts. PATIENTS AND METHODS: HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase. Plasma levels of HU were analyzed in all patients. To determine the role of HU in inhibiting ribonucleotide reductase, dNTP pools in the leukemia cells were quantitated. Correlations were sought with these parameters and DNA synthesis inhibition measured ex vivo by [3H]thymidine incorporation. RESULTS: The MTD of HU given as a 24-hour infusion was 27 g/m2. The dose-limiting toxicity was mucositis. There was a significant but transient myelosuppression, with nadir counts generally seen 3 to 4 days after the dose. The steady-state concentration of HU in plasma was achieved by 6 hours, and was proportional to the dose. There was a median 57% decrease in the deoxyadenosine triphosphate (dATP) pool in circulating blasts. In contrast, deoxyguanosine triphosphate (dGTP) and pyrimidine dNTPs were not significantly affected. The extent of DNA synthesis inhibition was related to the residual concentrations of intracellular dATP. CONCLUSION: A 24-hour infusion of HU results in significant but transient myelosuppression in advanced-phase CML. The specific decrease of intracellular dATP correlated with the inhibition of DNA synthesis in CML blasts. This pharmacodynamic action of HU provides a rationale for combination with other chemotherapeutic agents, the effects of which could be augmented by the decline in dATP pools.     

Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992

This study was a phase II evaluation of the activity of carboplatin in patients with Philadelphia chromosome positive accelerated or blastic phase of CML. Carboplatin, 250 mg/m2/day as an intravenous continuous infusion was given for 5 days, for a total dose of 1250 mg/m2 per course. If necessary, a second induction course could be given, and patients achieving complete remission were to receive an additional consolidation cycle at the same dose. Thirty-six patients were eligible and evaluable. There were five complete and three partial remissions for an overall response rate of 22% (95% CI 10.1-39.1%). The complete remission rate was 13.9% (95% CI 4.7-29.9%). The median remission duration was 3 months (range 1.4-8.94 months) and the median survival on study for all patients was 3.5 months (95% CI, 2.4-11.4 months). The median survival of responders was 12.8 months (95% CI, 3.6-17.2 months). Three eligible patients survived 2.0, 2.5 and 3.5 years following carboplatin therapy. Carboplatin has activity in blast crisis of CML, but responses are brief. Response did allow one patient to proceed to bone marrow transplantation and two other patients to continue therapy for chronic phase disease before returning to blast crisis. Activity in combination regimens should be explored.     

High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase

PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.     

The immunophenotype of blast transformation of chronic myelogenous leukemia: a high frequency of mixed lineage phenotype in "lymphoid" blasts and A comparison of morphologic, immunophenotypic, and molecular findings

Immunophenotypic studies have a limited role in the diagnosis of chronic myelogenous leukemia (CML) but are increasingly being used in CML blast transformation (BT). Determination of the cell lineage of CML blasts is clinically important because patients with lymphoid blast transformation have a better response to chemotherapy and longer survival than those with other lineages. We studied the morphologic, cytochemical, immunophenotypic, cytogenetic, and molecular features of 20 patients with Philadelphia chromosome-positive CML and more than 10% blast cells in peripheral blood or bone marrow. The blasts were morphologically heterogeneous. CD33 was expressed in 19 cases (95%), followed by CD13 (85%), CD11c (80%), CD36 (60%), CD117 (40%), and CD15 (30%). Seven cases (35%) had a precursor-B lymphoid immunophenotype, and 13 (65%) had a predominantly myeloid immunophenotype. Of the former group, of which only one had a pure lymphoid phenotype, terminal deoxynucleotidyl transferase (TdT) and CD19 were expressed in 100%, CD10 in 85.7%, and CD20 in 14.3%. Of the latter group, all 13 expressed from 3 to 6 myeloid antigens, with 46.2% myeloperoxidase positive and 69.2% CD61 positive. No cases were interpreted as T lineage, but the T-cell antigens CD3, CD4, CD5, and CD7 were expressed in 5.0, 40.0, 5.3. and 30.0% of all cases, respectively. In most cases, the immunophenotype of the CML blasts could not be predicted from their morphologic features. Polymerase chain reaction showed that 80.0% of the lymphoid group and 37.5% of the myeloid group had immunoglobulin heavy-chain gene rearrangements. The frequent lineage infidelity of the blast cells in CML BT seems to be related to the stem cell origin of this disorder. Such lineage infidelity, however, makes classification of many cases difficult and the significance of and criteria for biphenotypic blast crisis of CML is yet to be determined.     

Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia

PURPOSE: To investigate whether cytogenetic clonal evolution can be suppressed with interferon alfa (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Ninety patients with CML and cytogenetic clonal evolution who received IFN-alpha-based regimens were analyzed. Clonal evolution was defined as the presence of karyotypic abnormalities in addition to the Philadelphia (Ph) chromosome. Patients were evaluated for the suppression of cytogenetic clonal evolution after therapy, the cytogenetic response, and survival. RESULTS: The median age of the population was 39 years (range, 15 to 70 years), median time from diagnosis to clonal evolution 14 months (range, 0 to 145 months), and median percentage of abnormal metaphases 18% (range, 4% to 100%). Fifty six patients (62%) achieved some suppression of cytogenetic clonal evolution; in 41 patients (46%), the suppression was complete. The overall median survival was 51 months, with 43% alive at 5 years. Patients who achieved a complete suppression of cytogenetic clonal evolution had a median survival of 66 months, with 51% alive at 5 years. Characteristics associated with a better response include a lower percentage of abnormal metaphases, time to cytogenetic clonal evolution of 24 months or less, and absence of other features of accelerated disease. A prognostic classification for cytogenetic clonal evolution defined three groups with complete response (CR) rates of 85%, 34%, and 0% (P < .0001) and median survival times of 58, 31, and 30 months, respectively (P=.02). CONCLUSION: Patients with cytogenetic clonal evolution can respond to IFN-alpha therapy, and this response is associated with longer survival. A previously described prognostic model separates patients into subsets with different probabilities of response to IFN-alpha and survival.