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Keywords:

  • old age;
  • chronic myelogenous leukemia;
  • imatinib;
  • Gleevec;
  • STI571

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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 α (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 characteristics, responses to therapy, and survival were compared by univariate and multivariate 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.

DOI 10.1002/cncr.11629

Older age has been a consistent poor prognostic factor in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) and has been incorporated into most multivariate-derived prognostic models.1–5 The poor prognostic effect of old age has been persistent across different therapies, including busulfan, hydroxyurea, interferon-α (IFN), and allogeneic stem cell transplantation (SCT), although the reasons for its prognostic effect may differ. With allogeneic SCT, for example, a poor prognosis with older age may be due primarily to transplantation-related mortality, which is significantly higher in older patients regardless of the underlying disease.6–8 Older patients have significantly worse side effects with IFN therapy; thus, their poor prognosis may be due at least in part to poor treatment tolerance and inadequate treatment delivery.9 It is noteworthy that the median age in the IFN studies was 45–50 years,10–12 significantly younger than the median age of 55 years in the imatinib mesylate studies (Gleevec; imatinib; STI571 [Novartis, East Hanover, NJ]),13–20 or the median age of 67 years in the Surveillance, Epidemiology, and End Results Program data.21 Thus, the prognostic effect of older age in these studies may not reflect a universal effect in the CML population. Older patients tolerate hydroxyurea and busulfan as well as younger patients. Therefore, their poorer prognosis may be attributed to several factors: lack of adjustment of survival data for disease specific mortality; a different biology of CML in older patients (that may be reflected in a higher incidence of other poor prognostic features, e.g., more aggressive disease); a delayed diagnosis in older patients who may then present with more morbidity and tumor burden; comorbid, age-related conditions; or poorer compliance or less frequent follow-up or medical attention provided to older patients, which may compromise their care delivery.

Imatinib, a selective Bcr-Abl tyrosine kinase inhibitor, has changed the treatment paradigm and prognosis for patients with Ph-positive CML. The introduction of highly effective therapy in patients with other malignancies (e.g., velban, bleomycin, and cisplatin in patients with testicular carcinoma; 2-chlorodeoxyadenosine in patients with hairy cell leukemia) often has nullified or reduced significantly the prognostic significance of previously well established prognostic factors. Imatinib is taken orally and has been tolerated extremely well across age groups. Thus, the availability of a highly active Bcr-Abl-directed oral therapy with minimal toxicity should eliminate age as a prognostic factor in patients with Ph-positive CML, unless age is associated with as yet undefined biologic disease differences. This is the focus of the current study, which analyzes the clinicolaboratory differences of older patients versus younger patients with Ph-positive CML in early chronic, chronic post-IFN failure, accelerated, and blastic phases who were treated with imatinib, and investigates potential differences in treatment delivery, response to therapy, and overall prognosis.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study groups of patients with Ph-positive CML who were treated in the Leukemia Department at The University of Texas M. D. Anderson Cancer Center with imatinib for newly diagnosed (early chronic phase) CML, chronic phase CML after IFN failure, accelerated phase CML, and blastic phase CML were analyzed. Study eligibility criteria, treatment schedules, pretreatment and follow-up studies, and dose-schedule modifications have been detailed previously in publications on patients with CML in early chronic phase,22, 23 chronic phase post-IFN failure,13, 15 accelerated phase,14, 16 and blastic phase.17 Informed consent was obtained for all study patients, according to institutional guidelines. Accelerated phase CML was defined by the presence of any of the following criteria: ≥ 15% blasts, ≥ 30% blasts and promyelocytes, ≥ 20% basophils, or thrombocytopenia < 100 × 109/L not related to therapy.24 Blastic phase CML was defined by the presence of ≥ 30% blasts or extremedullary blastic disease.25

Response Criteria

Complete hematologic response/remission (CHR) required normalization for at least 4 weeks of the bone marrow (< 5% blasts) and peripheral blood with a leukocyte count < 10 × 109/L, without peripheral blasts, promyelocytes, or myelocytes, in addition to the disappearance of all signs and symptoms of CML. This was categorized further by the cytogenetic response (suppression of Ph-positive cells) as follows: no cytogenetic response, 100% Ph-positive; minimal cytogenetic response, 35–90% Ph-positive; partial cytogenetic response, 1–34% Ph-positive; and complete cytogenetic response, 0% Ph-positive. A major cytogenetic response included complete and partial cytogenetic responses (< 35% Ph-positive).

A partial hematologic response (PHR) was the same as a CHR, except for the persistence of immature cells (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 detailed previously.17

Statistical Analysis

Evaluation of cytogenetic response was based on routine cytogenetic studies. Cytogenetic studies were performed every 3 months in the first year and every 3–6 months thereafter. Pretreatment additional chromosomal abnormalities referred to the presence of cytogenetic abnormalities other than Ph (excluding Ph variants, complex Ph translocations, and loss of chromosome Y). Response rates were computed on an intention-to-treated basis. Survival was analyzed from the date therapy started until death from any cause. Differences in survival curves were compared using the log-rank test. Statistical methods and multivariate analysis studies were conducted as described previously.13, 15 Multivariate analyses used the logistic regression model for response and the Cox proportional hazards model for survival. Variables that demonstrated significant differences in the univariate analysis (P < 0.05) were included in the multivariate analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A total of 747 patients with CML were analyzed: 187 patients in early chronic phase, 351 patients in chronic phase after IFN failure, 133 patients in accelerated phase, and 76 patients in blastic phase (Table 1). We chose the cut-off age of 60 years in subsequent analyses for several reasons: 1) this was the cut-off age that was identified as prognostically relevant in previous multivariate analysis studies of CML prognosis at our institution; 2) these patients mostly are ineligible for allogeneic SCT and are offered non-SCT approaches to improve their prognosis; and 3) they have historically tolerated IFN therapy poorly9 and/or were not offered IFN therapy, hence, it is not known whether their poor prognosis is related to a different intrinsic disease biology or to ineffective, poorly tolerated therapy.

Table 1. Patient Accrual on Different Chronic Myelogenous Leukemia Trials (n = 747 patients)
CML phase/protocolNo. of patients
  • CML: chronic myelogenous leukemia; IFN: interferon α 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 Philadelphia 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.

Early chronic phase 
 DM01-015 (imatinib 400 mg)50
 DM01-151 (imatinib 800 mg)100
 DM01-163 (imatinib 400 mg) (Novartis 106)23
 Expanded access (Novartis 113)a14
Chronic phase post-IFN failure 
 FDA pivotal (Novartis 109)149
 Expanded access (Novartis 110)111
 Expanded access (Novartis 113)a91
Accelerated phase 
 FDA pivotal (Novartis 109)59
 Expanded access (Novartis 113)74
Blastic phase 
 FDA pivotal (Novartis 102)13
 Expanded access (Novartis 115)33
 Phase I study (Novartis 001)29
 Expanded access (Novartis 113)b1

Early Chronic Phase CML

One hundred eighty-seven patients were treated for early chronic phase CML: Seventy-three patients received imatinib at a dose of 400 mg daily, 14 patients received 600 mg daily, and 100 patients received 800 mg daily. Forty-nine patients (26%) were age 60 years or older. The characteristics of patients in the two age groups are detailed in Table 2. No significant differences in important clinical or laboratory features were noted, except for splenomegaly, which was more frequent in younger patients (P < 0.05). Older patients represented 18 of 73 patients (25%) who received imatinib at a dose of 400 mg daily and 31 of 114 patients (27%) who received imatinib at a dose of 600–800 mg daily. Response to imatinib therapy was similar in younger and older patients (Table 3). With a median follow-up of 16 months (range, 2–30 months), 7 patients have transformed to accelerated or blastic phases (2 of 49 patients age 60 years or older [1 patient in accelerated phase and 1 patient in blastic] vs. 5 of 138 patients younger than 60 years [3 patients in accelerated phase and 2 patients in blastic phase]), and only 3 of 187 patients have died (1 patient died after developing complications of graft-versus-host disease, 1 patient died a natural death from old age, and 1 patient died from blastic phase complications).

Table 2. Characteristics of Younger Patients versus Older Patients Treated with Imatinib for Early Chronic Phase Chronic Myelogenous Leukemia (N = 187 patients)
ParameterNo. of patients (%)P value
Age < 60 yrsAge ≥ 60 yrs
No. treated13849
Splenomegaly (yes)46 (33) 7 (14)0.01
Hemoglobin < 12 g/dL59 (43)17 (35)0.40
Leukocyte count > 50 × 109/L43 (31)15 (31)1.00
Platelets > 450 × 109/L49 (36)19 (39)0.73
Peripheral 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)1.00
Additional chromosomal abnormalities (yes) 6 (4) 4 (8)0.29
Table 3. Response to Imatinib by Age in Patients with Early Chronic Phase Chronic Myelogenous Leukemia
ResponseNo. of patients (%)P value
Age < 60 yrs (n = 128 patients)aAge ≥ 60 yrs (n = 46 patients)a
  • 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.

Cytogenetic response123 (96)45 (98)1.00
 Complete101 (79)40 (87)0.28
 Partial 14 (11) 5 (11)
 Minor  8 (6) 0 (0)
 Major (complete + partial)115 (90)45 (98)0.12

Chronic Phase CML Post-IFN Failure

Three hundred fifty-one patients were treated with imatinib for chronic phase CML after IFN failure; 120 patients (34%) were age 60 years or older. The characteristics of younger and older patients are compared in Table 4. Older patients had a lower incidence of pretreatment additional chromosomal abnormalities (P = 0.01), which constitute a well known adverse prognostic factor. Older patients also had more frequent leukocytosis (P = 0.04), bone marrow basophilia (P = 0.05), Ph positivity > 90% at the start of therapy (P = 0.05), and more therapies prior to imatinib (P = 0.05). Older patients had a significantly lower incidence of complete cytogenetic response compared with younger patients (Table 5). With a median 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 of death are shown in Table 6. Survival of patients by age was not different between patients in the two age groups (Fig. 1).

Table 4. Characteristics of Younger Patients and Older Patients Treated with Imatinib for Chronic Phase Chronic Myelogenous Leukemia after Failure on Interferon α Therapy
ParameterNo. of patients (%)P value
Age < 60 yrs (n = 231 patients)Age ≥ 60 yrs (n = 120 patients)
  1. IFN-α interferon α Ph: Philadelphia chromosome; CML: chronic myelogenous leukemia.

Last response to IFN-α immediately before entry on imatinib study (n = 223 patients age < 60 yrs; n = 115 patients age ≥ 60 yrs)   
 Hematologic resistance/recurrence34 (15)18 (16)0.14
 Cytogenetic resistance/recurrence111 (50)44 (38)
 IFN intolerance78 (35)53 (46)
Spelenomegaly (yes)40/229 (17)23 (19)0.81
Hemoglobin ≥ 10 g/dL206 (89)110 (92)0.57
Leukocyte count ≥ 10 × 109/L106 (46)71 (59)0.04
Platelets > 450 × 109/L45 (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)0.05
Additional chromosomal abnormalities (yes)54 (24)14 (12)0.01
CML duration   
 < 12 mos28 (12)11 (9)
 12–35 mos91 (39)45 (38)0.59
 ≥ 36 mos112 (48)64 (53)
Imatinib dose (mg/day)   
 400170 (74)90 (75)0.88
 60061 (26)30 (25)
No. of prior treatments   
 1190 (82)87 (72)
 2–341 (18)33 (28)0.05
Table 5. Response to Imatinib by Age in Patients with Chronic Phase Chronic Myelogenous Leukemia after Failure on Interferon α Therapy
ResponseNo. of patients (%)P value
Age < 60 yrs (n = 231 patients)Age ≥ 60 yrs (n = 120 patients)
Complete hematologic remission217 (94)113 (94)
Cytogenetic response169 (73) 76 (63)0.08
 Complete129 (56) 53 (44)0.05
 Partial 24 (10) 15 (12)
 Minor 16 (7)  8 (7)
 Major (complete + partial)153 (66) 68 (57)0.10
Table 6. Causes of Death by Age Group with Imatinib Therapy in Patients with Chronic Phase Chronic Myelogenous Leukemia after Failure on Interferon α Therapy
Cause of deathNo. of patients
Age < 60 yrs (n = 21 patients)Age ≥ 60 yrs (n = 14 patients)
Blastic/accelerated phase10/03/2
Infections/organ failure33
Cardiac event12
Intercurrent illness11
Bleeding10
Unknown (death outside the institution)53
thumbnail image

Figure 1. Survival by age group with imatinib therapy for patients with chronic phase chronic myelogenous leukemia after failure on interferon α therapy.

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A multivariate analysis of prognostic factors associated with lower complete cytogenetic response identified 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 for achieving a complete cytogenetic response. Older age was not an independent poor prognostic factor.

A multivariate analysis of survival identified the following factors as indicative of a poor prognostic trend: pretreatment additional chromosomal abnormalities (P = 0.10) and higher numbers of prior therapies (P = 0.05). Older age was not associated independently with poor survival.

Accelerated Phase CML

Forty-two of 133 patients (32%) who were analyzed in accelerated phase were age 60 years or older. The characteristics of older and younger patients who received treatment with imatinib for accelerated phase CML are shown in Table 7. Older patients had a significantly higher incidence of bone marrow blasts ≥ 15% (P = 0.04) and trends for higher percentages of peripheral blasts (P = 0.10), higher hemoglobin levels (P = 0.10), and leukocytosis (P = 0.07) (Table 7). Although there was a trend toward higher complete response rates (P = 0.07) and major cytogenetic response rates (P = 0.08) with imatinib in younger patients, it was not significant; however, the incidence of any cytogenetic response was 53% versus 33%, respectively (P = 0.04) (Table 8). With the current median follow-up of 22 months (range, 1–37 months), 47 of 133 patients have died from reasons shown in Table 9. There was a trend toward better survival with imatinib in younger patients (30-month estimated survival rates: 66% vs. 45%; P = 0.09) (Fig. 2).

Table 7. Characteristics of Younger Patients and Older Patients Treated with Imatinib for Accelerated Phase Chronic Myelogenous Leukemia (N = 133 patients)
ParameterNo. of patients (%)P value
Age < 60 yrs (n = 91 patients)Age ≥ 60 yrs (n = 42 patients)
  1. Ph: Philadelphia chromosome.

Spelenomegaly (yes)43 (47)21 (50)0.44
Hemoglobin ≥ 10 g/dL44 (48)27 (64)0.10
Leukocyte count ≥ 50 × 109/L15 (16)13 (31)0.07
Platelets (× 109/L)   
 < 10039 (43)14 (33)0.48
 > 45026 (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)0.30
Additional chromosomal abnormalities (yes)34 (37)17 (40)0.88
Imatinib dose (mg/day)   
 40019 (21)7 (17)
 60072 (79)35 (83)0.64
Chronic phase duration   
 < 12 mos29 (32)7 (17)
 12–35 mos26 (28)11 (26)0.11
 ≥ 36 mos36 (40)24 (57)
% Ph positive at initiation of therapy (> 90)79/89 (89)38/41 (93)0.75
Table 8. Response by Age Group in Patients with Accelerated Phase Chronic Myelogenous Leukemia
ResponseNo. of patients (%)P value
Age < 60 yrs (n = 91 patients)Age ≥ 60 yrs (n = 42 patients)
Complete hematologic remission70 (77)34 (81)0.66
Cytogenetic response48 (53)14 (33)0.04
 Complete33 (36) 8 (19)0.07
 Partial 6 (7) 3 (7)
 Minor 9 (10) 3 (7)
 Major (complete + partial)39 (43)11 (26)0.08
Table 9. Causes of Death by Age in Patients with Accelerated Phase Chronic Myelogenous Leukemia Treated with Imatinib
Cause of deathNo. of patients
Age < 60 yrs (n = 28 patients)Age ≥ 60 yrs (n = 19 patients)
  1. SCT: stem cell transplantation,.

Blastic phase187
Infections/organ failure14
Cardiac events01
Postallogenic SCT complications30
Cause unknown (death outside the institution)67
thumbnail image

Figure 2. Survival by age group with imatinib therapy for patients with accelerated phase chronic myelogenous leukemia.

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In the multivariate analysis, significant poor independent prognostic factors for achieving complete cytogenetic response were splenomegaly ≥ 10 cm bcm (P = 0.02), any peripheral blasts (P = 0.03), and Ph positivity > 90% at the initiation of therapy (P = 0.08). For survival, the multivariate-derived, independent poor prognostic factors were pretreatment additional chromosomal abnormalities (P = 0.02), bone marrow basophilia (P = 0.04), and lower imatinib dose (P = 0.03). Age, however, was not found to be an independent poor prognostic factor for achieving complete cytogenetic response and had a marginal independent effect on survival (P = 0.08).

Blastic Phase CML

Seventy-six patients received imatinib for CML in blastic phase, including 28 patients (37%) age 60 years or older. The characteristics of younger and older patients were similar, except for a longer duration of chronic phase in older patients (P = 0.01), and more patients in the older group received imatinib as their first blastic phase salvage therapy (P = 0.01) (Table 10). Response to imatinib salvage therapy was similar in younger and older patients (Table 11). With a median follow-up of 20 months (range, 6–37 months), 66 patients died from blastic phase complications. Survival of older and younger patients was similar (Fig. 3). Multivariate analysis for achievement of an objective response (CHR, PHR, hematologic improvement, and second chronic phase) identified thrombocytopenia < 50 × 109/L (P = 0.04) and high peripheral blasts > 50% (P = 0.07) as poor independent prognostic factors, whereas older age was not. Similarly, the multivariate analysis for survival identified only splenomegaly (P = 0.01) as a factor that had an adverse effect.

Table 10. Characteristics of Younger Patients and Older Patients Treated with Imatinib for Blastic Chronic Myelogenous Leukemia
ParameterNo. of patients (%)P value
Age < 60 yrs (n = 48 patients)Age ≥ 60 yrs (n = 28 patients)
Spelenomegaly (> 5 cm bcm)18/44 (41)10/25 (40)1.00
Hemoglobin < 10 g/dL26 (54)12 (43)0.48
Leukocyte count ≥ 50 × 109/L14 (29)8 (29)1.00
Platelets (× 109/L)   
 < 5012 (25)12 (39)0.37
 50–10012 (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)0.34
Blastic morphology (lymphoid)7 (15)3 (11)0.74
Chronic phase duration   
 < 12 mos14 (29)3 (11)
 12–35 mos16 (33)4 (14)0.01
 ≥ 36 mos18 (38)21 (75)
Blastic phase salvage (≥ second)21 (44)4 (14)0.01
Table 11. Response by Age Group in Patients with Blastic Phase Chronic Myelogenous Leukemia
ResponseNo. of patients (%)P value
Age < 60 yrs (n = 48 patients)Age ≥ 60 yrs (n = 28 patients)
Complete hematologic remission + hematologic improvement9 + 59 + 6
Cytogenetic response   
 Complete23
 Partial22
 Minor21
Partial hematologic response12
Second chronic phase50
Early death02
Response   
 Objective response20 (42)17 (61)0.15
 Any cytogenetic response 6 (13) 6 (21)0.34
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Figure 3. Survival by age group with imatinib therapy for patients with blastic phase chronic myelogenous leukemia.

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Prognostic Significance of Increasing Age in Patients with Chronic Phase CML

The cut-off age of 60 years was chosen for the reasons stated above (established prognostic cut-off age, the role of allogeneic SCT in younger patients, and intolerance to IFN in older patients). However, a different cut-off age or increasing age still may be relevant prognostically and would be important clinically (e.g., in the choice of allogeneic SCT in younger patients ages 40–60 years). For this purpose, a Martingale residual plot was examined for survival with increasing age for all patients with CML in chronic phase in this study (Fig. 4A). Increasing age was not associated with worse survival, as expected. When a similar plot was examined for patients who were treated with IFN for early chronic phase CML from 1982 to 1995, increasing age appeared to be associated with worse survival with IFN, with an optimal cut-off age older than 50–55 years (Fig. 4B).

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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) Increasing age was an adverse prognostic factor for survival in patients with early chronic phase CML who received interferon α therapy from 1982 until 1995.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Older age has been a consistently poor prognostic factor for outcome in patients with Ph-positive CML. This may be related to biologic differences of the disease in older patients, poor follow-up or compliance, inadequate delivery of effective therapy (e.g., with allogeneic SCT or IFN), or non-CML-related deaths. Several prognostic models previously reported that older age was an independent poor prognostic factor for outcome in patients with CML.1–4

This analysis focused on the prognostic significance of older age in the era of imatinib therapy. We hypothesized that, if the poor prognosis for older patients with CML was not related to intrinsic age-associated biologic features, then the prognostic effect of older age would be reduced significantly with an oral, well tolerated, highly effective therapy. With the current follow-up, the complete cytogenetic response rate and the survival rate were similar by age group in patients who received imatinib in early chronic phase. This is in contrast to the previously consistent poor prognosis associated with older age (e.g., with IFN therapy) (Fig. 5). Among patients with chronic phase CML post-IFN failure, older patients had a lower incidence of complete cytogenetic response, but survival was similar. In our previous experience in patients with late chronic phase CML with IFN therapy, age remained an independent poor prognostic factor,26, 27 which was not the case with imatinib therapy.

thumbnail image

Figure 5. Survival by age group with interferon α therapy for patients with early chronic phase chronic myelogenous leukemia (1982–1995).

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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 prognostic impact of older age in the literature in these patients with CML in advanced phases. However, in patients with blastic phase CML, older age often has not been of definite prognostic relevance, perhaps because the prognosis of those patients already is extremely poor and is determined by more important poor prognostic features.

The poor prognostic relevance of older age in patients with CML already appears to be minimized significantly with the availability of imatinib, an effective Bcr-Abl-targeted therapy that is delivered orally with minimal side effects. This finding suggests that the previously described prognostic effect of age may not have been related to a major extent to biologic differences in CML among older patients versus younger patients.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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