The M.D. Anderson Cancer Center experience with interferon-alpha therapy in chronic myelogenous leukaemia.
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Antineoplastic Agents↗
Biomedical subjects
M Talpaz
Publications and source records attributed to M Talpaz.
Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-alpha-resistant hairy cell leukemia: 7-year follow-up.
The long-term outcome of patients with hairy cell leukemia resistant to interferon-alpha (IFN-alpha) following treatment with deoxycoformycin (DCF) was examined, and the kinetics of recovery of lymphocyte subsets and factors influencing the rate of recovery investigated. Between May 1986 and May 1989, 15 patients with histologically confirmed hairy cell leukemia resistant to IFN-alpha received DCF 4 mg/m2 every 2 weeks with 12 cycles planned. All 15 patients were evaluable for response and have been followed for a median of 88 months (range, 72 to 106 months) from the start of therapy. Fourteen patients responded to DCF, all attaining complete remission (CR) (response rate 93%; 95% confidence interval, 69% to 100%). Seven patients have developed recurrent disease after 45 to 74 months. Using the method of Kaplan and Meier, the median remission duration is 74 months and, at 8 years, 46% (95% confidence interval, 33% to 59%) of patients are projected to be in ongoing CR. The seven relapsing patients have responded to treatment with 2-chlorodeoxyadenosine (2-CdA) and all 15 patients remain alive. After DCF, nadir CD4+ and CD8+ lymphocyte counts were significantly lower than prior to therapy (P < 0.0001 and P = 0.05, respectively), but returned to baseline levels during follow-up. Median times to attainment of the lower limit of the normal range of CD4+ and CD8+ lymphocytes were 54 and 36 months, respectively. Those patients who had previously undergone splenectomy (n=7) had higher baseline CD4+ (P= 0.073) and CD8+ (P= 0.043) lymphocyte counts and more rapid recovery of both CD4+ (P= 0.027) and CD8+ lymphocyte counts (P = 0.016) than non-splenectomized patients. One elderly patient (age, 78 years) was diagnosed with subsequent malignancy. No late opportunistic infections were observed. Resistance to IFN-alpha does not impair subsequent responsiveness of patients with hairy cell leukemia to treatment with DCF. Responses are durable and without evidence of long-term sequelae. CD4+ and CD8+ lymphocyte subsets recover slowly without clinical manifestations of immunodeficiency. Splenectomized patients appear to have higher baseline lymphocyte counts and more rapid lymphocyte recovery following treatment with DCF.
Adult↗
Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases.
New treatments which may change the course of a disease, or which have potential carcinogenicity, may result in the development of new cytogenetic or clinical disorders. Three patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia (CML) who developed new cytogenetic abnormalities after achieving a cytogenetic complete remission (CR) of their Ph-positive disease with interferon alpha (IFN-alpha) based therapy are described. Patient 1 developed chromosomal abnormalities involving chromosomes 5 (5q13-34) and later 7 (monosomy 7) 60 months after the start of therapy and 20 months after IFN-alpha was discontinued. A myelodysplastic syndrome was noted 83 months from the start of therapy. Patient 2 developed a myeloproliferative syndrome with 18p11 chromosomal abnormalities 90 months after the start of the therapy and 60 months after IFN-alpha was discontinued. Patient 3 developed a chromosome 11 abnormality (11q21-23) 23 months after the start of therapy, without hematological manifestations. All three patients remain in cytogenetic CR of Ph-positive disease with the hypermetaphase fluorescent in situ hybridization and polymerase chain reaction studies for BCR/ABL showing minimal residual disease. The emergence of new cytogenetic or clinical disorders in patients with CML on IFN-alpha therapy needs to be monitored. These findings may be related to changing the natural course of CML, to therapy, or to the emergence of suppressed clones in a stem cell disorder.
Aged↗
Treatment of chronic myelogenous leukemia with nucleoside analogs deoxycoformycin and fludarabine.
In vitro studies suggest that nucleoside analogs have an antileukemic effect against chronic myelogenous leukemia (CML). We investigated the antileukemia effect of deoxycoformycin (DCF) and fludarabine in patients with CML. Four patients with Philadelphia chromosome (Ph)-positive CML were treated with DCF at 4 mg/m2 every week for 4 weeks, then every other week for four doses, and then every month as maintenance. Two patients were in late chronic phase and two in accelerated phase. All had previously failed therapy with interferon-alpha (IFN-A). Nine patients were treated with fludarabine 30 mg/m2/day for 5 days every 28 days. Three had Ph-positive CML, and six Ph-negative disease. Five patients were in accelerated phase and four in late chronic phase. Three patients treated with DCF had normalization of WBC counts while on the weekly schedule but progressed when changed to every other week. The fourth patient had no objective response. There were no cytogenetic responses. DCF was well tolerated with only mild nausea and vomiting in all patients. Patients treated with fludarabine received a median of two courses (range 1-4). In two patients (both Ph-positive), disease progressed to blastic phase upon recovery. Two other patients died of hemorrhagic complications secondary to thrombocytopenia. In all other cases fludarabine produced a transient reduction of WBC counts, but counts recovered to levels equal to or greater than the pre-treatment values. There were no cytogenetic responses. These results, together with previous experience with 2-CDA producing only hematologic responses, suggest that nucleoside analogs may not have a significant role in the management of CML.
Adult↗
A pilot study of all-trans retinoic acid in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.
Retinoids have significant antiproliferative effect against chronic myelogenous leukemia (CML) cells in vitro. We conducted a pilot study to investigate the clinical effect of all-trans retinoic acid (ATRA) in patients with CML. Thirteen patients with Philadelphia chromosome (Ph)-positive CML in late chronic phase (n=7), accelerated phase (n=5), or blastic phase (n=1) were treated. All had been previously treated and 12 (92%) had disease refractory to interferon-alpha therapy. They received ATRA 175 mg/m2 orally in two divided doses daily until disease progression. The median duration of therapy was 56 days (range 11 to 190). Only one patient in late chronic phase had a transient decrease in WBC counts; all other patients in late chronic phase showed no response to therapy. Four of the five patients in accelerated phase showed evidence of antileukemia effect manifested by a decrease in bone marrow and/or peripheral blood blasts, promyelocyte and/or basophil percentages. In all cases the response was transient. The patient in blastic phase had no evidence of antileukemic effect. The treatment was well tolerated with the major side-effects being headache, nausea, dry skin, and dry mucosal membranes. One patient required dose reductions due to toxicity. We conclude that in this population of patients with extensively treated, advanced stage, Ph-positive CML, ATRA alone is ineffective for long-term therapy. The antileukemia effect seen in some patients warrants further investigation of retinoids in other schedules and in combinations in patients with CML.
Adolescent↗
Analysis of the BCR-ABL protein in Philadelphia chromosome-positive adult acute lymphocytic leukemia.
Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) constitutes 15-35% of all ALL in adults. Its detection is prognostically significant. The Ph abnormality is usually detected through standard cytogenetic analysis but 20-30% of patients have insufficient metaphases (IM) with such analysis. To detect the BCR-ABL oncoprotein in peripheral blood specimen of patients with ALL at the time of diagnosis and at follow-up, a new sensitive technique of enhanced chemiluminescence Western blot (ECL-WB) analysis was investigated. Among 41 patients with newly diagnosed ALL, nine were Ph positive by cytogenetic studies; they were also BCR-ABL positive according to ECL-WB. Eight had p190 disease, and one had p210 disease. Among the 16 patients with IM, none demonstrated the oncoprotein through ECL-WB or through simultaneous Southern blot (SB) for p210 rearrangement. Follow-up studies were available for seven patients: four had detectable protein and three of them relapsed 4-20 weeks later; three had undetectable protein and one of them (who had low level protein at the time of diagnosis) relapsed 11 weeks later. Although none of the patients with IM at diagnosis had detectable protein according to ECL-WB, this was probably due to the small number of patients studied. One patient with IM studied at follow-up demonstrated the protein by ECL-WB. In summary, we describe a technique that is useful in the detection of p190/p210 ALL at diagnosis. It is less time consuming, and more cost effective than standard chromosome banding techniques. It may also detect the oncoprotein in cases with IM. Although a larger number of patients should be studied to prove its clinical usefulness, this technique may also be of value for monitoring residual disease at follow-up.
Blotting, Western↗
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.
Adolescent↗
Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia.
The aim of the study was to evaluate the activity of decitabine, a hypomethylating agent, in the treatment of patients with chronic myelogenous leukemia (CML) in transformation. Thirty-seven patients with CML in blastic (20 patients) or accelerated phases (17 patients) were treated. Their median age was 52 years; 36 had Philadelphia chromosome-positive disease. Decitabine was given at 100 mg/m2 over 6 h every 12 h x 10 doses (1000 mg/m2) to 13 patients, and at 75 mg/m2 over 6 h every 12 h x 10 doses (750 mg/m2) to 24 patients. In blastic phase, two patients (10%) achieved a complete hematologic response (one with Ph suppression), and three (15%) had a hematologic improvement (marrow CR, platelets <100 x 10[3]/microl), for an overall response rate of 25%. In accelerated phase, six patients (35%) returned to a second chronic phase (two with Ph suppression), one (6%) had a hematologic improvement, and two (12%) had a partial hematologic response, for an overall response rate of 53%. Prolonged myelosuppression was the most significant side-effect. The median time to recovery of granulocytes above 500/microl was 48 days, and to recovery of platelets above 30 x 10(3)/microl, 31 days. Febrile episodes occurred in 25 patients (68%) including documented infections in 17 patients (46%). Decitabine has promising activity in CML. The most significant side-effect is prolonged myelosuppression. Decitabine may show activity in other myeloid disorders such as acute myeloid leukemia and myelodysplastic syndrome, as well as in other hematologic malignancies, alone or with other drug combinations. Its value in the context of stem cell support should also be investigated.
Adult↗
Fludarabine and granulocyte colony-stimulating factor (G-CSF) in patients with chronic lymphocytic leukemia.
The study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) following fludarabine would reduce the incidences of myelosuppression and infections. Twenty-five previously treated patients with Rai stage III-IV chronic lymphocytic leukemia (CLL) received fludarabine 30 mg/m2 daily for 5 days each month. G-CSF was given at 5 microg/kg subcutaneously starting 1 day after chemotherapy (day 6) and continued until the next course unless the granulocyte count was > or =10000/microl. The incidences of myelosuppression and infection were compared with those seen in an historical control population of 145 previously treated patients with Rai stage III-IV CLL who were given the same schedule of fludarabine without growth factor. There was a significant decrease in myelosuppression; patients receiving G-CSF developed neutropenia at a neutrophil count <1000/microl or 500/microl in 45% and 15% of courses vs 79% (P=0.002) and 63% (P < 0.001) of historical controls. Twenty percent of G-CSF-treated patients had therapy delayed by >35 days per course, vs 50% of historical controls (P=0.005). The incidence of pneumonia was 8% with G-CSF and 37% without in historical controls. Other infection rates (sepsis, fever of undetermined origin, minor infections) were similar. This decrease in pneumonia was noted even in high-risk groups such as patients older than 60 years and patients with hypogammaglobulinemia. The use of G-CSF following fludarabine in high-risk patients with CLL resulted in a significant decrease in myelosuppression and pneumonia. Larger trials to verify these results and to compare costs are indicated.
Adult↗
Second cancer risk in hairy cell leukemia: analysis of 350 patients.
PURPOSE: The discovery of effective therapy for hairy cell leukemia (HCL) has increased the relevance of long-term outcome. We have therefore examined the incidence of second cancers. PATIENTS AND METHODS: Data on 350 HCL patients was obtained from the M.D. Anderson Cancer Center Cancer Registry's computerized data base and from chart review. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) (observed/expected [O/E]) were calculated with the expected number determined using age, sex, and calendar-year-specific rates from the Connecticut Tumor Registry and from national mortality data, respectively. RESULTS: The median age of the patients was 50 years and the median follow-up duration was 6 years. Twenty-six patients developed a second cancer at least 6 months after the HCL diagnosis (O/E ratio, 1.34; P = .08). There was no excess of malignancy among patients treated with interferon alfa (IFN-alpha; P = .27), 2-chlorodeoxyadenosine (2CDA; P = .37), or deoxycoformycin (DCF; P = .7). However, an excess of myeloma-related neoplasms (O/E, 13.04; P < .001) and lymphomas (O/E, 8.7; P = .03) was observed. Survival from the advent of systemic therapy for HCL was better than before this time (P = .0009). Nevertheless, mortality remained excessive (O/E, 6.17; P < .001), mainly because of HCL-related infections and secondary malignancy. CONCLUSION: Among 350 patients with HCL, there was an increase in the number of second cancers; however, it did not reach statistical significance and was not associated with therapy. The incidence of lymphoid neoplasms was significantly higher than expected. Survival since the advent of effective systemic therapy was excellent, although excess mortality was still observed.
Adult↗
Apoptosis in chronic myelogenous leukemia: studies of stage-specific differences.
In this study we compared rates of apoptosis, survival and metabolic activity from CML peripheral blood neutrophils with peripheral blood and bone marrow neutrophils from healthy volunteer donors and studied the influence of the disease stage and of cytokines including G-CSF, GM-CSF and IL-1beta on these parameters. Quantification of apoptosis by morphology, diphenylamine DNA fragmentation assay and by gel electrophoresis showed similar rates of apoptosis in chronic phase CML and normal peripheral blood neutrophils when the cells were incubated in RPMI + FCS or in serum-free medium. However, there were lower rates of apoptosis in accelerated and blast phase CML neutrophils (p < .001) and in normal bone marrow neutrophils (p < .001) compared to normal peripheral blood neutrophils (incubated in RPMI + FCS). Survival among neutrophils from chronic phase or accelerated/blast phase CML patients was significantly longer (p < 0.002 and p < 0.001, respectively) than among normal peripheral blood neutrophils but neutrophils purified from normal bone marrow had a survival rate which fell between that of normal peripheral blood and chronic phase CML patients. When the cells were incubated in RPMI + autologous sera, neutrophils from chronic phase CML patients showed markedly lower rates of apoptosis (p < 0.001) and maintained higher metabolic activities (p < 0.002) compared to normal neutrophils. G-CSF and GM-CSF were found to considerably decrease the rate of apoptosis in chronic phase CML neutrophils (p < 0.001 and p = 0.008 respectively) while IL-1beta did not show any antiapoptotic effect. It is suggested that the endogenous production of growth factors may therefore participate in delaying apoptotic cell death, during the progression of CML.
Adult↗
Role of interleukin-1 beta converting enzyme (ICE) in acute myelogenous leukemia cell proliferation and programmed cell death.
The proinflammatory cytokine interleukin (IL)-1 has been shown to play a pivotal role in stimulating acute myelogenous leukemia (AML) cell proliferation. The gene for its prominent IL-1 beta form produces a 31-kDa precursor protein (pro-IL-1 beta) that is biologically inactive unless cleaved to its mature form by a cytoplasmic cysteine protease termed Il- 1 beta converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investigators have demonstrated that ICE shares sequence homology with the protein product of ced-3, the gene for cell death of the nematode Caenorhabditis elegans, and induces apoptosis in different experimental models. It was therefore hypothesized that ICE may either augment the production of mature IL-1 beta and stimulate the proliferation of cells, in which IL-1 beta acts as an autocrine growth factor, or induce apoptosis. Recent data indicate that ICE is a member of an increasingly recognized family of cysteine proteases. Unlike ICE, the other members of this family do not cleave pro-IL-1 beta but are effective inducers of apoptotic cell death, whereas ICE acts primarily as an IL-1 beta converting enzyme. Because IL-1 beta serves as either an autocrine or paracrine growth factor in AML, we recently investigated the effect of ICE inhibition on AML colony growth and found that ICE inhibition reduced the production of mature IL-1 beta and suppressed AML progenitor proliferation. Our data suggest that ICE does not function as an apoptosis gene in AML but rather increases mature Il-1 beta production and AML cell proliferation. It is possible, therefore, that ICE inhibitors may be beneficial in AML therapy.
Animals↗
Chronic myelogenous leukemia--progress at the M. D. Anderson Cancer Center over the past two decades and future directions: first Emil J Freireich Award Lecture.
The purpose of this study was to review the progress in clinical and translational research in chronic myelogenous leukemia (CML) over the past 20 years at M.D. Anderson Cancer Center. The CML database updating the clinical and basic research investigations was reviewed as the source of this report. Publications resulting from these investigations were summarized. The long-term results with intensive chemotherapy, IFN-alpha therapy alone or in combination, autologous stem cell transplantation, and new agents such as homoharringtonine and decitabine showed encouraging results. Biological studies related to the BCR-ABL molecular abnormality, other molecular events, and the detection of minimal residual disease were detailed. Future strategies with potential promise in CML were outlined. Significant progress in understanding CML biology and in treating patients afflicted with the disease has occurred. Several therapeutic and research tools are currently investigated, which should hopefully improve further the prognosis of patients with CML.
Antineoplastic Agents↗
Decitabine studies in chronic and acute myelogenous leukemia.
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Adult↗
Cost-effectiveness of interferon-alpha and conventional chemotherapy in chronic myelogenous leukemia.
OBJECTIVE: To compare the cost-effectiveness of interferon-alpha with that of hydroxyurea as initial therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase. DESIGN: A decision analysis and Markov model that described the natural history of the therapeutic process. The Markov model contained two treatment arms (interferon-alpha and hydroxyurea) and eight states of health (complete hematologic remission with cytogenetic response, complete hematologic remission without cytogenetic response, partial hematologic remission, chronic phase without hematologic remission, accelerated phase, blast crisis, bone marrow transplantation, and death). Probabilities, costs, and utilities were obtained from published clinical studies and clinical investigators. MEASUREMENT: Quality-adjusted years of life saved and costs and qualities discounted at 5% per year. SETTING: University medical centers in North America and Europe. PATIENTS: Meta-analysis of results from patients studied in clinical trials. RESULTS: The model's predictions of median survival (69 months with interferon-alpha therapy and 58 months with hydroxyurea therapy) were derived from data in the recent literature. In patients 50 years of age, interferon-alpha improved life expectancy over hydroxyurea by approximately 18 months. The marginal cost-effectiveness of interferon-alpha (incremental discounted cost of interferon-alpha compared with that of conventional therapy) was $34800 per quality-adjusted year of life saved. The model was sensitive to the monthly cost of interferon-alpha therapy (if the cost of interferon-alpha is reduced by one third, the cost-effectiveness becomes $19300 per quality-adjusted year of life saved) but was not particularly sensitive to the costs associated with blast crisis or bone marrow transplantation. The other significant variable was quality of life during therapy with interferon-alpha; when this measure was varied from 70% to 100% of the quality of life during hydroxyurea therapy, cost-effectiveness changed from $123200 to $25620 per quality-adjusted year of life saved. When the quality of life associated with interferon-alpha was less than 62% of the quality of life associated with hydroxyurea, the discounted quality-adjusted life expectancy with interferon-alpha was less than that with hydroxyurea. CONCLUSION: Compared with hydroxyurea, interferon-alpha is, in most clinical scenarios, a cost-effective initial therapy for patients with chronic-phase CML who can tolerate the drug.
Antineoplastic Agents↗
Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways.
Leukemia-inhibitory factor (LIF) is an inflammatory cytokine with pleiotropic activities. LIF was originally described as a differentiation factor of a murine leukemia cell line and was subsequently found to possess a broad spectrum of biological functions. Although LIF has been extensively studied in the hematopoietic system, little is known about its effects in solid tumors. We investigated the role of LIF in breast, kidney and prostate cancers. Using a clonogenic assay, we found that LIF significantly stimulated proliferation of 2 estrogen receptor-positive breast cancer cell lines (MCF-7 and T47-D) in a dose-dependent fashion at concentrations ranging from 10 to 200 ng/ml. This effect was observed both in the presence of FCS and under serum- and estrogen-free culture conditions, suggesting that the effect of LIF is direct and does not depend on estrogen or any other cytokine. Neither line produced LIF protein, as assessed by ELISA. In contrast, the estrogen receptor-negative breast cancer line MDA MB-231 produced LIF but did not respond to either LIF or its neutralizing antibodies. Similarly, increasing concentrations of LIF did not affect the growth of primary kidney (A-498), metastatic kidney (ACHN) and prostate (DU 145) cancer cell lines. These lines produce LIF, however, and antibodies to LIF significantly suppressed their proliferation, suggesting that they were maximally stimulated by the endogenously produced cytokine. Taken together, our data suggest that LIF acts as either a paracrine or an autocrine growth factor for breast, kidney and prostate cancers.
Breast Neoplasms↗
Treatment of myelogenous leukemia: current status and investigational options.
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Antineoplastic Agents↗
Chromatin nucleoprotein complexes containing tightly bound c-abl, p53 and bcl-2 gene sequences: correlation with progression of chronic myelogenous leukemia.
We previously developed a technique to isolate subchromatin nucleoprotein complexes (NPC) that contain tightly bound genes and enzymatic activities. NPC fractions (NPCF) were prepared by directly treating isolated nuclei with MspI to generate six NPCF (S1, M1, S2, M2, 0.1K and R). The NPCF have been used to predict the potential efficacy of interferon-alpha (IFN-alpha) treatment in patients with chronic myelogenous leukemia (CML) [Nicolson et al., Gene 159 (1995) 105-111]. Here the NPCF were probed for the presence of tightly bound c-abl, p53 and bcl-2 genes. We found that the NPCF isolated from the nuclei of leukocytes of normal individuals rarely contained detectable quantities of tightly-bound c-abl, p53 or blc-2 genes or gene sequences, whereas in CML nuclei these genes were often found in tight association with multiple NPCF. Examination of NPCF isolated from the leukocyte nuclei from patients with highly progressive CML for the presence of the three genes revealed that more NPCF contained the three tightly-bound genes than leukocyte NPCF from patients with stable or less progressed CML. These data suggest that as CML progresses to more malignant states, oncogenes, suppressor genes and apoptosis-associated genes become tightly associated with NPCF.
Adult↗