The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells.
BACKGROUND. Clonal cytogenetic abnormalities (CCA) were detected in Philadelphia chromosome (Ph)-negative cells in some patients with chronic myeloid leukemia (CML) who attained a cytogenetic response to imatinib mesylate. In some patients, CCA/Ph-negative status was associated with myelodysplasia or acute myeloid leukemia. The objective of the current study was to determine the prognostic impact of CCA/Ph-negative cells. METHODS. The authors compared the pretherapeutic risk factors (Kruskall-Wallis test), exposure to cytotoxic drugs (chi-square test), and overall and progression-free survival (Kaplan-Meyer and logistic regression analysis, respectively) of 515 patients with mostly chronic-…
Oxaliplatin and Capecitabine-Based Chemoradiotherapy for Gastric Cancer—An Extended Phase I MARGIT and AIO Trial
Purpose Adjuvant 5-fluorouracil–based chemoradiotherapy has been shown to improve the prognosis of gastric cancer. To optimize these results, in the present study oxaliplatin and capecitabine were used instead of 5-fluorouracil. We sought to determine the maximum tolerated dose and the dose-limiting toxicities (DLT) of these drugs in combination with intensity-modulated radiotherapy. Methods and Materials Patients with resected adenocarcinoma of the stomach or the gastroesophageal junction were included. They received two cycles of induction chemotherapy (oxaliplatin and capecitabine [XelOx] regimen). Using standard Phase I methodology, patients received 45 Gy in 1.8-Gy fractions either in …
Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia
Background: Anemia remains one cardinal symptom associated with reduced quality of life (QoL) in patients (pts) with myelofibrosis (MF) which is normally not being addressed by ruxolitinib (RUX). In our previous MPNSG-0109 trial, single-agent pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2.0 mg QD) of MF pts, respectively. In the MPNSG-0212 study, we sought to investigate the potential synergism of RUX plus POM to improve anemia and QoL in MF pts. Study Design: MPNSG-0212 is an ongoing multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts following a two-stage design (NCT01644110). Pts 1-40 in cohort 1 (co1) were treated with RU…
High BCR-ABL/GUS(IS) levels at diagnosis of chronic phase CML are associated with unfavorable responses to standard-dose imatinib
Abstract Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. Experimental Design: We correlated BCR–ABL/GUSIS and BCR–ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR–ABL/GUSIS and BCR–ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transform…
Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis.
BACKGROUND Despite advances in drug therapy and allogeneic stem cell transplantation (allo-SCT), the prognosis of patients with chronic myeloid leukemia (CML) in blast crisis remains poor. Imatinib has demonstrated synergistic effects in vitro with mitoxantrone, etoposide, and cytarabine. METHODS A Phase I/II trial was performed in patients with CML myeloid blast crisis. Patients were treated with imatinib + mitoxantrone/etoposide in four cohorts: mitoxantrone 10 mg/m2/day and etoposide 100 mg/m2/day for 2 or 3 consecutive days and imatinib 600 mg/day from Day 15 (cohorts 1 and 2) or from Day 1 (cohorts 3 and 4). After hematologic reconstitution after the cytopenic phase, cytarabine was giv…
Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT)
We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and…
A Multicenter Phase I/II Trial of the Combination of Imatinib Mesylate with Mitoxantrone/Etoposide and Cytarabine in Patients with CML in Myeloid Blast Crisis: A Trend to a Longer Survival in Patients Receiving More Aggressive Treatment Schedules.
Abstract The combination of imatinib with mitoxantrone, etoposide or cytarabine were shown to be additive to highly synergistic on BCR-ABL-positive leukemias in vitro by several investigators, including our group. Therefore, we initiated a phase I/II trial for patients with myeloid blast crisis of chronic myelogenous leukemia. Patients were treated in four cohorts starting from mitoxantrone 10 mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600 mg/d from day 15 (cohorts #1 and #2) or from day 1 (cohorts #3 and #4). Cytarabine was given at a dose of 10 mg/m2/d s.c. as maintenance treatment. Seventeen patients were included in the study: 8 pts in cohort 1, …
Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study
Purpose In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial. Patients and Methods As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. For…
Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia
The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy.We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events.The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best …
Quality assurance in RT-PCR-based BCR/ABL diagnostics--results of an interlaboratory test and a standardization approach.
Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 or b3a2 BCR/ABL transcripts were analyzed by PCR. In the second part of the test, cell samples containing various concentrations of BCR/ABL-positive cells were analyzed by RT-PCR. Overall PCR sensitivity was sufficient in approximately 90% of the tests, but a significant number of false positive results were obtained. There were significant differences in sensitivity in the cel…
Genomic Landscape and Molecular Risk in Patients with Advanced Myelofibrosis Treated within the Multicenter Phase Ib/II MPNSG0212 (POMINC) Trial
Abstract Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a more precised assessment of prognosis. For instance, CALR mutated MF is associated with favorable prognosis, while mutations in distinct high molecular-risk (HMR) genes are considered adverse. Our multicenter phase-Ib/II MPNSG-0212 trial (NCT01644110) investigating ruxolitinib plus pomalidomide in a total cohort of 92 patients with advanced …
Compassionate Use of Sorafenib in Relapsed and Refractory Flt3-ITD Positive Acute Myeloid Leukemia.
Abstract Abstract 2060 Poster Board II-37 Introduction: The Flt3-internal tandem duplication can be found in up to 30% of all acute myeloid leukemia (AML) patients and confers a poor risk status characterized by an increased relapse rate and poor overall survival. Moreover, Flt3-ITD-positive AML patients relapsing after allogenic stem cell transplantation (SCT) have very limited therapeutic options. Sorafenib is a multikinase inhibitor that is approved for the treatment of metastatic renal cell and hepatocellular carcinoma. Besides targeting Raf, the platelet derived growth factor receptor (PDGFR) and the vascular endothelial growth factor receptor (VEGFR) it has also significant inhibitory…
Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer
Abstract Background To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). Patients and methods At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m2 twice daily on days 1–14 plus oxaliplatin 130 mg/m2 on day 1 (CapOx), capecitabine 825 mg/m2 twice daily on days 1–14 plus gemcitabine 1000 mg/m2 on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m2 on days 1 and 8 plus oxaliplatin 130 mg/m2 on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carboh…
Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C.
We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 c…
Real Life Experience with ATRA-Arsenic Trioxide Based Regimen in Acute Promyelocytic Leukemia - Updated Results of the Prospective German Intergroup Napoleon Registry
Abstract Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany …
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.
Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML.We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression.Afte…
High BCR-ABL/GUSIS Levels At Diagnosis Are Associated With Unfavorable Responses To Imatinib
Abstract The approval of three tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated an urgent need for molecular parameters predictive of unfavorable therapeutic outcomes. Recent evidence suggests that failure to achieve early molecular responses (i.e. BCR-ABL/ABLIS levels <10% after 3 months or <1% after 6 months of TKI treatment) results in inferior rates of both overall and progression-free survival. With the current study, we wanted to establish if high BCR-ABL transcripts at diagnosis would be associated with unfavorable responses to Imatinib Mesylate (IM). Thus, we correlated quantitative determinations of BCR-ABL levels …
Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment
Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 mont…
Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome–positive (Ph+) leukemia in older versus younger patients (pts).
6511 Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity in Ph+ leukemia. Methods: Efficacy and safety of BOS 500 mg/d was evaluated in older (≥65 y; n = 119) and younger (<65 y; n = 451) pts in 3 cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib (IM; CP2L cohort; n = 287); CP CML after IM + dasatinib (DAS) and/or nilotinib (NIL; CP3L cohort; n = 119); and accelerated/blast phase (AP/BP) CML or acute lymphoblastic leukemia after IM ± DAS and/or NIL (ADV cohort; n = 164). Results: Baseline events (≥65 y vs <65 y) included respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and diabetes (4% vs 4%). Median baseline medicatio…
Combination Treatment with Imatinib and Mitoxantrone/Etoposide Is a Suitable Preparative Regimen before Allogeneic Transplantation in Patients with Myeloid Blast Crisis of Chronic Myeloid Leukemia.
Abstract In advanced BCR-ABL-positive leukemia, combination of chemotherapy with imatinib is expected to result in better reduction of leukemia cell load and may delay or offset clonal selection of resistant leukemia cells, thus improving the survival. We carried out a prospective phase I/II combination trial for patients (pts) with myeloid blast crisis of chronic myelogenous leukemia (CML). Pts were treated with imatinib+mitoxantrone/etoposide in four cohorts starting from mitoxantrone 10mg/m2/d and etoposide 100 mg/m2/d for 2 or 3 consecutive days and start of imatinib 600mg/d from day 15 (coh. 1 and 2) or from day 1 (coh. 3 and 4, respectively). After hematologic reconstitution following…
Durable Molecular Remissions in Patients with Relapsed CML Post Allogeneic Stem Cell Transplantation upon Treatment with Imatinib-Mesylate (Glivec®, STI-571). Follow-Up Results of a Phase II Open-Label Study.
Abstract Purpose: In a phase II clinical trial we have previously reported on the safety and efficacy of imatinib mesylate (IM) to induce hematologic, cytogenetic and molecular remissions in case of relapse post allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukaemia (CML). Here we report on an extended follow-up phase, which was performed to monitor stability of responses and further disease course in patients enrolled. Patients and Methods: Within the trial, patients, transplanted in chronic phase (CP) CML with molecular or cytogenetic relapse (n=37), received IM at a starting dose of 400mg. Close monitoring was performed, which, besides evaluation of sid…
Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205
Background: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Methods: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m−2 twice daily on days 1–14; oxaliplatin 100/130 mg m−2 on day 1; bevacizumab 7.5 mg kg−1 on day 1; imatinib 300 mg day−1 on days 1–21 every 21 days. The primary study endpo…
Ruxolitinib Plus Pomalidomide in Myelofibrosis: Updated Results from the Mpnsg-0212 Trial (NCT01644110)
Abstract Background: Although ruxolitinib (RUX) reduces constitutional symptoms and splenomegaly in myelofibrosis (MF) therapy options for anemia are limited. In our prior MPNSG-0109 trial of pomalidomide (POM) in MF with cytopenia, anemia responses were reported in 14% and 29% of subjects receiving POM 0.5 mg/d and 2 mg/d, respectively (Schlenk RF et al., ASH 2013, abstract #2822). We designed a phase-Ib/-II combination study of RUX plus POM to evaluate synergistic effects in subjects with anemia and splenomegaly (MPNSG-0212 trial, NCT01644110; Stegelmann et al., ASH 2015, abstract #826). Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according t…