effects of age on prognosis with imatinib mesylate therapy for patients with philadelphia...

Effects of Age on Prognosis with Imatinib MesylateTherapy for Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia

Jorge Cortes, M.D.1

Moshe Talpaz, M.D.2

Susan O’Brien, M.D.1

Francis Giles, M.D.1

Mary Beth Rios, R.N.1

Jianquin Shan, Ph.D.1

Stefan Faderl, M.D.1

Guillermo Garcia-Manero, M.D.1

Alessandra Ferrajoli, M.D.1

William Wierda, M.D., Ph.D.1

Hagop Kantarjian, M.D.1

1 Department of Leukemia, The University of TexasM. D. Anderson Cancer Center, Houston, Texas.

2 Department of Bioimmunotherapy, The Universityof Texas M. D. Anderson Cancer Center, Houston,Texas.

Jorge Cortes M.D. is a Clinical Research Scholarfor the Leukemia & Lymphoma Society.

Address for reprints: Hagop Kantarjian, M.D., De-partment of Leukemia, The University of TexasM. D. Anderson Cancer Center, 1515 HolcombeBoulevard, Box 428, Houston, TX 77030; Fax:(713) 792-2031; E-mail: [email protected]

Received February 12, 2003; revision receivedMay 27, 2003; accepted June 13, 2003.

BACKGROUND. Older age is a consistent poor prognostic factor in patients with

Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML).

Whether this is related to an intrinsic worse disease biology or to inadequate drug

delivery or excessive treatment-associated toxicity is unknown. The availability of

imatinib mesylate, a selective, Bcr-Abl-targeted therapy that is administered orally

with minimal side effects, may clarify whether older age would remain an adverse

factor (thus, implying a different age-related CML biology).

METHODS. Seven hundred forty-seven patients in different phases of Ph-positive

CML who were treated with imatinib from 1999 until the time of last follow-up

were evaluated. Among them, 187 patients had newly diagnosed, early chronic

phase CML; 351 patients had chronic phase CML after interferon � (IFN) failure;

133 patients had accelerated phase CML; and 76 patients had blastic phase CML.

The imatinib daily dose varied from 400 mg to 800 mg orally, according to the

protocol design. Patients were categorized into a group of older patients (age 60

years or older) or younger patients (age younger than 60 years). Their character-

istics, responses to therapy, and survival were compared by univariate and multi-

variate analyses.

RESULTS. One hundred eighty-seven patients had newly diagnosed CML, and 49

patients (26%) were in the older age group. Older patients had similar cytogenetic

response rates and survival compared with younger patients. Among 351 patients

with late chronic phase CML after IFN failure, 120 patients (34%) were in the older

age group. Although the older patients had a lower incidence of achievement of

complete cytogenetic response (Ph, 0%) by univariate analysis (56% vs. 44%; P

� 0.05), age was not found to be an independent poor prognostic factor in the

multivariate analysis. Similarly, older age was not an adverse poor prognostic

factor for survival. Forty-two of 133 patients (32%) with accelerated phase CML

were older. The incidence of any cytogenetic response was lower in older patients

(53% vs. 33%; P � 0.04), but age was not significant in the multivariate analysis.

Older patients also had a trend toward worse survival (P � 0.09) that was not

significant in the multivariate analysis. Twenty-eight of 76 patients (37%) evaluated

in blastic phase were older. Older age was not a significant prognostic factor either

for achieving response or for survival.

CONCLUSIONS. With imatinib therapy, older age appears to have lost much of its

prognostic relevance. This suggests that the previous poor prognosis observed with

older age was related to treatment-associated factors (e.g., toxicity with allogeneic

transplantation or with IFN therapy) rather than to an intrinsic, different disease

biology of CML in older patients. Cancer 2003;98:1105–13.

© 2003 American Cancer Society.

KEYWORDS: old age, chronic myelogenous leukemia, imatinib, Gleevec, STI571.

1105

© 2003 American Cancer SocietyDOI 10.1002/cncr.11629

O lder age has been a consistent poor prognosticfactor in patients with Philadelphia (Ph) chromo-

some-positive chronic myelogenous leukemia (CML)and has been incorporated into most multivariate-derived prognostic models.1–5 The poor prognostic ef-fect of old age has been persistent across differenttherapies, including busulfan, hydroxyurea, interfer-on-� (IFN), and allogeneic stem cell transplantation(SCT), although the reasons for its prognostic effectmay differ. With allogeneic SCT, for example, a poorprognosis with older age may be due primarily totransplantation-related mortality, which is signifi-cantly higher in older patients regardless of the un-derlying disease.6 – 8 Older patients have significantlyworse side effects with IFN therapy; thus, their poorprognosis may be due at least in part to poor treat-ment tolerance and inadequate treatment delivery.9 Itis noteworthy that the median age in the IFN studieswas 45–50 years,10 –12 significantly younger than themedian age of 55 years in the imatinib mesylate stud-ies (Gleevec; imatinib; STI571 [Novartis, East Hanover,NJ]),13–20 or the median age of 67 years in the Surveil-lance, Epidemiology, and End Results Program data.21

Thus, the prognostic effect of older age in these stud-ies may not reflect a universal effect in the CML pop-ulation. Older patients tolerate hydroxyurea andbusulfan as well as younger patients. Therefore, theirpoorer prognosis may be attributed to several factors:lack of adjustment of survival data for disease specificmortality; a different biology of CML in older patients(that may be reflected in a higher incidence of otherpoor prognostic features, e.g., more aggressive dis-ease); a delayed diagnosis in older patients who maythen present with more morbidity and tumor burden;comorbid, age-related conditions; or poorer compli-ance or less frequent follow-up or medical attentionprovided to older patients, which may compromisetheir care delivery.

Imatinib, a selective Bcr-Abl tyrosine kinase in-hibitor, has changed the treatment paradigm andprognosis for patients with Ph-positive CML. The in-troduction of highly effective therapy in patients withother malignancies (e.g., velban, bleomycin, and cis-platin in patients with testicular carcinoma; 2-chloro-deoxyadenosine in patients with hairy cell leukemia)often has nullified or reduced significantly the prog-nostic significance of previously well established prog-nostic factors. Imatinib is taken orally and has beentolerated extremely well across age groups. Thus, theavailability of a highly active Bcr-Abl-directed oraltherapy with minimal toxicity should eliminate age asa prognostic factor in patients with Ph-positive CML,unless age is associated with as yet undefined biologicdisease differences. This is the focus of the current

study, which analyzes the clinicolaboratory differ-ences of older patients versus younger patients withPh-positive CML in early chronic, chronic post-IFNfailure, accelerated, and blastic phases who weretreated with imatinib, and investigates potential dif-ferences in treatment delivery, response to therapy,and overall prognosis.

MATERIALS AND METHODSStudy groups of patients with Ph-positive CML whowere treated in the Leukemia Department at The Uni-versity of Texas M. D. Anderson Cancer Center withimatinib for newly diagnosed (early chronic phase)CML, chronic phase CML after IFN failure, acceleratedphase CML, and blastic phase CML were analyzed.Study eligibility criteria, treatment schedules, pre-treatment and follow-up studies, and dose-schedulemodifications have been detailed previously in publi-cations on patients with CML in early chronicphase,22,23 chronic phase post-IFN failure,13,15 accel-erated phase,14,16 and blastic phase.17 Informed con-sent was obtained for all study patients, according toinstitutional guidelines. Accelerated phase CML wasdefined by the presence of any of the following crite-ria: � 15% blasts, � 30% blasts and promyelocytes,� 20% basophils, or thrombocytopenia � 100 � 109/Lnot related to therapy.24 Blastic phase CML was de-fined by the presence of � 30% blasts or extremedul-lary blastic disease.25

Response CriteriaComplete hematologic response/remission (CHR) re-quired normalization for at least 4 weeks of the bonemarrow (� 5% blasts) and peripheral blood with aleukocyte count � 10 � 109/L, without peripheralblasts, promyelocytes, or myelocytes, in addition tothe disappearance of all signs and symptoms of CML.This was categorized further by the cytogenetic re-sponse (suppression of Ph-positive cells) as follows:no cytogenetic response, 100% Ph-positive; minimalcytogenetic response, 35–90% Ph-positive; partial cy-togenetic response, 1–34% Ph-positive; and completecytogenetic response, 0% Ph-positive. A major cytoge-netic response included complete and partial cytoge-netic responses (� 35% Ph-positive).

A partial hematologic response (PHR) was thesame as a CHR, except for the persistence of immaturecells (myelocytes and metamyelocytes), splenomegaly� 50% of the pretreatment level, or thrombocytosis� 450 � 109/L but � 50% of the pretreatment level.Response definitions in blastic phase were detailedpreviously.17

1106 CANCER September 15, 2003 / Volume 98 / Number 6

Statistical AnalysisEvaluation of cytogenetic response was based on rou-tine cytogenetic studies. Cytogenetic studies were per-formed every 3 months in the first year and every 3– 6months thereafter. Pretreatment additional chromo-somal abnormalities referred to the presence of cyto-genetic abnormalities other than Ph (excluding Phvariants, complex Ph translocations, and loss of chro-mosome Y). Response rates were computed on anintention-to-treated basis. Survival was analyzed fromthe date therapy started until death from any cause.Differences in survival curves were compared usingthe log-rank test. Statistical methods and multivariateanalysis studies were conducted as described previ-ously.13,15 Multivariate analyses used the logistic re-gression model for response and the Cox proportionalhazards model for survival. Variables that demon-strated significant differences in the univariate analy-sis (P � 0.05) were included in the multivariate anal-yses.

RESULTSA total of 747 patients with CML were analyzed: 187patients in early chronic phase, 351 patients in chronicphase after IFN failure, 133 patients in accelerated

phase, and 76 patients in blastic phase (Table 1). Wechose the cut-off age of 60 years in subsequent anal-yses for several reasons: 1) this was the cut-off age thatwas identified as prognostically relevant in previousmultivariate analysis studies of CML prognosis at ourinstitution; 2) these patients mostly are ineligible forallogeneic SCT and are offered non-SCT approachesto improve their prognosis; and 3) they have histori-cally tolerated IFN therapy poorly9 and/or were notoffered IFN therapy, hence, it is not known whethertheir poor prognosis is related to a different intrinsicdisease biology or to ineffective, poorly tolerated ther-apy.

Early Chronic Phase CMLOne hundred eighty-seven patients were treated forearly chronic phase CML: Seventy-three patients re-ceived imatinib at a dose of 400 mg daily, 14 patientsreceived 600 mg daily, and 100 patients received 800

TABLE 1Patient Accrual on Different Chronic Myelogenous Leukemia Trials(n � 747 patients)

CML phase/protocol No. of patients

Early chronic phaseDM01-015 (imatinib 400 mg) 50DM01-151 (imatinib 800 mg) 100DM01-163 (imatinib 400 mg) (Novartis 106) 23Expanded access (Novartis 113)a 14

Chronic phase post-IFN failureFDA pivotal (Novartis 109) 149Expanded access (Novartis 110) 111Expanded access (Novartis 113)a 91

Accelerated phaseFDA pivotal (Novartis 109) 59Expanded access (Novartis 113) 74

Blastic phaseFDA pivotal (Novartis 102) 13Expanded access (Novartis 115) 33Phase I study (Novartis 001) 29Expanded access (Novartis 113)b 1

CML: chronic myelogenous leukemia; IFN: interferon � FDA: Food and Drug Administration.a These patients had newly diagnosed chronic myelogenous leukemia (n � 14 patients) or chronic

phase post-IFN failure (n � 91 patients) but were categorized in accelerated phase based on the looser

definition of accelerated phase in the study (Novartis 113), which included spelenomegaly � 10 cm

below the costal margin, pretreatment additional chromosomal abnormalities only other than Phila-

delphia chromosome (Ph) abnormalities (but excluding Ph variants, complex Ph translocations, and

loss of chromosome Y), or the presence of � 10% blasts (see Kantarjian et al.16).b One patient who was treated on the accelerated phase study was reclassified in blastic phase.

TABLE 2Characteristics of Younger Patients versus Older Patients Treatedwith Imatinib for Early Chronic Phase Chronic MyelogenousLeukemia (N � 187 patients)

Parameter

No. of patients (%)

P valueAge < 60yrs

Age > 60yrs

No. treated 138 49 —Splenomegaly (yes) 46 (33) 7 (14) 0.01Hemoglobin � 12 g/dL 59 (43) 17 (35) 0.40Leukocyte count � 50 � 109/L 43 (31) 15 (31) 1.00Platelets � 450 � 109/L 49 (36) 19 (39) 0.73Peripheral blasts (yes) 53 (38) 12 (24) 0.08% Bone marrow blasts (� 5) 11 (8) 4 (8) 1.00% Peripheral basophils (� 7) 30 (22) 9 (18) 0.69% Bone marrow basophils (� 4) 42 (30) 15 (31) 1.00Additional chromosomal abnormalities (yes) 6 (4) 4 (8) 0.29

TABLE 3Response to Imatinib by Age in Patients with Early Chronic PhaseChronic Myelogenous Leukemia

Response

No. of patients (%)

P valueAge < 60 yrs(n � 128 patients)a

Age > 60 yrs(n � 46 patients)a

Cytogenetic response 123 (96) 45 (98) 1.00Complete 101 (79) 40 (87) 0.28Partial 14 (11) 5 (11) —Minor 8 (6) 0 (0) —Major (complete � partial) 115 (90) 45 (98) 0.12

a Of 138 patients age � 60 years, 1 patients was inevaluable, and 9 patients were treated for � 3 months;

thus, response was analyzed in 128 evaluable patients. Of 49 patients Age � 60 years, 3 patients were

treated for � 3 months; thus, response was analyzed in 46 evaluable patients.

Old Age and Prognosis in CML/Cortes et al. 1107

mg daily. Forty-nine patients (26%) were age 60 yearsor older. The characteristics of patients in the two agegroups are detailed in Table 2. No significant differ-ences in important clinical or laboratory features werenoted, except for splenomegaly, which was more fre-quent in younger patients (P � 0.05). Older patientsrepresented 18 of 73 patients (25%) who received ima-tinib at a dose of 400 mg daily and 31 of 114 patients(27%) who received imatinib at a dose of 600 – 800 mgdaily. Response to imatinib therapy was similar inyounger and older patients (Table 3). With a medianfollow-up of 16 months (range, 2–30 months), 7 pa-tients have transformed to accelerated or blasticphases (2 of 49 patients age 60 years or older [1 patientin accelerated phase and 1 patient in blastic] vs. 5 of138 patients younger than 60 years [3 patients in ac-celerated phase and 2 patients in blastic phase]), andonly 3 of 187 patients have died (1 patient died afterdeveloping complications of graft-versus-host disease,1 patient died a natural death from old age, and 1patient died from blastic phase complications).

Chronic Phase CML Post-IFN FailureThree hundred fifty-one patients were treated withimatinib for chronic phase CML after IFN failure; 120patients (34%) were age 60 years or older. The char-acteristics of younger and older patients are comparedin Table 4. Older patients had a lower incidence ofpretreatment additional chromosomal abnormalities(P � 0.01), which constitute a well known adverseprognostic factor. Older patients also had more fre-quent leukocytosis (P � 0.04), bone marrow baso-philia (P � 0.05), Ph positivity � 90% at the start oftherapy (P � 0.05), and more therapies prior to ima-tinib (P � 0.05). Older patients had a significantlylower incidence of complete cytogenetic responsecompared with younger patients (Table 5). With amedian follow-up of 24 months (range, 1–36 months),35 patients have died, 21 of 231 younger patients (9%)versus 14 of 120 older patients (12%). Their causes ofdeath are shown in Table 6. Survival of patients by agewas not different between patients in the two agegroups (Fig. 1).

TABLE 4Characteristics of Younger Patients and Older Patients Treated with Imatinib for Chronic Phase Chronic MyelogenousLeukemia after Failure on Interferon � Therapy

Parameter

No. of patients (%)

P valueAge < 60 yrs(n � 231 patients)

Age > 60 yrs(n � 120 patients)

Last response to IFN-� immediately before entry on imatinib study(n � 223 patients age � 60 yrs; n � 115 patients age � 60 yrs)

Hematologic resistance/recurrence 34 (15) 18 (16) 0.14Cytogenetic resistance/recurrence 111 (50) 44 (38) —IFN intolerance 78 (35) 53 (46) —

Spelenomegaly (yes) 40/229 (17) 23 (19) 0.81Hemoglobin � 10 g/dL 206 (89) 110 (92) 0.57Leukocyte count � 10 � 109/L 106 (46) 71 (59) 0.04Platelets � 450 � 109/L 45 (20) 30 (25) 0.49% Peripheral blasts (any) 51 (22) 35 (29) 0.18% Bone marrow blasts (� 5) 30 (13) 19 (16) 0.57% Peripheral basophils (� 7) 24 (10) 19 (16) 0.19% Bone marrow basophils (� 4) 46 (20) 36 (30) 0.05% Ph positive at start of therapy (� 90) 160/227 (70) 96/119 (81) 0.05Additional chromosomal abnormalities (yes) 54 (24) 14 (12) 0.01CML duration

� 12 mos 28 (12) 11 (9) —12–35 mos 91 (39) 45 (38) 0.59� 36 mos 112 (48) 64 (53) —

Imatinib dose (mg/day)400 170 (74) 90 (75) 0.88600 61 (26) 30 (25) —

No. of prior treatments1 190 (82) 87 (72) —2–3 41 (18) 33 (28) 0.05

IFN-� interferon � Ph: Philadelphia chromosome; CML: chronic myelogenous leukemia.


A multivariate analysis of prognostic factors asso-ciated with lower complete cytogenetic response iden-tified thrombocytosis (P � 0.03), Ph positivity � 90%at start of therapy (P � 0.01), bone marrow blasts� 5% (P � 0.02), and more than 1 prior therapy (P� 0.04) as independent poor prognostic factors forachieving a complete cytogenetic response. Older agewas not an independent poor prognostic factor.

A multivariate analysis of survival identified thefollowing factors as indicative of a poor prognostictrend: pretreatment additional chromosomal abnor-malities (P � 0.10) and higher numbers of prior ther-apies (P � 0.05). Older age was not associated inde-pendently with poor survival.

Accelerated Phase CMLForty-two of 133 patients (32%) who were analyzed inaccelerated phase were age 60 years or older. Thecharacteristics of older and younger patients who re-ceived treatment with imatinib for accelerated phaseCML are shown in Table 7. Older patients had a sig-nificantly higher incidence of bone marrow blasts� 15% (P � 0.04) and trends for higher percentages ofperipheral blasts (P � 0.10), higher hemoglobin levels

(P � 0.10), and leukocytosis (P � 0.07) (Table 7).Although there was a trend toward higher completeresponse rates (P � 0.07) and major cytogenetic re-sponse rates (P � 0.08) with imatinib in younger pa-tients, it was not significant; however, the incidence ofany cytogenetic response was 53% versus 33%, respec-tively (P � 0.04) (Table 8). With the current medianfollow-up of 22 months (range, 1–37 months), 47 of133 patients have died from reasons shown in Table 9.There was a trend toward better survival with imatinibin younger patients (30-month estimated survivalrates: 66% vs. 45%; P � 0.09) (Fig. 2).

In the multivariate analysis, significant poor inde-pendent prognostic factors for achieving complete cy-togenetic response were splenomegaly � 10 cm bcm(P � 0.02), any peripheral blasts (P � 0.03), and Phpositivity � 90% at the initiation of therapy (P � 0.08).For survival, the multivariate-derived, independentpoor prognostic factors were pretreatment additionalchromosomal abnormalities (P � 0.02), bone marrowbasophilia (P � 0.04), and lower imatinib dose (P� 0.03). Age, however, was not found to be an inde-pendent poor prognostic factor for achieving com-plete cytogenetic response and had a marginal inde-pendent effect on survival (P � 0.08).

Blastic Phase CMLSeventy-six patients received imatinib for CML inblastic phase, including 28 patients (37%) age 60 yearsor older. The characteristics of younger and older pa-tients were similar, except for a longer duration ofchronic phase in older patients (P � 0.01), and morepatients in the older group received imatinib as their

TABLE 5Response to Imatinib by Age in Patients with Chronic Phase ChronicMyelogenous Leukemia after Failure on Interferon � Therapy

Response

No. of patients (%)



Complete hematologic remission 217 (94) 113 (94) —Cytogenetic response 169 (73) 76 (63) 0.08

Complete 129 (56) 53 (44) 0.05Partial 24 (10) 15 (12) —Minor 16 (7) 8 (7) —Major (complete � partial) 153 (66) 68 (57) 0.10

TABLE 6Causes of Death by Age Group with Imatinib Therapy in Patientswith Chronic Phase Chronic Myelogenous Leukemia after Failure onInterferon � Therapy

Cause of death

No. of patients

Age < 60 yrs(n � 21 patients)


Blastic/accelerated phase 10/0 3/2Infections/organ failure 3 3Cardiac event 1 2Intercurrent illness 1 1Bleeding 1 0Unknown (death outside the institution) 5 3

FIGURE 1. Survival by age group with imatinib therapy for patients with

chronic phase chronic myelogenous leukemia after failure on interferon �

therapy.


first blastic phase salvage therapy (P � 0.01) (Table10). Response to imatinib salvage therapy was similarin younger and older patients (Table 11). With a me-dian follow-up of 20 months (range, 6 –37 months), 66patients died from blastic phase complications. Sur-

vival of older and younger patients was similar (Fig. 3).Multivariate analysis for achievement of an objectiveresponse (CHR, PHR, hematologic improvement, andsecond chronic phase) identified thrombocytopenia� 50 � 109/L (P � 0.04) and high peripheral blasts� 50% (P � 0.07) as poor independent prognosticfactors, whereas older age was not. Similarly, the mul-tivariate analysis for survival identified only spleno-megaly (P � 0.01) as a factor that had an adverseeffect.

Prognostic Significance of Increasing Age in Patientswith Chronic Phase CMLThe cut-off age of 60 years was chosen for the reasonsstated above (established prognostic cut-off age, therole of allogeneic SCT in younger patients, and intol-erance to IFN in older patients). However, a differentcut-off age or increasing age still may be relevantprognostically and would be important clinically (e.g.,

TABLE 7Characteristics of Younger Patients and Older Patients Treated withImatinib for Accelerated Phase Chronic Myelogenous Leukemia(N � 133 patients)

Parameter

No. of patients (%)



Spelenomegaly (yes) 43 (47) 21 (50) 0.44Hemoglobin � 10 g/dL 44 (48) 27 (64) 0.10Leukocyte count � 50 �

109/L 15 (16) 13 (31) 0.07Platelets (� 109/L)

� 100 39 (43) 14 (33) 0.48� 450 26 (28) 16 (38) —

% Peripheral blasts (� 10) 16 (18) 14 (33) 0.10% Peripheral blasts and

promyelocytes (� 20) 8 (9) 8 (19) 0.15% Peripheral basophils (�

20) 21 (23) 6 (14) 0.26% Bone marrow blasts (�

15) 24 (26) 21 (50) 0.04% Bone marrow blasts and

promyelocytes (� 20) 22 (24) 14 (33) 0.30Additional chromosomal

abnormalities (yes) 34 (37) 17 (40) 0.88Imatinib dose (mg/day)

400 19 (21) 7 (17) —600 72 (79) 35 (83) 0.64

Chronic phase duration� 12 mos 29 (32) 7 (17) —12–35 mos 26 (28) 11 (26) 0.11� 36 mos 36 (40) 24 (57) —

% Ph positive at initiationof therapy (� 90) 79/89 (89) 38/41 (93) 0.75

Ph: Philadelphia chromosome.

TABLE 8Response by Age Group in Patients with Accelerated Phase ChronicMyelogenous Leukemia

Response

No. of patients (%)



Complete hematologic remission 70 (77) 34 (81) 0.66Cytogenetic response 48 (53) 14 (33) 0.04

Complete 33 (36) 8 (19) 0.07Partial 6 (7) 3 (7) —Minor 9 (10) 3 (7) —Major (complete � partial) 39 (43) 11 (26) 0.08

TABLE 9Causes of Death by Age in Patients with Accelerated Phase ChronicMyelogenous Leukemia Treated with Imatinib

Cause of death

No. of patients

Age < 60 yrs(n � 28 patients)


Blastic phase 18 7Infections/organ failure 1 4Cardiac events 0 1Postallogenic SCT complications 3 0Cause unknown (death outside the

institution) 6 7

SCT: stem cell transplantation,.


accelerated phase chronic myelogenous leukemia.


in the choice of allogeneic SCT in younger patientsages 40 – 60 years). For this purpose, a Martingale re-sidual plot was examined for survival with increasingage for all patients with CML in chronic phase in thisstudy (Fig. 4A). Increasing age was not associated withworse survival, as expected. When a similar plot wasexamined for patients who were treated with IFN forearly chronic phase CML from 1982 to 1995, increas-ing age appeared to be associated with worse survivalwith IFN, with an optimal cut-off age older than 50 –55years (Fig. 4B).

DISCUSSIONOlder age has been a consistently poor prognosticfactor for outcome in patients with Ph-positive CML.

This may be related to biologic differences of the dis-ease in older patients, poor follow-up or compliance,inadequate delivery of effective therapy (e.g., with al-logeneic SCT or IFN), or non-CML-related deaths.Several prognostic models previously reported thatolder age was an independent poor prognostic factorfor outcome in patients with CML.1– 4

This analysis focused on the prognostic signifi-cance of older age in the era of imatinib therapy. Wehypothesized that, if the poor prognosis for older pa-tients with CML was not related to intrinsic age-asso-ciated biologic features, then the prognostic effect ofolder age would be reduced significantly with an oral,well tolerated, highly effective therapy. With the cur-rent follow-up, the complete cytogenetic response

TABLE 10Characteristics of Younger Patients and Older Patients Treated with Imatinib for Blastic Chronic Myelogenous Leukemia

Parameter

No. of patients (%)



Spelenomegaly (� 5 cm bcm) 18/44 (41) 10/25 (40) 1.00Hemoglobin � 10 g/dL 26 (54) 12 (43) 0.48Leukocyte count � 50 � 109/L 14 (29) 8 (29) 1.00Platelets (� 109/L)

� 50 12 (25) 12 (39) 0.3750–100 12 (25) 7 (25) —

Additional chromosomal abnormalities (yes) 26/45 (58) 17/27 (63) 0.80% Peripheral blasts (� 50) 18 (38) 8 (29) 0.46% Bone marrow blasts (� 50) 23 (48) 17 (61) 0.34Blastic morphology (lymphoid) 7 (15) 3 (11) 0.74Chronic phase duration

� 12 mos 14 (29) 3 (11) —12–35 mos 16 (33) 4 (14) 0.01� 36 mos 18 (38) 21 (75) —

Blastic phase salvage (� second) 21 (44) 4 (14) 0.01

TABLE 11Response by Age Group in Patients with Blastic Phase Chronic Myelogenous Leukemia

Response

No. of patients (%)



Complete hematologic remission � hematologic improvement 9 � 5 9 � 6 —Cytogenetic response

Complete 2 3 —Partial 2 2 —Minor 2 1 —

Partial hematologic response 1 2 —Second chronic phase 5 0 —Early death 0 2 —Response

Objective response 20 (42) 17 (61) 0.15Any cytogenetic response 6 (13) 6 (21) 0.34


rate and the survival rate were similar by age group inpatients who received imatinib in early chronic phase.This is in contrast to the previously consistent poorprognosis associated with older age (e.g., with IFNtherapy) (Fig. 5). Among patients with chronic phaseCML post-IFN failure, older patients had a lower inci-dence of complete cytogenetic response, but survivalwas similar. In our previous experience in patientswith late chronic phase CML with IFN therapy, ageremained an independent poor prognostic factor,26,27

which was not the case with imatinib therapy.In both the accelerated and blastic phases of CML,

older age did not appear to be of prognostic relevance.There are no definite data to suggest the prognosticimpact of older age in the literature in these patientswith CML in advanced phases. However, in patientswith blastic phase CML, older age often has not beenof definite prognostic relevance, perhaps because theprognosis of those patients already is extremely poorand is determined by more important poor prognosticfeatures.

The poor prognostic relevance of older age inpatients with CML already appears to be minimizedsignificantly with the availability of imatinib, an effec-tive Bcr-Abl-targeted therapy that is delivered orallywith minimal side effects. This finding suggests thatthe previously described prognostic effect of age maynot have been related to a major extent to biologicdifferences in CML among older patients versusyounger patients.

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FIGURE 4. (A) A Martingale residual plot of survival with increasing age

demonstrating no effect of increasing age on survival in patients with chronic

phase chronic myelogenous leukemia (CML) in the era of imatinib therapy. (B)

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1995.

FIGURE 5. Survival by age group with interferon � therapy for patients with

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effects of age on prognosis with imatinib mesylate therapy for patients with philadelphia...

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