- Email: [email protected]
Optimizing First-Line Therapy for Patients With Chronic Myeloid Leukemia
Optimizing First-Line Therapy for Patients With Chronic Myeloid Leukemia Carmen Fava and Jorge Cortes Imatinib is now established as the gold standard first-line therapy for patients with chronic myeloid leukemia (CML). Responses to imatinib are superior to those seen with interferon alfa and also occur earlier, demonstrating a stronger and deeper response to therapy. Imatinib therapy also provides long-term clinical benefit and outcomes, with improved progression-free survival (PFS) and overall survival (OS) compared with historical controls, at 6 years of follow-up. Recent data show that annual event rates decline over time with imatinib therapy, suggesting that long-term disease control is possible in continuously responding patients. Despite these treatment successes, new strategies are continually being evaluated to maximize responses to imatinib and ensure the best treatment outcomes for all patients. For example, high-dose imatinib therapy, with doses up to 800 mg/d, has been shown to improve response rates. Prospective, randomized trials are ongoing to assess the benefits of high-dose imatinib therapy and determine whether it extends PFS and OS compared with standard-dose imatinib. Semin Hematol 46:S5-S10. © 2009 Published by Elsevier Inc.
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rior to the imatinib era, the first-line treatments of choice for chronic myeloid leukemia (CML) were interferon alfa– based therapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), or cytoreductive chemotherapy with agents such as busulfan or hydroxyurea.1-5 Interferon-based therapy typically results in complete hematologic response (CHR) in up to 80% of patients with chronic-phase (CP) CML,6,7 while cytogenetic responses are uncommon, almost never reaching complete cytogenetic responses (CCyR).8 With interferon alfa a survival benefit was seen compared to what was achieved with chemotherapy. This survival benefit was dependent on the achievement of cytogenetic responses; patients achieving a CCyR have a 10-year survival rate of 78%, falling to 39% in patients with a partial cytogenetic response (PCyR), and 25% in those without any cytogenetic response.8,9 However, interferon alfa is associated with many treatment-limiting toxicities including myalgia, arthralgia, asthenia, weight loss, headache, and depression.10 Long-term remission and possible cure Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Editorial support was provided by Jeni Fagan (Health Interactions) on behalf of Novartis Oncology. STATEMENT OF CONFLICT OF INTEREST: Dr Cortes has received research grant support from Novartis Pharmaceuticals Corp; Dr. Fava has no relationships with the supplement sponsor to disclose. Address correspondence to Jorge Cortes, MD, Professor of Medicine, Deputy Chair, Department of Leukemia, Chief, CML Section, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030. E-mail: [email protected] 0037-1963/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2009.01.007
can be achieved with alloHSCT, with one long-term study describing a 15-year overall survival (OS) of 53%, with a plateau after 2.5 years.11 However, compatible donors are not available for the majority of patients, and even when a fully matched donor is available, transplant-related morbidity and mortality can limit this approach. The 100-day mortality risk after transplantation is approximately 15% but may be lowered by reduced-intensity conditioning.11-13 With the introduction of tyrosine kinase inhibitors for the treatment of CML, current treatment guidelines recommend that alloHSCT should only be considered as first-line therapy in very rare cases, usually for younger patients who are able to tolerate the treatment.14 Chemotherapy with busulfan or hydroxyurea can achieve prompt cytoreduction, but survival rates are lower compared with interferon alfa therapy,8,15 and these treatments are no longer recommended for the treatment of CML except for controlling the white blood cell count while awaiting confirmation of the diagnosis.8,14-16 The tyrosine kinase inhibitor imatinib mesylate (Gleevec or Glivec, Novartis Pharmaceuticals, East Hanover, NJ) was developed to specifically inhibit the BCR-ABL fusion protein, which is the product of the Philadelphia chromosome that defines CML.17,18 Imatinib also shows activity against other tyrosine kinases such as c-kit and the receptor for platelet-derived growth factor.19 The landmark study that first demonstrated the efficacy of imatinib as first-line therapy for CML was the International Randomized Study of Interferon and STI571 (IRIS) trial.20-22 In this prospective, randomized, open-label phase III study, 1,106 patients with newly diagnosed CP-CML were randomly assigned
Seminars in Hematology, Vol 46, No 2, Suppl 3, April 2009, pp S5-S10
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Figure 1. Comparison of survival free of progression to accelerated-phase or blast crisis disease between patients who received imatinib and those who received interferon alfa plus cytarabine in the International Randomized Study of Interferon and STI579 (IRIS) trial.20 This research was originally published in Blood. Guilhot F, Larson RA, O’Brien SG, Gathmann I, Druker BJ. Time to complete cytogenetic response (CCyR) does not affect long-term outcomes for patients on imatinib therapy. 2007;110:Abstract 27. © American Society of Hematology.
to 400 mg/d imatinib (n ⫽ 553) or interferon alfa escalated up to a target daily dose of 5 million units/m2 in combination with 20 mg/m2 cytarabine for 10 days per month (n ⫽ 553). Treatment was continued for as long as patients derived benefit from the medication, and crossover was permitted for patients with no response, loss of response, increased white blood cell count, intolerance to treatment, or immediately lifethreatening adverse events.20 The first analysis of this study, with a median follow-up of 19 months, showed significant improvements in CHR rates with imatinib compared with interferon alfa plus cytarabine (95.3% v 55.5%, respectively; P ⬍ .001). Importantly, responses occurred more rapidly in the imatinib arm, as demonstrated by a shorter median time to CHR (1 month v 2.5 months, respectively) and higher 18-month CHR rates (96.8% v 60.0%, respectively). Kaplan–Meier estimates of major cytogenetic response (MCyR) at 18 months were 87.1% (95% confidence interval [CI], 84.1%-90.0%) in the imatinib group compared with 34.7% (95% CI, 29.3%-40.0%) in the interferon alfa plus cytarabine group, and CCyR rates at 18 months were also significantly improved in the imatinib group (76.2% [95% CI, 72.5%-79.9%] v 14.5% [95% CI, 10.5%-18.5%], respectively; P ⬍ .001).20 A separate, smaller study of 50 patients with CML who also received 400 mg/d imatinib suggested that MCyRs and CCyRs also occur earlier than in historical controls treated with interferon alfa, further confirming the earlier and deeper responses seen with imatinib in the IRIS study.23 The improved early responses observed in the
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IRIS trial also translated into improved freedom from progression to accelerated-phase (AP) or blast crisis (BC) CML, with 96.6% of patients in the imatinib group remaining progression-free at 12 months, compared with 79.9% in the interferon alfa plus cytarabine group (P ⬍ .001; Figure 1).20 The continued efficacy and favorable tolerability profile of imatinib is reflected in the long-term follow up of the IRIS trial at 6 years.22 Estimated 6-year eventfree survival (EFS) is 83% (95% CI, 80%-86%), and 93% of patients are free of progression to AP or BC at 6 years (95% CI, 90%-95%). OS for all patients remaining on the study is 88%, although comparisons between the two treatment arms are no longer possible as the majority of patients randomized to interferon alfa plus cytarabine have now crossed over to receive imatinib. In fact, 66% of patients remain on study and on imatinib, compared with just 2% in the interferon alfa plus cytarabine arm. Although the survival data from IRIS can no longer provide a comparison between treatment arms, historical comparisons allow us to assess whether the improved outcomes with imatinib therapy extend to improved OS over time. A comparison was made between 551 patients from the imatinib arm of IRIS20 and 325 patients who received interferon alfa plus cytarabine as part of the CML91 trial,10,24 with a median follow-up of 42 months for both patient groups.25 This analysis
Figure 2. Comparison of overall survival between patients from the IRIS trial who received imatinib and patients from the CML91 trial who received interferon alfa plus cytarabine.25 This research was originally published in Blood. Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: Historical comparison between two phase 3 trials. 2006;108(5):1478-84. © American Society of Hematology.
Optimizing first-line therapy for patients with CML
Figure 3. Annual event rates over 6 years’ follow-up of the IRIS trial.21 This research was originally published in Blood. Hochhaus A, Drucker BJ, Larson RA, O’Brien SG, Gathmann I, Guilhot F. IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. ASH Annual Meeting Proceedings. 2007;110:Abstract 25. © American Society of Hematology.
showed significantly improved OS with imatinib (P ⬍ .001; Figure 2), with a 3-year OS of 92% in the imatinib group (95% CI, 90%-95%) and 84% in the interferon alfa plus cytarabine group (95% CI, 80%-88%). Importantly, this survival improvement was consistent across all Sokal risk groups.25 This finding is further reinforced by a separate retrospective comparison of survival in patients from a single institution treated with imatinib (n ⫽ 279) or interferon alfa (n ⫽ 650), which also demonstrated improved OS with imatinib (hazard ratio 0.44; P ⬍ .01).26 The most recent 6-year analysis of IRIS shows that the risk of disease progression falls over time, with no documented cases of progression to AP or BC disease in year 6 on imatinib study treatment, thus reaffirming the likelihood of long-term remission in continuously responding patients (Figure 3).22 Recently, the benefits of imatinib therapy have also been confirmed in a separate intent-to-treat (ITT) analysis of 204 patients with CP-CML.27 At 5 years, the cumulative rates of CCyR and MMR were 82.7% and 50.1%, respectively, with estimated EFS of 83.2% and OS rate of 82.7%. There was a 62.7% probability of remaining in MCyR at 5 years with continued imatinib treatment. Current treatment guidelines for CML recommend first-line therapy with imatinib at a dose of 400 mg/d.14,16 In rare cases of young patients with a human leukocyte antigen (HLA)-matched donor, alloHSCT may be a firstline treatment option, but imatinib is usually still preferred as it involves minimal risk of mortality. Although 400 mg/d is the recommended imatinib dose, early phase I, dose-finding trials in patients who had previously received interferon alfa demonstrated no doselimiting toxicities at imatinib doses up to 1,000 mg/d, and a dose–response relationship was observed.28 Based on these data, recent studies have assessed the efficacy of
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first-line therapy with high-dose imatinib, up to 800 mg/d. A single-arm study involving 114 patients with newly diagnosed CP-CML showed a CHR rate of 98% and a CCyR rate of 90% in patients who received an imatinib dose of 800 mg/d.29 These data compared favorably with historical controls from the same institution, with significantly higher CCyR rates observed in patients who received 800 mg/d compared with those who received 400 mg/d (90% v 74%, respectively; P ⫽ .01). Transformation-free survival (TFS) was also significantly improved with the higher imatinib dose (Figure 4).29 The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial also assessed high-dose imatinib at 800 mg/d in previously untreated patients, and was conducted across academic and community institutions.30,31 Patients who received high-dose imatinib (n ⫽ 175) were compared with 50 historical control patients who received standard-dose therapy, and higher rates of CCyR were again observed with the 800-mg/d dose (90% v 78%, respectively; P ⫽ .03). There was also a trend toward improved TFS with high-dose therapy compared with standard dose, but this was not statistically significant (P ⫽ .07).31 An analysis of the kinetics of response in the RIGHT trial showed that 44% of patients achieved a major molecular response (MMR) within 6 months of initiating therapy.30 Compared with data from the IRIS trial,20 which showed a 6-month MMR rate of 21% with standard-dose imatinib, these data suggest that high-dose imatinib can achieve more rapid responses. This analysis also showed that high-dose imatinib is well tolerated in patients of all ages, with no significant differ-
Figure 4. Comparison of transformation-free survival between patients who received high-dose imatinib at 800 mg/d and historical controls who received standard-dose imatinib at 400 mg/d.29 This research was originally published in Blood. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. 2004;103(8):2873-8. © American Society of Hematology.
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Figure 5. Tyrosine kinase inhibitor OPtimization and Selectivity (TOPS) trial design.
ence in the rate of adverse events or the adverse event profile between patients aged ⬍65 years and those aged ⬎65 years.30 Another study, the Therapeutic Intensification in DE-novo Leukaemia (TIDEL) trial, used imatinib 600 mg/d to explore the concept of high-dose imatinib as initial therapy for CML in early CP.32 At 12 and 24 months, CCyR rates of 88% and 90% were observed, and MMR rates were 47% and 73%, respectively. When these data were compared with the imatinib arm of the IRIS trial, in which all patients received a starting dose of 400 mg/d, the CCyR rate was significantly improved with the higher dose (P ⬍ .001).32 Two large, prospective, randomized trials are now ongoing to assess the optimal imatinib starting dose in previously untreated patients with CP-CML. The Tyrosine kinase inhibitor OPtimization and Selectivity (TOPS) trial is a phase III study involving 476 patients randomized in a 2:1 ratio to receive 800 or 400 mg/d imatinib.33,34 The primary endpoint is MMR at 12 months, and secondary endpoints include progressionfree survival (PFS) and OS, to assess the impact of high-dose imatinib on long-term outcomes (Figure 5). Recent reports from this trial indicate that imatinib 800 mg/d showed a rapid response and trend of improved MMR rates at 3, 6, 9, and 12 months compared with standard-dose imatinib therapy, although the improvement was not statistically significant at 12 months. Importantly, the TOPS trial confirmed the benefits and safety profile of standard-dose imatinib treatment observed in the IRIS trial and demonstrated that the majority of patients can tolerate higher imatinib doses, with only approximately 20% of patients unable to tolerate more than the standard dose by 12 months. Additional follow-up will be required to determine the long-term benefits of the more rapid response achieved with high-dose therapy.33,34 The European LeukemiaNet (Nordic, Italy, Turkey, Israel) study compared 400 versus 800 mg/d imatinib in 215 high Sokal-risk patients, with a primary endpoint of CCyR at 12 months.35 Results were similar to those in the TOPS trial. A trend toward higher rates of MMR with 800 mg/d compared with 400 mg/d was observed; however, the differences were not statistically significant.
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Following initial therapy with imatinib, patients should be routinely assessed for response, and therapy should be adjusted to maximize the chance of response for patients with lack of response or suboptimal response. Strategies for identifying and treating patients with a suboptimal response will be reviewed in detail in the accompanying article in this supplement by Hughes and Hochhaus. While response rates to firstline therapy with standard-dose imatinib are high, with a best observed CCyR rate of 82% by 60 months’ follow-up,21 18% of patients will not achieve a CCyR and others may lose an initial response. These patients may require dose adjustments or alternative therapy to optimize their treatment. Dose escalation can improve the response in some of these patients and was the main option for managing suboptimal responses and treatment failures before the introduction of second-generation tyrosine kinase inhibitors.36,37 In an analysis of patients dose-escalated during the IRIS trial due to resistance or suboptimal response to standard-dose therapy, freedom-from-progression and OS rates were 89% and 84%, respectively, at 3 years following dose increase.37 In another study,36 84 CP-CML patients were dose– escalated to imatinib 600 to 800 mg/d after failure to achieve hematologic response (n ⫽ 21), or failure to achieve cytogenetic response (resistance: n ⫽ 30; relapse: n ⫽ 33) to imatinib 400 mg/d. Among patients who met the criteria for cytogenetic failure, 75% (47/63) responded to imatinib dose escalation. For those patients achieving MCyR on imatinib dose escalation therapy, responses were durable, with a sustained MCyR in 88% and 74% of patients at 2 and 3 years, respectively. In contrast, for patients dose-escalated due to loss of hematologic response, 48% achieved a CHR and 14% (3/21) of patients attained a CyR after imatinib dose increase.36 Although the role of dose increase after failure to standard-dose imatinib has changed with the introduction of the secondgeneration tyrosine kinase inhibitors, dose increase is an important option for patients with suboptimal responses when a change in therapy is indicated. Randomized trials are assessing the relative benefit of imatinib dose increase compared to a change to new inhibitors in this setting. Treatment guidelines recommend dose escalation of imatinib to 600 or 800 mg/d in cases of suboptimal response or treatment failure, although alloHSCT is also an option following treatment failure.14,16 If a response is still not seen following imatinib dose escalation, alternative therapies should be considered, including second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib.16 For patients with treatment failure, the main option is to change to new tyrosine kinase inhibitors. Another important approach to optimizing therapy in patients with early CP-CML may be the use of second generation tyrosine kinase inhibitors as frontline therapy. Several phase II trials are underway studying nilotinib and dasatinib in this setting. In an ongoing study conducted at the M.D. Anderson Cancer Center, nilotinib
Optimizing first-line therapy for patients with CML
(800 mg/day) treatment is being assessed in previously untreated early CP-CML patients. To date, 47 patients have been treated for a median of 5 months.38,39 Nearly all patients (97%) experienced a rapid CCyR within 3 months and 50% achieved an MMR by 6 months of therapy. Both CCyRs and MMRs were maintained for 12 months. The primary endpoint of MMR at 12 months was observed in 48% of patients. Preliminary data demonstrate that nilotinib was well tolerated with infrequent reports of grade 3/4 hematologic laboratory abnormalities and nonhematologic adverse events. The frontline treatment of early CP-CML patients with nilotinib is also being evaluated in a single-arm, open-label, phase II study conducted by the Gruppo Italiano Malattie Ematogiche dell’Adulto (GIMEMA) working party.40,41 Seventy-three treatment-naive CP-CML patients received nilotinib 800 mg/d, which resulted in rapid and significant rates of CCyR, with 84% and 97% of patients achieving CCyR at 3 and 6 months, respectively. Among patients who attained a CCyR, an MMR was achieved in 62% and 75% of patients at 3 and 6 months. Overall, toxicities were minimal and mostly grade 1, resulting in no dose interruptions. Dasatinib has also been evaluated as front-line therapy in a phase II study.42 Patients with previously untreated CP-CML received dasatinib 50 mg twice daily (53%) or 100 mg daily (47%). CCyR rates at 3 and 6 months were 78% and 94%, respectively. MMR rates of 23% and 36% were observed at 3 and 6 months, respectively. Grade 3/4 hematologic toxicity included neutropenia (23%), thrombocytopenia (11%), and anemia (7%) and pleural effusions occurred in 13% (grade 1/2) and 2% (grade 3) of patients. In conclusion, frontline treatment of CP-CML has improved considerably with the introduction of imatinib. However, although most patients do well with this therapy, there is considerable interest in improving the outcome for most patients. The use of higher doses of imatinib and second generation tyrosine kinase inhibitors as initial therapy has resulted in rapid responses in most patients. Whether these responses will translate into improved long-term outcome remains to be confirmed, but it is our hope that these approaches will get us closer to the goal of cure for all patients with CML.
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treated with 800 mg imatinib daily: an update from the RIGHT trial study group. Blood. 2006;108:609a-610a. Aoki E, Kantarjian H, O’Brien S. High-dose imatinib mesylate treatment in patients (pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up. Journal of Clinical Oncology. 2006;24:345. Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood. 2008;112:3965-73. Hitt EP. TOPS trial: High-dose imatinib shows modest benefit in front-line chronic myeloid leukemia. (http:// www.medscape.com/viewarticle/576107) Medscape. 2008. Accessed June 20, 2008. Higher initial dose of Glivec achieved better early responses than standard dose for patients with chronic myeloid leukemia. Novartis Oncology Press Release. June 13, 2008. Baccarani M, Castagnetti F, Porkka K. A prospective study of imatinib 400 mg vs 800 mg as a front-line therapy in Sokal high risk Ph⫹ chronic myeloid leukemia patients. Haematologica. 2008;93:161-2. Jabbour E, Kantarjian HM, Jones D, Shan J, O’Brien S, Reddy N, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia post cytogenetic failure on standard-dose imatinib therapy. Blood. 2008 Dec 5. [Epub ahead of print]. Kantarjian HM, Larson RA, Guilhot F, O’Brien SG, Mone M, Rudoltz M, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer. 2009;115:551-60. Cortes J, Jones D, O’Brien S, Ferrajoli A, Borhtakur G, Burger J, et al. Efficacy of nilotinib in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Hematologica. 2008;93: 48. Cortes J, O’Brien S, Ferrajoli A, Borhtakur G, Burger J, Wierda W, et al. Efficacy of nilotinib (AMN107) in patients with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). J Clin Oncol. 2008;26: 376s. Rosti G, Castagnetti F, Palandri F. Nilotinib 800 mg daily as first line treatment of chronic myeloid leukemia in early chronic phase: results of a phase II trial of the GIMEMA CML working party. J Clin Oncol. 2008;26: 385s. Rosti G, Castagnetti F, Palandri F, Breccia M, Levato L, Capucci A, et al. Nilotinib 800 mg daily as first line treatment of chronic myeloid leukemia in early chronic phase: results of a phase 2 trial of the GIMEMA CML working party. Hematologica. 2008;93:161. Borthakur G, Kantarjian HM, O’Brien SM, Jones D, Koller C, Nicaise C, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). J Clin Oncol. 2008;26:375s.
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rior to the imatinib era, the first-line treatments of choice for chronic myeloid leukemia (CML) were interferon alfa– based therapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), or cytoreductive chemotherapy with agents such as busulfan or hydroxyurea.1-5 Interferon-based therapy typically results in complete hematologic response (CHR) in up to 80% of patients with chronic-phase (CP) CML,6,7 while cytogenetic responses are uncommon, almost never reaching complete cytogenetic responses (CCyR).8 With interferon alfa a survival benefit was seen compared to what was achieved with chemotherapy. This survival benefit was dependent on the achievement of cytogenetic responses; patients achieving a CCyR have a 10-year survival rate of 78%, falling to 39% in patients with a partial cytogenetic response (PCyR), and 25% in those without any cytogenetic response.8,9 However, interferon alfa is associated with many treatment-limiting toxicities including myalgia, arthralgia, asthenia, weight loss, headache, and depression.10 Long-term remission and possible cure Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Editorial support was provided by Jeni Fagan (Health Interactions) on behalf of Novartis Oncology. STATEMENT OF CONFLICT OF INTEREST: Dr Cortes has received research grant support from Novartis Pharmaceuticals Corp; Dr. Fava has no relationships with the supplement sponsor to disclose. Address correspondence to Jorge Cortes, MD, Professor of Medicine, Deputy Chair, Department of Leukemia, Chief, CML Section, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030. E-mail: [email protected] 0037-1963/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2009.01.007
can be achieved with alloHSCT, with one long-term study describing a 15-year overall survival (OS) of 53%, with a plateau after 2.5 years.11 However, compatible donors are not available for the majority of patients, and even when a fully matched donor is available, transplant-related morbidity and mortality can limit this approach. The 100-day mortality risk after transplantation is approximately 15% but may be lowered by reduced-intensity conditioning.11-13 With the introduction of tyrosine kinase inhibitors for the treatment of CML, current treatment guidelines recommend that alloHSCT should only be considered as first-line therapy in very rare cases, usually for younger patients who are able to tolerate the treatment.14 Chemotherapy with busulfan or hydroxyurea can achieve prompt cytoreduction, but survival rates are lower compared with interferon alfa therapy,8,15 and these treatments are no longer recommended for the treatment of CML except for controlling the white blood cell count while awaiting confirmation of the diagnosis.8,14-16 The tyrosine kinase inhibitor imatinib mesylate (Gleevec or Glivec, Novartis Pharmaceuticals, East Hanover, NJ) was developed to specifically inhibit the BCR-ABL fusion protein, which is the product of the Philadelphia chromosome that defines CML.17,18 Imatinib also shows activity against other tyrosine kinases such as c-kit and the receptor for platelet-derived growth factor.19 The landmark study that first demonstrated the efficacy of imatinib as first-line therapy for CML was the International Randomized Study of Interferon and STI571 (IRIS) trial.20-22 In this prospective, randomized, open-label phase III study, 1,106 patients with newly diagnosed CP-CML were randomly assigned
Seminars in Hematology, Vol 46, No 2, Suppl 3, April 2009, pp S5-S10
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Figure 1. Comparison of survival free of progression to accelerated-phase or blast crisis disease between patients who received imatinib and those who received interferon alfa plus cytarabine in the International Randomized Study of Interferon and STI579 (IRIS) trial.20 This research was originally published in Blood. Guilhot F, Larson RA, O’Brien SG, Gathmann I, Druker BJ. Time to complete cytogenetic response (CCyR) does not affect long-term outcomes for patients on imatinib therapy. 2007;110:Abstract 27. © American Society of Hematology.
to 400 mg/d imatinib (n ⫽ 553) or interferon alfa escalated up to a target daily dose of 5 million units/m2 in combination with 20 mg/m2 cytarabine for 10 days per month (n ⫽ 553). Treatment was continued for as long as patients derived benefit from the medication, and crossover was permitted for patients with no response, loss of response, increased white blood cell count, intolerance to treatment, or immediately lifethreatening adverse events.20 The first analysis of this study, with a median follow-up of 19 months, showed significant improvements in CHR rates with imatinib compared with interferon alfa plus cytarabine (95.3% v 55.5%, respectively; P ⬍ .001). Importantly, responses occurred more rapidly in the imatinib arm, as demonstrated by a shorter median time to CHR (1 month v 2.5 months, respectively) and higher 18-month CHR rates (96.8% v 60.0%, respectively). Kaplan–Meier estimates of major cytogenetic response (MCyR) at 18 months were 87.1% (95% confidence interval [CI], 84.1%-90.0%) in the imatinib group compared with 34.7% (95% CI, 29.3%-40.0%) in the interferon alfa plus cytarabine group, and CCyR rates at 18 months were also significantly improved in the imatinib group (76.2% [95% CI, 72.5%-79.9%] v 14.5% [95% CI, 10.5%-18.5%], respectively; P ⬍ .001).20 A separate, smaller study of 50 patients with CML who also received 400 mg/d imatinib suggested that MCyRs and CCyRs also occur earlier than in historical controls treated with interferon alfa, further confirming the earlier and deeper responses seen with imatinib in the IRIS study.23 The improved early responses observed in the
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IRIS trial also translated into improved freedom from progression to accelerated-phase (AP) or blast crisis (BC) CML, with 96.6% of patients in the imatinib group remaining progression-free at 12 months, compared with 79.9% in the interferon alfa plus cytarabine group (P ⬍ .001; Figure 1).20 The continued efficacy and favorable tolerability profile of imatinib is reflected in the long-term follow up of the IRIS trial at 6 years.22 Estimated 6-year eventfree survival (EFS) is 83% (95% CI, 80%-86%), and 93% of patients are free of progression to AP or BC at 6 years (95% CI, 90%-95%). OS for all patients remaining on the study is 88%, although comparisons between the two treatment arms are no longer possible as the majority of patients randomized to interferon alfa plus cytarabine have now crossed over to receive imatinib. In fact, 66% of patients remain on study and on imatinib, compared with just 2% in the interferon alfa plus cytarabine arm. Although the survival data from IRIS can no longer provide a comparison between treatment arms, historical comparisons allow us to assess whether the improved outcomes with imatinib therapy extend to improved OS over time. A comparison was made between 551 patients from the imatinib arm of IRIS20 and 325 patients who received interferon alfa plus cytarabine as part of the CML91 trial,10,24 with a median follow-up of 42 months for both patient groups.25 This analysis
Figure 2. Comparison of overall survival between patients from the IRIS trial who received imatinib and patients from the CML91 trial who received interferon alfa plus cytarabine.25 This research was originally published in Blood. Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: Historical comparison between two phase 3 trials. 2006;108(5):1478-84. © American Society of Hematology.
Optimizing first-line therapy for patients with CML
Figure 3. Annual event rates over 6 years’ follow-up of the IRIS trial.21 This research was originally published in Blood. Hochhaus A, Drucker BJ, Larson RA, O’Brien SG, Gathmann I, Guilhot F. IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. ASH Annual Meeting Proceedings. 2007;110:Abstract 25. © American Society of Hematology.
showed significantly improved OS with imatinib (P ⬍ .001; Figure 2), with a 3-year OS of 92% in the imatinib group (95% CI, 90%-95%) and 84% in the interferon alfa plus cytarabine group (95% CI, 80%-88%). Importantly, this survival improvement was consistent across all Sokal risk groups.25 This finding is further reinforced by a separate retrospective comparison of survival in patients from a single institution treated with imatinib (n ⫽ 279) or interferon alfa (n ⫽ 650), which also demonstrated improved OS with imatinib (hazard ratio 0.44; P ⬍ .01).26 The most recent 6-year analysis of IRIS shows that the risk of disease progression falls over time, with no documented cases of progression to AP or BC disease in year 6 on imatinib study treatment, thus reaffirming the likelihood of long-term remission in continuously responding patients (Figure 3).22 Recently, the benefits of imatinib therapy have also been confirmed in a separate intent-to-treat (ITT) analysis of 204 patients with CP-CML.27 At 5 years, the cumulative rates of CCyR and MMR were 82.7% and 50.1%, respectively, with estimated EFS of 83.2% and OS rate of 82.7%. There was a 62.7% probability of remaining in MCyR at 5 years with continued imatinib treatment. Current treatment guidelines for CML recommend first-line therapy with imatinib at a dose of 400 mg/d.14,16 In rare cases of young patients with a human leukocyte antigen (HLA)-matched donor, alloHSCT may be a firstline treatment option, but imatinib is usually still preferred as it involves minimal risk of mortality. Although 400 mg/d is the recommended imatinib dose, early phase I, dose-finding trials in patients who had previously received interferon alfa demonstrated no doselimiting toxicities at imatinib doses up to 1,000 mg/d, and a dose–response relationship was observed.28 Based on these data, recent studies have assessed the efficacy of
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first-line therapy with high-dose imatinib, up to 800 mg/d. A single-arm study involving 114 patients with newly diagnosed CP-CML showed a CHR rate of 98% and a CCyR rate of 90% in patients who received an imatinib dose of 800 mg/d.29 These data compared favorably with historical controls from the same institution, with significantly higher CCyR rates observed in patients who received 800 mg/d compared with those who received 400 mg/d (90% v 74%, respectively; P ⫽ .01). Transformation-free survival (TFS) was also significantly improved with the higher imatinib dose (Figure 4).29 The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial also assessed high-dose imatinib at 800 mg/d in previously untreated patients, and was conducted across academic and community institutions.30,31 Patients who received high-dose imatinib (n ⫽ 175) were compared with 50 historical control patients who received standard-dose therapy, and higher rates of CCyR were again observed with the 800-mg/d dose (90% v 78%, respectively; P ⫽ .03). There was also a trend toward improved TFS with high-dose therapy compared with standard dose, but this was not statistically significant (P ⫽ .07).31 An analysis of the kinetics of response in the RIGHT trial showed that 44% of patients achieved a major molecular response (MMR) within 6 months of initiating therapy.30 Compared with data from the IRIS trial,20 which showed a 6-month MMR rate of 21% with standard-dose imatinib, these data suggest that high-dose imatinib can achieve more rapid responses. This analysis also showed that high-dose imatinib is well tolerated in patients of all ages, with no significant differ-
Figure 4. Comparison of transformation-free survival between patients who received high-dose imatinib at 800 mg/d and historical controls who received standard-dose imatinib at 400 mg/d.29 This research was originally published in Blood. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. 2004;103(8):2873-8. © American Society of Hematology.
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Figure 5. Tyrosine kinase inhibitor OPtimization and Selectivity (TOPS) trial design.
ence in the rate of adverse events or the adverse event profile between patients aged ⬍65 years and those aged ⬎65 years.30 Another study, the Therapeutic Intensification in DE-novo Leukaemia (TIDEL) trial, used imatinib 600 mg/d to explore the concept of high-dose imatinib as initial therapy for CML in early CP.32 At 12 and 24 months, CCyR rates of 88% and 90% were observed, and MMR rates were 47% and 73%, respectively. When these data were compared with the imatinib arm of the IRIS trial, in which all patients received a starting dose of 400 mg/d, the CCyR rate was significantly improved with the higher dose (P ⬍ .001).32 Two large, prospective, randomized trials are now ongoing to assess the optimal imatinib starting dose in previously untreated patients with CP-CML. The Tyrosine kinase inhibitor OPtimization and Selectivity (TOPS) trial is a phase III study involving 476 patients randomized in a 2:1 ratio to receive 800 or 400 mg/d imatinib.33,34 The primary endpoint is MMR at 12 months, and secondary endpoints include progressionfree survival (PFS) and OS, to assess the impact of high-dose imatinib on long-term outcomes (Figure 5). Recent reports from this trial indicate that imatinib 800 mg/d showed a rapid response and trend of improved MMR rates at 3, 6, 9, and 12 months compared with standard-dose imatinib therapy, although the improvement was not statistically significant at 12 months. Importantly, the TOPS trial confirmed the benefits and safety profile of standard-dose imatinib treatment observed in the IRIS trial and demonstrated that the majority of patients can tolerate higher imatinib doses, with only approximately 20% of patients unable to tolerate more than the standard dose by 12 months. Additional follow-up will be required to determine the long-term benefits of the more rapid response achieved with high-dose therapy.33,34 The European LeukemiaNet (Nordic, Italy, Turkey, Israel) study compared 400 versus 800 mg/d imatinib in 215 high Sokal-risk patients, with a primary endpoint of CCyR at 12 months.35 Results were similar to those in the TOPS trial. A trend toward higher rates of MMR with 800 mg/d compared with 400 mg/d was observed; however, the differences were not statistically significant.
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Following initial therapy with imatinib, patients should be routinely assessed for response, and therapy should be adjusted to maximize the chance of response for patients with lack of response or suboptimal response. Strategies for identifying and treating patients with a suboptimal response will be reviewed in detail in the accompanying article in this supplement by Hughes and Hochhaus. While response rates to firstline therapy with standard-dose imatinib are high, with a best observed CCyR rate of 82% by 60 months’ follow-up,21 18% of patients will not achieve a CCyR and others may lose an initial response. These patients may require dose adjustments or alternative therapy to optimize their treatment. Dose escalation can improve the response in some of these patients and was the main option for managing suboptimal responses and treatment failures before the introduction of second-generation tyrosine kinase inhibitors.36,37 In an analysis of patients dose-escalated during the IRIS trial due to resistance or suboptimal response to standard-dose therapy, freedom-from-progression and OS rates were 89% and 84%, respectively, at 3 years following dose increase.37 In another study,36 84 CP-CML patients were dose– escalated to imatinib 600 to 800 mg/d after failure to achieve hematologic response (n ⫽ 21), or failure to achieve cytogenetic response (resistance: n ⫽ 30; relapse: n ⫽ 33) to imatinib 400 mg/d. Among patients who met the criteria for cytogenetic failure, 75% (47/63) responded to imatinib dose escalation. For those patients achieving MCyR on imatinib dose escalation therapy, responses were durable, with a sustained MCyR in 88% and 74% of patients at 2 and 3 years, respectively. In contrast, for patients dose-escalated due to loss of hematologic response, 48% achieved a CHR and 14% (3/21) of patients attained a CyR after imatinib dose increase.36 Although the role of dose increase after failure to standard-dose imatinib has changed with the introduction of the secondgeneration tyrosine kinase inhibitors, dose increase is an important option for patients with suboptimal responses when a change in therapy is indicated. Randomized trials are assessing the relative benefit of imatinib dose increase compared to a change to new inhibitors in this setting. Treatment guidelines recommend dose escalation of imatinib to 600 or 800 mg/d in cases of suboptimal response or treatment failure, although alloHSCT is also an option following treatment failure.14,16 If a response is still not seen following imatinib dose escalation, alternative therapies should be considered, including second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib.16 For patients with treatment failure, the main option is to change to new tyrosine kinase inhibitors. Another important approach to optimizing therapy in patients with early CP-CML may be the use of second generation tyrosine kinase inhibitors as frontline therapy. Several phase II trials are underway studying nilotinib and dasatinib in this setting. In an ongoing study conducted at the M.D. Anderson Cancer Center, nilotinib
Optimizing first-line therapy for patients with CML
(800 mg/day) treatment is being assessed in previously untreated early CP-CML patients. To date, 47 patients have been treated for a median of 5 months.38,39 Nearly all patients (97%) experienced a rapid CCyR within 3 months and 50% achieved an MMR by 6 months of therapy. Both CCyRs and MMRs were maintained for 12 months. The primary endpoint of MMR at 12 months was observed in 48% of patients. Preliminary data demonstrate that nilotinib was well tolerated with infrequent reports of grade 3/4 hematologic laboratory abnormalities and nonhematologic adverse events. The frontline treatment of early CP-CML patients with nilotinib is also being evaluated in a single-arm, open-label, phase II study conducted by the Gruppo Italiano Malattie Ematogiche dell’Adulto (GIMEMA) working party.40,41 Seventy-three treatment-naive CP-CML patients received nilotinib 800 mg/d, which resulted in rapid and significant rates of CCyR, with 84% and 97% of patients achieving CCyR at 3 and 6 months, respectively. Among patients who attained a CCyR, an MMR was achieved in 62% and 75% of patients at 3 and 6 months. Overall, toxicities were minimal and mostly grade 1, resulting in no dose interruptions. Dasatinib has also been evaluated as front-line therapy in a phase II study.42 Patients with previously untreated CP-CML received dasatinib 50 mg twice daily (53%) or 100 mg daily (47%). CCyR rates at 3 and 6 months were 78% and 94%, respectively. MMR rates of 23% and 36% were observed at 3 and 6 months, respectively. Grade 3/4 hematologic toxicity included neutropenia (23%), thrombocytopenia (11%), and anemia (7%) and pleural effusions occurred in 13% (grade 1/2) and 2% (grade 3) of patients. In conclusion, frontline treatment of CP-CML has improved considerably with the introduction of imatinib. However, although most patients do well with this therapy, there is considerable interest in improving the outcome for most patients. The use of higher doses of imatinib and second generation tyrosine kinase inhibitors as initial therapy has resulted in rapid responses in most patients. Whether these responses will translate into improved long-term outcome remains to be confirmed, but it is our hope that these approaches will get us closer to the goal of cure for all patients with CML.
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