Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia

Department of Pediatrics, University of Washington Seattle, Seattle, Washington, United States
Blood (Impact Factor: 10.45). 05/2007; 109(7):2791-3. DOI: 10.1182/blood-2006-04-019836
Source: PubMed


Relapse occurs frequently after allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk Philadelphia chromosome-positive (Ph+) leukemia. Administration of imatinib early after HCT might provide an effective approach for preventing recurrent Ph+ leukemia, but the feasibility of this approach has not been systematically tested. Twenty-two patients, 15 with Ph+ acute lymphoblastic leukemia and 7 with high-risk chronic myelogenous leukemia, were enrolled in a prospective study and given imatinib from the time of engraftment until 365 days after HCT. Before day 90, adults (n = 19) tolerated a median average daily imatinib dose of 400 mg/d (range, 200-500 mg/d), and children (n = 3) tolerated 265 mg/m2/d (range, 200-290 mg/m2/ d). The most common adverse events related to imatinib administration were grade 1-3 nausea, emesis, and serum transaminase elevations. We conclude that imatinib can be safely administered early after myeloablative allogeneic HCT at a dose intensity comparable to that used in primary therapy.

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    • "Retrospective studies have suggested that treatment with TKIs before allo-HSCT did not preclude the outcome of engraftment and did not increase transplant-related toxicity [21]–[23]. Prospective studies showed that early administration of TKIs after allo-HSCT at a dose intensity comparable to that used in primary therapy seem to be safe [24] and can result in favorable long-term survival [12]. But the vast majority of these patients did not take TKIs during the engraftment period to prevent graft delay or failure. "
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    ABSTRACT: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34(+) cells. After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice. TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34(+) cell cycle entry. Adhesion of CD34(+) cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.
    PLoS ONE 12/2012; 7(12):e52564. DOI:10.1371/journal.pone.0052564 · 3.23 Impact Factor
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    • "Thus, earlier initiation of imatinib treatment in the setting of low leukemia burden, or negative detection of MRD after HCT, may reduce the relapse rate and improve survival to an even greater extent. The feasibility and safety of early prophylactic administration of imatinib after HCT has been previously confirmed [13]. However, imatinib toxicity is relevant when started soon after HCT. "
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    ABSTRACT: Maintenance therapy with imatinib during the post-transplant period has been used for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL); however, its efficacy has not been demonstrated. A study was designed to investigate the safety of imatinib and its efficacy in preventing hematological relapse and improving disease-free survival (DFS) when administered after allogeneic hematopoietic stem cell transplantation (allo-HCT). Patients with Ph + ALL that received allo-HCT were enrolled in the study. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect BCR-ABL transcript levels. Imatinib therapy was initiated if patient neutrophil counts were > 1.0 × 10(9)/L and platelet counts were > 50.0 × 10(9)/L, or if they displayed either elevated BCR-ABL transcript levels in two consecutive tests, or a BCR-ABL transcript level ≥ 10(-2) after initial engraftment. Patients receiving imatinib after relapse were assigned to the non-imatinib group. The imatinib treatment was scheduled for 3-12 months, until BCR-ABL transcript levels were negative at least for three consecutive tests or complete molecular remission was sustained for at least 3 months. A total of 82 patients were enrolled. Sixty-two patients initiated imatinib therapy post-HCT. Imatinib therapy was initiated at a median time of 70 days post-HCT. Grade 3-4 adverse events (AEs) occurred in 17.7% of patients. Ten patients (16.1%) terminated imatinib therapy owing to AEs. Among the patients in imatinib and non-imatinib groups, the estimated 5-year relapse rate was 10.2% and 33.1% (p = 0.016), and the 5-year probability of DFS was 81.5% and 33.5% (p = 0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4-72 months), respectively. Multivariate analysis identified imatinib maintenance therapy post-HCT as an independent prognostic factor for DFS (p = 0.000, hazard ratio [HR] =4.8) and OS (p = 0.000, HR = 6.2). These results indicate that relapse rate can be reduced and DFS may be improved in Ph + ALL patients with imatinib maintenance therapy after HCT. BCR-ABLmonitoring by qRT-PCR can guide maintenance therapy with imatinib including initiation time and treatment duration after allo-HCT.
    Journal of Hematology & Oncology 06/2012; 5(1):29. DOI:10.1186/1756-8722-5-29 · 4.81 Impact Factor
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    • "Although Imatinib may have contributed to transaminase elevations, other temporal associations were noted, including GVHD, infection, and triazole antifungal medication. The same author found that administration of Imatinib do not affect calcineurin inhibitor (Cyclosporin and Tacrolimus) levels [96]. Recent data also suggest the safety of second-generation TKIs, in Ph+ ALL and CML patients who have undergone prior allogeneic SCT. "
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    ABSTRACT: Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.
    The Scientific World Journal 10/2011; 11(2):1908-31. DOI:10.1100/2011/924954 · 1.73 Impact Factor
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