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1
EVOLVING CONCEPTS IN THE MANAGEMENT OF CHRONIC MYELOID
LEUKEMIA. RECOMMENDATIONS FROM AN EXPERT PANEL ON BEHALF OF
THE EUROPEAN LEUKEMIANET.
Running title: Management of Chronic Myeloid Leukemia.
Michele Baccarani1, Giuseppe Saglio2, John Goldman3, Andreas Hochhaus4, Bengt Simonsson5,
FrederickAppelbaum6, Jane Apperley7, Francisco Cervantes8, Jorge Cortes9, Michael Deininger10,
Alois Gratwohl11, François Guilhot12, Mary Horowitz13, Timothy Hughes14, Hagop Kantarjian9,
Richard Larson15, Dietger Niederwieser16, Richard Silver17, Rudiger Hehlmann4
Authors institutional affiliations
1. M. Baccarani: Department of Hematology/Oncology “L. and A. Seràgnoli”, University of
Bologna, Bologna, Italy
2. G. Saglio: Universityof Turinat Orbassano, Turin, Italy
3. J. Goldman: Hematology Branch, National Heart, Lung & Blood Institute, NIH, Bethesda, MD,
USA
4. A. Hochhaus, R. Hehlmann: Faculty of Clinical Medicine Mannheim, University of Heidelberg,
Mannheim, Germany
5. B. Simonsson: Department of Hematology, UniversityHospital, Uppsala, Sweden
6. F. Appelbaum: FredHutchinsonCancerResearchCenter, Seattle, WA, USA
7. J. Apperley: Department of Hematology, HammersmithHospital, London, UK
8. F. Cervantes: Hematology Department, Hospital Clinic, IDIBAPS, Universityof Barcelona,
Barcelona, Spain
9. J. Cortes, H. Kantarjian: MD AndersonCancerCenter, Houston, TX, USA
10. M. Deininger: Oregon Health & Science University Cancer Institute, Portland, OR, USA
11. A. Gratwohl: Hematology, UniversityHospital, Basel, Switzerland
12. F. Guilhot: Oncology, Hematology and Cell Therapy, Medical Oncology, EA 3805 and Clinical
Research Centre, CHULa Miletrie,Poitiers, France
13. M. Horowitz: Centre for International Blood and Marrow Transplant Research, MedicalCollege
of Wisconsin, Milwaukee, IL, USA
14. T. Hughes: Instituteof Medicaland Veterinary Science, Adelaide, Australia
15. R. Larson: Universityof Chicago, Chicago, IL, USA
16. D. Niederwieser: Department of Hematology and Oncology, Universityof Leipzig, Leipzig,
Germany
Blood First Edition Paper, prepublished online May 18, 2006; DOI 10.1182/blood-2006-02-005686
Copyright © 2006 American Society of Hematology
2
17. R. Silver: New York Presbyterian-Weill Cornell Medical Center, New York, NY, USA
Work supported by the EU, Sixth Framework Programme, Contract No. LSHC-CT-2004-503216
(European LeukemiaNet)
Word count: Abstract 206
Manuscript 5414
Acknowledgement: The scientific contributions of Professor Jörg Hasford and of many members of
the European LeukemiaNet, Work Package 4, are acknowledged.
The scientific and the technical assistance of Simona Soverini, PhD, Alessandra Dorigo, PhD,
Chiara Ferri, and Katia Vecchi is also kindly acknowledged.
Correspondence:
Michele Baccarani, MD
Department of Hematology-Oncology “L. and A. Seràgnoli”
S.Orsola-MalpighiHospital
Via Massarenti 9
40138 Bologna– Italy
Tel: xx39 051 390413 Fax xx39 051 398973
e-mail: [email protected]
3
ABSTRACT
The introduction of imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid
leukemia (CML). Although experience is too limited to permit evidence-based evaluation of
survival, the available data fully justify critical reassessment of CML management. The panel
therefore reviewed treatment of CML since 1998. It confirmed the value of IM (400 mg/day) and of
conventional allogeneic hematopoietic stem cell transplantation (alloHSCT). It recommended that
the preferred initial treatment for most patients newly diagnosed in chronic phase should now be IM
400 mg daily. A dose increase of IM, or alloHSCT, or investigational treatments were
recommended in case of failure and could be considered in case of suboptimal response. Failure
was defined at 3 months (no hematologic response (HR)), 6 months (incomplete HR or no
cytogenetic response (CgR)), 12 months (less than partial CgR (Ph+ >35%)), 18 months (less than
complete CgR), and in case of HR or CgR loss, or appearance of IM-highly-resistant BCR/ABL
mutations. Suboptimal response was defined at 3 months (incomplete HR), 6 months (less than
partial CgR), 12 months (less than complete CgR), 18 months (less than major molecular response
(MMolR)), and in case of MMolR loss, other mutations or other chromosome abnormalities. The
importance of regular monitoring at experienced centers was highlighted.
4
INTRODUCTION
After the initial descriptions of chronic myeloid leukemia (CML) more than 150 years ago, little
meaningful progress was made in its treatment for more than a century. Radiation therapy and
busulfan contributed more to improving quality of life than to prolonging survival. Survival
prolongation was first achieved with hydroxyurea (HU), and much more with allogeneic
hematopoietic stem cell transplantation (alloHSCT) and, later, in a minority of patients with
recombinant interferon-alpha (rIFNá)1. Understanding the pathogenesis of the disease began with
the discovery of the Philadelphia(Ph) chromosome followed by appreciation of its molecular
counterpart, the BCR-ABL fusion gene2,3. Recognition of the tyrosine kinase (TK) activity of the
Bcr-Abl proteins led to the discovery of a new series of compounds targeted against BCR-ABL
encoded proteins, which inhibited the TK activity, thus aborting the signals controlling the leukemic
phenotype4. One of the TK inhibitors, imatinib mesylate (IM) was found to have a high and
relatively specific biochemical activity and an acceptable pharmacokinetic and toxicity profile, and
thus, was rapidly introduced into clinical practice5-7. This resulted in a revolutionary step in the
management of CML and by extension a shift in paradigm for the management of cancer in general.
The most recent comprehensive analysis of CML treatment was an evidence-based guideline
developed in 1998 by an expert panel convened by the American Society of Hematology (ASH),
covering conventional chemotherapy, rIFNá, and alloHSCT8. TK inhibitors were not considered at
that time but were subsequently the subjects of editorials and preliminary reviews7,9-14. Although it
is premature at this time to perform an evidence-based analysis of the effects of IM, the
implications and consequences of the introduction of TK inhibitors are so important that it is not too
early to review the available data and to discuss how the treatment of CML could be managed and
further progress could be pursued, based upon expert opinion. Therefore the European
LeukemiaNet appointed a panel of experts to review the current situation. This report constitutes its
opinion.
5
METHODS
Panel composition
The panel included nineteen members with recognized clinical and research expertise in CML, of
whom ten came from the European Union countries (France, Germany, Italy, Spain, Sweden, and
the United Kingdom), one from Switzerland, seven from the United States of America, and one
from Australia.
Scope of the Review
The first step was to perform a comprehensive and critical review of the literature after 1998 (the
date of the last ASH analysis) was performed. A computerized literature search of the MEDLINE
database was conducted in April 2005 and updated in November 2005. Relevant abstracts presented
at the 2004 and 2005 meetings of the ASH, the American Society of Clinical Oncology, the
European Group for Blood and Marrow Transplantation (EBMT), the European Hematology
Association and the International Society for Experimental Hematology were also reviewed.
Thereafter, the panel met several times to discuss definition, evaluation and monitoring of the
responses, as well as treatment policy. It was agreed that discussion and proposals should be limited
to early chronic phase (ECP) patients not only because the treatment of CML patients in a more
advanced phase is less amenable to generalizations, but also to focus on the importance of a firstline
treatment strategy, late therapeutic interventions being generally less effective.
Definitions
The criteria that we have used to distinguish CP from accelerated phase (AP) are those that have
been used in the most recent treatment reports15-19. These criteria are listed in Table 1, together with
WHO criteria, which differs slightly20. The relative risk (RR) of progression and death in early CP
(ECP) patients may be calculated by using either the Sokal24 or the Hasford25 formulations (Table
2).
6
WHO Other, and this report
– Blast cells in blood or bone marrow
(BM) 10-19%
– Blast cells in blood or BM 15-29%
– Blast cells plus promyelocytes in blood or
BM > 30%, with blast cells < 30%
– Basophils in blood ≥ 20% – Basophils in blood ≥ 20%
– Persistent thrombocytopenia
(<100×109L) unrelated to therapy
– Persistent thrombocytopenia
(<100×109L) unrelated to therapy
– Thrombocytosis (>1000×109L)
unresponsive to therapy
– (not included)
– Increasing spleen size and increasing
WBC count unresponsive to therapy
(not included)
– Cytogenetic evidence of clonal
evolution (the appearance of an additional
genetic abnormalities that was not present at
the time of diagnosis)
(not included)
TABLE 1 – List of the criteria that have been proposed by the World Health Organization
(WHO)15 and of the criteria that have been used in most recent studies15-19 and in this review,
for defining accelerated phase (AP). The definition of chronic phase (CP) implies that none of
these criteria is met. For the definition of blast crisis (BC), the WHO-recommended criteria are the
percentage of blast cells in blood or BM (≥ 20%), extramedullary blast proliferation or large foci or
clusters of blasts in the bone marrow biopsy20. In recent treatment reports17,21-23, and in this review,
the criteria for BC were limited to the percent of blast cells in PB or BM (≥30 rather than ≥20% as
for WHO), or extramedullary blast involvement. It should be noticed that the introduction of new
treatments could change the boundaries between CP, AP and BC, and modify to some extent the
classical subdivision of CML in three phases.
7
SOKAL(24) HASFORD(25)
Age (years) 0.116 (age – 43.4) 0.666 when age ≥ 50
Spleen (cm below costal
margin, max distance)
0.0345 (spleen – 7.51) 0.042 x spleen
Platelet count (׳109/L) 0.188 [(Platelets : 700)2 – 0.563] 1.0956 when platelets ≥ 1500
Blood myeloblasts (%) 0.0887 (myeloblasts – 2.10) 0.0584 ׳myeloblasts
Blood basophils (%) Non applicable 0.20399 when basophils > 3%
Blood eosinophils (%) Non applicable 0.0413 ׳eosinophils
RELATIVE RISK EXPONENTIAL OF THE TOTAL TOTAL ׳1000
LOW <0.8 ≤ 780
INTERMEDIATE 0.8-1.2 781-1480
HIGH >1.2 >1480
TABLE 2 – Calculation and definition of disease relative risk (RR). Sokal risk was defined
based on patients treated with conventional chemotherapy24. Hasford risk was defined based on
patients treated with rIFNá-based regimens25. We emphasize that calculation of the risk requires
use of clinical and hematologic data at diagnosis, prior to any treatment.
8
SUMMARY AND UPDATE OF RECOMBINANT INTERFERON-ALPHA (rIFNá)
The superiority of rIFNá-based regimens over conventional chemotherapy was reported previously
in the ASH analysis8 and was confirmed in a subsequent study26. A trial of rIFNá vs a combination
of rIFNá and low-dose arabinosyl cytosine (LDAC)27 partially confirmed an earlier study28,
reporting that the cytogenetic response (CgR) rate was higher with the combination but that overall
survival did not differ. A study testing 3 MIU of IFNá three times a week vs 5 MIU/sqm/day
indicated that the low dose was as effective and better tolerated than the high dose29. The last
updates of the major rIFNá studies reported a 9- or 10-year overall survival (OS) ranging from 27%
to 53%30. In one study of 317 patients who had achieved a CCgR, 50% were still in CCgR and 70%
were alive after 10 years, with a significant difference in OS between low and high Sokal risk
patients (10-year OS 90% vs 40%)31. Residual leukemia was detectable at the molecular level in
almost all these patients. Several studies have provided some insights into the biologic and
molecular bases of the therapeutic effects of rIFNá30 but there have been no new or updated clinical
studies.
9
SUMMARY AND UPDATE OF ALLOGENEIC AND AUTOLOGOUS HEMATOPOIETIC
STEM CELL TRANSPLANTATION (HSCT)
The ASH panel reported that about 50% of the patients submitted to alloHSCT in first CP from a
matched related donor remained alive and leukemia-free after 5 years8. Several subsequent reports
confirmed the data and extended the follow up to 10 years, with an OS of 60% and an event-free
survival (EFS) of 50%32,33, and to 15 years, with an OS of 47%34 and 52%35. In a meta-analysis of
three randomized studies of 316 CP patients, 10-year survival estimates were 63% and 65%36. The
Center for International Blood and Marrow Transplant Research (CIBMTR) reported on 4513
patients, with a median age of 35 years, who were transplanted between 1978 and 199737. OS at 18
years was 50% for 3372 first CP patients and 20% for 1141 non-first CP patients. The cumulative
incidence of relapse at 18 years was 25% for CP patients and 37% for the others. Relapses were
seen up to 21 years after treatment. The longest follow-up of patients transplanted from a matched
related donor is that reported by the EBMT, on 2628 patients transplanted between 1980 and
199038. OS at 20 years was 34% for all patients, 41% for patients transplanted in first CP from an
HLA-identical sibling, and 49% for those who had an EBMT risk score (see below) of 0-1. In
children, 10-year OS estimates were reported to be 65-70%39.
An EBMT survey analyzed 3142 patients submitted to conventional alloHSCT in any phase of
CML and from any donor40. This analysis led to the formulation of a prognostic score subsequently
validated by two other analyses41,42. Depending on the risk score, survival ranged from 72% to 11%
in all patients and from 70% to 25% in the patients who were transplanted in ECP (Table 3).
Progress in molecular DNA typing of HLA alleles, in the management of opportunistic infections
and in supportive care, as well as modifications and improvement of conditioning regimes and
immunosuppresive therapy, have contributed to improved results of alloHSCT, using both family
members and unrelated donors43. For CML patients receiving conventional transplants, the use of
peripheral blood stem cells has not been shown to be better than the use of marrow cells44.
10
Reduced intensity conditioning (RIC) is currently being evaluated for CML45-48. The EBMT has
reported on registry data of 187 patients (median age 50 years) who were submitted to RICalloHSCT,
between 1994 and 2002, mainly from matched related donors49. Three-year OS was 70%
for the patients with an EBMT score of 0-2, 50% for the patients with a score of 3-4, and about 30%
for those with a score ≥ 5. The use of RIC may permit transplantation also in older patients, but the
long term impact of these and other experimental procedures of alloHSCT on OS, EFS and quality
of life cannot yet be assessed.
The role of treatment intensification with autologous HSCT (autoHSCT) rescue has been the
subject of a number of studies and reviews covering a period of more than 20 years50. Several
observations suggested that the procedure was useful to achieve more remissions and to prolong
survival. Several randomized studies were initiated but none was completed. A meta-analysis of six
such trials in which patients were randomly allocated to receive autoHSCT or a rIFNá-based
regimen did not show an advantage for autoHSCT51.
11
PROGNOSTIC FACTORS RISK SCORE
Age 0 if < 20 years
1 if 20 – 40 years
2 if > 40 years
Interval from diagnosis to HSCT 0 if ≤ 1 year
1 if > 1 year
Disease phase 0 if chronic
1 if accelerated
2 if blastic
Donor-recipient sex match 1 if female donor and male recipient
0 if any other match
Donor type 0 if HLA-identical sib
1 if any other
TOTAL RISK SCORE 5-YEAR OVERALL SURVIVAL
EBMT series
CIBMTR
series, all
patients
CIBMTR
series, ECP
patients
0 – 1 72% 69% 70%
2 62% 63% 67%
3 48% 44% 50%
4 40% 26% 29%
5 – 7 22% 11% 25%
TABLE 3 – EBMT transplantation risk score. The table lists the prognostic factors and the
corresponding risk score, and reports five-year overall survival rates, as they were calculated in the
original EBMT (European Group for Blood and Marrow Transplantation) report40 and in the
subsequent CIBMTR (Center for International Blood and Marrow Transplant Research) study41. All
EBMT and CIBMTR patients were treated by conventional alloHSCT procedures between 1989
and 1997. Leukemia free survival (calculated only in the EBMT study) at 5 years was 61% for risk
12
score 0-1, 47% for risk score 2, 37% for risk score 3, 35% for risk score 4, and 19% for risk score 5-
7.
13
SUMMARY AND UPDATE OF IMATINIB (IM) DATA
IM vs rIFNá in ECP
The superiority of IM 400 mg daily over rIFNá and LDAC was established in a prospective
randomized international study of 1106 ECP patients (IRIS study). IM was superior to rIFNá for
efficacy, with a complete hematologic response (CHR) rate of 95% vs 55%, a complete CgR
(CCgR) rate of 76% vs 15% and progression free survival (PFS, survival free from progression to
AP/BC) at 19 months of 97% vs 91% (P < 0.001). It was better also for compliance, toxicity, and
quality of life17,52. As expected, molecular response (MolR) rates were also significantly better, with
an estimated major MolR (MMolR) rate at 12 months of 40% vs 2%53. Since many patients who
had been assigned to rIFNá and LDAC were crossed over to IM, it is difficult to meaningfully
compare the long term results of the two treatment arms. However, two independent retrospective
analyses provided independent confirmation that IM was better than any other non-transplant
treatment54,55. Studies have shown that IM is a cost-effective first line therapy compared to rIFNá56.
Follow-up clinical results in ECP
When IM was given at 400 mg daily for initial treatment of ECP patients, the CHR rate after one
year was 95% and the CCgR rate was 76%17. Of those patients who had achieved a CCgR, a
MMolR was achieved in 57% (40% of the patients who had been assigned to IM)53. The proportion
of MMolR patients was reported at 55% of all patients, after two years57. After 54 months followup,
PFS was 93%, OS was 90%, and survival freedom from progression to AP/BC as well as from
hematologic or cytogenetic relapse was 84%58. Currently, this survival outcome is better than for
14
any other reported treatment. The annual rate of progression to AP/BC appeared to be fairly
constant during the first 4 years of treatment, namely 1.5%, 2.8%, 1.6%, and 0.9% 58.
Clinical results in late chronic phase (LCP), accelerated phase (AP) and blast crisis (BC)
Before IM was initially administered as first line treatment for CML, it was given to patients who
were in CP, but resistant or intolerant to rIFNá or who had been treated with conventional
chemotherapy. These patients are classified as “late CP” (LCP). Four international studies reported
a CCgR rate ranging from 41% to 64% with a 5-year PFS of 69% and a 4-year OS of 86-
88%15,18,19,23,59-61. Moreover, one retrospective analysis found that survival of LCP IM-treated
patients was superior to that of historical controls, even when a CCgR was not achieved62.
For AP patients the best results were achieved at a daily dose of 600 mg, with a CHR rate of 37% ,
a CCgR rate of 19% and a 3-year PFS of 40%17,63. In BC the rate of CHR was about 25% and
several responders achieved also a CCgR, but PFS was short, with a median of 10 months or less,
and only 7% remained alive after 3 years5,21-23, 63, 64.
Molecular response (MolR)
Since the frequency of CCgR is very high in IM treated patients, it is necessary to measure the level
of the BCR-ABL transcripts to determine minimal residual disease (MRD) (FIGURE 1). In about
50% of all patients, corresponding to about 70% of the patients who have achieved a CCgR, a
substantial reduction, commonly referred to as a 3-log reduction from a standard baseline or “major
molecular response” (MMolR), was reported in ECP53,65-67, while in LCP the responses were
consistently lower19,20,67,68. The actual frequency with which no residual BCR-ABL transcripts can
be detected by use of the most sensitive available methods, sometimes imprecisely referred to as
“complete” MolR (CMolR), is very variable, and ranges from 4% to 34%18,19,57,67,69. The rate at
15
which the BCR-ABL transcript levels continue to fall reduces with time57,70,71. This is consistent
with the reports that Ph+ stem cells may be less sensitive to IM than later Ph+ progenitors72-75. The
question of whether the inability to detect BCR-ABL transcripts over the long-term is consonant
with “cure” cannot yet be answered. Some case reports suggest that the disease may recur shortly
after IM discontinuation, so that until more information becomes available IM treatment should not
be discontinued without reasons76-80.
Dose issues
The issue of the optimal dose of IM is not yet settled. In early studies for drug registration the
maximum tolerated dose was not identified. A dose of 300 mg daily was sufficient to achieve a
CHR in almost all LCP patients and at 400 mg daily the blood concentration of IM was consistently
higher than that required to inhibit 50% of Bcr-Abl TK activity in vitro81,82. It was also found that a
daily dose of 600 mg was likely to be more effective than 400 mg for AP/BC patients16,21 and that
increasing the IM dose to 600 or 800 mg could benefit a subgroup of patients with inadequate
response or disease progression83. Since at higher concentrations IM may inhibit more effectively
unmutated Bcr-Abl and some mutants, studies were initiated to test higher doses also in CP. In
patients with both prior hematologic and cytogenetic resistance to 400 mg of IM daily, increasing
the IM dose to 800 mg resulted in a CHR in 65% of patients and a CCgR in 18%84. In LCP patients
who had not received prior IM, 66% achieved a CCgR85. In ECP patients a CCgR was achieved in
90% of patients, with 30% CMolR86. In a multicenter Australian study of IM-naive ECP patients
whose dose was escalated from 600 to 800 mg daily, the CCgR rate and the MMolR rate were 81%
and 53%70,87. These studies had no controls and the median follow up was short (6 to 16 months).
Thus, whether increased doses of IM,compared to standard dose of IM, will achieve an increased
overall number of CCgR and MMolR, or whether these effects will merely occur only earlier,
remains to be determined. Answers are expected from prospective studies that are in progress13,88,89.
16
In contrast no studies have yet explored the response to lower IM doses, probably because the 400
mg dose is usually well tolerated and several reports have discouraged the use of low IM doses
because of the possible development of resistance18,19,58,59,66.
Combination with other drugs
Since rIFNá and AC are effective in the treatment of CML and since their mechanisms of action
differ, the combinations of IM with rIFNá and with AC were the first to be tested. In an exploratory
study of 77 patients, the combination of IM 400 mg daily with pegylated rIFNá2b (PegIntron,
Schering Plough), 50 to 150 ìg weekly, was administered66. The compliance to the combination
was limited, since the median tolerated dose of rIFNá was only 35 ìg/week and 50% of patients
discontinued rIFNá before the end of the first year of treatment; after one year the CCgR and the
MMolR rates were 70% and 48%66. The combination of IM 400 mg with LDAC has been
investigated in 30 ECP patients90; at one year the CCgR rate was 70% , with grade 3 and 4
hematologic toxicity in 53% of patients. Prospective randomized studies of IM alone vs IM in
combination with rIFNá, LDAC and high dose AC are ongoing13,89,91.
Several drugs have been shown to overcome IM resistance or to synergize with IM in preclinical
models, including leptomycin B, proteasome inhibitors, mTOR-inhibitors, arsenic trioxide,
mycophenolic acid, farnesyl-transferase inhibitors, bryostatin, decitabine, histone-deacetylase
inhibitors, homoharringtonine, and phosphoinositol-dependent kinase-1 inhibitors92-106, but results
are still preliminary and limited107-110.
17
Relationship with allogeneic hematopoietic stem cell transplantation (alloHSCT)
Treatment with IM prior to alloHSCT was not reported to be associated with an increase of
transplant related morbidity and mortality111-115. IM was also found to control leukemia in patients
relapsing after alloHSCT116,117. In a multicentric retrospective study of 128 patients, the CCgR rates
were 58% in CP, 48% in AP, and 22% in BC, with molecular negativity in 37%, 33%, and 11% of
cases respectively118. In patients treated in early molecular relapse after alloHSCT, molecular
negativity was reinduced in 15/18 cases78. A synergy of IM with donor lymphocyte infusion has
been suggested119.
Factors affecting drug concentration in target cells
Several factors can influence IM concentration in target cells, including intestinal absorption, liver
metabolism through cytochrome P450 isoenzyme-3A4, plasma binding to á1-acid-glycoprotein,
and the transporters involved in multidrug resistance. P-glycoprotein (Pgp) was found to influence
IM intracellular concentration in some studies120-125 but not in others126,127. Interestingly, some
studies have suggested that Pgp inhibition restored IM sensitivity120,124,125 IM does not cross the
blood brain barrier128 Also, the expression of the organic cation transporter hOCT was reported to
influence intracellular drug concentration123.
Resistance and mutations
Resistance may be multifactorial, including BCR-ABL mutations of the kinase domain interfering
with IM binding, BCR-ABL amplification or overexpression, clonal evolution and decreased IM
biovailability or cell exposure120,130-141. Clonal evolution and mutations (Table 4) are likely to be the
most important factors and are related to each other133,142. The frequency of BCR-ABL mutations in
18
resistant patients was reported to range from 42%139 to 90%133 depending on the methodology of
detection, the definition of resistance and the phase of the disease. Mutations are found more
frequently in AP/BC. In CP patients they are rarer and were identified more frequently in patients
with more than 2-fold increase of the BCR-ABL transcript levels than in those with stable or
decreasing levels143. However, mutant Ph+ sub-clones may remain at low levels, may be transient
or unstable and may not be consistently associated with subsequent relapse144,145. In many cases the
mutations have been detected in samples that were collected during IM treatment, but in several
cases the mutation was also traced back to samples collected before treatment, especially in cases of
AP/BC133,146,147. With more sensitive techniques, mutations were also found in some cases of IMnaive
patients and in patients who were in CCgR147-149. It is important to note that Ph+ primitive
cells have been reported to be less sensitive to IM in vitro and in vivo, to harbor BCR-ABL
mutations even prior to IM exposure and to develop rapidly mutations under IM pressure72,74,147,149-
151. Not all mutations have the same biochemical and clinical properties (Table 4). The T315I
mutation and some mutations affecting the so-called P-loop of BCR-ABL confer a greater level of
resistance, whereas the biochemical resistance of other mutations can be overcome by a dose
increase, and some mutations are functionally irrelevant133,137-140,152,153. Thus, the detection of a
kinase domain mutation must be interpreted within the clinical context.
19
imatinib IC50 (nM)
BCR-ABL
Biochemical Cellular
Wild-type 300 260-500
M244V 380 2000
L248V n.a. 1500
G250E 1000 1350-3900
Q252H n.a. 1200-2800
Y253F >5000 3475
Y253H* >5000 >10000
E255K 2800 4400-8400
P-loop
E255V >5000 >5000
D276G n.a. 1500
T277A n.a. n.a.
F311L 775 480
F311I n.a. n.a.
T315I* >5000 >10000
F317L* 900 810-1500
M343T n.a. n.a.
M351T 820 930
M351V n.a. n.a.
E355D n.a. n.a.
E355G n.a. 400
Catalytic
domain
F359V* 4700 1200
V379I 800 1630
A380T* 340 2450
F382L n.a. n.a.
L387M 1500 1000
L387F n.a. 1100
H396P 340-800 850-4200
Activation loop
H396R 1950 1750
S417Y n.a. n.a.
E459K n.a. n.a.
F486S 1230 2800
Table 4 – IC50 values of BCR-ABL mutations observed in patients resistant to IM154. Shaded
boxes highlight residues belonging to the P-loop, catalytic domain and activation loop, as indicated.
Residues marked with an asterisk (*) represent IM contact sites. Other mutations which have not yet
been detected in patients were recovered from in vitro saturation mutagenesis screenings for
mutations conferring resistance to IM or other TK inhibitors. They include: M237I, G250A,
G250V, E255D, A269V, E281K, E282D, K285N, V289S, V299L, T315A, F317C, V338G, Q346H,
S348L, M451L, E352K, E355A, A366D, G398R, G463D, M472I, E494A, with a cellular IC50
20
<1460 nM (that is the mean trough plasma level of IM in patients treated with 400 mg daily), and
E255R, E275K, M278L, E279K, E281K, E292Q, Q300H, F311V, T315S, E316D, G321W,
D325N, A380S, L384M, M388L, E450K, E499K, with a cellular IC50 >1460 nM . IC50 is the
concentration that inhibits by 50% the biochemical TK activity of BCR/ABL and suppresses by
50% the growth of Ph+ cell lines. n.a., not available.
21
Additional chromosome abnormalities (ACA) in Ph+ cells (clonal evolution) and other
chromosome abnormalities (OCA) in Ph- cells
Within the Ph+ clone additional chromosome abnormalities (ACA) can be found in a variable
proportion of metaphases and in a variable number of patients. This phenomenon, also known and
described as clonal evolution, is rare in ECP and becomes more frequent over time and with disease
progression23,134,155-160. A negative relationship of ACA with IM response has been shown,
including a lower CgR rate157, a higher hematologic relapse rate (50% vs 9%)155 and a shorter OS
(75% vs 90% at 2 years)156. Chromosome 9q+ deletions (del9q+) were reported to be associated
with less CHR, less CgR and a shorter PFS in LCP, AP and BC patients in one study161 but not in
another162.
Other chromosome abnormalities (OCA) have been reported in the Ph- cells of about 5% of the
patients who had achieved a CCgR with IM166-170. Many of these patients were in LCP and had been
pretreated with rIFNá based regimens. OCA included trisomy 8 alone in about 50% of such cases,
trisomy 8 with other abnormalities in about 10% of cases, a deletion of chromosome 7 alone or with
other abnormalities in about 15% of cases, and other abnormalities in the remaining cases. The
balance between the Ph+ clone and the Ph- clone with OCA fluctuated depending on IM treatment,
which suppressed Ph+ cells and allowed the Ph- clone with OCA to expand. In some cases Phclone
with ACA were reported to be associated with a myelodysplastic syndrome, mainly in
patients with a deletion of chromosome 7 and/or other complex abnormalities but also in patients
with isolated trisomy 8. It was also reported that many patients remained in complete cytogenetic
and hematologic response after the detection of OCA and that OCA may be transient166,167,169,170 but
the follow-up is still short.
22
Prognostic factors
Two sets of prognostic factors can be considered, namely those that can be identified prior to
treatment (baseline factors) and those that can be identified during the treatment (response-related
factors). The main baseline factors are the phase of disease and the relative risk (RR). Although
different definitions of AP and BC have been used (Table 1), the phase of the disease influences
strongly the response, the duration of the response and OS, with better results in CP than in AP and
in AP than in BC. The RR, either by Sokal’s24 or Hasford’s methods25, predicts the cytogenetic
response to IM 400 mg daily (Table 5) 53,171,172. Moreover, Sokal’s RR has been reported to predict
also MolR and OS. In the IRIS study, the rate of 12-month MMolR among CCgRs was 66%, 45%
and 38% in low, intermediate and high risk patients respectively (P = 0.007)53. The OS at 54
months was 94%, 88% and 81% for low, intermediate and high Sokal risk patients (P <0.001)58.
These risk definitions which were derived from patients treated with conventional chemotherapy or
IFNá, are still useful and should be used until further studies identify and confirm other factors of
possible prognostic relevance, such as genomic profile173-177, genetic polymorphisms178,179, Wilms
tumor gene expression180, total phosphotyrosine levels in CD34+ cells181 and the phosphorylation
level of the adaptor protein Crkl182. In addition, it has been reported that BCR-ABL expression
levels affect the CgR to IM19 and determine the rate of development of resistance to IM141. ACA,
including Ph duplication, and del9q+, are also candidate adverse prognostic factors.
As data from IRIS study are continuously updated58,172,183, early cytogenetic response seems to be
the most important response-related prognostic factor (Table 6). If no CgR is achieved after 3
months, there is still a 50% chance of achieving a CCgR later on. If there is any (even minimal)
CgR after 6 months of treatment, there is still a fair chance of achieving a CCgR later on, but if the
6-month karyotype remains more than 95% Ph+, the probability is only 15%. After 12 months of
treatment, if the CgR is partial the probability of achieving a CCgR at 2 years is still 50%, but if the
23
response is less than partial, this probability becomes less than 20%. The data reported in Table 6
also highlight the relationship between early CCgR and EFS.
The level of MolR was also found to be an important dynamic factor of prognosis. It was reported
that transcript levels after 1 or 2 months of treatment predicted late responses184,185, that a low level
of residual disease was associated with continuous remission68, and that a MMolR after 12 months
of treatment was associated with a better EFS and PFS53,58. A rise of BCR/ABL transcript level has
been consistently associated with mutations or response loss143,186.
24
Complete cytogenetic response
Relative Risk Low Interm High
Italian multicenter study, 77 patients, IM 400 mg, response at
6 months171 70% 41% 8%
International multicenter IRIS study, 383 patients, IM 400 mg
– response at 12 months53 76% 67% 49%
– response at 42 months172 91% 84% 69%
Single-center study, 187 patients, IM 400-800
mg, overall response54
84% 85% 69%
TABLE 5 – Cytogenetic response by relative risk. Two independent studies of newly diagnosed,
ECP patients who were treated initially with IM 400 mg daily have shown that the cytogenetic and
the molecular response to that dose of IM was significantly related to Sokal’s risk. In one study171
the relationship was found also using Hasford’s risk. In another study54 the differences were not
significant, but IM dose was higher, 800 mg in 100 patients, 600 mg in 14 patients, and 400 mg in
73 patients. The last update of the IRIS study58 reported OS was also risk related, being 94% for
low risk patients, 88% for intermediate risk patients and 81% for high risk patients (P < 0.001),
after 54 months of therapy.
25
Months on
treatment
Cytogenetic
response
Probability of CCgR
at 2 years
EFS
at 42 months
Partial 90% NA
3 Minor 60% NA
Minimal/None 50% NA
Complete NA
Partial 80%
95%
Minor or Minimal 50%
6
None 15%
75%
Complete NA
12 Partial 50%
90%
Minor/Minimal/None <20% 65%
TABLE 6 – Relationship between the degree of early CgR, the CCgR rate at 2 years, and EFS
at 42 months in IRIS study172,183. From the same study it was reported that after 54 months,
survival free from progression to AP/BC was 97% for the patients with a CCgR at 12 months, 95%
for those with a PCgR and 81% for those who at 12 months had achieved less than a PCgR58. NA =
Not applicable or not available.
26
DEFINING AND MONITORING THE RESPONSE
Hematologic Response (HR) and Cytogenetic Response (CgR)
In almost all recent reports on the treatment of CML, HR and CgR were defined virtually the same
way, and with only minor differences15,17-19,26-29,66. We propose to use the definitions that are listed
in Table 7. We recommend that HR be evaluated every 2 weeks until a CHR has been achieved and
confirmed, and a conventional cytogenetic examination of marrow cells be performed before
treatment, at least every 6 months until a CCgR has been achieved and confirmed, then every 12
months. Once a MMolR has been achieved and confirmed, conventional cytogenetic examination of
marrow cells may be performed less frequently, depending on clinical, hematologic and molecular
findings.
Fluorescence-In-Situ-Hybridization (FISH) on interphase cells has the potential advantage of
evaluating many more cells and of using peripheral blood instead of marrow187,188, but since the
data obtained so far are all based on conventional cytogenetics, we recommend using FISH only
before treatment, to identify cases of Ph-, BCR-ABL+ CML, and those with variant translocations,
Ph amplification or del9q+.
Molecular response (MolR)
The necessity for a quantitative definition of MolR has developed with the introduction of IM,
because with IM most patients achieve a CCgR, so that molecular methods for measuring minimal
residual disease (MRD) are required (Figure 1). The IRIS trial provided evidence for the first time
that a reduction of BCR-ABL transcripts by 3 or more logs below a standard baseline value
correlated with PFS53. The use of the “log reduction” terminology has led to some degree of
27
confusion since it seems to imply that the value is a relative one. For this reason, at a consensus
conference held in Bethesdaunder the auspices of the NIH, it was proposed to move away from the
term “log reduction” and to introduce a standardized numerical International Scale (IS) expressing
the amount of BCR-ABL as a percentage of a control gene and anchored to two “absolute” values
based on validated reference materials (plasmids, lyophilised cells or cell extracts) of known
value189. The first value will be designated 100% on the proposed IS and the second value will
represent a 3-log reduction, i.e. 0.1%. A given laboratory will use the validated reference material to
determine the local value that is equivalent to MMolR as determined in the IRIS trial. By
comparing the value for a 3-log reduction with the value on the internationally agreed scale, each
laboratory can derive a conversion factor which can then be used to express the results in any given
patient on the IS.
In ECP patients, evaluating MRD with real-time quantitative polymerase chain reaction (RQ-PCR)
does not require bone marrow cells. Blood is drawn, e.g. 10 ml, which contains a sufficient amount
of leukocytes for RNA extraction from the whole buffy coat. We propose RQ-PCR on peripheral
blood cells be performed at regular intervals of 3 months, even after RQ-PCR becomes negative.
Assessing the molecular status of a patient is not limited to the evaluation of the level of the BCRABL
transcripts. We propose performing a mutational analysis immediately in any case of
treatment failure or suboptimal response, including a confirmed rise of BCR-ABL transcript level.
We recognize, however, that there is currently no consensus regarding the degree of increase which
should cause concern189 and that there is at present only a limited number of laboratories worldwide
currently performing these analyses.
28
HEMATOLOGIC RESPONSE (HR) CYTOGENETIC RESPONSE (CgR)
MOLECULAR RESPONSE (MolR)
(BCR/ABL to control gene ratio according to
the international scale)
Complete – Platelet < 450×109L
– WBCC < 10 x109L
– Differential without immature
granulocytes and with less than 5%
basophils
– Non palpable spleen
Complete Ph+ 0
Partial Ph+ 1-35%
Minor Ph+ 36-65%
Minimal Ph+ 66-95%
None Ph+ > 95%
“Complete” = transcript non quantifiable
and non detectable
Major ≤ 0.10
Check every 2 weeks until a complete response
has been achieved and confirmed, then every 3
months unless otherwise required
Check at least every 6 months until a complete
response has been achieved and confirmed,
hence at least every 12 months
Check every 3 months
Mutational analysis in case of failure,
suboptimal response, or transcript level increase
TABLE 7 – Response definition and monitoring. Complete HR (CHR), complete CgR (CCgR) and major MolR (MmolR) should be confirmed in
two subsequent occasions. CgR is evaluated by morphologic cytogenetics of at least 20 marrow metaphases. FISH of peripheral blood cells should
be used only if marrow cells cannot be obtained. MolR is assessed on peripheral blood cells. The international scale for measuring MolR is that
proposed by Hughes et al189.
29
Failure and suboptimal response
The goals of treatment, in order of time and importance, are CHR, CCgR, MMolR, and “complete”
molecular response. Although the time to response may not always affect the prognosis, it is
operationally useful to define at which time point a response may be satisfactory, thus encouraging
continuation of current treatment, or if it is not satisfactory, thus requiring or suggesting a change in
the therapeutic strategy. Based on the available information, as summarized in prior sections, we
propose to define the response to the treatment at different time points as “failure” and
“suboptimal”. In this context “failure” means that continuing IM treatment at the current dose is no
longer appropriate for these patients, who would likely benefit more from other treatments.
“Suboptimal response” means that the patient may still have a substantial benefit from continuing
IM, but that the long-term outcome of the treatment would not likely be as favorable. Moreover, we
propose that some factors should “warn” that standard dose IM treatment may not be the best
choice and that patients with these factors requires a more careful monitoring. The proposed criteria
for failure, suboptimal response and warning are listed in Table 8.
30
TIME FAILURE SUBOPTIMAL RESPONSE WARNINGS
Diagnosis NA NA – High risk
– Del9q+
– Additional chromosome abmormalities
(ACA) in Ph+ cells
3 months – No hematologic response (HR) (stable
disease or disease progression
– Less than Complete HR (CHR)
6 months – Less than Complete HR (CHR)
– No cytogenetic response (CgR) (Ph+
more than 95%)
– Less than Partial CgR (PCgR) (Ph+
more than 35%)
12 months – Less than PCgR
(Ph+ more than 35%)
– Less than Complete CgR (CCgR)
– Less than major MolR (MMolR)
18 months
– Less than CCgR – Less than MMolR
Any time – Loss of CHR (1)
– Loss of CCgR (2)
– Mutation (3)
– ACA in Ph+ cells (4)
– Loss of MMolR (4)
– Mutation (5)
– Any rise in transcript level
– Other chromosome abnormalities in Phcells
(1) To be confirmed on two occasions unless associated with progression to AP/BC (2)
(2) To be confirmed on two occasions, unless associated with CHR loss or progression to AP/BC
(3) High level of insensitivity to IM
(4) To be confirmed on two occasions, unless associated with CHR or CCgR loss
(5) Low level of insensitivity to IM
31
TABLE 8 – Operational definition of failure and suboptimal response for previously untreated, ECP, CML patients who are treated with
IM 400 mg daily. Failure implies that the patient should be moved to other treatments whenever available. Suboptimal response implies that the
patient may still have a substantial benefit from continuing IM treatment, but that the long term outcome is not likely to be optimal, so that the
patient becomes eligible for other treatments. Warnings imply that the patient should be monitored very carefully and may become eligible for
other treatments. The same definitions can be used to define the response after IM dose escalation. For risk definitions refer to Table 2. For
mutations refer to Table 4. For the definition of HR, CgR and MolR, refer to Table 7. Abbreviations: ACA = Additional Chromosome
Abnormalities; HR = Hematologic Response; CHR = Complete Hematologic Response; CgR = Cytogenetic Response; PCgR = Partial Cytogenetic
Response; CCgR = Complete Cytogenetic Response; MMolR = Major Molecular Response; NA = Not Applicable.
33
TREATMENT POLICY
Standard (non-investigational) treatment of ECP Ph+ CML includes HU, rIFNá±LDAC, IM 400
mg daily and alloHSCT. The superiority of IFNá±LDAC over HU was already demonstrated and
confirmed8,30. The superiority of IM 400 mg over IFNá±LDAC has also been demonstrated17,53.
Standard alloHSCT is a recognized therapeutic procedure achieving long lasting molecular
remissions or cures in about 50% of the patients who are eligible for the procedure, with substantial
differences among recognized risk groups40,41. In countries where IM is available and standard
alloHSCT is feasible we are now in a rather privileged situation to have two potent strategies which
are both established but are neither perfect nor mutually exclusive. IM is preferred as initial
treatment. In a patient with a high disease risk and a low EBMT risk score the choice between IM
and alloHSCT should be discussed, but there is little reason to deny such a patient a trial with IM
since the early response to IM can either reinforce or weaken the indication for alloHSCT.
The motivations for treatments other than IM are intolerance or excess toxicity, failure, suboptimal
response, and “warnings”.
In case of intolerance or excess toxicity, the choices are either alloHSCT or rIFNá±LDAC, which
must be weighed against investigational trials of new agents and should follow the principle of
shared decision-making wherein the patient is explained the risks and rewards of each treatment
decision.
In case of failure (Table 8 ) we propose that the first choice be alloHSCT, or dose-escalation of IM
to 600 or 800 mg daily, provided that the patient tolerated 400 mg and that resistance to IM was not
associated with a BCR-ABL mutation with a high level of insensitivity to IM.
In case of suboptimal response (Table 8) we propose that the first choice be dose-escalation of IM
to 600 or 800 mg daily, provided that the patient tolerated 400 mg. AlloHSCT could be offered to
patients with a low or intermediate EBMT risk score and high RR or other warning features.
34
In patients presenting with “warning” features, standard treatment is still IM 400 mg, but any
“warning” (Table 8) should alert that the patient may become eligible for IM dose escalation, for
alloHSCT, or in selected cases for investigational agents.
There are several other possible scenarios. The first is the patient in whom other treatment options
are not available; in such case the choice would be between continuing IM treatment, if a CHR is
maintained, or to resort to HU. The second scenario is the patient requiring IM dose reduction or
frequent treatment discontinuations. We recommend that the treating physician advise the patient to
adhere to the 400 mg dose insofar as possible; appropriate supportive care should be provided,
including myeloid growth factors and erythropoietin; the response should be monitored frequently.
Monitoring of blood IM concentration is not required, but it would be desirable in case of failure, in
patients who must take drugs interfering with cytochrome P450, and in those who experience a
severe drug-related adverse event.
The proposals and recommendations discussed in this paper focus on ECP patients but sometimes
patients are first diagnosed when initially in AP or BC. There are few data pertaining to treatment
results in these patients. We propose patients in early BC to be treated initially with IM or other TK
inhibitors (based on mutational analysis) and then to proceed to alloHSCT. Since some temporal
latitude exists after the diagnosis of AP, a more prolonged trial with IM is possible.
35
CONCLUSIONS
Progress in drug development, in molecular and cellular biology and in HSCT obliges the medical
community to maintain a critical attitude to the management of Ph+ CML. On the one hand it must
be recognized that the introduction of IM has marked an important and hopefully revolutionary
step, but the long term outcome of this treatment cannot yet be assessed. On the other hand
alloHSCT holds the promise of cure, but with definite toxicity and mortality. At the same time other
TK inhibitors and targeted agents are already in preclinical and clinical evaluation13,154,190-194. The
proposals described in this report have been generated by a panel of experts to strike a balance
between the magic freedom of research in progress and the practice of advising patients and
managing treatment. The proposals concerning treatment policy may be provisional, in the absence
of the evidence that will be provided only by longer follow-up of prospective studies; however, the
recommendations concerning the methods that must be used to evaluate and to monitor the response
are nonetheless cogent. Cytogenetic and molecular monitoring, including mutational analysis, is
expensive and requires appropriate resources and sophisticated facilities. However the cost of
monitoring is negligible by comparison with the cost of treatment, whether it is a targeted agent or
HSCT. Moreover, careful monitoring is required to ensure that an individual patient receives the
proper treatment and to decide if and when a therapy should be changed. Finally, it should be
realized that progress makes treatment more effective but not necessarily easier. Thus the treatment
of Ph+ CML should be provided under the guidance of an experienced center, offering and asking
patients to be registered on investigational studies. This is necessary to ensure that all the data,
clinical and biological, that are urgently required to answer the present questions, are collected and
analysed in an accurate and timely manner, for the benefit of the subsequent patients and for further
progress in the treatment of leukemia.
36
Diagnosis, Pretreament
or Hematologic Relapse
Complete Hematologic Response
Undetectable transcript
(Complete Molecular Response)
Complete Cytogenetic Response
Major Molecular Response
100
10
1
0.1
0.01
0.001
0.0001
BCR-ABL ratio
(according to the International Scale)
1012
1011
1010
109
108
107
106
Number of leukemic cells
37
Figure 1 – Approximate relationship between response, the putative number of leukemic cells
and the level of BCR-ABL transcripts. When a complete cytogenetic response has been achieved,
the (putative) number of residual Ph+ cells can be measured only with quantitative molecular
methods. The figure highlights the importance of molecular methods in the evaluation of the
response to treatment. However, the sensitivity of current methods may vary substantially and in
any case no method can detect the transcript at very low cellular levels. For this reason the term
“complete molecular response” may be misleading, since it might erroneously be interpreted as an
equivalent of complete disease eradication and cure. The term “undetectable BCR-ABL” may better
describe the biological situation.
38
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