No data are available regarding the management of cancer patients requiring interruption of long-term vitamin-K antagonist (VKA) therapy. For this purpose, we tested the efficacy and safety of fixed doses of lowmolecular weight heparin (LMWH) in substitution of VKA because of invasive procedures or chemotherapyinduced thrombocytopenia. In cancer patients on VKA, therapy was discontinued 5 ± 1 days before surgery or chemotherapy. Heparin was given at prophylactic dosage in patients at low risk and at fixed subtherapeutic doses (3,800 or 4,000 UI anti-FXa, b.i.d.) in those at high-risk for thrombosis. LMWH was reinitiated 12 hr after surgery and VKA the day after. In patients receiving chemotherapy, LMWH was reinitiated 12/24 hr after obtaining a stable platelet count 30,000 mmc 3 and VKA after a stable platelet count 50,000 mmc 3 . Thromboembolism and major bleeding events were recorded from the time of VKA suspension to 30 ± 2 days postprocedure or until the next chemotherapy. Overall, 156 patients (56.4% at low risk and 43.5% at high risk for thrombosis) were enrolled; 34.6% underwent major surgery, 40.4% nonmajor surgery, and 25% chemotherapy. Thrombotic events occurred in five patients [3.2%, 95% confidence interval (CI): 1.41-7.27], four belonging to the high-risk and one to the low-risk group. Major bleeding occurred in five patients (3.2%,), all belonging to the high-risk group (three during major surgery and two during chemotherapy). In conclusion, LMWH given at fixed subtherapeutic is a feasible and relatively safe approach for bridging therapy in cancer patients on long-term VKA. Am. J. Hematol. 87:388-391, 2012. V
Outcome for elderly patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. Sixty-six newly diagnosed AML patients (median age: 76years), ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10mg/day orally, days 1-21) plus 10mg/m low-dose cytarabine, subcutaneously, twice a day (days 1-15) every six weeks, up to 6 cycles. Complete remission (CR) rate was 36.3% according to intention-to-treat. Responding patients had a longer median overall survival than non-responders (517 vs. 70days, P<0.001). The achievement of CR was not predicted by bone marrow blast count, cytogenetics, molecular markers, prior MDS, white blood cell count. Conversely, by studying the global gene expression profile, we identified a molecular signature, including 309 genes associated with clinical response (CR versus no CR). Based on the expression of a minimal set of 16 genes, we developed an algorithm to predict treatment response, that was successfully validated by showing an overall accuracy of 88%. We met the primary endpoint of the study, by beating the estimated successful CR rate (P1) fixed at 30%. Moreover, CR induced by this 2-drug combo was efficiently predicted by genetic profiling, identifying a biomarker that warrants validation in independent series.
Background/Aim: Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or secondgeneration tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients. Case Report: We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib. Conclusion: CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder deriving from the transformation of hematopoietic stem cells (1). It is characterized by the presence of the Philadelphia (Ph) chromosome (2), resulting from a reciprocal translocation involving the long arms of chromosomes 9 and 22. This cytogenetic alteration t(9;22)(q34;q11) causes a genomic recombination between the breakpoint cluster region (BCR) gene on chromosome 22 and the abelson (ABL1) gene on chromosome 9, resulting in their juxtaposition, which generates the BCR-ABL1 fusion gene (3). This chimeric oncogene encodes for a constitutively active tyrosine kinase conferring growth advantages to leukemic cells by deregulating cell proliferation, favouring cytokine-independent growth, inhibiting apoptosis and altering several cell-adhesion pathways (4-8). The essential role of BCR-ABL1 for the pathogenesis of CML has been confirmed by the therapeutic success of selective first, second or third-generation tyrosine kinase inhibitors (TKIs) (9-14).About 5-10% of newly diagnosed chronic-phase (CP) CML patients show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22 (15, 16). Although ACA have low incidence in these patients, their occurrence is high in CML patients in accelerated phase (AP) (30-40%) or blast crisis (BC) (50-80%) (17, 18). Their higher incidence in the last phases of the disease is certainly related to increasing genomic instability and linked to unfavourable prognosis (19).Data regarding the prognostic significance of ACA at the time of diagnosis are controversial. Indeed, ACA are heterogeneous collections of karyotypic abnormalities with a different prognostic impact on the outcome of CML patients (20,21). In general, ACAs are classified into "major" or "mino...
We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 10 CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 10 CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful minimal harvest, was €40.6 per patient.
In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR 3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses ( p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR 3.0 (after 6 months; p = 0.003) or an MR 4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR 3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.
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