Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia—Comparison with historic experience

Authors


Abstract

BACKGROUND

The effect of imatinib mesylate on survival in the accelerated phase of chronic myelogenous leukemia (CML) is unknown. The objectives of this study were to update the long-term experience with imatinib in patients who had accelerated-phase CML and to compare outcomes with historic experience.

METHODS

The outcomes of 176 patients who received treatment with imatinib were reviewed and compared with the outcomes of 213 historic control patients with accelerated-phase CML who received treatment with interferon-α or with other modalities.

RESULTS

With imatinib, the complete hematologic response rate was 82% versus a rate ≤ 50% for others, and the complete cytogenetic response rate was 43% versus rates of 0–6% for others. The estimated 4-year survival rates were 53% with imatinib, 42% with interferon-α, and 0–21% for others. A multivariate analysis of the total population of 389 patients indicated that imatinib therapy (vs. other therapies) was an independent, favorable prognostic factor for survival (P < 0.0001; hazard rate, 0.62). A subset analysis that included only patients who were treated with imatinib and interferon-α (276 patients) also identified imatinib as an independent favorable prognostic factor (P < 0.0001; hazard rate, 0.65). The 3-month cytogenetic response to imatinib was associated with significantly different survival outcomes (P < 0.0001). A multivariate analysis that included pretreatment characteristics and 3-month cytogenetic response among 150 patients who received imatinib and were alive at 3 months identified only 2 adverse independent prognostic factors: lack of a cytogenetic response at 3 months (P < 0.001) and anemia (hemoglobin < 10 g/dL; P = 0.003). Patients who had neither factor (41%) had an estimated 4-year survival rate of 88%; in the other patients, the 4-year survival rate was ≤ 60%. This may have implications in relation to subsequent therapy, because, according to the outcomes of patients who underwent allogeneic transplantation in accelerated phase at the authors' institution and from literature reports, the estimates of 5-year survival were 25–30%.

CONCLUSIONS

The current results suggest that imatinib improved survival compared with other therapies in patients with accelerated-phase CML. Cancer 2005. © 2005 American Cancer Society.

Chronic myelogenous leukemia (CML) is a proliferative disorder of the hematopoietic stem cell and is linked causally to the Philadelphia chromosome (Ph)-related BCR-ABL molecular events.1, 2 Most patients present in the chronic phase, with the disease later evolving into the accelerated and blastic phases.3, 4 The accelerated phase of CML is associated with the development of multiple features of resistance and transformation, including increasing percentages of blasts, promyelocytes, and basophils; thrombocytopenia or thrombocytosis; and cytogenetic clonal evolution.5–7 The accelerated phase of CML usually has been associated with a median survival that ranges from 6 months to 24 months.

Imatinib mesylate, a selective Bcr-Abl kinase inhibitor, has shown major anti-CML activity and now is considered front-line therapy in all phases of CML.8–15 In the only randomized study published to date of imatinib versus standard therapy (interferon-α plus cytarabine) in patients with newly diagnosed CML, imatinib was associated with significantly better rates of complete cytogenetic response, major molecular response, time to disease progression, and transformation to accelerated-blastic phase. However, survival was similar with imatinib and interferon-α plus cytarabine, because 89% of patients who were randomized to receive interferon-α plus cytarabine changed to imatinib therapy after a median of 8 months after the start of therapy.15 A survival advantage with imatinib versus standards of care was documented only through comparisons with historic experiences in patients with chronic phase CML.16–18

In patients with accelerated-phase CML, oral imatinib at a dose of 400–600 mg daily has been associated with favorable rates of complete hematologic response (CHR) and cytogenetic response. However, whether imatinib therapy is associated with improved survival compared with previous standards of care has not been investigated. This was the objective of the current analysis.

MATERIALS AND METHODS

Study Group

Adults (age ≥ 18 years) with a confirmed diagnosis of Ph-positive CML in accelerated phase who were treated on imatinib studies were analyzed.13, 19 Eligibility criteria included adequate performance status (Eastern Cooperative Oncology Group scale 0–2), adequate renal function (creatinine ≤ 2.0 mg/dL), and adequate hepatic function (bilirubin, aspartate aminotransferase, and alanine aminotransferase levels no more than twice the upper limits of normal).

Women of childbearing age were required to have a negative pregnancy test, and all patients were required to use barrier contraception during therapy. Patients provided written informed consent. Studies were approved by the Internal Review Board of the institution and were conducted in accordance with the Declaration of Helsinki.

Accelerated-phase disease was defined by the following criteria: blasts ≥ 15%, basophils ≥ 20%, blasts plus promyelocytes ≥ 30%, the presence of chromosomal abnormalities in addition to Ph, and thrombocytopenia (platelets < 100 × 109/L) unrelated to therapy. Constitutional cytogenetic abnormalities, loss of the Y chromosome, and Ph variant translocations were not considered evidence of clonal evolution.5

Therapy

Twenty-seven patients were given imatinib at a dose of 400 mg daily, and 149 patients were given imatinib at a dose of 600 mg daily. Dose adjustments for toxicities were detailed previously.13, 19

Response criteria

Response criteria have been described previously.19 A CHR required the disappearance of all signs and symptoms related to disease, including normalization of blast counts in the peripheral blood and bone marrow (≤ 5% bone marrow blasts); leukocyte counts < 10 × 109/L; normal differential counts without peripheral blasts, promyelocytes, or myelocytes; and platelet counts < 450 × 109/L. If thrombocytopenia (< 100 × 109/L) was present before treatment, then a CHR required normalization of platelet counts > 100 × 109/L. Patients who began treatment with normal platelet counts and achieved a CHR but had platelet counts < 100 × 109/L attributable to imatinib were considered to have achieved a CHR, but it was noted that they had low platelet counts. Patients in CHR were evaluated by the degree of cytogenetic response, which was categorized as complete if no Ph-positive cells were present, partial if the percentage of Ph-positive cells was reduced to between 1% and 34%, and minor if the percentage of Ph-positive cells was reduced to between 35% and 90%. A major cytogenetic response referred to complete and partial cytogenetic responses (i.e., < 35% Ph-positive cells). Patients were evaluated for cytogenetic response every 3 months during the first year after treatment and every 3–6 months in the second year. Cytogenetic response was based on standard cytogenetic analysis of 20 metaphase spreads.

Cytogenetic and polymerase chain reaction analysis

Cytogenetic analysis was performed by the G-banding technique. Bone marrow specimens were examined on direct short-term (24-hour) cultures, and at least 20 metaphases were analyzed. BCR-ABL transcripts were detected by real-time quantitative RT-PCR (Q-PCR) analysis on peripheral blood and/or bone marrow aspirate, and negative results (i.e., undetectable transcript) were confirmed by nested PCR, as reported previously.20 The lower limit of detection in the nested PCR assay is approximately 1 BCR-ABL-expressing cell per 100,000. Normalization ratios of BCR-ABL transcript levels were done by comparison with the levels of ABL transcript. For the purpose of this analysis, a complete molecular response was defined as negative (undetectable) BCR-ABL transcript levels. A major molecular response was defined as BCR-ABL:ABL ratios < 0.05%. This cut-off ratio was based on previous studies that identified BCR-ABL:ABL ratios of 0.045–0.1% as important prognostically.21–23 A BCR-ABL:ABL ratio of 0.05% is roughly equivalent to a 3-log reduction in BCR-ABL transcript levels compared with that oberved in samples before imatinib treatment (the median pretreatment Q-PCR value at the University of Texas M. D. Anderson Cancer Center is 37%).23

Statistical Considerations

Differences between patient subgroups in categorical characteristics and response rates were evaluated by chi-square or Fisher exact tests. Rank correlation coefficients were computed for pairs of interval-scaled variables. Survival distributions were estimated by the method of Kaplan and Meier and were compared using the log-rank test.24, 25 Survival was measured from the date of study registration to the date of death from any cause. The association of cytogenetic response with survival was assessed using a landmark of 3 months. A Cox proportional hazards model was used to evaluate independent prognostic factors for survival.26 The proportional hazard assumption was confirmed based on the Schoenfeld residuals.

Historic Group

To compare the outcome from treatment with imatinib with previous experience, we analyzed the results from patients with accelerated-phase CML treated who had received nonimatinib regimens since 1982. These patients had similar good performance status and organ (renal and hepatic) functions. Treatment for accelerated-phase CML included interferon-α (n = 100 patients), homoharringtonine (n = 35 patients), daunorubicin plus cytarabine (n = 23 patients), decitabine (n = 47 patients), and other therapies (n = 8 patients).

RESULTS

Treatment Results

One hundred seventy-six patients with accelerated-phase CML who received imatinib therapy between May 1999 and May 2001 were analyzed. Their median age was 50 years, and 25% of patients were age ≥ 60 years (Table 1). Accelerated-phase criteria included blasts ≥ 15% in 16 patients, basophils ≥ 20% in 21 patients, thrombocytopenia < 100 × 109/L in 23 patients, cytogenetic clonal evolution in 63 patients, and ≥ 2 such factors in 53 patients. Overall, 144 patients (82%) achieved a CHR, and 86 patients (49%) had a major cytogenetic response, which was complete in 76 patients (43%). With a median follow-up of 41 months (range, 3–60 months), 68 patients had died. The estimated 4-year survival rate was 53% (Fig. 1). Sixty-five of 176 patients (37%) remained on imatinib therapy, including 51 patients (29%) in complete cytogenetic response and 53 patients (30%) in major cytogenetic response. Fourteen patients have undergone allogeneic stem cell transplantation (SCT) after imatinib therapy from related donors (n = 7 patients) or unrelated donors (n = 7 patients). Allogeneic SCT was performed in accelerated phase (n = 6 patients) or while patients were responding to imatinib (n = 8 patients). Seven of 14 patients remained in remission without evidence of disease (NED) after a median of 14 + months after undergoing SCT (range, from 3 + to 51 + months).

Table 1. Characteristics of Patients Treated with Imatinib versus Other Regimens for Accelerated- Phase Chronic Myelogenous Leukemia
ParameterNo. of patients (%)P value
ImatinibOther
  1. CML: chronic myelogenous leukemia; WBC: white blood cells.

Total176213 
Age (yrs)   
 > 6044 (25)32 (15)0.01
 [Median][50][44] 
CML duration (mos)   
 < 1242 (24)71 (33)0.09
 12–3554 (31)51 (24) 
 ≥ 3680 (45)91 (43) 
Splenomegaly69 (39)108/207 (52)0.01
Hemoglobin < 10 g/dL61 (35)81 (38)0.49
Platelet count < 100 × 109/L46 (26)39 (18)0.06
WBC ≥ 50 × 109/L30 (17)72/212 (34)< 0.01
Peripheral blasts ≥ 5%38 (22)72/210 (34)0.01
Bone marrow blasts ≥ 5%70 (40)93/206 (45)0.29
Peripheral basophils > 5%65 (37)91/210 (43)0.20
Bone marrow basophils > 5%70 (40)72/206 (35)0.33
Cytogenetic clonal evolution108 (61)149/188 (79)< 0.01
Accelerated-phase features  0.002
 Blasts ≥ 15%16 (9)12 (6) 
 Basophils ≥ 20%21 (12)25 (12) 
 Thrombocytopenia23 (13)7 (3) 
 Clonal evolution alone63 (36)103 (48) 
 Combination of the above53 (30)66 (31) 
Figure 1.

Survival with imatinib versus other therapies in patients with accelerated-phase chronic myelogenous leukemia.

Among the 176 patients who received imatinib, 88 patients underwent quantitative PCR studies. Forty-four patients achieved a major molecular response, and 28 patients achieved a complete molecular response.

Table 1 compares the characteristics of the 176 patients who received imatinib to the characteristics of 213 historic patients who received nonimatinib therapy for accelerated-phase CML. Patients who were treated with imatinib were significantly older but had significantly lower rates of splenomegaly, leukocytosis, peripheral blasts, and cytogenetic clonal evolution.

Table 2 shows the response to imatinib versus other therapies. The rates of CHR and of major and complete cytogenetic response were significantly higher with imatinib versus interferon-α or other therapies: The CHR rates were 82%, 50%, and 27%, respectively (P < 0.001). The major cytogenetic response rates were 49%, 17%, and 10%, respectively (P < 0.001).

Table 2. Response to Therapy
TherapyNo. of evaluable patientsCHR (%)Cytogenetic response (%)Estimated 4-yr survival (%)
MajorComplete
  1. CHR: complete hematologic response.

Imatinib17682494353
Interferon-α1005017542
Homoharringtonine354311021
Daunorubicin and cytarabine23309413
Decitabine47191166
Other80000

With a median follow-up of 85 months (range, 3–206 months) in the historic control group, 178 patients have died. Survival was significantly better with imatinib therapy than with other therapies overall (Fig. 1) and by individual therapies (Fig. 2). The estimated 4-year survival rates were 53% with imatinib, 42% with interferon-α, and < 25% with other therapies.

Figure 2.

Survival in patients with accelerated-phase chronic myelogenous leukemia by type of therapy. Dauno: daunorubicin; chemo: chemotherapy.

Prognostic Factors for Survival

Because of differences in the pretreatment characteristics of the patients who received imatinib versus other therapies, first, we analyzed the association of pretreatment characteristics with survival in the total cohort of 389 patients (176 imatinib-treated patients and 213 patients treated with other therapies). Factors associated with significantly adverse survival included longer disease duration, the presence of splenomegaly, anemia, thrombocytopenia, higher percentages of peripheral and bone marrow blasts, bone marrow basophilia, increased percentages of peripheral and bone marrow blasts plus promyelocytes, and therapy with nonimatinib regimens (Table 3). The significance of pretreatment characteristics for survival in patients with accelerated-phase CML was similar within treatment groups (data not shown).

Table 3. Factors Associated with Survival in Patients with Accelerated-Phase Chronic Myelogenous Leukemia
ParameterTotal no. of patientsNo. of deathsSurvival rate (%)Median survival (mos)P value
2 Yrs4 Yrs
  1. CML: chronic myelogenous leukemia; WBC: white blood cells; NR: not reached.

Total389249563732 
Age      
 < 60 yrs3131965940360.055
 ≥ 60 yrs7650452822 
CML duration (mos)      
 < 12113647150530.001
 12–3510563563731 
 ≥ 36171119482922 
Splenomegaly      
 No206110684743< 0.001
 Yes177131462820 
Hemoglobin (g/dL)      
 < 10.0142112392215< 0.001
 10.0–11.913676644340 
 ≥ 12.011158725148 
Platelet count (× 109/L)      
 < 10085594127180.004
 100–450194115614337 
 > 45011072613736 
WBC (× 109/L)      
 < 10107575941360.233
 10–49179111593835 
 ≥ 5010277523427 
Peripheral blasts (%)      
 015168715562< 0.001
 1–412586553430 
 5–95144411715 
 10–142418451522 
 ≥ 153528342515 
Bone marrow blasts (%)      
 05530725558< 0.001
 1–416485685048 
 5–94933462821 
 10–144338291915 
 ≥ 157155451422 
Peripheral basophils (%)      
 ≤ 52301366142370.063
 6–1910273513124 
 ≥ 205435482822 
Bone marrow basophils (%)      
 ≤ 52401436042370.024
 6–1910474573127 
 ≥ 203824452622 
Peripheral blasts and promyelocytes (%)      
 ≤ 5242127664844< 0.001
 6–1910787452321 
 20–293125291811 
 ≥ 30552009 
Bone marrow blasts and promyelocytes (%)      
 < 10208101715458< 0.001
 10–199874452718 
 20–296353351017 
 ≥ 301917421817 
Cytogenetic clonal evolution      
 No10755634238< 0.001
 Clonal evolution only16695694947 
 Clonal evolution and other accelerated features9174342014 
Therapy      
 Imatinib176687153NR< 0.001
 Others213178452621 

A multivariate analysis that included the total population cohort identified that the following were independent poor prognostic factors for survival in patients with accelerated-phase CML (P < 0.05): anemia, older age, splenomegaly, longer disease duration, higher percentages of peripheral or bone marrow blasts, and cytogenetic clonal evolution. Adding therapy (imatinib vs. other) to the multivariate analysis (Table 4) identified imatinib therapy as the most significant, favorable prognostic factor for survival in accelerated phase (P < 0.0001; hazard rate, 0.62). It is noteworthy that some treatment variables differed widely between the treatment groups. For example, prior exposure (and progression) on interferon-α therapy was noted in 150 of 176 patients (85%) who received treatment with imatinib and in 79 of 113 other patients (70%) who received treatment with other modalities (homoharringtonine, decitabine, other chemotherapy). However, only 18 of 100 patients (18%) who received treatment with interferon-α in accelerated phase had received prior interferon-α for chronic phase CML. In addition, although it is not an adverse factor (Table 3), cytogenetic clonal evolution as the only accelerated-phase feature was present in 76% of patients who were treated in accelerated phase with interferon, but in only 36% of patients who were treated with imatinib, and in 37% of patients who received other therapies (P < 0.001). To account more precisely for the benefit of imatinib versus interferon-α, we repeated the multivariate analysis of prognostic factors associated with survival among the 276 patients who received imatinib or interferon-α. Again, the analysis associated similar pretreatment factors with a poor prognosis: age ≥ 50 years (P = 0.002), hemoglobin < 10/g/dL (P = 0.01), splenomegaly (P = 0.04), bone marrow blasts ≥ 4% (P = 0.01), and cytogenetic clonal evolution with other accelerated features (P = 0.0001). Therapy with imatinib was selected again as the most significant, favorable prognostic factor compared with interferon-α (P < 0.0001; hazard rate, 0.65).

Table 4. Multivariate Analysis of Prognostic Factors (Including Therapy) Associated with Survival in Patients with Accelerated-Phase Chronic Myelogenous Leukemia
ParameterEstimated HRP value
  1. HR: hazard ratio; CML: chronic myelogenous leukemia.

Older age1.02< 0.001
CML duration ≥ 12 mos1.43< 0.001
Splenomegaly present1.260.002
Hemoglobin < 10 g/dL2.11< 0.001
Higher % of peripheral blasts1.030.048
Imatinib therapy0.62< 0.001

The association between cytogenetic response to imatinib and survival is illustrated in Figure 3A. To be able to advise patients on imatinib therapy with regard to their next therapy step (continuing imatinib vs. proceeding to allogeneic SCT), we included cytogenetic responses to imatinib after 3 months of therapy in a new multivariate analysis that included only the 150 patients who received imatinib and also were alive at 3 months, using a 3-month landmark analysis for survival. The multivariate analysis identified the following significant, independent poor prognostic factors: no cytogenetic response at 3 months (P < 0.001) and pretreatment hemoglobin < 10 g/dL (P = 0.003). Patients could be categorized into good risk (no factors; n = 61 patients; 41%) or poor risk (either or both factors; n = 89 patients; 59%), with estimated 4-year survival rates of 88% versus ≤ 60%, respectively (Fig. 3B).

Figure 3.

These charts illustrate the survival of patients who received imatinib therapy by (A) 3-month cytogenetic response and (B) the number of adverse prognostic factors identified in multivariate analysis.

DISCUSSION

The discovery of new, effective therapies may reduce or eliminate the prognostic significance of previously well established prognostic factors, which is what happened with cladribine in hairy cell leukemia and with cisplatin in testicular carcinoma. The introduction of imatinib therapy for CML has shown similar effects, reducing the prognostic significance of several established prognostic factors, such as age, cytogenetic clonal evolution, and deletions in chromosome 9.27, 28 Imatinib-associated response parameters also are emerging as more significant prognostic factors.29

Impressive response rates have been documented with imatinib in patients with accelerated-phase CML; however, the impact of such therapy on survival has not been studied to date. Because no randomized studies of imatinib versus other standards of care have been performed in patients with accelerated-phase CML (and they are unlikely to be done in the future for ethical and practical reasons), we resorted to comparing the outcomes with imatinib versus our historic experience. We found that imatinib was associated with a 4-year estimated survival rate of 53%: higher than past experience. The results from treatment with imatinib compared favorably with the results from treatment with interferon-α and other therapies.

Because there were differences in the characteristics of patients who received treatment with imatinib and patients who received other therapies (Table 1), and because some of the different patient characteristics also were important prognostic factors for survival, we conducted a multivariate analysis that included the entire cohort of patients to identify important, independent, pretreatment prognostic factors. After accounting for these, imatinib therapy remained the most important favorable prognostic factor for survival in patients with accelerated-phase CML compared with other therapies (P < 0.0001; hazard rate, 0.62) or, specifically, with interferon-α (P < 0.0001; hazard rate, 0.65).

An important concern is whether delaying allogeneic SCT in accelerated phase in favor of an imatinib trial may harm some patients. Although it was not integral to the current analysis, it was interesting to compare the outcomes of patients who received imatinib with the results of patients who underwent allogeneic SCT in accelerated phase from our institutional experience and from the experience reported in the literature. Between 1984 and 2004, 111 patients with Ph-positive CML in accelerated phase underwent allogeneic SCT at The University of Texas M. D. Anderson Cancer Center. Their median age was 37 years (range, 16–63 years). Sixty-eight patients underwent related-donor SCT, and 43 patients underwent unrelated-donor SCT. Their outcomes are illustrated in Figure 4. This suggests that imatinib therapy does not appear to harm patients and, in fact, may benefit them. The most recent International Bone Marrow Transplant Registry (IBMTR) update analyzed 753 patients with Ph-positive CML who underwent transplantation in accelerated or second chronic phase. Their estimated 5-year survival rate was 22%.30

Figure 4.

Survival of 176 patients who received imatinib and 111 patients who underwent allogeneic stem cell transplantation (Allo-SCT) at The University of Texas M. D. Anderson Cancer Center according to the year of transplantation (1984–1994 [n = 52 patients] and 1995–2004 [n = 59 patients]).

Another consideration is the timing of allogeneic SCT by imatinib response. Based on our predictive model, patients without pretreatment anemia (hemoglobin ≤ 10 g/dL) and who achieved a cytogenetic response by 3 months had an estimated 4-year survival rate of 88%; in such patients, allogeneic SCT may be considered if there is evidence of imatinib resistance. The other patients (with no cytogenetic response by 3 months and/or with pretreatment hemoglobin < 10 g/dL) have estimated 4-year survival rates ≤ 60% and should undergo transplantation immediately.

In summary, the results of the current analysis suggest that imatinib therapy improves survival significantly in patients with accelerated-phase CML. Further improvement in prognosis may occur with the use of imatinib combinations, imatinib and allogeneic SCT, or new selective Bcr/Abl or dual Abl/Src inhibitors.31 It also is clear that the criteria for accelerated-phase no longer satisfy the original concept of identifying poor prognostic factors associated with very short median survival estimates of 6–18 months. New “accelerated-phase” criteria need to be redefined in the context of imatinib therapy for patients with CML.

Ancillary