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: 9.78). 05/2007; 109(7):2791-3. DOI: 10.1182/blood-2006-04-019836
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Approximately 23% of acute myeloid leukemia (AML) patients younger than 60 years of age carry a mutation in the transmembrane domain of the FMS-like tyrosine kinase-3 (FLT3) gene (FLT3/internal tandem duplications [ITD]). In normal karyotype AML, the presence of a FLT3/ITD mutation is associated with poor prognosis, as mirrored by a high risk of relapse even after allogeneic stem cell transplantation. The poor prognostic impact along with the observation that FLT3 is frequently overexpressed in the majority of AML cases has formed the platform for the development of FLT3-targeted strategies. To date, several FLT3 kinase inhibitors have been investigated in preclinical and clinical studies. However, as of yet, none of the studied FLT3 inhibitors has received FDA approval for routine clinical use in AML. This is in part due to the 'off target' effects observed with most inhibitors when administered at concentrations needed to achieve sustained levels of FLT3 inhibition, which are required to exhibit substantial cytotoxic effects against leukemic blasts. Furthermore, the development of resistance mutations has emerged as a clinical issue posing a threat to successful FLT3 inhibitor therapy. Areas covered: In this review, the authors provide a brief summary of FLT3 inhibitors investigated thus far, and discuss current treatment approaches and strategies how to best incorporate FLT3 tyrosine kinase inhibitors (TKIs) into therapy. Expert opinion: The combination of a FLT3 inhibitor with conventional chemotherapeutic regimens, epigenetic modifiers or inhibitors of FLT3 downstream and collateral effectors has emerged as a promising strategy to improve treatment outcome. The future of a tailored, molecular-based treatment approach for FLT3-mutated AML demands novel clinical trial concepts based on harmonized and aligned research goals between clinical and research centers and industry.
    Expert Opinion on Therapeutic Targets 09/2014; 19(1):1-18. DOI:10.1517/14728222.2014.960843 · 4.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: JAK 1/2 inhibitors have broadened the therapeutic options in myelofibrosis. Though not curative, they result in a meaningful clinical benefit with relatively fewer side effects. In contrast, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option, but is associated with significant morbidity and mortality. Hence, an important question is the optimal timing of HCT in the era of JAK inhibitors. Timing of HCT is a crucial decision, and need to be individualized based on the personal preferences and goals of therapy; in addition to patient, disease, and transplant related factors. Risk stratification by the currently established prognostic scoring systems need to be further refined by incorporation of prognostically significant mutations to guide the treatment choices better. Data on use of JAK inhibitors prior to HCT have just started to emerge. We discuss some of the current controversies and dilemmas in transplantation for myelofibrosis based on a few real life scenarios.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; 27(2). DOI:10.1016/j.beha.2014.07.007 · 2.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation, and thus whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph+ ALL at our institution between 2000 and 2010, and identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph+ ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days post-HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days following transplant, based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplant population, are persistently detectable in the majority of patients after transplant. We propose that such resistance patterns should be considered when selecting TKIs in the post-HSCT setting, including clinical trials of post-HSCT TKI prophylaxis.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2014; 21(1). DOI:10.1016/j.bbmt.2014.09.012 · 3.15 Impact Factor