Biomedical subjects

Francis Giles

Publications and source records attributed to Francis Giles.

At least 37 records · Page 2Linked to original sources

PubMed2006

Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome.

BACKGROUND: Elderly patients (age > or = 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I-II studies, low-intensity regimens, or 'targeted' therapies. However, baseline expectations for outcomes of elderly AML with 'standard' AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated. METHODS: A total of 998 patients age > or = 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods. RESULTS: The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age > or = 75 years, unfavorable karyotypes (often complex), poor performance (3-4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50-55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25-30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%. CONCLUSIONS: Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups.

Age Factors↗

PubMed2006

Pregnancy among patients with chronic myeloid leukemia treated with imatinib.

PURPOSE: Imatinib has potential teratogenicity in animals, but the effect of exposure to imatinib during conception and pregnancy in humans is not known. PATIENTS AND METHODS: The records of all patients with chronic myeloid leukemia (CML) treated with imatinib were reviewed. We report the experience on 19 pregnancies involving 18 patients (10 females and eight males) who conceived while receiving imatinib for the treatment of CML. RESULTS: All female patients discontinued therapy immediately on recognition of pregnancy. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 babies had minor abnormalities at or shortly after birth (hypospadias in one baby and rotation of small intestine in one baby) that were surgically repaired. All babies have continued normal growth and development. Among female patients who interrupted therapy, five of nine in complete hematologic remission (CHR) at the time of treatment interruption eventually lost CHR, and six experienced an increase in Philadelphia chromosome-positive metaphases. At a median of 18 months after resuming therapy with imatinib, eight patients had a cytogenetic response (complete in three patients). CONCLUSION: Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Patients receiving imatinib should be advised to practice adequate contraception.

Abortion, Spontaneous↗

PubMed2006

A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens.

BACKGROUND: Combining therapeutics with single-agent activity has improved treatment for patients with many malignancies. Debate continues about the impact of treatment on survival in patients with chronic lymphocytic leukemia (CLL). Purine analogues are the most active agents for treatment of patients with CLL. Recently, it was shown that a chemoimmunotherapy regimen combining fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) was very effective in treating patients with recurrent and/or refractory CLL. The objective of the current analysis was to determine whether improvements in treatment have had an impact on survival for patients with CLL. METHODS: Three nonoverlapping, sequential groups of patients enrolled on Phase II studies who received treatment with F (n = 251 patients), FC (n = 111 patients), or FCR (n = 143 patients) were analyzed. Pretreatment characteristics, responses to treatment, and overall survival were compared. RESULTS: Patients who were treated with FCR had a higher complete remission rate compared with patients who were treated with combined F and C or with F alone. Statistically significantly longer estimated median survival was noted for patients who received FCR. A Cox proportional hazards, multivariable model for overall survival that included all patients (n = 505) showed that patients who received FCR had longer survival (P < 0.0001) after adjusting for other significant (P < 0.05) pretreatment characteristics, including age, hemoglobin, beta-2 microglobulin, and the number of prior treatments. CONCLUSIONS: The results of this retrospective comparison of patients with recurrent and refractory CLL indicated a higher complete remission rate and the longest estimated survival for patients who were treated with FCR, providing the basis for randomized clinical trials of this regimen.

Adult↗

PubMed2006

Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.

BACKGROUND: Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models. METHODS: In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon-alpha and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks). RESULTS: Two patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade > or = 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments. CONCLUSIONS: Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib.

Adult↗

PubMed2006

Arsenic derivatives in hematologic malignancies: a role beyond acute promyelocytic leukemia?

The importance of arsenic trioxide (As2O3) has been underscored over the last decade due to its efficacy against acute promyelocytic leukemia (APL), a disease in which this agent has been associated with complete hematologic and molecular remission rates of 87% and 83%, respectively. The different molecular mechanisms of action of As2O3 suggest its applicability in hematologic malignancies other than APL. However, responses obtained thus far have consisted of improvements in signs and symptoms without the elimination of a given disease. Toxicities derived from As2O3 are significant but manageable and reversible. However, the risk/benefit ratio of As2O3 in hematologic malignancies other than APL is still unclear. The development of new generations of orally bioavailable inorganic, as well as new organic, arsenic compounds with improved toxicity profiles may bolster the therapeutic application of arsenic derivatives in hematologic malignancies such as leukemia, multiple myeloma and myelodysplastic syndromes.

Administration, Oral↗

PubMed2006

Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders.

The conventional management of patients with high-risk Philadelphia chromosome-negative (Ph-negative) myeloproliferative disorders (MPDs) revolves around the administration of cytoreductive agents such as hydroxyurea, anagrelide, and recombinant human interferon alpha (IFN-alpha). IFN-alpha has shown significant activity in the treatment of chronic myelogenous leukemia (CML) and Ph-negative MDPs. However, the response rates of IFN-alpha therapy frequently have been hampered by high dropout rates due to side effects and inconvenient dosing schedules. Pegylated (PEG) IFN-alpha is formulated by covalently attaching polymers of ethylene glycol of large molecular weight to the native IFN-alpha molecule. Such chemical modification increases serum half-life, decreases renal excretion, and results in prolonged patient exposure to PEG-IFN-alpha, thus allowing for weekly administration while maintaining acceptable toxicity, tolerability, and activity profiles. The lack of adequate therapies for patients with MPDs and the superior pharmacokinetic and pharmacodynamic profile of PEG-IFN-alpha relative to standard IFN-alpha has prompted the investigation of the activity and safety of PEG-IFN-alpha in patients with essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis. We summarize the available data on the use of PEG-IFN-alpha in patients with Ph-negative MPDs.

Antineoplastic Agents↗

PubMed2006

Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse.

In order to validate the European Prognostic Index (EPI) for patients <or=60 years with acute myeloid leukaemia in first relapse, a cohort of 599 such patients, treated between 1980 and 2004 at the MD Anderson Cancer Center, were assessed using this prognostic index. Three risk groups were defined: favourable, 76 patients (13%) [Overall survival (OS), 64% at 1 year, 22% at 5 years]; intermediate, 137 patients (23%) (OS, 38% at 1 year, 12% at 5 years); and poor, 386 patients (64%) (OS, 17% at 1 year 6% at 5 years). The EPI is reproducible and useful.

Acute Disease↗

PubMed2006

Advances in the therapy of chronic idiopathic myelofibrosis.

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.

Antineoplastic Agents↗

PubMed2005

Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.

PURPOSE: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. DESIGN: Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. RESULTS: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. CONCLUSION: The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.

Adult↗

PubMed2005

AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells.

BACKGROUND: Previous studies have shown that patients with Bcr-Abl-positive acute lymphoblastic leukemia (ALL) either have primary disease that is refractory to imatinib mesylate or develop disease recurrence after an initial response. METHODS: The authors investigated the effects of a newly designed Bcr-Abl inhibitor, AMN107, by comparing its in vitro inhibitory potency on p190 Bcr-Abl ALL cell lines with that of imatinib. RESULTS: In two Philadelphia (Ph)-positive ALL cell lines, AMN107 was found to be 30-40 times more potent than imatinib in inhibiting cellular proliferation. AMN107 was also more effective than imatinib in inhibiting phosphorylation of p190 Bcr-Abl tyrosine kinase in cell lines and primary ALL cells. The inhibition of cellular proliferation was associated with the induction of apoptosis in only one of the cell lines. No activity was observed in cell lines lacking the BCR-ABL genotype. CONCLUSIONS: The results of the current study suggest the superior potency of AMN107 compared with imatinib in Ph-positive ALL and support clinical trials of AMN107 in patients with Ph-positive ALL.

Antineoplastic Agents↗

PubMed2005

Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain.

Activating mutations in the FLT3 tyrosine kinase (TK) occur in approximately 35% of patients with acute myeloid leukemia (AML). Therefore, targeting mutated FLT3 is an attractive therapeutic strategy, and early clinical trials testing FLT3 TK inhibitors (TKI) showed measurable clinical responses. Most of these responses were transient; however, in a subset of patients blast recurrence was preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is unclear but is of major significance for the development of future therapeutic strategies. We searched for mechanisms of resistance in 6 patients with AML who had relapses upon PKC412 treatment. In an index AML patient, an algorithm of analyses was applied using clinical material. In vivo and in vitro investigation of primary blasts at relapse revealed persistent TK phosphorylation of FLT3 despite sufficient PKC412 serum levels. Through additional molecular analyses, we identified a single amino acid substitution at position 676 (N676K) within the FLT3 kinase domain as the sole cause of resistance to PKC412 in this patient. Reconstitution experiments expressing the N676K mutant in 32D cells demonstrated that FLT3-ITD-N676K was sufficient to confer an intermediate level of resistance to PKC412 in vitro. These studies point out that a genetically complex malignancy such as AML may retain dependence on a single oncogenic signal.

Acute Disease↗

PubMed2005

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center.

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.

Adult↗

PubMed2005

Significance of myelofibrosis in early chronic-phase, chronic myelogenous leukemia on imatinib mesylate therapy.

BACKGROUND: Myelofibrosis is associated historically with a poor prognosis in patients with chronic myelogenous leukemia (CML). Its significance in the recent era of effective therapy with imatinib mesylate is unknown. METHODS: The current study evaluated the significance of the degree of pretreatment myelofibrosis on response and survival with imatinib therapy in patients with newly diagnosed CML. The study group comprised 198 patients with newly diagnosed Philadelphia chromosome-positive, chronic-phase CML treated with imatinib mesylate therapy. They were analyzed for the prognostic significance of bone marrow reticulin fibrosis. RESULTS: Severe reticulin (Grade 3-4) fibrosis was observed in 75 patients (38%): Grade 3 in 46 (23%) patients and Grade 4 in 29 (15%) patients. There was a trend towards a lower incidence of a complete cytogenetic response in patients with Grade 4 reticulin fibrosis (76% vs. 89%; P = 0.07), and a significantly worse survival (estimated 3-year survival rate of 87% vs. 97%; P = 0.04). CONCLUSIONS: Although the prognostic significance of severe reticulin fibrosis in patients with newly diagnosed CML receiving imatinib therapy was better, 15% of patients with Grade 4 reticulin fibrosis still had a worse outcome.

Adolescent↗

PubMed2005

2-Chlorodeoxyadenosine and cytarabine combination therapy for idiopathic hypereosinophilic syndrome.

BACKGROUND: Hypereosinophilic syndrome (HES) is a rare, disabling, and incurable disease. In this study, a combination of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (ara-C) chemotherapy was evaluated in patients with HES. METHODS: Nine patients with HES were treated with ara-C (1 g/m(2)) given intravenously over 2 hours at 0 hours, 48 hours, 72 hours, 96 hours, and 120 hours; and 2-CdA (12 mg/m(2) per day) was given as a continuous intravenous infusion over 5 days starting at 24 hours. A second course of the same therapy was administered in patients who had a response. RESULTS: All patients had signs and symptoms of end-organ involvement. The median time from diagnosis to therapy was 25 months. Seven patients had received prior therapies. Five patients (55%) achieved a complete remission (CR), 1 after receiving 2 courses of therapy. Elimination of eosinophilia was accompanied by the resolution of symptoms. The median disease-free survival and overall survival after the diagnosis for patients who achieved CR was 26 months and 44 months, respectively. Treatment was tolerated well. Febrile neutropenia occurred in 28% of the 14 courses that were given. The median time to recovery from neutropenia and thrombocytopenia was 17 days and 39 days, respectively. CONCLUSIONS: The combined 2-CdA and ara-C chemotherapy regimen had activity in patients with HES.

Adolescent↗

PubMed2005

Outcome of patients with acute myelogenous leukemia after second salvage therapy.

BACKGROUND: Although the prognosis is poor for patients with acute myelogenous leukemia (AML) who have disease recurrence after frontline therapy, this is a general reflection of first salvage therapies. The outcome of patients undergoing second salvage therapy in relation to complete response (CR) rates and survival has not been documented. The authors analyzed the outcome of patients with AML undergoing second salvage therapy, and identified prognostic factors associated with response and survival. METHODS: The records of 594 patients with AML undergoing second salvage therapy from 1980 until 2004 were reviewed. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT) in 74 patients, standard-dose cytosine arabinoside (ara-C) combinations in 30 patients, high-dose ara-C combinations in 171 patients, non-ara-C combinations in 73 patients, and Phase I-II single agents in 246 patients. RESULTS: Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration < 6 months; second CR duration < 6 months; salvage therapy not including allogeneic SCT; non-inversion 16 AML; platelet counts < 50 x 10(9)/L, and leukocytosis > 50 x 10(9)/L. Patients were divided into low-risk (1-2 adverse factors; 8%), intermediate 1 (3 factors; 20%), intermediate 2 (4 factors; 38%), and high-risk groups (5-6 factors; 33%) with respective CR rates of 54%, 26%, 8%, and 0%. The respective 1-year survival rates were 36%, 21%, 6%, and 1%. A multivariate analysis for survival identified the following 7 independent adverse factors: first CR duration < 12 months; second CR duration < 6 months; bilirubin level > or = 1 mg/dL; albumin level < 3 g/dL; age > 60 years; bone marrow blasts > or = 50%; and year of therapy before 1991. Patients were divided into low-risk (0-2 adverse factors; 39%), intermediate (3 factors; 27%), and high-risk groups (> or = 4 factors; 34%) with estimated 1-year survival rates of 22%, 6%, and 0%, respectively. The respective CR rates were 26%, 8%, and 2%. CONCLUSIONS: The current analysis established the outcome and prognostic factors associated with second salvage therapy in AML. It also proposed risk models and groups that could be used for comparison of results of present and future investigational strategies.

Adolescent↗

PubMed2005

AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia.

Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.

Animals↗

PubMed2005

Interferon alpha therapy for patients with essential thrombocythemia: final results of a phase II study initiated in 1986.

BACKGROUND: In 1986, a Phase II trial of recombinant interferon-alpha (IFN-alpha) was initiated as therapy for patients with essential thrombocythemia (ET). METHODS: Patients were treated with subcutaneous IFN-alpha at a dose of 5 x 10(6) units/m(2) daily. In responding patients, the therapy lasted at least 3 years. RESULTS: Twenty-three patients (14 females and 9 males; median age, 41 years; age range, 20-63 years) with a median platelet count of 1350 x 10(9)/L were treated. After a median follow-up of 174 months (14.5 years), 15 of 20 evaluable patients (75%) responded, including 14 patients who achieved a complete hematologic response (CHR) (6 of them with bone marrow remission) and 1 patient who demonstrated a partial response. The median time to response was 6 months (range, 0.5-36 months), and the median response duration was 48 months (range, 5-114 months). Seven patients who achieved a CHR and were taken off therapy after they completed 3 years of maintenance therapy sustained their response for a median of 28 months. No symptoms or signs of thrombosis or hemorrhage were observed in responding patients. Eleven of 14 patients (78%) who achieved a CHR developed a recurrence, and 2 of 5 patients with recurrences who were rechallenged with IFN-alpha achieved a second response. The treatment was tolerated relatively well. CONCLUSIONS: IFN-alpha was safe and effective therapy for patients with ET, and the ability of IFN-alpha to reverse disease pathology and possibly modify the clinical course of patients with ET warrants its investigation in larger, prospective trials.

Adult↗

PubMed2005

Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience.

BACKGROUND: The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown. The objectives of this study were to update the long-term experience with imatinib in patients who had accelerated-phase CML and to compare outcomes with historic experience. METHODS: The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated-phase CML who received treatment with interferon-alpha or with other modalities. RESULTS: With imatinib, the complete hematologic response rate was 82% versus a rate < or = 50% for others, and the complete cytogenetic response rate was 43% versus rates of 0-6% for others. The estimated 4-year survival rates were 53% with imatinib, 42% with interferon-alpha, and 0-21% for others. A multivariate analysis of the total population of 389 patients indicated that imatinib therapy (vs. other therapies) was an independent, favorable prognostic factor for survival (P < 0.0001; hazard rate, 0.62). A subset analysis that included only patients who were treated with imatinib and interferon-alpha (276 patients) also identified imatinib as an independent favorable prognostic factor (P < 0.0001; hazard rate, 0.65). The 3-month cytogenetic response to imatinib was associated with significantly different survival outcomes (P < 0.0001). A multivariate analysis that included pretreatment characteristics and 3-month cytogenetic response among 150 patients who received imatinib and were alive at 3 months identified only 2 adverse independent prognostic factors: lack of a cytogenetic response at 3 months (P < 0.001) and anemia (hemoglobin < 10 g/dL; P = 0.003). Patients who had neither factor (41%) had an estimated 4-year survival rate of 88%; in the other patients, the 4-year survival rate was < or = 60%. This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5-year survival were 25-30%. CONCLUSIONS: The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated-phase CML.

Adult↗