Imatinib mesylate (STI571) treatment in patients with chronic-phase chronic myelogenous leukaemia previously submitted to autologous stem cell transplantation

Imatinib mesylate (STI571) is a highly effective and well-tolerated treatment for patients with chronic-phase chronic myeloid leukaemia (CML), but information on its efficacy and tolerance in intensively pretreated patients is scarce. Thirty-three chronic-phase CML patients who were resistant or intolerant to interferon (IFN) and had been previously submitted to autologous stem cell transplantation were treated with imatinib for a median of 14 months (range: 6-19 months). Seven patients were in haematological response (HR) at the start of treatment; the remaining 26 attained a HR at a median of 3 weeks (range: 1-4 weeks). Major cytogenetic response rates at 3, 6 and 12 months were 42%, 45% and 55%, respectively, including 21%, 24% and 33% complete responses. Grade 3-4 neutropenia, thrombocytopenia and anaemia developed in 33%, 27% and 12% of patients respectively. Non-haematological toxicity included superficial oedema (21% of patients), gastrointestinal symptoms (18%), muscle cramps (15%), skin rash and liver enzyme increase (3% each). These results were not significantly different from those in 65 chronic-phase CML patients, resistant or intolerant to interferon without a previous ASCT, who were included in the same protocol. Imatinib mesylate is effective and safe in chronic-phase CML patients with a previous history of intensive treatment.     

Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase

Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.     

Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines

The tyrosine kinase activity of the Bcr/Abl oncogene is required for transformation of hematopoietic cells. The tyrosine kinase inhibitor STI571 (formerly called CGP57148B, Novartis Pharmaceuticals) inhibits BCR/ABL, TEL/ABL, and v-ABL kinase activity and inhibits growth and viability of cells transformed by any of these ABL oncogenes. Here we report the generation of 2 BCR/ABL-positive cell lines that have developed partial resistance to STI571. BCR/ABL-transformed Ba/F3 hematopoietic cells and Philadelphia-positive human K562 cells were cultured in gradually increasing concentrations of STI571 over a period of several months to generate resistant lines. Resistant Ba/F3.p210 cells were found to have an increase in Bcr/Abl messenger RNA, amplification of the Bcr/Abl transgene, and a greater than tenfold increase in the level of BCR/ABL protein. In contrast to Ba/F3.p210 cells, drug-resistant K562 cells did not undergo detectable amplification of the BCR/ABL gene, although they displayed a 2-fold to 3-fold increase in p210BCR/ABL protein. The addition of STI571 to both resistant Ba/F3. p210 and K562 cells resulted in a rapid reduction of tyrosine phosphorylation of cellular proteins, similar to that observed for nonresistant cells. However, the inhibition of kinase activity was transient and partial and was not accompanied by apoptosis. The results suggest that resistance to STI571 may be multifactorial. Increased expression of the target protein BCR/ABL was observed in both lines, and resulted from oncogene amplification in one line. However, altered drug metabolism, transport, or other related mechanisms may also contribute to drug resistance.     

Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease that is often associated with several chromosomal and molecular abnormalities. Patients who have the Philadelphia (Ph) chromosome and associated BCR-ABL1 oncogene have a particularly poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only known curative treatment for Ph+ ALL and facilitating allo-HSCT in eligible patients is a key treatment goal. However, many patients relapse after allo-HSCT, particularly those with measurable residual disease prior to transplantation, and a significant percentage of patients are ineligible for allo-HSCT, particularly older patients. Hence, many patients require additional/alternative therapies to prolong survival. Studies are ongoing to determine the most effective first-line drug regimens for patients who subsequently undergo allo-HSCT and ineligible patients. Tyrosine kinase inhibitors targeted to Bcr-Abl are important novel therapies for Ph+ ALL. Although imatinib administered in combination with chemotherapy is established as the current first-line strategy, relapse is common, even among allo-HSCT recipients. Emerging data indicate that more potent multi-targeted kinase inhibitors (including dasatinib, nilotinib, and bosutinib) have promising efficacy in the first- or second-line setting. Here, the evidence base for existing drug treatments for Ph+ ALL is discussed and emerging therapeutic strategies are explored.     

Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation

The main outcomes of the Programa Español para Tratamiento de Hemopatías (PETHEMA)‐acute lymphoblastic leukaemia (ALL)‐Ph‐08 trial were described and compared with those of the historical PETHEMA‐CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL‐Ph‐08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant‐related mortality observed in the ALL‐Ph‐08 trial resulted in an improved 2‐year event‐free survival (63% vs. 37%, P = 0·009).     

Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph(+)) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m(2). Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1. There were 31 children who received 479 courses of imatinib. The most common toxicities encountered, which occurred in less than 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea, and reversible increases in serum transaminases. One patient at the 440-mg/m(2) dose level had dose-limiting weight gain. There were no other first-course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among 12 chronic myeloid leukemia (CML) patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among 10 acute lymphoblastic leukemia (ALL) patients evaluable for morphologic response, 7 achieved an M1 and 1 achieved an M2 bone marrow. We observed marked interpatient variability in the pharmacokinetic parameters. In conclusion, we found that daily oral imatinib is well tolerated in children at doses ranging from 260 to 570 mg/m(2). Doses of 260 and 340 mg/m(2) provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.     

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.     

Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RARalpha and PML-RARalpha

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c-Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases and is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the cyto-differentiating, growth-inhibitory, and apoptogenic actions of all-trans-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid maturation program set in motion by the retinoid in the PML-RARalpha(+) acute promyelocytic leukemia NB4 and the PML-RARalpha(-) myeloblastic HL60 and U937 cell lines. In addition, STI571 relieves the cyto-differentiation block observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and NB4.007. In NB4 promyelocytes, a RARalpha agonist, but not an RXR agonist, can substitute for ATRA and interact with STI571. By contrast, STI571 is unique among c-Abl-specific tyrosine kinase inhibitors in modulating the pharmacologic activity of ATRA. In NB4 cells, enhanced cyto-differentiation results in increased up-regulation of the expression of a number of genes coding for myeloid differentiation markers, including CD11b, CD11c, and some of the components of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphorylation and retardation of the retinoid-dependent degradation of PML-RARalpha and RARalpha. Stabilization of the 2 retinoic acid receptors is likely to be the result of augmented and accelerated inhibition of the proteasome-dependent proteolytic activity observed on ATRA treatment.     

亲缘异基因造血干细胞移植与STI571治疗慢性粒细胞白血病的临床对比研究

目的：评价对比亲缘异基因造血干细胞移植与酪氨酸激酶抑制剂STI571治疗慢性粒细胞白血病的有效性及安全性。方法：90例慢性粒细胞白血病慢性期患者，分为2组，其中亲缘异基因造血干细胞移植组23例，均采用经典或改良BuCy2方案预处理，短程甲氨蝶呤联合环孢素A（MTX＋CsA）方案预防移植物抗宿主病（GVHD）。STI571组67例，每天应用STI571 400mg，每周复查血常规，每3个月进行骨髓象及细胞遗传学检查，根据血象和骨髓象调整剂量。结果：观察截止时，移植组和STI571组获得细胞遗传学完全缓解率分别为100％和60％（P〈0．01），但移植组和STI571组的2年生存率分别为77．03％和83．33％，2组患者生存率比较差异无统计学意义（P〉0．05）。结论：与异基因造血干细胞移植相比，STI571治疗慢性粒细胞白血病患者治疗相关并发症较少较轻，但获得细胞遗传学完全缓解率较低。     

Early minimal residual disease (MRD) analysis during treatment of Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia with the Abl-tyrosine kinase inhibitor imatinib (STI571)

The Abl kinase inhibitor imatinib mesylate (STI571) has significant and rapid antileukemic activity in Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia (Ph(+) ALL) but such activity is usually of short duration except for a small proportion of patients. To determine the prognostic significance of early Bcr-Abl levels and changes in peripheral blood (PB) and bone marrow (BM), serial samples of 56 patients with relapsed or refractory Ph(+) ALL treated in phase 2 trials of imatinib were analyzed by quantitative polymerase chain reaction (PCR). Imatinib induced a complete hematologic response (CHR) or complete marrow response (marrow-CR) in 40 patients (good responders) and a partial (n = 2) or no (n = 14) remission in the remaining patients (poor responders). Compared with baseline, the median Bcr-Abl/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ratios decreased significantly in PB by 2.65, 2.64, and 3.11 log steps after 2 weeks, 4 weeks, and at the time of best response, respectively. In BM, the decline of median Bcr-Abl/GAPDH was 0.75, 1.37, and 2.78 logs, respectively. Thus, Bcr-Abl levels decreased more rapidly in PB than in BM (median time to best level 31 vs 39 days). Low Bcr-Abl/GAPDH ratios below 10(-4) in PB and below 10(-2) in BM after 2 weeks were significantly associated with good responses after 4 weeks. Moreover, Bcr-Abl levels (< 10(-2)) in BM of good responders after 4 weeks discriminated between 2 groups of patients with significantly different median time to progression (139 vs 22 days). The data show that Bcr-Abl levels in PB and BM after 2 weeks of imatinib treatment and in BM after 4 weeks have predictive relevance and may guide the application of additional therapies.