Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinibbased chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n ¼ 33), late molecular responders (LMRs, n ¼ 35), intermediate molecular responders (IMRs, n ¼ 9) and poor molecular responders (PMRs, n ¼ 18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

“…The combination of imatinib with conventional chemotherapy as the first-line treatment has demonstrated an improved CR rate and an increased applicability in allogeneic SCT, thus allowing better outcomes in adults with Ph-positive ALL [33][34][35][36][37]. Previously, we also conducted a prospective, phase II trial of allogeneic SCT following firstline imatinib-based chemotherapy, and our recently updated results continue to show the positive impact of imatinib on long-term outcomes of allogeneic SCT [21][22][23]. Conversely, the survival benefit of RIC-SCT for adults with Ph-negative ALL remains uncertain.…”

“…Induction therapy was started with hyper-fractionated cyclophosphamide (300 mg/m 2 , every 12 hr, days 1-3), vincristine (1.4 mg/m 2 , maximum dose 2 mg, days 4 and 11), idarubicin (12 mg/m 2 , days 4 and 11), and dexamethasone (40 mg, days 1-4 and days [11][12][13][14] [18,[21][22][23][24][25]. Subsequently, patients in CR received consolidation courses consisting of high-dose cytarabine (2 g/m 2 , every 12 hr, days 1-5) and mitoxantrone (12 mg/m 2 , days 1-2) therapy (at each odd cycle of consolidation) alternating with the above induction regimens (at each even cycle of consolidation), which were dependent on donor availability and the time of transplantation.…”

“…Central nervous system prophylaxis was performed by intrathecal administration of triple agents (methotrexate, cytarabine, and methylprednisolone; 6 times in total). Patients with Philadelphia chromosome (Ph)-positive ALL received imatinib-based chemotherapy before transplantation, as previously described [18,[21][22][23][24][25]. No prophylactic imatinib therapy was planned after transplantation.…”

“…The MAC regimen consisted of total body irradiation (13.2 Gy) and cyclophosphamide (120 mg/kg) [21][22][23][24][25]. As previously described [18,[21][22][23][24][25], GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for RD transplants, tacrolimus for URD transplants) plus methotrexate. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.…”

“…Minimal residual disease (MRD) monitoring for BCR-ABL1 transcript was centrally evaluated by real-time quantitative polymerase chain reaction (4.5 log sensitivity) through handling of BM samples from all Ph-positive ALL transplants. As previously described [23], major molecular response (MMR) was defined as a ratio of BCR-ABL1 to ABL1 of 0.1% on the international scale (for p210 BCR-ABL1 ) or a reduction in BCR-ABL1 transcript level by at least 3-log from the standardized pooled baseline value (for p190 BCR-ABL1 ). Complete molecular response (CMR 4.5 ) was defined as undetectable levels of BCR-ABL1 transcript.…”