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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-02-0360.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Medizinische Klinik III, Abteilung für
Hämatologie und Onkologie of the Johann Wolfgang
Goethe-Universität, Frankfurt, Germany; Red Cross
Blood Donation Service, Oldenburg, Germany; and Novartis
Pharma AG, Nürnberg, Germany.
The Abl kinase inhibitor imatinib mesylate (STI571)
has significant and rapid antileukemic activity in Philadelphia
chromosome/Bcr-Abl-positive acute lymphoblastic leukemia
(Ph+ ALL) but such activity is usually of short
duration except for a small proportion of patients. To determine the
prognostic significance of early Bcr-Abl levels and changes in
peripheral blood (PB) and bone marrow (BM), serial samples of 56 patients with relapsed or refractory Ph+ ALL treated
in phase 2 trials of imatinib were analyzed by quantitative polymerase chain reaction (PCR). Imatinib induced a complete
hematologic response (CHR) or complete marrow response (marrow-CR) in
40 patients (good responders) and a partial (n = 2) or no (n = 14)
remission in the remaining patients (poor responders). Compared
with baseline, the median Bcr-Abl/glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) ratios decreased significantly in PB by
2.65, 2.64, and 3.11 log steps after 2 weeks, 4 weeks, and at the time
of best response, respectively. In BM, the decline of median
Bcr-Abl/GAPDH was 0.75, 1.37, and 2.78 logs, respectively. Thus,
Bcr-Abl levels decreased more rapidly in PB than in BM (median time to
best level 31 vs 39 days). Low Bcr-Abl/GAPDH ratios below
10 In adult patients with newly diagnosed Philadelphia
chromosome/Bcr-Abl-positive acute lymphoblastic leukemia
(Ph+ ALL), current chemotherapy regimens induce complete
remissions (CR) in 70% or more, but most patients relapse within the
first year of treatment (median, 9 months).1 Disease-free
survival with intensive chemotherapy alone ranges from 0% to
15%,2-4 and outcome in relapsed and refractory patients
is even inferior. Allogeneic stem cell transplantation (SCT) is
at present the only curative treatment option, although it is
associated with substantial morbidity and mortality as well as high
relapse rates ranging from 29% to 71%.5 Recently, the
ABL protein tyrosine kinase inhibitor imatinib mesylate (also referred
to as Glivec or STI571) has been demonstrated to induce a complete
hematologic response (CHR) or complete marrow response
(marrow-CR) in 60% to 70% of patients with relapsed or refractory
acute Ph+ ALL, including patients previously undergoing
transplantation. Unfortunately, the median time to progression is only
2 to 2.5 months overall6 and 3 months in CHR and
marrow-CR patients, reflecting the development of resistance to
imatinib.7,8 As a consequence, most patients with
advanced Ph+ ALL in whom imatinib induces a complete
remission will require additional treatment, of which allogeneic SCT is
the preferred modality. Because results of allogeneic SCT correlate
with disease status at the time of conditioning, additional treatments
additive or synergistic to imatinib are frequently
necessary9-11 to ensure CR at the time of SCT. A minority
of patients remains in remission for longer than 4 to 6 months.
Accordingly, it would be important to predict the duration of response
to imatinib at an early time point to guide timing and aggressiveness
of additional therapies.
Sensitive quantitative reverse transcription-polymerase chain reaction
(qRT-PCR) techniques that enable detection of a single leukemia cell in
a background of 104 to 106 normal cells have
revealed that the level of residual leukemia reflects the probability
of relapse. An inverse relationship between minimal residual disease
(MRD) level after induction chemotherapy and length of remission has
been documented in large cohorts of Ph To date, it is not known whether peripheral blood (PB) or bone
marrow (BM) samples and whether absolute Bcr-Abl levels or the
magnitude of decline are suitable predictive parameters for clinical
outcome in Ph+ ALL, especially during imatinib therapy. It
was therefore the major aim of this study to determine the prognostic
relevance of Bcr-Abl expression and reduction in BM and PB samples
after 2 and 4 weeks of imatinib treatment in regard to type and
duration of response for Ph+ ALL patients.
Patients and study design
Imatinib was started as a single agent at a daily oral dose of 400 mg
or 600 mg. Prednisone was permitted in patients who previously
underwent transplantation if it was needed to control graft-versus-host
disease (GVHD). Imatinib administration was continued as long
as a clinical benefit was evident unless adverse events or toxicity as
defined by the protocol necessitated interruption or termination of treatment.
A CHR was defined as a reduction of marrow blasts to less than 5% with
no blasts in peripheral blood, hematopoietic recovery with absolute
neutrophil counts (ANCs) and platelet counts at least
1.5 × 109/L and at least 100 × 109/L,
respectively, and no evidence of extramedullary disease. A Marrow-CR
was defined as a reduction of marrow blasts to less than 5% with no
blasts in peripheral blood, no evidence of extramedullary involvement,
but incomplete hematopoietic recovery. Partial response (PR) was
defined as reduction of bone marrow blasts to 6% to 25%. Relapse was
defined as disease recurrence with bone marrow blasts exceeding 5% or
reappearance of PB blasts in a patient who had achieved a CHR or
marrow-CR. Patients were considered refractory to imatinib if there was
no elimination of PB blasts or of extramedullary disease and/or a
failure to reduce marrow blasts to below 25%.
For the purpose of this MRD study, to establish an early predictive
parameter a good response was defined by CHR or marrow-CR and a poor
response by PR or refractory disease.
Molecular remission was defined by negative quantitative PCR reactions
at good sensitivity (> 105 glyceraldehyde-3-phosphate
dehydrogenase [GAPDH] copies) in both BM and PB for at least
1 month.
All patients had received chemotherapy, 18 patients allogeneic SCT, and
4 autologous SCT prior to imatinib. At start of imatinib, 1 patient was
in marrow-CR, 2 patients in PR, 22 in first relapse, 10 in
second relapse, 1 in fourth relapse, and 20 refractory (19 in primary
chemotherapy). Nine patients in first relapse (additional autologous
SCT: n = 1), 8 patients in second relapse (SCT: 3 in CR1; 5 in CR2),
and 1 in fourth relapse (2 autologous, 3 allogeneic SCT) had
undergone prior allogeneic SCT. One patient in first relapse received
an autologous SCT in addition to allogeneic SCT, another patient in
second relapse received 3 autologous SCT, and another patient 1 in CR1.
Four patients received intrathecal chemotherapy (15 mg methotrexate, 40 mg cytarabine, 10 mg prednisone) during imatinib therapy because of
central nervous (CNS) system relapse (n = 3) or as a prophylaxis
(n = 1). One additional patient had CNS relapse concomittant with
marrow relapse. Immunosuppression had been withdrawn prior to imatinib
therapy in 15 of 18 patients having undergone transplantation. Only in
4 of these 18 patients did GVHD occur during imatinib
treatment. Thirteen patients who were taken off the study to
receive an allogeneic SCT discontinued imatinib 2 days prior to
myeloablative therapy and were censored for our present analysis of
time to progression at this time point: 10 patients in marrow-CR or CHR
achieved by imatinib (28, 38, 41, 43, 49, 55, 57, 66, 66, and 67 days
after starting imatinib), 1 patient after reaching marrow-CR with
imatinib and relapsing (discontinued after 31 days), 1 patient with
partial remission (53 days), and 1 patient with cytoreduction (58 days).
Thirty-nine patients expressed minor Bcr-Abl (e1a2), 10 patients major
Bcr-Abl (b2a2), and 7 patients major Bcr-Abl (b3a2).
Cell samples and real-time PCR
Statistical analysis Statistical analysis of differences in Bcr-Abl levels and changes between good and poor responders was performed by nonparametric Mann-Whitney U test. The Fisher exact probability test was employed to detect whether Bcr-Abl levels below a set threshold were significantly associated with good responses versus Bcr-Abl levels above this threshold with poor responses. Time to progression and overall survival were evaluated by Kaplan-Meier plots and log-rank tests. For Kaplan-Meier curves, time to progression (TTP) or survival was calculated from the time the particular PB or BM specimen was taken to relapse, death, or censoring, respectively. Logarithmic changes of Bcr-Abl levels with negative PCR results were calculated by substituting the value of the particular sensitivity of the PCR reaction for the negative result. These values were depicted as empty symbols in diagrams.
Hematologic response during imatinib treatment Forty of 56 patients achieved a good response after at least 4 weeks of imatinib. Sixteen patients displayed a poor response due to persisting PB blasts (n = 4) or more than 5% blasts in BM. At the time of analysis, 24 of 40 patients with good response had relapsed after a median time of 104.5 days (range, 45 to 441 days) of imatinib therapy. Continuous CR was observed in 4 patients at the time of analysis, with a duration of follow-up at 228, 257, 524, and 746 days, respectively. Additionally, one death due to pneumonia and septicemia occurred in a well-responding patient with a history of allogeneic stem cell transplantation. Thirteen patients were transferred to SCT early at a median of 49 days (range, 26 to 67 days) after starting imatinib and censored at the start of conditioning. Median time to progression of poor responders was 43.5 days (range, 19 to 62 days).Correlation of Bcr-Abl levels in PB and BM with clinical response To determine the degree with which Bcr-Abl levels and kinetics corresponded to clinical response, we analyzed PB and BM samples collected serially throughout imatinib treatment. The median Bcr-Abl/GAPDH ratio prior to study did not differ between patients with subsequent good or poor response (Figure 1). Good responders showed a rapid significant decline of Bcr-Abl levels in PB, with the major reduction already seen after 2 weeks (2.65 logs). Although a further decline of Bcr-Abl level was observed in a small number of patients after 4 weeks, turning undetectable in some, the median Bcr-Abl level did not change between 2 and 4 weeks (again, 2.64 logs lower than at start). The median Bcr-Abl level at the time of best response was 3.11 logs below the median at the beginning of treatment. Conspicuously, the range of Bcr-Abl levels spanned several log steps (about 7) in good responders even at the time of best response (Figure 1).
In BM, a similar pattern of Bcr-Abl levels was observed and the median level at the time of best response was close to that of PB samples at best (Figure 1). However, the kinetics of significantly decreasing Bcr-Abl levels in BM of good responders were much slower and had not even by far reached the best level at 4 weeks (Figure 1). The median Bcr-Abl/GAPDH ratio decreased by 0.75 logs, 1.37 logs, and 2.78 logs after 2 and 4 weeks and at best response, respectively, compared with levels prior to imatinib therapy. Good responders reached best Bcr-Abl levels 31 days (range, 13 to 140 days) in PB and 39 days (range, 12 to 166 days) in BM after starting imatinib. As expected, poor responders (PR or failure) showed no decrease but rather an increase of Bcr-Abl expression in BM. However, even poor responders showed some reduction of median Bcr-Abl levels in PB at 2 and 4 weeks, indicating a low degree effect of imatinib in this compartment (Figure 1). Relation between individual Bcr-Abl changes in PB and BM and subsequent remission After displaying Bcr-Abl levels (Figure 1) to analyze the kinetics of MRD response collectively in clinical response groups, we also evaluated the kinetics of leukemic blasts by Bcr-Abl expression in individual patients in relation to clinical outcome. Therefore, we determined the change of Bcr-Abl/GAPDH ratio for each patient at 2 and 4 weeks and at best compared with start (Figure 2). Individual Bcr-Abl changes basically confirmed the pattern described for Bcr-Abl levels. There were gradually increasing significant reductions of Bcr-Abl/GAPDH in BM of good responders by median 0.94, 1.45, and 2.40 logs at 2 and 4 weeks and at best, respectively. Compared with BM, reductions of
Bcr-Abl in PB of good responders are much more pronounced after 2 weeks
(1.56 logs) without further change after 4 weeks (1.45 logs) almost
reaching the maximum degree (1.93 logs). Interestingly, the
median of changes shows a stronger best response in BM than in PB
(2.40 vs 1.93 logs). Despite Bcr-Abl increases by median in BM of
poor responders, those patients showed some early Bcr-Abl decreases
(1.53 logs) after 2 weeks in PB (Figure 2). Therefore, imatinib
appears to exert a faster or stronger effect on leukemic blasts in
PB.
Predictive potential of Bcr-Abl levels at 2 weeks in terms of response In view of the highly significant differences between Bcr-Abl levels in good and poor responders after 2 and 4 weeks, we examined whether early Bcr-Abl quantification could be used to predict subsequent quality of remission. Because the time to identify good and poor responders was 4 weeks in general, Bcr-Abl determinations only before this time (eg, after 2 weeks of imatinib treatment) appeared to be useful in predicting the type of response. Bcr-Abl/GAPDH ratios below 10 4 in PB samples after 2 weeks of imatinib
treatment were significantly (P = .0003) associated with
good responses at 4 weeks opposed to higher levels and poor responses
(Table 1). Although low PB levels
(< 104) were found only in good responders (n = 19),
8 of 17 patients with high PB levels ( 104) finally
attained a good response. Thus, very early low Bcr-Abl levels
(< 104) in PB are a strongly prognostic indicator of
subsequent good response, whereas high levels are only a weak indicator
of subsequent poor response.
Statistical analysis revealed that Bcr-Abl levels in BM below
10
In contrast, Bcr-Abl changes in PB after 2 weeks did not and changes in
BM (< Prognostic role of Bcr-Abl levels regarding response duration and survival We wondered whether qRT-PCR of Bcr-Abl could be used to predict response duration during imatinib therapy. This issue is important in regard to practical implications concerning whether allogeneic stem cell transplantation, donor lymphocyte infusions, or other treatment options have to be initiated. Bcr-Abl levels after 4 weeks of imatinib were evaluated for their predictive potential because preliminary data had shown that this time point was superior to that at 2 weeks. On the other hand, later time points after 4 weeks could not be considered to be predictive due to frequent early relapses. Kaplan-Meier plots of good responders with low Bcr-Abl levels at 4 weeks versus those with high levels revealed a significant difference regarding time to progression (Figure 3). A Bcr-Abl/GAPDH ratio of 102 was the significantly
discriminatory threshold between early and late progressors
(P = .0002). Whereas median time to progression in
patients with Bcr-Abl levels below 102 amounted to 139 days, it was only 22 days in patients with Bcr-Abl levels
102 or more.
Bcr-Abl reductions in BM samples after 4 weeks did not discriminate prognostic groups significantly. Neither Bcr-Abl levels nor changes in PB samples of good responders at 4 weeks were associated with significant differences in time to progression for any threshold. A further important prognostic criterion is overall survival. However, neither assignment by Bcr-Abl level nor by Bcr-Abl change in PB or BM at 4 weeks, respectively, generated significantly different patient groups in regard to overall survival. Relevance of negative qRT-PCR findings Negative quantitative TaqMan PCR results were considered only if the sensitivity of the particular PCR reaction was adequate by sufficient GAPDH copy numbers (> 105). By these criteria, 14 patients exhibited at least 1 negative PCR result either in PB (13 patients; 42 samples) or in BM (3 patients; 13 samples). There were 10 simultaneously taken paired samples from PB and BM (8 patients) of which 9 were PBBM+ and 1 was
PB+BM. Thus, PCR results from BM samples are
more sensitive.
Nine paired PCR results simultaneously negative in both PB and BM were
found in 2 patients. One of these with an allogeneic stem cell graft
became Bcr-Abl Overall, 10 of the 14 patients in whom imatinib induced Bcr-Abl negativity in either PB or BM relapsed except for the patient in long-term molecular remission (see previous paragraph), 1 good responder dying due to septicemia, and 2 patients who were subjected to SCT early. The time interval between most recently negative PCR and relapse was 112 and 66 days for BM and by a median of 81 days (range, 24 to 286 days) for PB samples (9 patients).
Imatinib induces hematologic responses in 60% to 70% of patients
with relapsed or refractory Ph+ ALL, but remission quality
is usually poor as indicated by a median response duration of only 2 to
3 months.6,27 The ability to identify early the subgroup
of patients who will fail to achieve a hematologic response and to
differentiate between patients with a high probability of early relapse
and those likely to have a more sustained response could considerably
assist patient management. To determine whether quantitative real-time
PCR analysis of Bcr-Abl transcripts could be used to monitor the
efficacy of imatinib and predict response and response duration, we
examined serial PB and BM samples from 56 patients with relapsed or
refractory Ph+ ALL treated with imatinib. In good
responders, Bcr-Abl levels decreased more rapidly in PB than in BM.
Median Bcr-Abl levels were consistently lower in PB than in BM after 2 and 4 weeks and at the time of best molecular response, although at the
latter time point the median log reduction was greater in BM than in PB. Moreover, an early decrease of Bcr-Abl/GAPDH ratios to below 10 It has been shown that analysis of PB samples from patients with ALL
might cause an underestimation of MRD levels compared with
BM.19 Our results are similar to data by Brisco et al, which showed that the median MRD level in PB was approximately 12 times
lower than the median in BM at the end of induction therapy of children
with Bcr-Abl MRD analysis was also applied to characterize the pharmacodynamic
efficacy of imatinib. Bcr-Abl quantitative MRD results have not been
published for imatinib-treated Ph+ ALL patients elsewhere,
but there are data on Bcr-Abl levels under chemotherapy19
that may serve for comparison. MRD levels of minor Bcr-Abl decreased in
responding patients by a median of It is noteworthy that negative PCR results occur in BM or PB only sporadically and even in case of good sensitivity have no significance in terms of long-term outcome. BM analysis proved to be more sensitive than PB, and simultaneous PCR negativity in both compartments was exceedingly rare. Such a complete molecular response was sustained for at least 4 weeks in only 2 patients, 1 of whom nevertheless relapsed 3 months later. Only one of the patients analyzed in this study remains in ongoing continuous complete molecular and hematologic remission, as assessed in parallel PB and BM samples, more than 24 months after initiating imatinib for relapsed Ph+ ALL. Interestingly, one patient previously undergoing transplantation is in ongoing hematologic remission at 524 days despite evidence of MRD with Bcr-Abl expression constant at a low level and no evidence of GVHD. This observation is reminiscent of findings by Radich et al,22 who showed that detection of Bcr-Abl transcripts by RT-PCR after allogeneic stem cell transplantation was highly predictive of eventual relapse in patients with p185 (e1a2) Ph+ ALL but not necessarily in patients with p210 (b3a2)-positive ALL. Possibly, these differences reflect that less proliferative capacity is mediated by p210 (b3a2) compared with p185 (e1a2) as shown in a mouse model.33 Taken together, our data emphasize that most patients with relapsed or refractory Ph+ ALL who are treated with imatinib as a single agent eventually relapse even if a complete molecular response of several weeks' duration was achieved. More prolonged PCR negativity of several months' duration confirmed at a good level of sensitivity in both PB and BM may indicate long-term remission, but criteria on which to base safe discontinuation of imatinib remain to be established. Although occasional patients may experience prolonged hematologic remissions despite persistent MRD positivity, continued detection of Bcr-Abl transcripts after the first few weeks of imatinib therapy should prompt additional therapy. Our observation that the level of Bcr-Abl transcripts determined 4 weeks after starting imatinib is predictive of remission duration but not of overall survival may be due to confounding effects of subsequent therapy (eg, allogeneic SCT or salvage therapy). An alternative explanation is that the mechanisms underlying secondary resistance to imatinib differ from those responsible for up-front refractoriness to this kinase inhibitor; this would preclude detection by techniques that primarily assess the initial blast population prior to or during early stages of treatment (eg, by gene expression profiling34 or PCR-based MRD analysis). In accordance with this hypothesis, point mutations in the adenosine triphosphate (ATP)-binding domain of Abl have been identified as a frequent cause of secondary resistance7 but have so far not been reported prior to imatinib treatment. Given the often rapid kinetics of relapse in Ph+ ALL, it is therefore plausible that the outgrowth of a mutant ALL clone due to the selective pressure of imatinib cannot be anticipated by assessing the initially dominant population of leukemic blasts and its early response to treatment. In summary, determination of Bcr-Abl levels by quantitative real-time RT-PCR was able to discriminate different prognostic groups among refractory or relapsed Ph+ ALL treated with imatinib. Low Bcr-Abl levels in PB and BM after 2 weeks of imatinib were predictive of achieving a CHR or marrow-CR. Moreover, low Bcr-Abl levels in BM after 4 weeks of treatment were prognostic to identify patients with prolonged responses. Although these results do not obviate the need for employing alternative therapies in conjunction with imatinib (eg, allogeneic SCT or combination therapy), the results of MRD analysis performed at small intervals during initial treatment with imatinib may guide treatment decisions regarding the timing and/or intensity of additional therapeutic modalities. In this respect, the optimal cutoff has yet to be validated. Serial determination of Bcr-Abl transcripts by quantitative RT-PCR may also be useful for assessing the efficacy of combination strategies incorporating imatinib, some of which are being evaluated in ongoing clinical studies.
We are indebted to S. Kriener for the pathological review of marrow histologies, Anja Binckebank for coordinating the study, and Holger Thüringer, Anja Goodwin, Heike Nürnberger, Martine Pape, and Sandra Wagner for their excellent technical assistance.
Submitted February 14, 2002; accepted August 1, 2002.
Prepublished online as Blood First Edition Paper, August 22, 2002; DOI 10.1182/blood-2002-02-0360.
Supported by grants from the Adolf Messer Stiftung, Germany; Kompetenznetzwerk akute und chronische Leukämien, Mannheim, Germany; and Novartis AG, Nürnberg, Germany.
H.G. is employed by Novartis AG, which has developed Glivec.
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: Urban J. Scheuring, Medizinische Klinik III, Abteilung für Hämatologie und Onkologie der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-6090 Frankfurt, Germany; e-mail: scheuring{at}em.uni-frankfurt.de.
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© 2003 by The American Society of Hematology.
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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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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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Top
Abstract
Introduction
) and poor
responders (
) separately. The medians are represented by lines, and
negative PCR results are shown (
) at the level of the particular
sensitivity of the PCR reaction.
Childhood Leukemia Cooperative Group.
N Engl J Med.
1998;339:591-598