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PubMed2003

Towards combination target-directed chemotherapy for chronic myeloid leukemia: role of farnesyl transferase inhibitors.

Chronic myeloid leukemia (CML) is arguably the best understood of all human malignancies. Its origins in the hematopoietic stem cell can be traced to a reciprocal translocation involving chromosomes 9 and 22, dubbed the Philadelphia chromosome, which is observed in essentially all patients. The resulting fusion gene, BCR/ABL, encodes an activated tyrosine kinase that can act alone to induce a CML-like syndrome in mouse models. These animal models have validated BCR/ABL as a target for the development of specific pharmaceutical inhibitors. The kinase inhibitor imatinib mesylate (Gleevec) is highly specific, effective, and minimally toxic, but may not effect cures as a single agent, particularly in patients with accelerated and blast-phase disease. Resistance to imatinib can confound therapy. Surprisingly, a high percentage of resistant cases manifest intact or augmented BCR/ABL signaling, suggesting that this oncoprotein, or signaling pathways emanating from it, remain viable targets. Combination chemotherapy is under active investigation, and among the most compelling strategies is dual treatment with agents that both target BCR/ABL signal transduction. BCR/ABL activates Ras, and compounds designed to antagonize Ras function called farnesyl transferase inhibitors (FTIs) have shown potent activity in vitro and in animal models of BCR/ABL-induced leukemia. Initial clinical trials in patients with refractory acute myeloid leukemia and CML in blast crisis have shown significant activity, suggesting that trials combining imatinib and FTIs are warranted.

Alkyl and Aryl Transferases↗

PubMed2005

Imatinib mesylate in Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon alpha.

Imatinib mesylate (STI 571; Glivec) is a potent and selective tyrosine kinase inhibitor. The introduction of imatinib has chanced the philosophy of mechanisms of cancer therapy and already changed current management of patients with chronic myeloid leukemia (CML). A total of 49 patients with later chronic phase CML in whom previous therapy with interferon alpha had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for hematologic and cytogenetic responses. Time to progression, survival, and toxic effects were also evaluated. Complete hematologic responses were reported for 48 of 49 patients studied (98 percent). The median time to a complete hematologic response was 1.2 month; 89% of patients who had a response did so within 4 months. Imatinib induced major cytogenetic responses in 73%; 62% had a complete responses. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 98% of patients, and 100 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were manageable. No one of patients discontinued treatment due to of drug-related adverse events, and no treatment-related deaths occurred. The results of current study indicate that imatinib has a significant therapy benefit in CML patients in whom treatment with IFN alpha had failed. Therefore, has favorably changed the prognosis for patients with chronic myelogenous leukemia.

Administration, Oral↗

PubMed1996

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↗

PubMed1987

Uracil-DNA glycosylase activity in human acute leukemia.

The expression of the DNA excision repair enzyme uracil-DNA glycosylase was investigated in bone marrow and peripheral samples from seven patients with acute lymphoblastic leukemia (ALL), from 17 patients with acute non-lymphocytic leukemia (ANLL), and from one patient with chronic granulocytic leukemia (CGL) in blast crisis. In addition, uracil-DNA glycosylase activities were determined in nine human leukemia/lymphoma cell lines. There was a clear correlation between the percentage of blast cells and the enzyme activity when mononuclear cell fractions from patient samples were analysed. The following uracil-DNA glycosylase activities were recorded (mean +/- S.D., number of samples): ALL = 45.6 +/- 14.8 U/mg of protein, N = 10; ANLL = 41.1 +/- 13.8 U/mg of protein, N = 22; CGL (blast crisis) = 44.7 U/mg of protein. The uracil-DNA glycosylase activity in nine human leukemia/lymphoma cell lines ranged from 35.2 to 66.0 U/mg of protein, and no striking differences were observed between the T-ALL, B-ALL, null cell ALL or myeloid lines. Similarly, the various biological features, such as the common ALL surface antigen, the terminal deoxynucleotidyl transferase enzyme, the sub-type of leukemia, chromosomal aberrations, or previous chemotherapy, did not apparently affect the expression of uracil-DNA glycosylase. We propose that the integrity of the genetic information is well protected by uracil-DNA glycosylase in different forms of leukemia, including cases with a low proportion of S-phase blasts, as assessed by flow cytometry in the present work. When compared to the activities in benign hematopoietic progenitor cells, studied previously in this laboratory, no big differences between the benign and malignant hematopoiesis were demonstrated. Hence, it is unlikely that selectivity of chemotherapy towards malignant vs benign hematopoietic growth could be based on the enzyme uracil-DNA glycosylase.

Cell Line↗

PubMed1996

Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: direct comparison of cytotoxicity and cellular Ara-C uptake enhancement.

This study was designed to compare the effects of fludarabine and gemcitabine on cytosine arabinoside (Ara-C) uptake and retention, and their specific cytotoxicity on HL 60 human acute myeloid leukemia cells. The leukemic blasts were exposed to either drug at equimolar concentrations (10 microM) for 3 h and further incubated with Ara-C (5 microM), added immediately (day 0) or after an interval of 24 h in cells were kept in a drug free medium (day 1). On day 0, leukemic cells exposed to fludarabine 10 microM had a significant (P<0.01) increase in Ara-C uptake (297 +/- 11 pmol/10(7) cells) with respect to control cells (not pre-treated: 195 +/- 10 pmol/10 (7) cells). After treatment of leukemic cells with fludarabine, cytoplasmic Ara-C peaked after 180 min of exposure, as well as nuclear bound Ara-C. At the same time, a significant decrease in the number of S-phase leukemic cells, consistent with depressed [3 H]TdR uptake was observed. Although on day 0 gemcitabine 10 microM did not have potentiating effects on Ara-C uptake, it showed a high degree of intrinsic cytotoxicity as a single agent(clear from cell cycle distribution, [3H]TdR uptake, plating efficiency (PE) data and percentage of apoptotic cells). Cells exposed to gemcitabine, on the other hand, showed on day 1 a significant increase in Ara-C uptake (2.4 x control values in the cytoplasmic and 3x in the nuclear fractions) and a reduced number of S-phase blasts, [3H]TdR uptake and PEs, as well as an increased apoptotic cell death. Evidently, it is possible to modulate Ara-C uptake by leukemic cells with gemcitabine. Although this effect is similar to that demonstrated with fludarabine, its kinetics and time of efficacy are different and also, because of its intrinsic higher cytoxicity and lack of important side effects, gemcitabine could be considered a suitable candidate for Ara-C association therapy in acute leukemia.

Antimetabolites, Antineoplastic↗

PubMed2000

Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML.

The human t(3;21)(q26;q22) translocation is found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in therapy-related myelodysplasia and acute myelogenous leukemia. One result of this translocation is a fusion between the AML1, MDS1, and EVI1 genes, which encodes a transcription factor of approximately 200 kDa. The role of the AML1/MDS1/EVI1 (AME) fusion gene in leukemogenesis is largely unknown. In this study, we analyzed the effect of the AME fusion gene in vivo by expressing it in mouse bone marrow cells via retroviral transduction. We found that mice transplanted with AME-transduced bone marrow cells suffered from an acute myelogenous leukemia (AML) 5-13 mo after transplantation. The disease could be readily transferred into secondary recipients with a much shorter latency. Morphological analysis of peripheral blood and bone marrow smears demonstrated the presence of myeloid blast cells and differentiated but immature cells of both myelocytic and monocytic lineages. Cytochemical and flow cytometric analysis confirmed that these mice had a disease similar to the human acute myelomonocytic leukemia. This murine model for AME-induced AML will help dissect the molecular mechanism of AML and the molecular biology of the AML1, MDS1, and EVI1 genes.

Animals↗

PubMed2004

Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

OBJECTIVES: To evaluate the effectiveness of imatinib as first-line treatment for chronic myeloid leukaemia (CML) compared with interferon-alpha (IFN-alpha), hydroxyurea and bone marrow transplantation (BMT), and the cost-effectiveness of imatinib compared with IFN-alpha and hydroxyurea. DATA SOURCES: Electronic databases. REVIEW METHODS: Selected studies and full-text articles were screened and rigorously selected. Survival was the key outcome measure. Surrogate outcome measures included haematological (blood) response and cytogenetic (bone marrow) response (CR). As no published cost-effectiveness studies were found that compared imatinib and IFN-alpha, an independent Markov model was constructed and this was compared with models submitted to the National Institute for Clinical Excellence by the manufacturer of imatinib. RESULTS: Intention-to-treat analysis showed that imatinib was associated with complete CR at 12 months follow-up of 68% compared with 20% for the IFN-alpha plus Ara-C group. The estimated proportion of people taking imatinib who had not progressed to accelerated or blast phases at 12 months was 98.5%, and 93.1% for IFN-alpha plus Ara-C. Overall survival was not statistically significantly different. Withdrawal due to side-effects was 2% for imatinib and 5.6% for IFN-alpha plus Ara-C. Cross-over due to intolerance was 0.7% and 22.8% for imatinib and for IFN-alpha plus Ara-C, respectively. Quality of life was better in the imatinib group than the IFN-alpha group when assessed at 1, 3 and 6 months. Median survival across the four IFN-alpha versus hydroxyurea studies was 66 and 56.2 months, respectively. Median complete CR was 6% for IFN-alpha and 0 for hydroxyurea. Median withdrawal due to side-effects was 24% and 4% for IFN-alpha and hydroxyurea, respectively. Four out of the five studies comparing BMT and IFN-alpha showed a long-term survival advantage for BMT over IFN-alpha, but a short-term disadvantage. In four of the five studies comparing BMT and IFN-alpha, median survival had not yet been reached in the BMT groups in 6--10 years. Median survival in the IFN-alpha arms ranged from 5.2 to 7 years. The BMT group gained a survival advantage over IFN-alpha at 3--5.5 years. In the BMT group death due to transplant-related complications ranged from 36 to 45%. The incremental cost-effectiveness ratio (ICER) of imatinib compared with IFN-alpha from the independent model was GBP26,180 per quality-adjusted-life-years (QALY) gained and was relatively robust. Imatinib was less cost-effective than hydroxyurea with an ICER of GBP86,934. CONCLUSIONS: Imatinib appears to be more effective than current standard drug treatments in terms of cytogenetic response and progression-free survival, with fewer side-effects. However, there is uncertainty concerning longer term outcomes, the development of resistance to imatinib, the duration of response and the place of imatinib relative to BMT. New issues are continually arising, such as optimal management pathways and combination therapies. Recommendations for research include: long-term follow-up data from the first- and second-line imatinib trials; investigation into specific subgroups, e.g. high-risk patients, the elderly, children or those eligible for BMT; long-term comparisons of imatinib with BMT performed in early stages of CML; the use of imatinib in combination with other therapies, and further detailed economic studies. Investigation of the impact of CML and imatinib on quality of life is also important.

Antineoplastic Agents↗

PubMed1999

Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and clinical significance.

We investigated the significance of p185BCR/ABL expression in patients with chronic myelogenous leukaemia (CML) in relation to disease features, therapy and outcome. Results of Western blot analysis for 1384 patients referred with a diagnosis of CML to our institution from 1989 to 1997 were reviewed. Clinical characteristics, results of cytogenetic analysis and RT-PCR for BCR rearrangement were analysed. Five patients with Ph-positive CML expressing the p185BCR/ABL hybrid protein were identified. By RT-PCR, bone marrow specimens of these patients were confirmed to have an e1a2 junction. The median age at diagnosis of these patients was 55 years (range 43-76). All had elevated white cell counts at diagnosis (median 50 x 109/l, range 11.7-163 x 109/l). Four patients had monocytosis (range 10-16%) with a low neutrophil/monocyte ratio in the peripheral blood (range 3.4-5.7). Patients presented with various stages of the disease (two in chronic-phase CP, two in accelerated-phase AP, and one in blastic-phase BP). The clinical course and therapy of the patients varied, with one patient receiving hydroxyurea only, three patients receiving hydroxyurea followed by interferon-alpha based regimens and bone marrow transplantation. The patient presenting in BP was treated with combination chemotherapy. The clinical outcome of the patients was also varied with one patient alive and in complete remission (with complete cytogenetic remission after transplant) and four patients dead after progression to more advanced stages. We conclude that patients with Ph-positive p185BCR/ABL CML frequently present with monocytosis and a low neutrophil/monocyte ratio in the peripheral blood, aiding the speculation that the presence of the p185BCR/ABL hybrid protein may contribute to a phenotype intermediate between CML and CMML. Of interest, the only other specific clinical feature identified was the absence of splenomegaly in four of five patients. There was no definite association with transformation to lymphoid blast phase.

Adult↗

PubMed1999

Phase I study of liposomal daunorubicin in patients with acute leukemia.

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome; DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m2 on each cycle, to a total dose of 225, 300, 450, and 600 mg/m2, respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3-4) in 3 of 5 patients treated at 200 mg/m2, 2 of 9 treated at 150 mg/m2 and 1 of 6 at 100 mg/m2. Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m2 and has significant anti-leukemia activity.

Acute Disease↗

PubMed2003

Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). Bone marrow histopathology and correlation with genetic status.

We evaluated bone marrow pathologic features and cytogenetic and molecular genetic status of 13 patients with interferon-resistant, chronic-phase chronic myeloid leukemia (CML), treated with imatinib mesylate (Gleevec). All had morphologic evidence of CML in the blood and bone marrow and were positive for bcr-abl by reverse transcriptase-polymerase chain reaction, fluorescence in situ hybridization (FISH), or both. Follow-up marrow biopsies, interphase FISH for bcr-abl, and conventional cytogenetics were performed at 3-month intervals (up to 24 months) after therapy initiation. All patients exhibited a reduction in bone marrow cellularity with decreases in myeloid/erythroid ratios at 3 to 6 months after therapy. The percentage of bcr-abl-positive cells by FISH decreased in all patients (pretherapy median, 73%; 3 months median, 47%). Cytogenetic and FISH data defined 2 groups after 6 months of follow-up: 5 patients became negative for bcr-abl by FISH; 8 remained positive, 4 of whom developed signs of clonal cytogenetic evolution. Patients who became negative for bcr-abl had no morphologic evidence of CML at 15 to 24 months of follow-up, whereas patients who remained positive redeveloped morphologic features of CML as cellularity increased. Some bcr-abl-positive patients showed signs of progression, including 2 patients who developed myeloid blast phase. Although all patients demonstrated an initial decrease in bone marrow cellularity after imatinib mesylate therapy, continued follow-up showed that histopathologic findings correlated with genetic response.

Antineoplastic Agents↗

PubMed1981

Successful engraftment of blood derived normal hemopoietic stem cells in chronic myelogenous leukemia.

The ability of blood-derived stem cells to restore hemopoietic function was investigated in a patient with chronic myelogenous leukemia with bone marrow cells containing the Philadelphia chromosome marker (Ph1+). After treatment with high dose cyclophosphamide, 26.3 X 10(9) blood mononuclear leukocytes, among them 26.2 X 10(5) granulocyte/macrophage progenitor cells (CFUC), were harvested by means of 5 successive leukaphereses when the bone marrow cells had converted to Ph1--. When the patient entered the aggressive phase (blast crisis), myeloablative treatment with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) was given, followed by transfusion of the cryopreserved blood leukocytes. Restoration of marrow and blood cellularity was completed about 20 days after this autologous blood stem cell transplantation (ABSCT). Marrow CTUC recovery was complete 2 weeks after ABSCT, and all karyotypes of the patient's marrow cells were free of the marker chromosome. The patient died of toxicity but with normal bone marrow cellularity. This report confirms the therapeutic usefulness of autologous blood-derived stem cells harvested in remission in restoring hemopoietic function after myeloablative treatment.

Adult↗

PubMed1996

Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia.

Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the determination of cell lineages involved by the Ph chromosome may be used for distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+ ALL (presumably lymphoid-restricted), although others have suggested the term 'stem cell ALL' for the multilineage process. Because it has been difficult to perform lineage studies of the Ph chromosome, we investigated the use of fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22) and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic malignancies. We analyzed routine blood and marrow specimens from eight patients who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the 9;22 translocation, distinguished between the two common molecular variants, and readily identified multilineage vs lymphoblast-restricted disease. In our series, four patients had multilineage and four had lymphoblast-restricted disease. Multilineage disease was associated with morphologic features of CML at diagnosis and/or reversion to chronic phase CML after treatment leading us to consider it as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such findings. The survival of three of our four patients with multilineage disease was prolonged, at 25, 28+, and 126+ months, and when data from our entire series are added to those of 18 previously reported cases that were studied for lineage involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall survival between patients with multilineage and lymphoblast-restricted disease is significant (median overall survival of 47 months vs 8 months, respectively; P=0.013, log rank). Our findings illustrate that FISH analysis can be used to recognize lineage involvement in patients presenting with Ph+ lymphoblastic malignancies, and they provide further support to the notion that multilineage and lymphoblast-restricted disease are distinct clinically as well as biologically.

Adolescent↗

PubMed2002

Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia.

Imatinib mesylate, a specific inhibitor of the BCR-ABL tyrosine kinase, has been very effective in the treatment of chronic myeloid leukemia (CML) in chronic phase with high rates of hematological and cytogenetic remissions. Resistance to therapy can develop and transformation to blast crisis may occur, particularly in patients without a cytogenetic response. We report a case of a patient with CML treated in chronic phase who developed blast crisis; withdrawal of imatinib mesylate resulted in spontaneous reversion to chronic phase.

Aged↗

PubMed1998

Differential growth patterns in SCID mice of patient-derived chronic myelogenous leukemias.

The development of an in vivo model for the study of CML would be of significant importance in studying its biological behavior and developing novel therapeutic strategies. We examined the ability of human leukemic cells derived from patients in either chronic (CP), accelerated (AP) or blast phase (BP) CML to grow and disseminate in CB17-SCID mice by subcutaneous (s.c.) inoculation without conditioning treatment or administration of cytokines. Additionally, samples derived from patients with CP-CML were injected s.c. into CB17-SCID mice treated with anti-Asialo GM1 (an anti-NK cell antibody) and NOD-SCID mice (absent NK cell activity) to study the potential role of NK cell-mediated anti-leukemic activity in preventing the propagation of CP-CML cells. We observed a significant differential growth pattern of CML cells in the mice such that BP-CML grew rapidly as s.c. tumors and disseminated, while AP-CML or CP-CML cells grew temporarily as small nodules that spontaneously regressed and did not disseminate. This differential growth pattern suggests possible important biological differences. Furthermore, no significant difference in s.c. growth or dissemination of CP-CML samples derived from newly diagnosed patients in untreated CB17-SCID mice and CB-17 SCID mice treated with Anti-Asialo GM1 and NOD-SCID mice occurred, suggesting that factors other than NK cell anti-leukemic activity may be important.

Adolescent↗

PubMed1996

Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia.

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Myeloperoxidase cytochemical negativity: an unexpected but intrinsic property of blasts of all phases of chronic myeloid leukemia.

Myeloperoxidase (MPO) cytochemical activity, recognized as a very important hallmark of myeloblasts, is generally negative in chronic myeloid leukemia (CML) blast crisis (BC). Because this finding is unexpected, being not in keeping with the myeloproliferative nature of CML, we tried to ascertain if MPO cytochemical negativity could be an intrinsic property of blasts of CML and hence present in the preblastic phases as well. Myeloperoxidase cytochemistry of peripheral blood blasts in 161 cases of CML, including 103 in chronic phase (CP) and 29 each in accelerated phase (AP) and BC, was assessed and compared with that of 30 cases of acute myeloid leukemia, AML-M2. Blasts of 97 (94.2%) of 103 cases of CP, 28 (96.6%) of 29 cases of AP, and 22 (75.9%) of 29 cases of BC were negative for MPO (<3% MPO-positive blasts). Compared with the strong MPO positivity, both in terms of intensity and proportion, in the AML-M2 cases, the positivity in the CML cases was generally weak and was seen in a small number of blasts (5-15%), except in one case of BC with 20% positive blasts. Absence or, at times, weak MPO cytochemical activity is an intrinsic property of blasts of all phases of CML, and use of the term myeloblast in CML should be understood to refer to a cell with this property. This also explains why MPO cytochemistry, despite its high reputation as a myeloid-lineage marker, generally does not help in CML BC. CML BC should therefore be considered as a possible diagnosis along with acute lymphoblastic leukemia, AML-M0, AML-M7, etc., in the setting of MPO-negative blasts. Similarity between MPO expression pattern in CML, i.e., negative in blasts and positive in the more mature cells, and that during maturation of normal myeloid series of cells shows the deranged myelopoiesis of CML to be undisturbed at least with respect to MPO expression. There is need for a more comprehensive study of blasts of preblastic phases.

Biomarkers, Tumor↗

PubMed2002

Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

Adult↗

PubMed1997

dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53.

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.

Acute Disease↗