Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT)

Abstract

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.

Introduction

Allogeneic bone marrow transplantation still represents the only curative therapy for CML.1 However, despite recent improvements in transplantation regimens and in management of transplantation-related complications, it is generally accepted that only about one-third of all CML patients is suitable for this therapy.

Therapeutic options in order to achieve prolongation of stable chronic phase are treatment with hydroxyurea, interferon-alpha (IFN-alpha) and low-dose Ara-C. Currently, IFN-alpha represents first-line treatment for newly diagnosed CML patients in chronic phase, as it significantly prolongs survival.2,3,4,5 However, side-effects frequently limit the therapeutic use, and alternative therapies have to be chosen.2,3,4,5 Recently, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) in highly selected patients has resulted in transient restoration of a Ph-negative hematopoiesis.6 However, for most patients, remission is only of limited duration since Ph-positive stem cells either contaminating the transplant, or surviving the conditioning chemotherapy, contribute to relapse of CML.7 Taken together, there is still a considerable proportion of patients who cannot be treated efficiently by one of the above-mentioned therapeutic strategies due to age, side-effects or lack of a suitable stem cell donor. Therefore, new therapeutic modalities are warranted.

In 95% of CML patients, the somatic balanced translocation between the long arms of chromosomes 9 and 22 t(9;22)(q34;q11) is found, which leads to formation of the fusion bcr-abl tyrosine kinase.8,9 Two chimeric bcr-abl mRNA types have been identified, comprising either the b3a2 or the b2a2 junction of the bcr-abl gene and leading to expression of a 210-kDa fusion protein.10,11 This protein represents a constitutively activated tyrosine kinase, which is essential for malignant transformation in CML.12,13,14,15 Recently, specific targeted therapies such as vaccination, using a bcr-abl-derived peptide vaccine for T cell stimulation, and STI-571 have been developed (for review see Ref. 16).

STI-571, (Gleevec, imatinib mesylate, formerly CGP57148B), is an inhibitor of bcr-abl, platelet-derived growth factor receptor (PDGF-R), and c-kit receptor tyrosine kinases.17,18 These kinases are characterized by a so-called activation loop, which represents the catalytic active site.19 In vitro and in vivo, STI-571 has a high affinity for the abl-kinase and binds to the ATP binding site of the tyrosine kinase.19 The drug is highly bioavailable in oral form and showed a low rate of grade III/IV toxicity in phase I studies.20,21

Currently, the therapeutic effects and safety of STI-571 as a single agent are being investigated in phase II studies for bcr-abl-positive CML patients.22,23,24 Until now, no data concerning the feasibility, efficacy and toxicity profile of the drug in patients status post autologous PBSCT have been available. This report describes a cohort of 24 patients consecutively included in one of the STI-571 international multicenter trials. All patients had received extensive pretreatment with myelosupressive mobilization chemotherapy, followed by high-dose chemotherapy and autologous stem cell transplantation.

Our target was to assess toxicity, feasibility and clinical efficacy of STI-571 in this cohort of patients, and to investigate molecular responses using FISH and quantitative PCR analysis.

Materials and methods

Patients

Twenty-five CML patients, who had received prior treatment with mobilizing chemotherapy and high-dose chemotherapy followed by autologous PBSCT were enrolled in several international multicenter clinical phase II studies using STI-571 according to the disease status at study entry. All patients gave written informed consent to the study prior to entry, and all studies were reviewed and approved by the recognized Ethics Review Committee at each individual center. The studies were performed in accordance with the Declaration of Helsinki (as amended in Tokyo, Venice and Hong Kong). Three patients in blast crisis were enrolled into CSTI 571 trials No. 102, one patient was included in the accelerated phase and lymphatic blast crisis protocol No. 109, five patients were enrolled in the accelerated phase protocol No. 114 and 15 patients in chronic phase in trial CSTI 571 No. 113. The studies 113, 114 and 115 are part of the extended access program for STI-571. Disease history and patient characteristics are given in Tables 1 and 2. During treatment, all patients were monitored regularly including peripheral blood counts, bone marrow evaluation, clinical chemistry and physical examinations.

Table 1 Patient characteristics at study entry

The overall treatment results of four of these patients who were treated within the CSTI 571 102 and 109 trials, are given in two previous reports by the international STI study group,22,23 however, these reports do not contain any data on autologous PBSCT, quantitative real-time PCR and FISH analysis.

Assignment of disease status

Blast crisis (BC) was defined by at least 30% blasts in peripheral blood and/or bone marrow aspirates. Accelerated phase (AP) CML was defined as either 15% to <30% blasts in peripheral blood or marrow, or 30% blasts plus promyelocytes in peripheral blood or marrow (provided that <30% blasts were present), or 20% peripheral basophils, or thrombocytopenia corresponding to platelet counts of <100 × 109/l, unrelated to therapy. Patients with karyotypic evolution suggesting advanced CML but without other evidence of accelerated phase were not eligible for enrollment into protocol 109 but were eligible for protocol 114. Criteria for accelerated phase CML were required to be demonstrated within 4 weeks prior to enrollment. Chronic phase (CP) patients either did not respond to IFN-alpha treatment (hematologically or cytogenetically) or were intolerant to IFN-alpha. They were characterized by having less than 10% blasts, less than 20% blasts plus promyelocytes, and less than 20% basophils in peripheral blood or bone marrow. In addition, patients should have no evidence of extramedullary leukemic involvement and no secondary cytogenetic aberration, other than t(9;22). Hematologic failures were defined as patients who were resistant to or who were refractory to treatment with IFN. Hematologic resistance was defined as failure to achieve a complete hematologic response of at least 1 month duration, following at least 6 months of treatment with IFN. Hematologic refractoriness was defined for patients with a rising WBC count to 20 × 109/l (confirmed by two samples taken at least 2 weeks apart) while receiving IFN. Cytogenetic failures were similarly defined as patients who were resistant or who relapsed during IFN-based therapy. Cytogenetic resistance was defined as 65% Ph positivity in bone marrow after 1 year of IFN-based therapy. Cytogenetic relapse was defined for patients who had previously achieved a major cytogenetic response, as Ph-positive metaphases in bone marrow increased by at least 30% (confirmed by two samples at least 1 month apart), or increased to 65%. Intolerance to IFN was defined as any non-hematologic toxicity of grade 3 (as defined by NCI Common Toxicity Criteria) persisting for more than 2 weeks.

Treatment with STI-571

In general, treatment was started at a dose of 400 mg STI-571 (Gleevec) daily for patients in CP and at a dose of 600 mg daily for patients in AP and BC. Doses were administered once a day. Study drug was supplied by Novartis (Nürnberg, Germany) as 50 mg and/or 100 mg containing capsules. Three hundred milligrams of allopurinol was applied prophylactically. No additional chemotherapy was added to STI-571 treatment. Short interruptions of therapy were made in case of grade III–IV toxicities. According to the protocol, dose reductions were allowed in cases of recurrent side-effects.

Response evaluation

According to the study protocol for patients in CML BC and AP, complete hematologic remission required adequate bone marrow cellularity with a blast count of <5%, no peripheral blasts, ANC 1.5 × 109/l, platelet count of 100 × 109/l and no evidence of extramedullary involvement. No evidence of leukemia in peripheral blood and bone marrow, without full peripheral blood recovery required all of the following: blast count of <5% in bone marrow, no peripheral blood blasts, ANC 1.0 × 109/l, platelet count of 20 × 109/l and no evidence of extramedullary involvement. Return to chronic phase hematopoiesis required all of the following: blasts in peripheral blood or bone marrow <15%, percentage of blasts plus promyelocytes in peripheral blood or bone marrow <30% and peripheral blood basophils <20%. For patients in CML chronic phase, a complete hematologic response was defined as normalization of peripheral blood counts (WBC and platelet count <ULN at the laboratory where the analysis was performed), with a normal WBC differential, and no immature granulocytes present.

Sample acquisition

Collection of patient samples was performed according to a protocol which was approved by the local ethics committee.

Real-time PCR and multiplex PCR

Bcr-abl PCR positivity and breakpoint characteristics of all CML patients were controlled before study entry using a nested PCR procedure as published elsewhere.25 For follow-up of patients, after initiation of study medication, a commercially available quantitative PCR assay was applied using hybridization probes and detection on the LightCycler device (Roche, Mannheim, Germany). In brief, mononuclear cells (MNC) of blood or bone marrow samples were prepared and RNA was extracted using a commercially available kit (HighPure RNA extraction kit; Roche) or a standard protocol using tripure reagent (Roche). cDNA synthesis was performed according to the manufacturer's instruction and real-time PCR was performed using a defined amount of the transcription product. Using a second PCR reaction as internal standard resulted in expression of bcr-abl levels relative to GAPDH levels in percent (copy number bcr-abl/copy number GAPDH × 100). To avoid interassay variation, samples of each patient were analyzed in a single run whenever possible. Three patients (patient numbers (PN) 16–18) were followed up by PCR according to Cross et al26 and Emig et al.27

Cytogenetic analysis

Bone marrow samples were analyzed as described previously.25 At least 15 mitoses were judged in each sample. Karyotypic reponse was evaluated according to the clinical study protocols: (% of Ph-positive mitoses) no response: 96–100%, minimal response: 66–95%, minor response: 36–65%, partial response: 1–35%, complete response: 0%.

FISH analysis

Fresh bone marrow aspirates and peripheral blood samples were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum for 4–8 h. After centrifugation, cells were incubated in 0.075 mol/l KCl at 37°C for 10 min. Cells were fixed and washed in ice-cold methanol/acetic acid. Slides were prepared and treated according to the manufacturer's protocol. Fluorescence in situ hybridization was performed with commercially available dual-color DNA probes for bcr-abl from Vysis (Stuttgart, Germany). Results were obtained by counting a minimum of 200 interphase cells. If less than 200 cells had sufficient hybridization quality, a sample was considered as not evaluable. Response criteria were similarly defined as those for cytogenetic response, considering that FISH can produce a percentage of about 5% false positive signals. Response criteria in FISH analysis were defined as (% Ph-positive cells): no FISH response 96–100%, minimal FISH response 66–95%, minor FISH response: 36–65%, partial FISH response: 6–35%, complete FISH response: 5%.

Results

Patients and treatment

Fourteen male and 10 female patients with a median age of 56 years (range 25–64 years), were included in this analysis. At start of treatment with STI-571, four patients were in blast crisis (three in myeloid BC and one in lymphatic BC) and five patients presented in accelerated phase (AP). Fifteen patients were included in chronic phase. Median time between diagnosis of CML and start of STI-571 was 64 months, with a range from 27 to 131 months. Median time between autologous PBSCT and start of STI-571 therapy was 36.5 months (7–105). Table 1 presents a summary of patient characteristics at study entry.

All patients included had been treated with at least one mobilizing chemotherapy. Disease history is summarized in Table 2. Mobilization chemotherapy consisted of idarubicin combined with cytarabine or of ICE regimens as previously published.25,28,29 Patient numbers (PN) 6 and 17 received two courses of mobilization chemotherapy due to insufficient harvest. Median time between diagnosis and mobilization chemotherapy was 10.5 months, (range 1–92 months). All patients had undergone autologous PBSCT.

Table 2 Disease history

Median time from diagnosis to autologous PBSCT was 21 months (range 5–93 months).

Conditioning chemotherapy combinations for autologous PBSCT consisted of total body irradation (TBI) and cyclophosphamide (Cy), or IVT (idarubicin, VP-16, TBI (single dose)) as well as busulfan alone (BU) or in combination with melphalan (BU/Mel). Pretransplantation antileukemic therapies such as hydroxyurea (HU) and IFN-alpha are also summarized in Table 2.

All patients with CML CP had failed IFN-alpha and/or hydroxyurea therapy post autologous PBSCT and were in cytogenetic relapse at the start of STI-571 (Table 3).

Table 3 Cytogenetic responsesa, FISHb and quantitative PCRc in chronic phase patients

At the time of data analysis, median duration of treatment for all enrolled patients was 28 weeks (range 5–68 weeks). Five patients have withdrawn from treatment due to disease progression (one patient in BC, one patient in AP) or death during therapy (two patients in BC, one patient in AP).

Efficacy

CML in transformation:

Four patients with blast crisis and five patients in accelerated phase were included in this analysis. Due to short follow-up at the time of data analysis, 3/4 BC patients were evaluable for hematologic response. Of the three patients evaluable, two patients responded transiently with reductions in WBC and blasts and one patient achieved a sustained hematologic response (no evidence of leukemia). The clinical course of these patients was as follows: one patient in lymphatic blast crisis (PN6) and one patient in myeloid blast crisis (PN5) exhibited transient responses. These patients presented initially with a WBC of 105.6 × 103/μl (blasts 84%) and of 23.8 × 103/μl (blasts 73%), respectively. In both patients, a WBC of <1.5 × 103/μl with 0% peripheral blasts was achieved in week 4 and in week 6, respectively. However, both patients relapsed in week 8 and in week 10, respectively. Both patients had received prior chemotherapy regimens without satisfactory therapeutic response. PN1 (myeloid BC) experienced a sustained hematologic response and was followed up to week 68 (Figure 1a). In week 37, this patient had no evidence of leukemia and a rising platelet count. However, the platelet and red blood cell counts decreased again in week 56 (Figure 1a). The WBC showed 4% blasts, indicating relapse into blast crisis. The patient received an escalated dose of STI-571 with limited clinical benefit. Subsequently, STI-571 was discontinued and the patient received allogeneic unrelated stem cell transplantation, which he had refused in the past. The overall course of WBC, blasts, Hb and platelets is shown in Figure 1a.

Figure 1
figure1

(a) Peripheral blood counts during treatment with STI-571 in patient PN1 with CML blast crisis. Depicted are available leukocyte counts (in 109/l), peripheral blood blasts (in %) and platelets (in 109/l) during 69 weeks of treatment with STI-571. (b) Cytogenetic and molecular response in a patient with CML blast crisis (PN1) during STI-571 treatment. Depicted are Ph-positive metaphases (in %) and bcr/abl-positive interphases (in %) in bone marrow samples, and quantitative PCR in either bone marrow or PB samples (in % bcr-abl copy numbers relative to GAPDH copy numbers).

At baseline, cytogenetic aberrations in addition to t(9;22)(q34;q11) were observed in all patients in blast crisis and in two patients in accelerated phase, but not in chronic phase patients. As an example, for patient PN1, results of FISH, cytogenetic analysis, and quantitative PCR since start of treatment are depicted in Figure 1b. The patient developed a major cytogenetic response at week 21. Secondary aberrations were no longer detectable by cytogenetics in week 36 and qPCR revealed a 1000-fold decrease in bcr-abl expression in weeks 21 and 36. Upon overt relapse into blast crisis in week 58 (Figure 1a), cytogenetic karyotyping revealed 95% Ph-positive metaphases (Figure 1b) with reappearance of secondary aberrations. In parallel, FISH showed an increase in bcr-abl-positive cells from 20% to 65% and qPCR detected a significant increase of bcr-abl copies of more than 3 logs compared to this patient's best response.

Of the five patients in accelerated phase, two patients were evaluable for sustained hematologic response (due to short follow-up). They experienced ‘return to chronic phase’. Cytogenetic and molecular analyses are available on two AP patients. One patient (PN3) showed no response and one patient showed a minimal cytogenetic response (PN7). In patient PN7 additional chromosomal aberrations were no longer detectable after 13 weeks of treatment.

CML in chronic phase:

All patients in chronic phase had failed IFN-alpha and/or hydroxyurea post autologous PBSCT and were in cytogenetic relapse at start of STI-571 (Table 3). All patients achieved a complete hematologic response in peripheral blood. Peripheral blood counts of six representative CP patients during treatment with STI-571 are depicted in Figure 2a–d. Responses typically occurred within 4 weeks of treatment (Figure 2). With a median follow-up of 28 weeks, all patients in CP (15/15) were alive and in complete hematologic remission at the time of data analysis.

Figure 2
figure2

Peripheral blood counts during treatment with STI-571 in chronic phase patients. (a) Available leukocyte counts in (109/l), (b) hemoglobin (in g/dl), (c) platelets (in 109/l), and (d) peripheral blood blasts (in %) during treatment with STI-571.

Follow-up results on cytogenetic responses are available for 13 patients and are presented in Table 3. Complete and major cytogenetic responses occurred as early as 13 weeks after initiation of STI-571 treatment (Table 3). The rate of major cytogenetic repsonse was 61% with 46% complete cytogenetic responses (Table 4). Some degree of cytogenetic response was reported for 77% of patients (Table 4). Among the eight patients who experienced a major cytogenetic response, five (62.5%) had achieved this response by week 13, at the first scheduled evaluation for cytogenetic response.

Table 4 Hematologic and cytogenetic responses with STI-571 therapy in chronic phase patients

Table 3 also presents results of FISH analysis and of quantitative PCR. In general, in patients responding cytogenetically there was a parallel decrease in bcr-abl-positive interphases and in bcr-abl-positive transcripts. At the time of data analysis, no patient in complete cytogenetic remission evaluated by quantitative PCR (PNs 4, 9, 11) tested negative for bcr-abl messenger RNA.

Safety

In general, STI-571 was well tolerated in patients after previous autologous PBSCT. The safety profile of STI-571 was similar to that observed in the previous phase I-II studies. Table 5 summarizes treatment related adverse events. The most frequently reported side-effects were mild nausea and vomiting (grade I/II toxicity) and occurred in 5/24 patients (21%) (Table 5). Overall, grade I/II toxicities were reported in 10/24 patients (42%). Some of the initial non-hematologic side-effects disappeared after 4–6 weeks of treatment. Hemorrhage grade IV and cardiac failure/edema grade III represented the only grade III/IV non-hematologic toxicities. One patient (PN5) developed a grade IV hemorrhage (subdural hematoma) while in blast crisis during a phase of grade IV thrombocytopenia. No elevations in liver enzyme levels of grade III or IV were observed. Table 5 also summarizes the incidence of grade III/IV hematologic side-effects. Six patients with CML in transformation, and four patients with CML in chronic phase experienced grade III/IV neutropenia and/or thrombocytopenia. No significant infections were observed in patients experiencing grade III/IV neutropenia.

Table 5 Toxicity during STI-571 treatment

STI-571 was temporarily discontinued due to hematologic toxicity in four patients. In two patients, STI-571 had to be discontinued permanently due to cardiac failure/edema grade III and due to sustained thrombocytopenia grade IV, respectively.

Discussion

The bcr/abl selective tyrosine kinase inhibitor STI-571 binds to the ATP binding site of bcr/abl and downregulates its tyrosine kinase activity.17,18 STI-571 was shown to inhibit cell growth in bcr/abl-positive cell lines and in primary CML cells.18,30 These in vitro results encouraged clinical trials with STI-571. Excellent results from phase I trials give hope for improvement of therapeutic outcome for CML patients, especially for those not responding to IFN-alpha.20,21

In this analysis, safety and efficacy of STI-571 treatment was investigated in 24 patients who had received myelosuppressive mobilization chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation.

Overall, STI-571 was well tolerated. Forty-two percent of patients reported non-hematologic side-effects grades I–II. There was only one event of a non-hematologic grade III/IV toxicity which required permanent dose discontinuation. Mild non-hematologic side-effects such as nausea, vomiting and orbital edema usually occurred during the first weeks of therapy. In some patients, these symptoms ameliorated after the first 2 months of therapy without the need of dose reduction.

Six of nine (67%) patients in transformed phases of CML suffered from grades III–IV hematologic toxicity with low WBC, platelet counts and anemia requiring transfusions. In the chronic phase patient group, grade III/IV hematologic side-effects were reported in 4/15 (27%) patients only. Thus, severe hematologic side-effects occurred more often in transformed phases of CML as compared to chronic phase. This suggests that in this cohort, STI-571-induced myelosuppression is related primarily to limited presence of residual bcr-abl-positive stem cells in advanced phases of CML and not to prior high-dose chemotherapy and TBI. Therefore, myelosuppression in CML blast crisis and acccelerated phase may be viewed as therapeutic efficacy in these cases. In this context it is interesting to note that STI-571-induced inhibition of c-kit-mediated hematopoietic signals is apparently not associated with additional hematologic toxicity in patients post autologous PBSCT. Concerning the management of hematologic side-effects in transformed phases of CML, we have experienced no benefit in stopping STI-571 medication during thrombocytopenia or granulocytopenia as disease progression can hardly be controlled. Rather, it seems advisable to continue STI-571 treatment, repeat PB counts of high-risk patients frequently, and transfuse platelets and red blood cells. Evaluation of efficacy in patients with AP and BC revealed a therapeutic benefit in 5/5 evaluable patients. Three of five patients showed sustained hematologic responses.

All chronic phase patients achieved a complete hematologic response within 4 weeks. Only 27% of patients suffered from hematologic toxicity grades III–IV, with one patient having experienced similar episodes during previous therapy with hydroxyurea.

Molecular response evaluation by qPCR and FISH revealed appropriate correlation with classical cytogenetics. At 6 months, 61% of evaluable patients in CP showed a major cytogenetic response with 46% of patients achieving a complete cytogenic response. In addition, cytogenetics and FISH detected some minor and minimal responses.

These results compare favorably with cytogenetic response rates in the phase II STI-571 trial for chronic phase CML patients without prior PBSCT.24 That study enrolled 532 patients who either failed IFN-alpha hematologically or cytogenetically or were intolerant to IFN. At 6 months, a major cytogenetic response rate was achieved in 40% of patients with 21% achieving a complete cytogenetic response. However, firm conclusions from a comparison of these studies cannot be drawn due to the limited number of patients in this trial and due to differences in baseline characteristics of patients.

qPCR revealed a concordant decrease in bcr-abl levels and an increase preceding development of second blast crisis as shown in patient PN1. However, it remains to be shown in a large patient population whether molecular methods are useful for predicting prognosis in response to STI-571. This is certainly of special interest for the long-term management of chronic phase patients.31

As synergistic effects of STI-571 with Ara-C, and IFN-alpha, and with other cytostatics have been shown in vitro,32,33 the evaluation of these promising approaches will be the subject of further clinical trials. In the field of autologous transplantation, the therapeutic potential of autologous PBSCT may reach a new level of efficacy.

This report indicates that STI-571 is a safe and effective drug in patients post autologous PBSCT. In comparison to the results from phase II clinical trials, no apparent additional side-effects were noted in this patient cohort. However, the number of patients investigated is limited and the observation period is still short. Therefore, feasibility, toxicity and efficacy of PBSC purging using STI-571 followed by PBSCT plus post-transplant treatment with STI-571 needs to be evaluated carefully in phase II trials. In this patient cohort, STI-571 was able to induce a high rate of complete hematologic and significant cytogenetic responses, combined with good quality of life. This is even more remarkable, as intensive treatment approaches failed to be efficient in achieving long-term stabilization of the underlying disease in this patient cohort.

References

  1. 1

    Goldman JM, Druker BJ . Chronic myeloid leukemia: current treatment options Blood 2001 98: 2039–2042

    CAS  Article  Google Scholar 

  2. 2

    Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S . An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemias: developed for the American Society of Hematology Blood 1999 94: 1517–1536

    CAS  PubMed  Google Scholar 

  3. 3

    Hehlmann R, Hochhaus A, Berger U, Reiter A . Current trends in the management of chronic myelogenous leukemia Ann Hematol 2000 79: 345–354

    CAS  Article  Google Scholar 

  4. 4

    Italian Cooperative Study Group on CML. IFN-alpha2a as compared with conventional chemotherapy for the treatment of CML N Engl J Med 1994 330: 820–825

  5. 5

    Chronic Myeloid Leukemia Triallists’ Collaborative Group. Interferon alpha versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials J Natl Cancer Inst 1997 89: 1616–1620

  6. 6

    McGlave PB, De Fabritiis P, Deisseroth A, Goldman J, Barett M, Reiffers J, Simonsson B, Carella A, Aeppli D . Autologous transplants for chronic myelogenous leukaemia: results Lancet 1994 343: 486–488

    Article  Google Scholar 

  7. 7

    Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF, Hester J, Korbling M, Durett A, Moen R, Berenson R, Heimfeld S, Hamer J, Clavert L, Tibbits P, Talpaz M, Kantarjian H, Champlin R, Reading C . Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow transplantation in CML Blood 1994 83: 3068–3076

    CAS  Google Scholar 

  8. 8

    Rowley JD . A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining Nature 1973 243: 290–293

    CAS  Article  Google Scholar 

  9. 9

    Sawyers CL . Chronic myeloid leukaemia N Engl J Med 1999 340: 1330–1340

    CAS  Article  Google Scholar 

  10. 10

    Shtivelman E, Lifshitz B, Gale RP, Roe BA, Canaani E . Alternative splicing of RNAs transcribed from the human abl gene and from the BCR/ABL fused gene Cell 1986 27: 277–284

    Article  Google Scholar 

  11. 11

    Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene Science 1986 233: 212–214

    CAS  Article  Google Scholar 

  12. 12

    Heisterkamp N, Jenster G, tenHoeve J, Zovich D, Pattengale PK, Groffen J . Acute leukemia in bcr/abl transgenic mice Nature 1990 344: 251–253

    CAS  Article  Google Scholar 

  13. 13

    Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 1990 247: 824–830

    CAS  Article  Google Scholar 

  14. 14

    Kelliher MA, McLaughlin J, Witte ON, Rosenberg N . Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL Proc Natl Acad Sci USA 1990 87: 6649–6653

    CAS  Article  Google Scholar 

  15. 15

    Elefanty AG, Hariharan IK, Cory S . Bcr/abl, the hallmark of chronic myelogenous leukemia in man, induces multiple hematopoietic neoplasms in mice EMBO J 1990 9: 1069–1078

    CAS  Article  Google Scholar 

  16. 16

    Kindler T, Meyer RG, Fischer T . BCR-ABL as a target for novel therapeutic interventions Exp Opin Ther Targets 2002 6: 85–101

    CAS  Article  Google Scholar 

  17. 17

    Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB . Inhibition of the Abl protein-tyrosin kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 1996 56: 100–104

    CAS  Google Scholar 

  18. 18

    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells Nat Med 1996 2: 561–566

    CAS  Article  Google Scholar 

  19. 19

    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase Science 2000 289: 1938–1942

    CAS  Article  Google Scholar 

  20. 20

    Druker BJ, Talpaz M, Resta D, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

    CAS  Article  Google Scholar 

  21. 21

    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of CML and ALL with the Philadelphia chromosome N Engl J Med 2001 344: 1038–1042

    CAS  Article  Google Scholar 

  22. 22

    Sawyers CL, Hochhaus A, Silver RT, Goldman JM, Miller C, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Niederwieser D, Fischer T, O'Brien SG, Stone R, Corneo G, Russell N, Reiffers J, Shea T, Chapuis B, Coutre S, Tura S, Morra E, Larsen R, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker B . Glivec (imatinib mesylate) induces hematologic and cytogenetic responses in patients with CML in myeloid blast crisis: results of a phase II study Blood 2002 99: 3530–3539

    CAS  Article  Google Scholar 

  23. 23

    Talpaz M, Silver RT, Druker B, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL . Glivec (imatinib mesylate) induces durable hematologic and cytogenetic responses in patients with accelerated phase CML: results of a phase II study Blood 2002 99: 1928–1937

    CAS  Article  Google Scholar 

  24. 24

    Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B . Glivec (imatinib mesylate) induces hematologic and cytogenetic responses in the majority of patients with chronic myeloid leukemia in chronic phase: results of a phase II study N Engl J Med 2002 346: 645–652

    CAS  Article  Google Scholar 

  25. 25

    Hess G, Reifenrath C, Friedrich-Freksa A, Beyer V, Naumann S, Schuch B, Huber C, Fischer T, Decker HJ . Autologous transplantation of in vivo purged PBSC in CML: comparison of FISH, cytogenetics, and PCR detection of Philadelphia chromosome in leukapheresis products Cancer Genet Cytogenet 2000 117: 1–8

    CAS  Article  Google Scholar 

  26. 26

    Cross NC, Melo JV, Feng L, Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders Leukemia 1994 8: 186–189

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A, Berger U, Hehlmann R, Cross NC, Hochhaus A . Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR Leukemia 1999 13: 1825–1832

    CAS  Article  Google Scholar 

  28. 28

    Fischer T, Neubauer A, Mohm J, Huhn D, Busemann C, Link H, Arseniev L, Bussing B, Novotny J, Ganser A, Duyster J, Bunjes D, Westermeier T, Flohr T, Despres D, Gamm H, Decker J, Derigs G, Aulitzky W, Huber C . Outcome of peripheral blood stem cell mobilization in advanced phases of CML is dependent on the type of chemotherapy applied Ann Hematol 1998 77: 21–26

    CAS  Article  Google Scholar 

  29. 29

    Fischer T, Neubauer A, Mohm J, Huhn D, Busemann C, Link H, Arseniev L, Bussing B, Novotny J, Ganser A, Duyster J, Bunjes D, Kreiter S, Aulitzky W, Hehlmann R, Huber C . Chemotherapy-induced mobilization of karyotypically normal PBSC for autografting in CML Bone Marrow Transplant 1998 21: 1029–1036

    CAS  Article  Google Scholar 

  30. 30

    Deininger MW, Goldman JM, Lydon N, Melo JV . The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells Blood 1997 90: 3691–3698

    CAS  PubMed  Google Scholar 

  31. 31

    Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J, Schultheis B, Berger U, Shepherd PC, Allan NC, Hehlmann R, Goldman JM, Cross NC . Molecular heterogeneity in complete cytogenetic responders after interferon alpha therapy for chronic myeloid leukemia: low levels of minimal residual disease are associated with continuing remission Blood 2000 95: 62–66

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Fang G, Naekyung Kim C, Perkins CL, Ramadevi N, Winton E, Wittmann S, Bhalla KN . CCGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs Blood 2000 96: 2246–2253

    CAS  PubMed  Google Scholar 

  33. 33

    Thiesing TJ, Ohno-Jones S, Kolibaba KS, Druker BJ . Efficacy of STI-571, an ABL tyrosine kinase inhibitor, in conjunction with other antileukemic agents against BCR-ABL-positive cells Blood 2000 96: 3195–3199

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Deutsche José Carreras Leukämie-Stiftung eV and a research grant from Novartis Pharmaceuticals.

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Correspondence to T Fischer.

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Fischer, T., Reifenrath, C., Hess, G. et al. Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT). Leukemia 16, 1220–1228 (2002). https://doi.org/10.1038/sj.leu.2402565

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Keywords

  • STI-571 (imatinib mesylate)
  • CML
  • autologous peripheral blood stem cell transplantation

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