Imatinib compared with chemotherapy as front‐line treatment of elderly patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL)

Abstract

BACKGROUNDElderly patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL) have a poor prognosis, with a low complete remission (CR) rate, high induction mortality, and short remission duration. Imatinib (IM) has a favorable toxicity profile but limited antileukemic activity in advanced Ph+ALL. Imatinib in combination with intensive chemotherapy has yielded promising results as front‐line therapy, but its value as monotherapy in newly diagnosed Ph+ALL is not known.METHODSPatients with de novo Ph+ALL were randomly assigned to induction therapy with either imatinib (IndIM) or multiagent, age‐adapted chemotherapy (Indchemo). Imatinib was subsequently coadministered with consolidation chemotherapy.RESULTSIn all, 55 patients (median age, 68 years) were enrolled. The overall CR rate was 96.3% in patients randomly assigned to IndIM and 50% in patients allocated to Indchemo (P = .0001). Nine patients (34.6%) were refractory and 2 patients died during Indchemo; none failed imatinib induction. Severe adverse events were significantly more frequent during Indchemo (90% vs 39%; P = .005). The estimated overall survival (OS) of all patients was 42% ± 8% at 24 months, with no significant difference between the 2 cohorts. Median disease‐free survival was significantly longer in the 43% of patients (21 of 49 evaluable) in whom BCR‐ABL transcripts became undetectable (18.3 months vs 7.2 months; P = .002).CONCLUSIONSIn elderly patients with de novo Ph+ALL, imatinib induction results in a significantly higher CR rate and lower toxicity than induction chemotherapy. With subsequent combined imatinib and chemotherapy consolidation, this initial benefit does not translate into improved survival compared with chemotherapy induction. Cancer 2007. © 2007 American Cancer Society.

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

“…Thus, there was no correlation between detection of a mutation and response. To further evaluate whether the early detection of a mutation was predictive of response duration, we performed a Kaplan --Meier 2,8 Only patients in whom samples from at least two of the three time points were available are included in this analysis. As a consequence, this graphical depiction of mutations omits four baseline mutations in recurrent and two baseline mutations in de novo Ph þ ALL.…”

“…2 Results of mutational analyses performed in the latter study have been published previously, 16 but did not include data on the dynamics and absolute levels of bcr-abl mutations during imatinib monotherapy, the central elements of the present communication. The studies were approved by the responsible Institutional Review Boards, and all patients gave informed consent according to the Declaration of Helsinki.…”

“…2 These elderly patients subsequently received combined imatinib and repetitive cycles of consolidation chemotherapy. Patient characteristics are shown in Table 1.…”

Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker

“…While the addition of tyrosine kinase inhibitors (TKI) to intensive chemotherapy has improved the response rate, their effect on overall survival remains unclear and the overall prognosis for adult patients, especially >55 years of age, with this subtype remains poor. [4][5][6][7] The proteasome inhibitors, of which bortezomib is a prototype, were initially FDA approved for use in multiple myeloma but have shown activity in other diseases such as mantle cell lymphoma and refractory acute leukemias. 6,8 Recently, we and others BCR-aBL is a key mediator in the pathogenesis of all cases of chronic myelogenous leukemia (CML) and a subset of precursor B-acute lymphoblastic leukemia (Ph+aLL).…”

Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia

“…In a recent study in 55 older patients-median age 68, beyond the age at which HSCT is typically offered-imatinib was randomized between co-administration with induction chemotherapy or subsequent co-administration with consolidation chemotherapy. 43 The CR rates were 96 and 50% respectively. However, there was no significant difference between the two cohorts in OS.…”