The evidence supporting this protocol is provided by a phase 3, multicentre, international, randomised trial (GRAAPH-2005), involving 268 patients, which examined the hypothesis that a reduced-intensity induction regimen was non-inferior to a standard intensity regimen in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Imatinib was given for a total 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.r
Between 2006 and 2011, after a prednisolone pre-phase, 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 along with the hyper-CVAD part A regimen (arm B). Patients in both arms then received the hyper-CVAD part B regimen (methotrexate and cytarabine) along 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.r The GRAAPH-2005 study used steady state mobilization with filgrastim.r The haematologic CR rate was higher in arm A than arm B (98.5% vs 91%) due to fewer induction deathsr and therefore has been included in the eviQ GRAAPH-2005 protocol.
The primary end point 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).r
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.r
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
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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
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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 alloSCT. 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.
Unsurprisingly, the less-intensive induction cycle 1 was associated with less toxicities, and as shown above, with less deaths. However, toxicities were higher in arm A during cycle 2. Overall there were less deaths within the first 60 days in the reduced-intensity arm (2.2% vs. 9.7%, p = 0.17).r
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