Early prediction of response in patients with relapsed or refractory Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib

Abstract

Imatinib has pronounced but brief antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). We assessed the prognostic impact of pretreatment disease features and the early bone marrow (BM) response in 68 consecutive patients with Ph(+)ALL receiving imatinib salvage therapy. A complete hematologic or marrow response was achieved by 92% of patients with BM blasts below 5% on day 14, whereas 62.5% of patients with more than 5% BM blasts on day 14 were nonresponders. Similarly, time to progression (TTP) was superior in patients with a good day 14 response (5.2 versus 0.9 months; P <.0001). Prior complete remission of less than 6 months, white blood cell count of more than 10 x 10(9)/L, circulating peripheral blood blasts at diagnosis, additional Philadelphia chromosomes, or at least 2 Bcr-Abl fusion signals were associated with significantly inferior remission rate and response duration. In patients without poor prognostic features, single-agent imatinib may be appropriate before transplant salvage therapy. Conversely, patients with clinically or cytogenetically defined poor-risk features are candidates for trials of upfront imatinib in combination with other agents.

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

“…This is an analysis of 91 patients with Ph þ acute lymphoid leukemias who were enrolled in the initial phase II studies of imatinib for treatment of BCR-ABL positive leukemias after chemotherapy failure (n ¼ 65), 8,9 or in a prospective, randomized clinical trial assessing frontline imatinib therapy in elderly patients with newly diagnosed Ph þ ALL (n ¼ 26). 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.…”

“…We serially assessed the mutation status of patients with imatinib-naïve Ph þ ALL (n ¼ 64) or lymphoid blast crisis (n ¼ 1) who had failed prior chemotherapy and were treated with imatinib at 400 or 600 mg per day, 8,9 and of 26 elderly patients with de novo Ph þ ALL who received 4 weeks of single-agent imatinib as induction therapy as described recently. 2 These elderly patients subsequently received combined imatinib and repetitive cycles of consolidation chemotherapy.…”

Autologous stem cell transplant in ALL: who should we be transplanting in first remission?

“…The German Multicenter ALL cooperative have already shown that molecular response at the time of stem cell harvest are noted when imatinib is incorporated into the induction regimen. 32 …”

Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

“…The encouraging results obtained with imatinib in CML prompted initiation of several phase I and II studies in patients with relapsed or refractory Ph + ALL. [13][14][15] Approximately 60% of patients achieved a remission or clearance of peripheral blood blasts, with 19% CR. Disappointingly, these responses were short lived with median time to progression and overall survival of only 2.2 and 4.9 months, respectively.…”