Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group

Abstract

Background Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763). Methods Patients aged 18 to 55 years with de novo Ph+ ALL were treated with imatinib concurrently with standard‐dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo‐HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes. Results Of the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo‐HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease‐free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months [P = .05] and 28.7 months vs 11.5 months [P = .05] for DFS and OS, respectively). Conclusions Disease recurrence was frequent in young and older adults with Ph+ ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.

Therapeutic approach and outcome of children with Philadelphia chromosome‐positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors: An SFCE retrospective study

“…However, we showed a lower prevalence of ABL KD mutations (41.2% of tested patients) than in adult relapses, detected in 70% of patients 25 . The T315I mutation was the prevalent ABL KD mutation in our cohort, as in others, conferring resistance to imatinib and all second‐generation TKIs, in accordance with reports for adults with Ph + ALL 25–27 . As we did not screen for ABL KD mutations at the initial diagnosis in pediatric cases, we could not determine whether these mutations were pre‐existing and could have been detected at low rates at diagnosis, as described for 20% of adult Ph + ALL relapses 26,28 …”

“…25 The T315I mutation was the prevalent ABL KD mutation in our cohort, as in others, conferring resistance to imatinib and all second-generation TKIs, in accordance with reports for adults with Ph + ALL. [25][26][27] As we did not screen for ABL KD mutations at the initial diagnosis in pediatric cases, we could not determine whether these mutations were pre-existing and could have been detected at low rates at diagnosis, as described for 20% of adult Ph + ALL relapses. 26,28 Our retrospective study found very promising results in the setting of relapsed Ph + ALL.…”

Next‐generation sequencing improves BCR‐ABL1 mutation detection in Philadelphia chromosome‐positive acute lymphoblastic leukaemia

“…[2][3][4] Disease persistence or recurrence have been associated with point mutations in the BCR-ABL1 kinase domain (KD). [5][6][7][8][9] Detection of some imatinib-resistant mutations predicts for the efficacy or the inefficacy of the other TKIs. 1 The T315I mutation, in particular, can only be addressed, as yet, by the third-generation TKI ponatinib.…”

“…Moreover, the persistence of detectable minimal residual disease (MRD) is a well‐established negative prognostic factor 2–4 . Disease persistence or recurrence have been associated with point mutations in the BCR‐ABL1 kinase domain (KD) 5–9 . Detection of some imatinib‐resistant mutations predicts for the efficacy or the inefficacy of the other TKIs 1 .…”

IKZF1plus alterations are not associated with outcomes in Philadelphia‐positive acute lymphoblastic leukemia patients enrolled in the FBMTG ALL/MRD2008 trial

“…Additionally, early detection of relapse and early re‐treatment have also been reported to influence the outcome. Ribera et al from the PETHEMA group reported median DFS and OS of 16.9 (95% CI, not reported) versus 6.3 months (95% CI, 2.1–10.4 months) and median OS 28.7 (95% CI, not available) versus 11.5 months (95% CI, 8.5–14.5 months), respectively 40 . In our study, we observed a similar trend to this report, although we did not find significant differences due to the small number of patients.…”