The evidence supporting this protocol is provided by a multicentre, randomised trial (GRAAPH-2005)r, involving 268 patients aged 18 to 60 years with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), who are planned to receive a stem cell transplant (allogeneic or autologous) if a major molecular remission is achieved. GRAAPH-2005 examined the hypothesis that a reduced-intensity induction regimen was non-inferior to a standard intensity regimen in patients with Ph+ ALL. Imatinib was given for a total of 8 weeks during induction with the reduced-intensity regimen, and for a total of 6 weeks with the standard regimen. All patients were planned to receive stem cell transplantation (SCT) (either allogeneic or autologous) if a major molecular remission (MMolR, defined as BCR-ABL1/ABL1 ratio < 0.1%) was achieved. Patients who did not achieve a major molecular response after 2 induction cycles received further treatment according to the imatinib/hyper-CVAD protocol.
Between 2006 and 2011, after a prednisolone prephase, 135 patients were randomised to receive imatinib for 4 weeks along with vincristine and dexamethasone (arm A), and 133 patients were randomised to receive imatinib for 2 weeks with the hyper-CVAD part A regimen (arm B). Patients in both arms then received the hyper-CVAD part B regimen (methotrexate and cytarabine) with continuous imatinib. If CR was achieved a further 2 ‘interphase’ cycles, consisting of imatinib along with 6-mercaptopurine and oral methotrexate, were given prior to transplant. The GRAAPH-2005 study used steady state mobilisation with filgrastim in between the two interphase cycles. The haematologic CR rate was higher in arm A than arm B (98.5% vs 91%) due to fewer induction deaths and therefore has been included in the eviQ GRAAPH-2005 protocol.
A myeloablative conditioning regimen (total body irradiation and cyclophosphamide) was used for patients < 55 years receiving allogeneic SCT as well as for all those undergoing autologous SCT. Patients > 55 years undergoing allogeneic SCT received a reduced intensity conditioning regimen (fludarabine, busulfan, and antithymocyte globulin). No maintenance was planned after allogeneic SCT. Maintenance with alternating months of imatinib and 6-mercaptourine/methotrexate was given for 2 years after autologous SCT.
The primary endpoint was the major molecular response at the end of cycle 2. Secondary endpoints included event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS).
The study demonstrated the non-inferiority of the reduced-intensity arm with respect to MMolR. CR rates were higher, and EFS and OS were similar in this arm. Essentially, the trial showed that the continuous use of imatinib allowed the intensity of the initial induction therapy to be reduced without compromising outcomes, provided that all patients were intended to receive a transplant.
Efficacy
MMolR rates were similar (66.1% vs 64.5%), and CR rates were higher (98.5% vs 91.0%, p = 0.006), in the reduced-intensity arm after 2 cycles due to fewer early deaths.r
Figure 1: Response to the first 2 treatment cyclesr
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After a median follow-up of 4.8 years, the median EFS estimates were 2.5 years and 1.8 years (HR 1.27 [95% CI, 0.93-1.72]) in the reduced and standard intensity arms respectively. Median OS was 4.1 vs 3.3 years (HR 1.17 [95% CI, 0.84-1.62]) in the two groups respectively.r
Figure 2: Event-free survival and overall survivalr
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The percentage of patients proceeding to SCT was identical (73%) in both arms. Allogeneic SCT was included as a time-dependent covariate in a multivariate model and found to significantly improve RFS. A donor no-donor comparison also suggested better outcomes with allogeneic SCT although the differences did not reach statistical significance. It is possible that patients who had presenting WBC < 30x109/L and/or those who were MRD negative after the 2nd cycle did not benefit greatly from allo-SCT. However, these findings are not conclusive as the study was not designed to evaluate the role of allogeneic SCT in first-line treatment of Ph+ ALL.r
No QOL data were reported in the primary publication.
Toxicity
Unsurprisingly, the less-intensive induction cycle 1 was associated with fewer toxicities, and as shown above, with fewer deaths. However, toxicities were higher in arm A during cycle 2. Overall there were fewer deaths within the first 60 days in the reduced-intensity arm (2.2% vs. 9.7%, p = 0.17).r
Table 1: Toxicity during the first two treatment cyclesr
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