High-dose imatinib in AP/BP of CML
The ELN definitions of AP and BP of CML differ from those recommended by the World Health Organization (WHO), but are used in almost all recent major studies of CML.
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According to ELN, AP is defined by 15%–29% blast cells or by 30%–49% blast cells plus promyelocytes in blood or bone marrow. BP is defined by a percentage of blast cells ≥30% in blood or bone marrow or by blast cells involvement of nonhematopoietic tissues, excluding liver and spleen.4
In the WHO definition, the percentage of blast cells for AP is 15%–19% and ≥20% for BP in blood or bone marrow. Treatment recommendations are different when patients are diagnosed with AP and BP at baseline, prior to any treatment, or when progression occurs during the treatment of CP. HD imatinib is one of the recommended standards in the therapy of advanced-phase CML.
Several studies regarding efficacy of imatinib at the dose of ≥600 mg daily in AP/BP CML have been published. In AP patients, the reported CHR rates ranged from 40% to 82%, with MCyR rates between 24% and 49%.30–32 These response rates are low, compared to those achieved in CML-CP, but significantly higher than those provided by IFN-α or any other previous agent.
In 2009, Palandri et al presented the outcome of the study on 111 patients in newly diagnosed AP treated with imatinib at a dose of 600 mg daily. Imatinib was given in doses of 600 mg daily to all patients. Treatment was continued until disease progression, death, intolerance to imatinib, or allogeneic stem cell transplantation (alloSCT).
The median follow-up was 82 months (range: 73–87). In all, 107 patients (96%) returned to chronic phase and 79 (71%) achieved CHR. Cumulative best rates of MCyR and CCyR were 30% and 21%, respectively. All responses were maintained for a minimum of 4 weeks. At last follow-up, four patients were alive in complete remission after allogeneic transplant, 16 patients (14%) had switched to a 2G-TKIs, and 21 patients (19%) were alive on imatinib therapy.
No late toxicities were observed. PFS and EFS rates were 36.5% and 15%, respectively, at 7 years.33 Sawyers et al conducted the study on 260 patients, of whom 229 had a confirmed diagnosis of CML in myeloid BP. Most of the patients had not received any specific therapy for advanced CML except for IFN and palliative therapy with hydroxyurea or low-dose cytosine arabinoside.
When Phase I dose-escalation data demonstrated the safety of prolonged treatment with imatinib at higher doses, the initial daily dose was increased from 400 to 600 mg daily. Imatinib-induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including CHR in 8%.
For patients with a sustained response, the estimated median response duration was 10 months. Imatinib-induced MCyR in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Non-hematologic adverse reactions were frequent but generally mild or moderate.
Episodes of severe cytopenia were also frequent and were attributable to both the underlying condition and the treatment.34 Obviously, the development of the 2G- and recently the 3G- TKIs has changed the landscape of advanced-phase CML therapy. These agents might be effective in patients with HD imatinib-resistant AP/BP.35 The summary of responses to imatinib in BP patients is shown in Table III.31,33–34,36–38
| Table III – Summary of the outcomes of trials with imatinib (from most recent) in CML-BP patients |
| Imatinib dosage (mg) | Study | Cytogenetic response (%) | Overall survival at 12 months (%)* | ||||||||
| 400-600 | Silver et al36 | 9 | NA | ||||||||
| 600 | Palandri et al33 | 17 | 29 | ||||||||
| 600 | Sureda et al37 | 13 | 36 | ||||||||
| 400–600 | Sawyers et al34 | 16 | 30 | ||||||||
| 300–1,000 | Kantarjian et al31 | 16 | 22 | ||||||||
| 300-600 | Druker et al38 | 12 | NA |
| Note: *Cytogenetic response includes complete, partial, minimal, and minor responses when available. |
| Abbreviations: CML-BP, blastic phase of chronic myeloid leukemia; NA, not available. |
According to the recent ELN recommendations, newly diagnosed TKI-naïve patients with AP or BP should be treated with imatinib 400 mg twice daily, or dasatinib 70 mg twice daily or 140 mg once daily.
Subsequently, alloSCT is recommended for all BP patients and for those AP patients who do not achieve an optimal response. AP or BP that develops as a progression from CP in TKI-pretreated patients should be managed with any of the TKIs that were not used before progression. Then, alloSCT is recommended in all patients, if eligible.4
