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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2001-12-0181.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Medizinische Klinik III, Johann Wolfgang
Goethe Universität, Frankfurt, Germany; Division of
Hematology, Oregon Health Sciences University, Portland; Department of
Medicine and Molecular Biology Institute, University of
California at Los Angeles; Department of Haematology,
Hammersmith Hospital/Imperial College School of Medicine, London,
United Kingdom; Laboratoire de Greffe de Moelle, Université
Victor Segalen, Bordeaux, France; New York-Presbyterian Hospital Weill
Medical College of Cornell University, New York, NY; Instituto di
Ematologia, Ospedale Policlinico Sant'Orsola-Malpighi, Bologna,
Italy; Universitätsklinikum, 3 Medizinische Klinik und
Poliklinik, Mainz, Germany; Abteilung Hämatologie/Onkologie,
Universität Leipzig, Leipzig, Germany; Barbara Ann Karmanos
Cancer Institute, Wayne State University, Detroit, MI; Division of
Hematology, Udine University Hospital, Udine, Italy; Division of
Hematology, Universitätsklinik, Kantonspital, and Novartis
Pharma, Basel, Switzerland; III Medizinische
Universitätsklinik Mannheim der Universität
Heidelberg, Mannheim, Germany; Department of Haematology, Royal
Victoria Infirmary, University of Newcastle, United Kingdom.
The translocation (9;22) gives rise to the
p190Bcr-Abl and p210Bcr-Abl tyrosine kinase
proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph+) acute leukemia patients failing
to respond to initial induction therapy have a poor prognosis with few
effective treatment options. Imatinib is an orally
administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We
conducted a clinical trial in 56 patients with relapsed or refractory
Ph+ acute lymphoblastic leukemia (ALL; 48 patients)
or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg.
Imatinib induced complete hematologic responses (CHRs) and complete
marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%;
marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of
patients. Median estimated time to progression and overall survival for
ALL patients were 2.2 and 4.9 months, respectively. CHRs were
reported for 3 (38%) of the patients with LyBC (one sustained CHR).
Grade 3 or 4 treatment-related nonhematologic toxicity was reported for
9% of patients; none of the patients discontinued therapy because of
nonhematologic adverse reactions. Grade 4 neutropenia and
thrombocytopenia occurred in 54% and 27% of patients, respectively.
Imatinib therapy resulted in a clinically relevant hematologic response
rate in relapsed or refractory Ph+ acute lymphoid leukemia
patients, but development of resistance and subsequent disease
progression were rapid. Further studies are warranted to test the
effects of imatinib in combination with other agents and to define the
mechanisms of resistance to imatinib.
(Blood. 2002;100:1965-1971) The Philadelphia translocation (Ph) is the most
common cytogenetic abnormality associated with adult acute
lymphoblastic leukemia (ALL), occurring in 20% to 40% of
patients.1-4 It is also detected in 2% to 5% of children
with ALL5 and in approximately 1% of patients with acute
myeloid leukemia (AML).6 The Philadelphia chromosome is
the result of a t(9;22) (q34; q11) reciprocal translocation leading to
the formation of a BCR-ABL fusion gene, the
transcription of which results either in an 8.5-kb mRNA that
encodes a 210-kDa protein or in a 7.5-kb mRNA that codes for a 190-kDa
protein.7,8 These BCR-ABL proteins display constitutively
active tyrosine kinase activity that is considerably greater than that
of the normal 145-kDa ABL gene product.9,10 Expression of
the deregulated BCR-ABL kinase has been shown to induce resistance to
apoptosis11 and growth factor independence12
and to possess pronounced transforming potential in mouse models, and
it accounts for the malignant phenotype of chronic myelogenous leukemia
(CML).13
The presence of the BCR-ABL translocation is the single most important
adverse prognostic parameter in Ph+ acute leukemia, with
long-term survival of less than 10% with current chemotherapy
regimens.4,14-16 Conventional induction chemotherapy, as
well as recently developed regimens such as hyper-CVAD (fractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone), generally achieves response rates of 60% to
80% in newly diagnosed patients, which are slightly inferior to those in Ph Imatinib (Glivec, also imatinib mesylate [Gleevec]; formerly STI571;
Novartis Pharma, Basel, Switzerland) is a rationally designed,
potent selective competitive inhibitor of the BCR-ABL protein-tyrosine
kinase.28-30 In an ascending-dose phase 1 study, imatinib
induced substantial and durable responses with minimal toxicity, at
daily doses of 300 mg and higher, in nearly all patients with chronic
phase CML,31 results that were recently confirmed in a
phase 2 trial.32 Imatinib was also shown to have
significant antileukemic activity in patients with accelerated-phase
CML or in myeloid blast crisis, although results were inferior to
results in chronic phase.33,34 In patients with
lymphoid blast crisis (LyBC) or Ph+ ALL entered in the
initial phase 1 study, imatinib at daily doses of 300 to 1000 mg
induced hematologic responses in 14 of 20 patients (70%), including 4 complete hematologic responses (20%) and 7 marrow responses
(35%).35
In view of the possible therapeutic activity of imatinib, its low
toxicity, and the limited options available to relapsed ALL patients,
we conducted a phase 2 study of imatinib in patients with
Ph+ ALL or LyBC who had failed first-line treatment.
Patients
Patients were required to have alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) not higher than 3 × the upper normal limit in cases without suspected leukemic involvement of
the liver, or not higher than 5 × the upper normal limit in cases of
suspected liver involvement; serum total bilirubin levels not higher
than 3 × the upper normal limit; and serum creatinine levels not
higher than 2 × the upper normal limit. Women of
childbearing potential were required to have a negative pregnancy test
prior to starting treatment, and both male and female patients
were required to use barrier contraceptive measures throughout therapy with imatinib. Patients were excluded from the trial if they had an
Eastern Co-operative Oncology Group (ECOG) performance status of 3 or 4, grade 3/4 cardiac disease, leukemic central nervous system
involvement, or any serious concomitant medical condition. Exclusion criteria also included treatment with anthracyclines, mitoxantrone, etoposide, methotrexate, or cyclophosphamide within 21 days before starting therapy; treatment with any other investigational agent or with high-dose cytosine arabinoside (1-3 g/m2
every 12 to 24 hours for 6 to 12 doses) within 28 days before starting
therapy; treatment with hematopoietic SCT within 6 weeks before
starting therapy; or if recovery from SCT was not complete. Patients were also excluded from enrollment if they had a history of
noncompliance with therapy or if they were considered by the investigator to be potentially unreliable.
All patients gave written informed consent to participate in the study,
and the study was reviewed and approved by a recognized ethics review
committee at each trial center. The study was performed in accordance
with the Declaration of Helsinki (as amended in Tokyo, Venice, and
Hong Kong).
Study design and treatment
Patients started treatment with imatinib at daily doses of 400 or 600 mg. For patients who relapsed, dose escalation to a maximum of 400 mg twice daily was permitted at the discretion of the investigator. On a case-by-case basis following discussion between the investigator and sponsor, dose escalation was also permitted for patients who did not achieve hematologic response after at least 1 month of therapy. Patients were scheduled to receive treatment for 24 weeks and then were continued indefinitely in cases where the investigator judged that further treatment was of clinical benefit. Treatment was interrupted or reduced in response to nonhematologic, hepatic, or hematologic toxicity, which was graded according to National Cancer Institute/National Institutes of Health (NCI/NIH) Common Toxicity Criteria. For patients requiring dose reduction, daily doses were reduced from 600 to 400 mg, or from 400 to 300 mg. Dose reductions below 300 mg per day were not allowed by study design. If grade 2 nonhematologic toxicity occurred, therapy was interrupted until recovery to grade 1 or lower and was then resumed at the original dosage. If grade 2 toxicity recurred following resumption, treatment was again interrupted until recovery and was resumed at a reduced dose. If grade 3 or 4 nonhematologic toxicity occurred, therapy was interrupted until recovery to grade 1 or lower and then resumed at a reduced dose. Specific dose reduction rules for hepatic toxicity were applied to patients who enrolled with elevated baseline aminotransferase levels (3-fold to 5-fold above upper normal limits). If such patients developed increases in one or more aminotransferase levels of greater than 3-fold, therapy was interrupted until levels returned to baseline and was then resumed at a reduced dose. For patients who experienced clinically relevant, but lower than 3-fold increases in aminotransferase levels, treatment was interrupted until recovery and was then resumed at the same dose. If patients experienced a subsequent clinically relevant increase in aminotransferase levels, treatment was interrupted until recovery and resumed at a reduced dose. Dose reductions for hematologic toxicity were to be considered only for patients with grade 4 neutropenia (neutrophil count below 0.5 × 109/L) lasting at least 2 weeks, after a minimum of 28 days of therapy. In practice, however, imatinib doses were also reduced in cases of grade 4 thrombocytopenia considered to be unrelated to leukemia. Bone marrow examinations were performed routinely, and biopsies were obtained insofar as possible, until recovery from grade 4 neutropenia or thrombocytopenia. For patients with persistent marrow cellularity of less than 10% and blasts exceeding 10%, the daily dosage was successively reduced at 2-week intervals or was interrupted until recovery of neutropenia or thrombocytopenia to at least grade 2. Upon recovery, treatment was resumed at the full initial dose. Treatment was not interrupted or reduced for patients with marrow cellularity or blasts greater than 10%. No concomitant anticancer drugs were to be administered. Treatment with allopurinol at 300 mg per day was recommended until stabilization of white blood cell (WBC) counts, and patients with febrile neutropenia or infection could receive treatment with colony-stimulating factors at the investigator's discretion. Evaluation of patients Patients were evaluated for hematologic and cytogenetic response and relapse at frequent intervals during the initial 24 weeks of imatinib treatment. Peripheral blood samples were obtained and analyzed at baseline, 3 times weekly for the first 4 weeks, weekly from weeks 5 to 13, every 2 weeks after week 13, and on the last day of treatment. Bone marrow aspirates were performed at screening; weeks 5, 9, 13, and 25; and on the last day of treatment; bone marrow biopsies were optional and were obtained as indicated. Physical examination to evaluate liver and spleen size and extramedullary involvement was carried out at screening, every 4 weeks during therapy, and on the last day of treatment. After the initial 24 weeks of treatment, bone marrow aspirates or biopsies for analysis of disease status were obtained every 3 months for the first 6 months and every 4 months thereafter. Following treatment, patients were followed for survival at least every 3 months, until death. Treatment toxicity was evaluated by patient interview at each office visit. Toxicity was graded according to NCI/NIH Common Toxicity Criteria.The primary efficacy endpoint in this study was sustained hematologic response lasting at least 4 weeks, assessed as (1) complete hematologic response (CHR), defined according to conventional criteria as blast count below 5% in bone marrow, no blasts in peripheral blood, neutrophil count at least 1.5 × 109/L, platelet count at least 100 × 109/L, and no evidence of extramedullary involvement36; (2) complete marrow response (marrow-CR) in patients achieving a blast count of less than 5% in bone marrow, no blasts in peripheral blood, no evidence of extramedullary involvement, a neutrophil count at least 1.0 × 109/L, but no platelet recovery (platelet count at least 20 × 109/L); (3) partial response, defined as fewer than 15% blasts in peripheral blood and bone marrow. Sustained responses were required to be observed at 2 consecutive evaluations at least 4 weeks apart. Secondary efficacy endpoints were the induction of cytogenetic response, time to disease progression, and overall survival. Complete cytogenetic response was defined as the absence of Ph+ metaphases. Time to progression was calculated as the time from treatment start until relapse after initial response, or the interval when treatment was discontinued owing to unsatisfactory therapeutic response, adverse events, or patient death from any cause. Time to progression was censored at the last examination date for patients continuing treatment without progression, or at the time treatment was discontinued for reasons other than adverse events, unsatisfactory therapeutic response, or death. Overall survival was calculated as the time from treatment start to the date of death from any cause. Survival was censored at the time treatment was discontinued to allow bone marrow transplantation, or at the last recorded contact or evaluation when patients were alive at time of analysis. Statistical analysis Planned sample sizes of 30 patients with ALL were based upon practical considerations rather than inferential hypothesis testing, as this trial was regarded as a preliminary investigation of imatinib in acute leukemias. Enrollment of patients with CML in LyBC was discontinued before accrual of the 29 patients initially planned, on the basis of emerging phase 1 data suggesting that single-agent therapy with imatinib in patients with LyBC induced less durable responses than in the other Ph+ advanced leukemia disease groups. Response rates are reported as intent-to-treat analyses. Patients who withdrew from treatment before a sustained response was reported were counted as nonresponders. Time to progression and survival were computed by means of standard Kaplan-Meier methods. Safety results are reported for all enrolled patients who received at least one dose of imatinib.
Patients and treatment A total of 56 patients were enrolled at 18 centers in France, Germany, Italy, Switzerland, the United Kingdom, and the United States from September 1999 to May 2000. During screening examinations for study enrollment, patients had a confirmed diagnosis of Ph+ acute leukemia consisting of ALL (48 patients) or LyBC (8 patients).Table 1 summarizes patient
characteristics and disease history at baseline for all 56 enrolled
patients. The first 10 patients (5 with ALL and 5 with LyBC) started
initial therapy with imatinib at daily doses of 400 mg, and in the
subsequent 46 patients, the initial dose was 600 mg/d. However, dose
escalation or reduction was permitted for all patients, and no
substantial difference in efficacy or toxicity was observed between
patients who started therapy at these different doses. Median treatment
durations were similar for patients with ALL (62 days; range, 14-343 days) and LyBC (56 days; range, 32-325 days). Of the 56 patients
enrolled, 3 were still on treatment at the time of analysis. The
remaining patients withdrew from treatment owing to disease progression (72%), adverse events (5%), death during therapy (9%), or elective SCT (9%).
Efficacy Table 2 summarizes hematologic response rates for the 48 ALL and 8 LyBC patients. Values represent the best response observed at any time during therapy. Of the 48 ALL patients, 9 (19%) achieved a CHR; a marrow-CR or partial marrow response was observed in 5 patients (10%) and 15 patients (31%), respectively. Thus, 60% had reductions in blast counts in peripheral blood and in bone marrow corresponding to hematologic response on at least one occasion. Hematologic responses lasting at least 4 weeks were reported for 13 patients (27%), including 3 CHRs (6%). Many patients with an initial hematologic response did not have adequate bone marrow evaluations at later assessments, and sustained response could not be confirmed solely for that reason. The median time to hematologic response was 1 month, corresponding to the first scheduled evaluation of hematologic response; reduction in peripheral blood blasts typically occurred within 1 week after initiation of imatinib therapy. Complete cytogenetic responses were reported for 8 (17%) of the 48 patients with ALL.
One of the 3 patients with a sustained CHR has maintained an ongoing response 11 months after the start of therapy, with no evidence of Ph+ cells in bone marrow. Of the remaining 2 patients with sustained CHR, 1 relapsed after 4.7 months and withdrew from imatinib therapy. Another was found to have Ph+ cells in a marrow sample after 5.6 months, and started concomitant treatment with interferon alfa 1 month later. Concomitant therapy with interferon alfa and imatinib has been maintained, and the patient remains relapse-free 3 months after starting combined therapy. This patient has been censored from all evaluations of efficacy and safety for this trial, from the start date of concomitant interferon therapy. Among the 19 patients with no reported hematologic response at any time, 12 had transient (duration of no more than 4 weeks in 8 patients, 5 weeks in 2 patients, and 9 and 10 weeks in 1 patient each) but marked reductions in peripheral blood blasts, indicating some degree of hematologic improvement. Of the remaining 7 patients, 6 were not assessable for hematologic improvement owing to low circulating blasts at study entry. Figure 1 presents the time to progression
for patients with ALL. The estimated median time to progression was 2.2 months (95% CI = 1.8-2.8 months), and the estimated progression-free
rate at 6 months was 12% (95% CI = 2%-22%).
Figure 2 presents overall survival (OS)
for the 48 patients with ALL. The Kaplan-Meier estimate for median OS
was 4.9 months (95% CI = 4.1-7.1 months), and the estimated overall
survival rate at 6 months was 40% (95% CI = 25% to 54%).
To determine whether patients achieving any form of hematologic
response had a survival advantage compared with nonresponders, we
compared patients with a CHR or marrow-CR (n = 14), those with a
partial response (n = 15), and the 14 patients who were treated for
at least 4 weeks but did not have documented response. Whereas median
survival was 9.2 months for patients who had CHR/marrow-CR and 7.1 months for patients with a partial response, all of the nonresponders
died and their median survival was only 3.6 months (P < .001) (Figure 3).
When we analyzed other factors potentially affecting treatment outcome,
only the WBC count at baseline was shown to have a significant
effect on survival, with a longer median survival (7.2 months) in
patients with a WBC count below 10 × 109/L compared with
patients with a baseline WBC count exceeding 10 × 109/L
(median survival, 4.1 months) (P = .0163 by log-rank
test). None of the other clinical or laboratory parameters Among 11 patients who had undergone prior SCT procedures, treatment with imatinib induced sustained hematologic responses in 3 (27%; 2 CHRs and 1 partial response), and a further 5 patients (45%) met criteria for hematologic response on at least one occasion (1 CHR and 4 partial responses). These rates of response are comparable to those observed for all 48 patients with ALL (Table 2). Five patients with ALL discontinued treatment with imatinib in order to undergo allogeneic SCT. Of these, 3 discontinued within 1 month, with blood counts consistent with CHR or marrow response (1 patient each), or without a valid response evaluation (1 patient); and 2 discontinued within 2 months, with CHR and marrow response (1 patient each). Sustained marrow response was documented for one patient who discontinued after 1.9 months of therapy, while other patients had too few evaluations to determine response duration. Of these 5 patients, 1 died of treatment-related complications; 2 have relapsed and died of leukemia; and 2 were alive at the time of analysis 10 months after they had started imatinib. Efficacy results for patients with LyBC were generally similar to those for patients with ALL (Table 2). Sustained hematologic responses (lasting at least 4 weeks) were reported for 2 of the 8 patients with LyBC (one CHR and one partial response). Of the other 6 LyBC patients, 2 had unsustained CHRs and 4 had reductions in blast counts in peripheral blood and/or bone marrow, but did not satisfy criteria for hematologic response. Complete cytogenetic responses were reported for one with LyBC. Median overall survival for the 8 patients with LyBC was 6.6 months (95% CI = 2.4-9.9 months). One LyBC patient who achieved CHR and complete cytogenetic response remained progression-free and receiving imatinib therapy after 11 months. Toxicity The toxicity of imatinib in this trial was generally similar to that observed in patients with CML.31,33-35 Table 3 presents treatment-related nonhematologic adverse reactions observed in 10% of patients or more. The most frequently reported events were nausea, vomiting, and edema, with few of these events described as grade 3 or 4. Table 4 presents the incidence of grade 3 or 4 hematologic toxicity and abnormal laboratory findings. The most common grade 3 or 4 findings were leukopenia or neutropenia.
None of the 56 patients enrolled in this study discontinued therapy with imatinib because of treatment-related nonhematologic adverse events. Treatment-related adverse events regarded as serious were reported for 9 patients (16%), and comprised neutropenia or febrile neutropenia (4 patients), elevated liver aminotransferases (2 patients), fever of unknown origin, cerebral edema, headache, anorexia, cachexia, nausea, vomiting, and generalized rash (1 patient each; some patients experienced multiple serious adverse events). No treatment-related deaths were reported.
The treatment of patients with Ph+ acute leukemia who have failed primary therapy poses a difficult clinical challenge. Patients who relapse after intensive combination chemotherapy or allogeneic transplantation, or who are refractory to treatment, have few therapeutic options.16,18,27 We conducted this phase 2 trial to determine whether imatinib, a potent inhibitor of the oncogenic Bcr-Abl tyrosine kinase, when administered at well-tolerated doses as defined in an earlier trial,31,35 could induce meaningful and durable hematologic responses in patients with relapsed or refractory Ph+ ALL or LyBC. In the present study, the rates of CHR and of marrow-CR with imatinib given orally at 400 mg or 600 mg per day were 19% and 10% in patients with relapsed or refractory ALL. In the vast majority of patients, these responses were of short duration, with a median time to disease progression of only 2.2 months, an estimated progression-free rate of 12% at 6 months, and an overall survival rate of 40% at 6 months by Kaplan-Meier analysis. Thus, CHRs were sustained for at least 4 weeks in only 6% of patients with ALL. Overall, these findings are similar to those of a recently published phase 1 study, which demonstrated an overall response rate of 70%, a marrow response with blasts fewer than 15% in 50%, and a complete hematologic response rate of 20% in patients with a lymphoid phenotype.35 Reasons for the slightly inferior results in our phase 2 study may be (1) patient selection, particularly as the number of patients with Ph+ ALL in the phase 1 study was small and the results of ALL and LyBC patients were combined, and (2) slightly different definitions of response. Published results of conventional salvage chemotherapy in adult ALL have shown poor treatment outcome independently of the presence of the BCR-ABL translocation, with median disease-free survival (DFS) ranging from 2 to 7.5 months18,37; in patients with adverse risk factors, some series have reported the chance of long-term DFS to be less than 5%.38 Therefore, DFS and OS observed in the present study of single-agent imatinib is within the range of previous experience with aggressive chemotherapy regimens. While the initial CHR rates of 30% to 60% that have been reported for salvage chemotherapy appear higher than the 19% achieved in our study, more detailed analyses have demonstrated that the presence of additional unfavorable clinical features has a profound negative impact on the response to chemotherapy. In a multivariate analysis, worse survival was observed with an increasing numbers of adverse features, permitting stratification into risk groups with median survival as low as 2 months and corresponding CR rates of 9% in patients with 3 unfavorable features.39 As a large proportion of patients in our study had several unfavorable risk factors in addition to the Philadelphia chromosome, eg, higher age, second or subsequent relapse, relapse after SCT and short (less than 1 year) duration of first CR, the results achieved with imatinib are comparable to those observed with intensive chemotherapy regimens. In contrast to chemotherapy, which is associated with significant morbidity and induction mortality of up to 40%,18 imatinib was associated with comparatively few severe adverse events and an overall death rate during study treatment of 9%. Imatinib was well tolerated despite pronounced hematologic toxicity in many patients, which did not require discontinuation of therapy, however, and was associated with remarkably few serious infectious or bleeding complications. Nonhematologic adverse reactions were grade 1 or 2 in the majority of cases. These observations are most likely attributable to the more selective mechanism of action of imatinib as opposed to conventional cytotoxic agents, which induce considerably greater organ damage, such as mucositis, which predisposes to subsequent complications of therapy. The low rate of complete absolute neutrophil count and platelet recovery that we observed even in patients demonstrating a good marrow response and clearance of circulating blasts is unclear. Inhibition of c-kit kinase activity by imatinib could conceivably compromise normal hematopoietic recovery, but this is largely speculative.40 Development of resistance to imatinib has become the central
issue concerning the use of imatinib in advanced
BCR-ABL+ leukemias. In Ph+ ALL,
secondary resistance has been shown to be associated with point
mutations in the adenosine triphosphate binding domain or activation loop of the BCR-ABL oncoprotein in a large proportion, and
possibly the majority, of patients with lymphoid BCR-ABL+
leukemias.41,42 No point mutations have so far been
identified prior to imatinib therapy in patients showing primary
resistance to this agent, suggesting that mechanisms of resistance are
multifactorial. On the basis of in vitro models, genomic amplification
of the BCR-ABL fusion gene, increased expression of
the BCR-ABL protein, enhanced drug efflux due to up-regulation of
multidrug resistance proteins, or decreased cellular bioavailability of
imatinib have been postulated to play a role in
resistance.43-46 Further investigation of resistance
mechanisms is likely to suggest treatment strategies able to circumvent
or delay resistance in patients with advanced Ph+ acute
leukemia. This outlook is supported by the recent demonstration that
gene expression profiling of Ph+ ALL blasts by microarray
analysis is able to discriminate between imatinib-sensitive and
imatinib-refractory leukemias, and that genes related to apoptosis
pathways and cell cycle control While the lack of long-term efficacy of imatinib is at first glance sobering, the inability of a single agent to cure patients with the most unfavorable leukemic subtype following failure of primary therapy should come as no surprise. Rather, our observation of pronounced, albeit brief, hematologic responses in the majority of relapsed and refractory patients, in conjunction with imatinib's favorable safety profile encourages further investigation of imatinib as an adjunct to established antileukemic therapy. For example, the antileukemic activity of imatinib may open a window of opportunity for patients who are resistant to chemotherapy but are otherwise eligible for allogeneic SCT. In our study, 2 of 5 patients who were transferred to allogeneic SCT exhibit prolonged DFS; these encouraging but preliminary results need more extensive testing in prospective clinical trials. Because of its low toxicity, imatinib may also be useful as palliative treatment for patients who are not candidates for aggressive salvage therapy, and incorporation of this selective agent in trials in the setting of first-line treatment of Ph+ acute leukemia seems justified. Recent reports of additive or synergistic in vitro activity of imatinib in combination with cytotoxic agents active against ALL, such as daunorubicin or cytarabine,48-50 or in combination with other novel signal transduction modulators, such as farnesyl transferase inhibitors,51,52 support clinical trials to test the feasibility of combination regimens. Our current study provides the basis for investigations aimed at identifying combination therapies most appropriate in the various clinical settings of Ph+ acute leukemias.
We wish to thank the numerous coinvestigators, nursing staff, and clinical trial monitors who participated in this study. The contributions of data managers and programmers at Novartis Pharmaceuticals are gratefully acknowledged. Dr David Parkinson and Dr Greg Burke (Novartis) provided invaluable support, and we thank Marianne Rosamilia, Dr John Ford, and Dr Elisabeth Wehrle (Novartis) for their collaboration in implementing the protocol and reporting of the study results. Dr Thomas Brown provided valuable assistance in preparing the manuscript. We are also indebted to Ann Bolton for assisting in data analysis and preparation of the manuscript.
Submitted December 6, 2001; accepted April 17, 2002.
Prepublished online as Blood First Edition Paper, May 24, 2002; DOI 10.1182/blood-2001-12-0181.
Supported by a grant from Novartis.
S. F.-R., I. G., and R. C. are employees of Novartis Pharma.
This study was presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 1-5, 2000, San Francisco, CA.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: O. G. Ottmann, Medizinische Klinik III/Abteilung Hämatologie, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany; e-mail: ottmann{at}em.uni-frankfurt.de.
1.
Gleissner B, Gökbuget N, Bartram CR, et al.
Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis.
Blood.
2002;99:1536-1543 2. Maurer J, Janssen JW, Thiel E, et al. Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction. Lancet. 1991;337:1055-1058[CrossRef][Medline] [Order article via Infotrieve].
3.
Radich J, Gehly G, Lee A, et al.
Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation.
Blood.
1997;89:2602-2609
4.
Westbrook CA, Hooberman AL, Spino C, et al.
Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762).
Blood.
1992;80:2983-2990
5.
Schrappe M, Arico M, Harbott J, et al.
Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.
Blood.
1998;92:2730-2741 6. Paietta E, Racevskis J, Bennett JM, et al. Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: the Eastern Cooperative Oncology Group experience. Leukemia. 1998;12:1881-1885[CrossRef][Medline] [Order article via Infotrieve]. 7. Chan LC, Karhi KK, Rayter SI, et al. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature. 1987;325:635-637[CrossRef][Medline] [Order article via Infotrieve].
8.
Shtivelman E, Gale RP, Dreazen O, et al.
bcr-abl RNA in patients with chronic myelogenous leukemia.
Blood.
1987;69:971-973
9.
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
10.
Lugo TG, Pendergast AM, Muller AJ, Witte ON.
Tyrosine kinase activity and transformation potency of bcr-abl oncogene products.
Science.
1990;247:1079-1082
11.
Bedi A, Barber JP, Bedi GC, et al.
BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents.
Blood.
1995;86:1148-1158
12.
Sirard C, Laneuville P, Dick JE.
Expression of bcr-abl abrogates factor-dependent growth of human hematopoietic M07E cells by an autocrine mechanism.
Blood.
1994;83:1575-1585
13.
Sawyers CL.
Chronic myeloid leukemia.
N Engl J Med.
1999;340:1330-1340 14. Faderl S, Kantarjian HM, Thomas DA, et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2000;36:263-273[Medline] [Order article via Infotrieve]. 15. Hoelzer D, Gokbuget N. Recent approaches in acute lymphoblastic leukemia in adults. Crit Rev Oncol Hematol. 2000;36:49-58[Medline] [Order article via Infotrieve]. 16. Radich JP. Philadelphia chromosome-positive acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2001;15:21-36[CrossRef][Medline] [Order article via Infotrieve]. 17. Preti HA, O'Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994;97:60-65[CrossRef][Medline] [Order article via Infotrieve]. 18. Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2001;15:163-205[CrossRef][Medline] [Order article via Infotrieve].
19.
Dekker AW, van't Veer MB, Sizoo W, et al.
Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia.
J Clin Oncol.
1997;15:476-482
20.
Kantarjian HM, O'Brien S, Smith TL, et al.
Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.
J Clin Oncol.
2000;18:547-561 21. Snyder DS, Nademanee AP, O'Donnell MR, et al. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia. 1999;13:2053-2058[CrossRef][Medline] [Order article via Infotrieve]. 22. Dunlop LC, Powles R, Singhal S, et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant. 1996;17:365-369[Medline] [Order article via Infotrieve]. 23. Stockschlader M, Hegewisch-Becker S, Kruger W, et al. Bone marrow transplantation for Philadelphia-chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant. 1995;16:663-667[Medline] [Order article via Infotrieve].
24.
Cornelissen JJ, Carston M, Kollman C, et al.
Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome.
Blood.
2001;97:1572-1577
25.
Sierra J, Radich J, Hansen JA, et al.
Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood.
1997;90:1410-1414 26. Martin TG, Linker CA. Autologous stem cell transplantation for acute lymphoblastic leukemia in adults. Hematol Oncol Clin North Am. 2001;15:121-143[CrossRef][Medline] [Order article via Infotrieve]. 27. Martin TG, Gajewski JL. Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults. Hematol Oncol Clin North Am. 2001;15:97-120[CrossRef][Medline] [Order article via Infotrieve].
28.
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 29. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566[CrossRef][Medline] [Order article via Infotrieve]. 30. Gambacorti-Passerini C, le Coutre CP, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394[CrossRef][Medline] [Order article via Infotrieve].
31.
Druker BJ, Talpaz M, Resta DJ, et al.
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
32.
Kantarjian H, Sawyers C, Hochhaus A, et al.
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.
N Engl J Med.
2002;346:645-652
33.
Talpaz M, Silver RT, Druker BJ, et al.
Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.
Blood.
2002;99:1928-1937
34.
Sawyers CL, Hochhaus A, Feldman E, et al.
Imatinib mesylate induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.
Blood.
2002;99:3530-3539
35.
Druker BJ, Sawyers CL, Kantarjian H, et al.
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med.
2001;344:1038-1042 36. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol. 1990;8:813-819[Abstract].
37.
Bassan R, Lerede T, Barbui T.
Strategies for the treatment of recurrent acute lymphoblastic leukemia in adults.
Haematologica.
1996;81:20-36 38. Butturini A, Arlinghaus RB, Gale RP. BCR/ABL and leukemia. Leuk Res. 1996;20:523-529[CrossRef][Medline] [Order article via Infotrieve]. 39. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999;86:1216-1230[CrossRef][Medline] [Order article via Infotrieve].
40.
Buchdunger E, Cioffi CL, Law N, et al.
Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
J Pharmacol Exp Ther.
2000;295:139-145
41.
Hofmann WK, Jones LC, Lemp NA, et al.
Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation.
Blood.
2002;99:1860-1862 42. von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002;359:487-491[CrossRef][Medline] [Order article via Infotrieve].
43.
Gambacorti-Passerini C, Barni R, le Coutre P, et al.
Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571.
J Natl Cancer Inst.
2000;92:1641-1650
44.
le Coutre P, Tassi E, Varella-Garcia M, et al.
Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification.
Blood.
2000;95:1758-1766
45.
Mahon FX, Deininger MW, Schultheis B, et al.
Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance.
Blood.
2000;96:1070-1079
46.
Weisberg E, Griffin JD.
Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines.
Blood.
2000;95:3498-3505 47. Hofmann WK, de Vos S, Elashoff D, et al. Relation between resistance of Philadelphia-chromosome positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet. 2002;359:481-486[CrossRef][Medline] [Order article via Infotrieve]. 48. Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia. 2001;15:342-347[CrossRef][Medline] [Order article via Infotrieve].
49.
Kano Y, Akutsu M, Tsunoda S, et al.
In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents.
Blood.
2001;97:1999-2007
50.
Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ.
Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells.
Blood.
2000;96:3195-3199 51. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyltransferase inhibitor SCH66336 [abstract]. Blood 2002;98:2585a.
52.
Peters DG, Hoover RR, Gerlach MJ, et al.
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
Blood.
2001;97:1404-1412
In addition to the authors, the following investigators participated in this trial: B. Wassmann, MD, Medizinische Klinik III, Johann Wolfgang Goethe University, Frankfurt, Germany; M. O'Dwyer, MD, Portland, OR; Ron Paquette, Department of Medicine and Molecular Biology Institute, University of California at Los Angeles; J. F. Apperly, MD, London, United Kingdom; F. X. Mahon, MD, Laboratoire de Greffe de Moelle, Université Victor Segalen, Bordeaux, France; M. Schuster, MD, New York, NY; G. Rosti, MD, Bologna, Italy; Joachim Beck, MD, Universitätsklinikum, 3 Medizinische Klinik und Poliklinik, Mainz, Germany; Haifa-Kathrin Al-Ali, MD, Abteilung Hämatologie/Onkologie, Universität Leipzig, Germany; D. Russo, MD, Udine, Italy; Dr Monika Ebnoether, Division of Hematology, Universitätsklinik, Kantonspital, Basel, Switzerland; Dr Tanja Lahaye, III Medizinische Universitätsklinik Mannheim der Universität Heidelberg, Mannheim, Germany; and Professor S. J. Proctor and Dr A. L. Lennard, Department of Haematology, Royal Victoria Infirmary, University of Newcastle, United Kingdom.
© 2002 by The American Society of Hematology.
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|
 |
|
  Y. Chen, S. Agarwal, N. M. Shaik, C. Chen, Z. Yang, and W. F. Elmquist P-glycoprotein and Breast Cancer Resistance Protein Influence Brain Distribution of Dasatinib J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 956 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-Q. Xu, J.-M. Wang, S.-Q. Lu, L. Chen, J.-M. Yang, W.-P. Zhang, X.-M. Song, J. Hou, X. Ni, and H.-Y. Qiu Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population Haematologica, July 1, 2009; 94(7): 919 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kantarjian, J. Cortes, D.-W. Kim, P. Dorlhiac-Llacer, R. Pasquini, J. DiPersio, M. C. Muller, J. P. Radich, H. J. Khoury, N. Khoroshko, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up Blood, June 18, 2009; 113(25): 6322 - 6329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Castagnetti, F. Palandri, M. Amabile, N. Testoni, S. Luatti, S. Soverini, I. Iacobucci, M. Breccia, G. Rege Cambrin, F. Stagno, et al. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party Blood, April 9, 2009; 113(15): 3428 - 3434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. O'Brien, D. A. Thomas, and S. Faderl A La Carte Therapy of Specific Acute Lymphocytic Leukemia Subsets ASCO Educational Book, January 1, 2009; 2009(1): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Druker Translation of the Philadelphia chromosome into therapy for CML Blood, December 15, 2008; 112(13): 4808 - 4817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Liapis, J. Apostolidis, E. Charitaki, F. Panitsas, N. Harhalakis, and E. Nikiforakis Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Imatinib Ann. Pharmacother., December 1, 2008; 42(12): 1882 - 1886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zhang, W. Fu, S. Prabhu, J. C. Moore, J. Ko, J. W. Kim, B. J. Druker, V. Trapp, J. Fruehauf, H. Gram, et al. Inhibition of Polysome Assembly Enhances Imatinib Activity against Chronic Myelogenous Leukemia and Overcomes Imatinib Resistance Mol. Cell. Biol., October 15, 2008; 28(20): 6496 - 6509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Laport, J. C. Alvarnas, J. M. Palmer, D. S. Snyder, M. L. Slovak, A. M. Cherry, R. M. Wong, R. S. Negrin, K. G. Blume, and S. J. Forman Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen Blood, August 1, 2008; 112(3): 903 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Capdeville, T. Krahnke, A. Hatfield, J. M. Ford, I. Van Hoomissen, and I. Gathmann Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias Ann. Onc., July 1, 2008; 19(7): 1320 - 1326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Croce Oncogenes and Cancer N. Engl. J. Med., January 31, 2008; 358(5): 502 - 511. [Full Text] [PDF]
|
|
|
|
|
|
G. J.L. Kaspers and C. M. Zwaan Pediatric acute myeloid leukemia: towards high-quality cure of all patients Haematologica, November 1, 2007; 92(11): 1519 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. White, V. Saunders, A. Grigg, C. Arthur, R. Filshie, M. F. Leahy, K. Lynch, L. B. To, and T. Hughes Measurement of In Vivo BCR-ABL Kinase Inhibition to Monitor Imatinib-Induced Target Blockade and Predict Response in Chronic Myeloid Leukemia J. Clin. Oncol., October 1, 2007; 25(28): 4445 - 4451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Ottmann, H. Dombret, G. Martinelli, B. Simonsson, F. Guilhot, R. A. Larson, G. Rege-Cambrin, J. Radich, A. Hochhaus, A. M. Apanovitch, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study Blood, October 1, 2007; 110(7): 2309 - 2315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O'Hare, C. A. Eide, and M. W. N. Deininger Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia Blood, October 1, 2007; 110(7): 2242 - 2249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Quintas-Cardama, H. Kantarjian, S. O'Brien, G. Borthakur, J. Bruzzi, R. Munden, and J. Cortes Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure J. Clin. Oncol., September 1, 2007; 25(25): 3908 - 3914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Atallah, J.-B. Durand, H. Kantarjian, and J. Cortes Congestive heart failure is a rare event in patients receiving imatinib therapy Blood, August 15, 2007; 110(4): 1233 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Schiffer BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia N. Engl. J. Med., July 19, 2007; 357(3): 258 - 265. [Full Text] [PDF]
|
|
|
|
|
|
H. Pfeifer, B. Wassmann, A. Pavlova, L. Wunderle, J. Oldenburg, A. Binckebanck, T. Lange, A. Hochhaus, S. Wystub, P. Bruck, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) Blood, July 15, 2007; 110(2): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cortes, P. Rousselot, D.-W. Kim, E. Ritchie, N. Hamerschlak, S. Coutre, A. Hochhaus, F. Guilhot, G. Saglio, J. Apperley, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis Blood, April 15, 2007; 109(8): 3207 - 3213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Bartholomeusz, M. Talpaz, V. Kapuria, L. Y. Kong, S. Wang, Z. Estrov, W. Priebe, J. Wu, and N. J. Donato Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells Blood, April 15, 2007; 109(8): 3470 - 3478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Carpenter, D. S. Snyder, M. E. D. Flowers, J. E. Sanders, T. A. Gooley, P. J. Martin, F. R. Appelbaum, and J. P. Radich Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia Blood, April 1, 2007; 109(7): 2791 - 2793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Weisberg, L. Catley, R. D. Wright, D. Moreno, L. Banerji, A. Ray, P. W. Manley, J. Mestan, D. Fabbro, J. Jiang, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias Blood, March 1, 2007; 109(5): 2112 - 2120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. de Labarthe, P. Rousselot, F. Huguet-Rigal, E. Delabesse, F. Witz, S. Maury, D. Rea, J.-M. Cayuela, M.-C. Vekemans, O. Reman, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study Blood, February 15, 2007; 109(4): 1408 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rosti, I. Iacobucci, S. Bassi, F. Castagnetti, M. Amabile, D. Cilloni, A. Poerio, S. Soverini, F. Palandri, G. R. Cambrin, et al. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party Haematologica, January 1, 2007; 92(1): 101 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Thomas Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges Hematology, January 1, 2007; 2007(1): 435 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yokota, S. Kimura, S. Masuda, E. Ashihara, J. Kuroda, K. Sato, Y. Kamitsuji, E. Kawata, Y. Deguchi, Y. Urasaki, et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood, January 1, 2007; 109(1): 306 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Kantarjian, M. Talpaz, F. Giles, S. O'Brien, and J. Cortes New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance Ann Intern Med, December 19, 2006; 145(12): 913 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Puttini, A. M. L. Coluccia, F. Boschelli, L. Cleris, E. Marchesi, A. Donella-Deana, S. Ahmed, S. Redaelli, R. Piazza, V. Magistroni, et al. In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells Cancer Res., December 1, 2006; 66(23): 11314 - 11322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Wassmann, H. Pfeifer, N. Goekbuget, D. W. Beelen, J. Beck, M. Stelljes, M. Bornhauser, A. Reichle, J. Perz, R. Haas, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) Blood, September 1, 2006; 108(5): 1469 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. von Bubnoff, P. W. Manley, J. Mestan, J. Sanger, C. Peschel, and J. Duyster Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107) Blood, August 15, 2006; 108(4): 1328 - 1333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Talpaz, N. P. Shah, H. Kantarjian, N. Donato, J. Nicoll, R. Paquette, J. Cortes, S. O'Brien, C. Nicaise, E. Bleickardt, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med., June 15, 2006; 354(24): 2531 - 2541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kantarjian, F. Giles, L. Wunderle, K. Bhalla, S. O'Brien, B. Wassmann, C. Tanaka, P. Manley, P. Rae, W. Mietlowski, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N. Engl. J. Med., June 15, 2006; 354(24): 2542 - 2551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Tokarski, J. A. Newitt, C. Y. J. Chang, J. D. Cheng, M. Wittekind, S. E. Kiefer, K. Kish, F. Y.F. Lee, R. Borzillerri, L. J. Lombardo, et al. The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants Cancer Res., June 1, 2006; 66(11): 5790 - 5797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mishra, B. Zhang, J. M. Cunnick, N. Heisterkamp, and J. Groffen Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. Cancer Res., May 15, 2006; 66(10): 5387 - 5393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, C. Zang, M. H. Fenner, D. Liu, K. Possinger, H. P. Koeffler, and E. Elstner Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPAR{alpha}/{gamma} ligand TZD18 Blood, May 1, 2006; 107(9): 3683 - 3692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Koyama, S. Koschmieder, S. Tyagi, I. Portero-Robles, J. Chromic, S. Myloch, H. Nurnberger, T. Rossmanith, W.-K. Hofmann, D. Hoelzer, et al. Inhibition of phosphotyrosine phosphatase 1B causes resistance in BCR-ABL-positive leukemia cells to the ABL kinase inhibitor STI571. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2025 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cai, Y. Wang, O. G. Ottmann, P. J. Barth, A. Neubauer, and A. Burchert FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment Blood, March 1, 2006; 107(5): 2094 - 2097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Iacobucci, G. Rosti, M. Amabile, A. Poerio, S. Soverini, D. Cilloni, N. Testoni, E. Abruzzese, E. Montefusco, E. Ottaviani, et al. Comparison Between Patients With Philadelphia-Positive Chronic Phase Chronic Myeloid Leukemia Who Obtained a Complete Cytogenetic Response Within 1 Year of Imatinib Therapy and Those Who Achieved Such a Response After 12 Months of Treatment J. Clin. Oncol., January 20, 2006; 24(3): 454 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yanada, J. Takeuchi, I. Sugiura, H. Akiyama, N. Usui, F. Yagasaki, T. Kobayashi, Y. Ueda, M. Takeuchi, S. Miyawaki, et al. High Complete Remission Rate and Promising Outcome by Combination of Imatinib and Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia: A Phase II Study by the Japan Adult Leukemia Study Group J. Clin. Oncol., January 20, 2006; 24(3): 460 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kimura, H. Naito, H. Segawa, J. Kuroda, T. Yuasa, K. Sato, A. Yokota, Y. Kamitsuji, E. Kawata, E. Ashihara, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia Blood, December 1, 2005; 106(12): 3948 - 3954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Willis, T. Lange, S. Demehri, S. Otto, L. Crossman, D. Niederwieser, E. P. Stoffregen, S. McWeeney, I. Kovacs, B. Park, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy Blood, September 15, 2005; 106(6): 2128 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Armstrong and A. T. Look Molecular Genetics of Acute Lymphoblastic Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6306 - 6315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Wassmann, H. Pfeifer, M. Stadler, M. Bornhauser, G. Bug, U. J. Scheuring, P. Bruck, M. Stelljes, R. Schwerdtfeger, N. Basara, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) Blood, July 15, 2005; 106(2): 458 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Maziarz Ph+ ALL: another success for imatinib Blood, May 1, 2005; 105(9): 3388 - 3389. [Full Text] [PDF]
|
|
|
|
|
|
S. Lee, Y.-J. Kim, C.-K. Min, H.-J. Kim, K.-S. Eom, D.-W. Kim, J.-W. Lee, W.-S. Min, and C.-C. Kim The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia Blood, May 1, 2005; 105(9): 3449 - 3457. [Abstract] [Full Text] [PDF]
|
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M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF]
|
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S. Appel, A. Rupf, M. M. Weck, O. Schoor, T. H. Brummendorf, T. Weinschenk, F. Grunebach, and P. Brossart Effects of Imatinib on Monocyte-Derived Dendritic Cells Are Mediated by Inhibition of Nuclear Factor-{kappa}B and Akt Signaling Pathways Clin. Cancer Res., March 1, 2005; 11(5): 1928 - 1940. [Abstract] [Full Text] [PDF]
|
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N. von Bubnoff, D. R. Veach, H. van der Kuip, W. E. Aulitzky, J. Sanger, P. Seipel, W. G. Bornmann, C. Peschel, B. Clarkson, and J. Duyster A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor Blood, February 15, 2005; 105(4): 1652 - 1659. [Abstract] [Full Text] [PDF]
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O. G. Ottmann and B. Wassmann Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Hematology, January 1, 2005; 2005(1): 118 - 122. [Abstract] [Full Text] [PDF]
|
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M. Wadleigh, D. J. DeAngelo, J. D. Griffin, and R. M. Stone After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies Blood, January 1, 2005; 105(1): 22 - 30. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
M. Towatari, M. Yanada, N. Usui, J. Takeuchi, I. Sugiura, M. Takeuchi, F. Yagasaki, Y. Kawai, S. Miyawaki, S. Ohtake, et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia Blood, December 1, 2004; 104(12): 3507 - 3512. [Abstract] [Full Text] [PDF]
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M. A. Champagne, R. Capdeville, M. Krailo, W. Qu, B. Peng, M. Rosamilia, M. Therrien, U. Zoellner, S. M. Blaney, and M. Bernstein Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study Blood, November 1, 2004; 104(9): 2655 - 2660. [Abstract] [Full Text] [PDF]
|
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I. J. Griswold, L. J. Shen, P. La Rosee, S. Demehri, M. C. Heinrich, R. M. Braziel, L. McGreevey, A. D. Haley, N. Giese, B. J. Druker, et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis Blood, November 1, 2004; 104(9): 2912 - 2918. [Abstract] [Full Text] [PDF]
|
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 J. Lee, S. N. Sait, and M. Wetzler Characterization of dendritic-like cells derived from t(9;22) acute lymphoblastic leukemia blasts Int. Immunol., October 1, 2004; 16(10): 1377 - 1389. [Abstract] [Full Text] [PDF]
|
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J. P. Radich Targeting ALL leukemia Blood, September 1, 2004; 104(5): 1235 - 1236. [Full Text] [PDF]
|
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|
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M. Harata, Y. Soda, K. Tani, J. Ooi, T. Takizawa, M. Chen, Y. Bai, K. Izawa, S. Kobayashi, A. Tomonari, et al. CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells Blood, September 1, 2004; 104(5): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
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Y. Soda, K. Tani, Y. Bai, M. Saiki, M. Chen, K. Izawa, S. Kobayashi, S. Takahashi, K. Uchimaru, T. Kuwabara, et al. A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia Blood, July 15, 2004; 104(2): 356 - 363. [Abstract] [Full Text] [PDF]
|
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M. A. Weiss Hyper-CVADinib for Ph+ ALL Blood, June 15, 2004; 103(12): 4377 - 4377. [Full Text] [PDF]
|
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D. A. Thomas, S. Faderl, J. Cortes, S. O'Brien, F. J. Giles, S. M. Kornblau, G. Garcia-Manero, M. J. Keating, M. Andreeff, S. Jeha, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate Blood, June 15, 2004; 103(12): 4396 - 4407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Neville, R. A. Parise, P. Thompson, A. Aleksic, M. J. Egorin, F. M. Balis, L. McGuffey, C. McCully, S. L. Berg, and S. M. Blaney Plasma and Cerebrospinal Fluid Pharmacokinetics of Imatinib after Administration to Nonhuman Primates Clin. Cancer Res., April 1, 2004; 10(7): 2525 - 2529. [Abstract] [Full Text] [PDF]
|
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|
G. Rosti, G. Martinelli, S. Bassi, M. Amabile, E. Trabacchi, B. Giannini, D. Cilloni, B. Izzo, A. De Vivo, N. Testoni, et al. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia Blood, March 15, 2004; 103(6): 2284 - 2290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Okada, S. Adachi, T. Imai, K.-i. Watanabe, S.-y. Toyokuni, M. Ueno, A. S. Zervos, G. Kroemer, and T. Nakahata A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity Blood, March 15, 2004; 103(6): 2299 - 2307. [Abstract] [Full Text] [PDF]
|
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B. Wassmann, H. Pfeifer, U. J. Scheuring, A. Binckebanck, N. Gokbuget, J. Atta, P. Bruck, H. Rieder, C. Schoch, L. Leimer, et al. Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib Blood, February 15, 2004; 103(4): 1495 - 1498. [Abstract] [Full Text] [PDF]
|
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S. Appel, A. M. Boehmler, F. Grunebach, M. R. Muller, A. Rupf, M. M. Weck, U. Hartmann, V. L. Reichardt, L. Kanz, T. H. Brummendorf, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells Blood, January 15, 2004; 103(2): 538 - 544. [Abstract] [Full Text] [PDF]
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 K. Takeuchi, K. Koike, T. Kamijo, S. Ishida, Y. Nakazawa, Y. Kurokawa, K. Sakashita, T. Kinoshita, S. Matsuzawa, M. Shiohara, et al. STI571 inhibits growth and adhesion of human mast cells in culture J. Leukoc. Biol., December 1, 2003; 74(6): 1026 - 1034. [Abstract] [Full Text]
|
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T. Tanvetyanon and S. Nand Overcoming Recurrent Cutaneous Reactions from Imatinib Using Once-Weekly Dosing Ann. Pharmacother., December 1, 2003; 37(12): 1818 - 1820. [Abstract] [Full Text] [PDF]
|
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B. J. Druker Imatinib As a Paradigm of Targeted Therapies J. Clin. Oncol., December 1, 2003; 21(90230): 239s - 245. [Full Text] [PDF]
|
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|
H. Pfeifer, B. Wassmann, W.-K. Hofmann, M. Komor, U. Scheuring, P. Bruck, A. Binckebanck, E. Schleyer, N. Gokbuget, T. Wolff, et al. Risk and Prognosis of Central Nervous System Leukemia in Patients with Philadelphia Chromosome-Positive Acute Leukemias Treated with Imatinib Mesylate Clin. Cancer Res., October 15, 2003; 9(13): 4674 - 4681. [Abstract] [Full Text] [PDF]
|
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|
|
S. Lee, D.-W. Kim, Y.-J. Kim, N.-G. Chung, Y.-L. Kim, J.-Y. Hwang, and C.-C. Kim Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia Blood, October 15, 2003; 102(8): 3068 - 3070. [Abstract] [Full Text] [PDF]
|
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N. von Bubnoff, D. R. Veach, W. T. Miller, W. Li, J. Sanger, C. Peschel, W. G. Bornmann, B. Clarkson, and J. Duyster Inhibition of Wild-Type and Mutant Bcr-Abl by Pyrido-Pyrimidine-Type Small Molecule Kinase Inhibitors Cancer Res., October 1, 2003; 63(19): 6395 - 6404. [Abstract] [Full Text] [PDF]
|
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|
|
J. Kuroda, S. Kimura, H. Segawa, Y. Kobayashi, T. Yoshikawa, Y. Urasaki, T. Ueda, F. Enjo, H. Tokuda, O. G. Ottmann, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate Blood, September 15, 2003; 102(6): 2229 - 2235. [Abstract] [Full Text] [PDF]
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 M. W. N. Deininger and B. J. Druker Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib Pharmacol. Rev., September 1, 2003; 55(3): 401 - 423. [Abstract] [Full Text] [PDF]
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M. W.N. Deininger, S. G. O'Brien, J. M. Ford, and B. J. Druker Practical Management of Patients With Chronic Myeloid Leukemia Receiving Imatinib J. Clin. Oncol., April 15, 2003; 21(8): 1637 - 1647. [Abstract] [Full Text] [PDF]
|
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B. Sanchez-Gonzalez, J. C. Pascual-Ramirez, P. Fernandez-Abellan, I. Belinchon-Romero, C. Rivas, and G. Vegara-Aguilera Severe skin reaction to imatinib in a case of Philadelphia-positive acute lymphoblastic leukemia Blood, March 15, 2003; 101(6): 2446 - 2446. [Full Text] [PDF]
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U. J. Scheuring, H. Pfeifer, B. Wassmann, P. Bruck, J. Atta, E. K. Petershofen, B. Gehrke, H. Gschaidmeier, D. Hoelzer, and O. G. Ottmann 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) Blood, January 1, 2003; 101(1): 85 - 90. [Abstract] [Full Text] [PDF]
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D. Hoelzer, N. Gokbuget, O. Ottmann, C.-H. Pui, M. V. Relling, F. R. Appelbaum, J. J.M. van Dongen, and T. Szczepanski Acute Lymphoblastic Leukemia Hematology, January 1, 2002; 2002(1): 162 - 192. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
ALL, but these responses are not
durable.
by hematologic response.
This analysis of overall survival by best achieved hematologic
response on treatment included 14 patients with CHR or marrow response,
15 patients with partial response, and 14 patients who were treated for
at least 4 weeks but did not have documented response (5 patients were
excluded). Whereas median survival was 9.2 months for patients who had
CHR/marrow response and 7.1 months for patients with partial response,
all of the nonresponder died and their median survival was only 3.6 months (P < .001).