המאמר החדש של 19 מומחים עולמיים לגבי נוהל טיפול בחולי CML- באנגלית


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

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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 BolognaItaly

Tel: xx39 051 390413 Fax xx39 051 398973

e-mail: baccarani@med.unibo.it

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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.

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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.

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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).

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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

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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

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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.

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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.

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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

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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.

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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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