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  • American Society of Hematology  (34)
  • 2005-2009  (34)
  • 1
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    Optimaization of Imatinib Therapy by Combination. 5 Year Survival and Response Results of the Pilot Phase of the Randomized German CML STUDY IV.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 862-862
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 862-862
    Abstract: Abstract 862 Rapid relapse after discontinuation of imatinib, the need for indefinite therapy and residual disease in most patients are the major challenges in management of CML. Combinations of imatinib with IFN simultaneously, or consecutively preceding imatinib, or with araC may improve treatment outcome. The German CML Study Group therefore designed a randomized trial to compare standard imatinib vs. imatinib + interferon alpha (IFN) vs. imatinib + low dose araC vs. imatinib after IFN failure (for low- and intermediate-risk patients, high risk patients received imatinib 800 mg instead). The current evaluation represents the prefinal results of the pilot phase of the trial. Inclusion criteria were newly diagnosed BCR/ABL positive CML in chronic phase (CP). Primary aims are: prolongation of survival (overall, OS, and progression free, PFS), determination of rates of hematologic, cytogenetic and molecular remissions, adverse events (AE) and role of allografting. By the end of 2005, 670 patients were randomized, 13 had to be excluded (no CML (n=3), pregnancy, no CP (n=1 each), imatinib 800 mg (n=8)). Analysis was according to intention to treat. 657 patients were evaluable (174 with imatinib 400 mg, 196 with imatinib+IFN, 158 with imatinib+araC and 129 with imatinib after IFN-failure). 656 patients were evaluable for hematologic, 611 for cytogenetic, and 618 for molecular responses. Patient characteristics of treatment arms were similar for age (median 53 years), sex (40% female), median values for Hb (12.6 g/dl), WBC (66.2/μl), platelets (383/μl) and for Euro risk score (low 35%, intermediate 54%, high 10%). The median dose of imatinib was 400mg/die in all arms, of araC 10 mg per treatment day and of IFN 4.2 Mio I.U./die in the imatinib after IFN arm and 1.8 Mio I.U./die in the imatinib+IFN arm. Median observation time was 57.3 months. 55 patients died, 73 patients were transplanted in 1st CP, 81 patients progressed, 59 patients were switched to second generation TKIs. After 3 years 126 patients (72%) of the imatinib 400mg arm still received the initial therapy as well as 60 patients (30%) of the imatinib+IFN arm and 53 patients (34%) of the imatinib+araC arm. 9 patients (7%) of the imatinib after IFN arm are still on IFN. 5-year OS of all patients is 91%. 5-year PFS of all patients (no death, patient still in first chronic phase) is 87%. 5-year-OS and PFS according to treatment arm are shown in the Table. At 5 years, the cumulative incidences of achieving complete cytogenetic remission or major molecular remission (MMR) as determined by competing risks (death, progression) are not different (Table). Type and severity of adverse events (AE) over a 5-years period did not differ from those reported previously (Table). Hematologic AEs grade III/IV were similar in all therapy arms except leukopenia grade III/IV, which was more frequently observed in the imatinib after IFN arm (14%). Non hematologic AEs were mainly fluid retention, neurological and gastrointestinal symptoms and fatigue. Neurologic symptoms and fatigue were more often reported for the therapy arms with IFN. Imatinib 400mgImatinib+IFNImatinib+AraCImatinib after IFN5-Year Survival and Response RatesOS87%93%92%92% PFS84%91%88%84% CCR92%92 %89%83% MMR83%78%80%70% Adverse Events, WHO Grade III/IVAnemia7%1%3%3% Leukopenia4%5%2%14% Thrombocytopenia5%6%6%6% WHO Grade I-IVEdema15%13%5%0% Neurological5%15%5%22% Gastrointestinal17%27%21%15% Fatigue8%13%9%23% This analysis shows excellent survival and durable response rates in all arms. Currently, survival in all treatment arms is equal to, or better than in IRIS. To verify possible differences in survival, e.g. imatinib 400 mg vs. imatinib + IFN, longer observation is planned. Although cytogenetic and molecular responses in the imatinib after IFN failure arm at 5 years are inferior to that in the other treatment arms, the question of whether the consecutive therapy with IFN first and imatinib after IFN-failure provides a survival advantage requires long term follow-up. Imatinib in combination with, or after IFN, or with low dose araC are feasible and safe treatment modalities. We expect that the study will optimize and improve therapy outcome in CML. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; German Competence Net : Research Funding; European LeukemiaNet: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.862.862
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    Randomized Comparison of Imatinib 800 Mg Vs. Imatinib 400 Mg +/- IFN in Newly Diagnosed BCR/ABL Positive Chronic Phase CML: Analysis of Molecular Remission at 12 Months; The German CML-Study IV.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 339-339
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 339-339
    Abstract: Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR= 〈 0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p 〈 0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.339.339
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
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    Molecular Response to First Line Imatinib Therapy Is Predictive for Long Term Event Free Survival in Patients with Chronic Phase Chronic Myelogenous Leukemia – An Interim Analysis of the Randomized German CML Study IV
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 333-333
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 333-333
    Abstract: The introduction of imatinib has significantly changed prognosis of CML patients. Despite favourable hematologic and cytogenetic response (CyR) data, patients (pts) on first line imatinib therapy may relapse. Thus, studies have been conducted to improve initial therapy by dose escalation or combination with other drugs. CML Study IV was designed to compare imatinib in standard dose (400 mg/d) vs high dose (800 mg/d) vs combinations with low dose cytarabine or interferon alpha. We sought to evaluate the predictive impact of early molecular response for long term event free survival (EFS). 539 pts (59% m, median age 54 years, range 16–84) randomized to imatinib based therapies by December 2005 were investigated, the median follow up was 39 mo (range, 0–69). At baseline, multiplex PCR was applied to determine the dominating BCR-ABL transcript: b2a2 (n=204), b3a2 (n=247), b2a2 and b3a2 (n=80), e1a2 (n=2), e19a2 (n=4), b3a3 (n=1) and e8a2 (n=1). Quantitative PCR from 5,419 peripheral blood samples was performed using the LightCycler technology in two central labs. PCR data were aligned to the international scale (IS) by introduction of conversion factors (Hughes et al., BLOOD 2006). Cumulative molecular response of 539 pts at 3, 6, 12, 18, and 24 mo after randomization is summarized in the Table: Month 3 6 12 18 24 BCR-ABLIS Achieved by % of pts ≤10% 41 66 81 85 86 ≤1% 16 41 65 76 78 ≤ 0.1% (MMR) 3 16 37 51 59 ≤0.01% 1 3 10 21 28 For analysis of prognostic impact, events were defined as (i) loss of complete hematologic response, (ii) loss of major CyR following loss of complete CyR, (iii) accelerated phase, (iv) blast crisis, and (v) death for any reason. Pts were censored at the time of allogeneic stem cell transplantation or switch to 2nd generation tyrosine kinase inhibitors because of imatinib intolerance or resistance. The minimum molecular response levels predictive for EFS were BCR-ABLIS of 10% after 6 mo (p=0.0029), 1% after 12 mo (p 〈 0.0001), and 0.1% (major molecular response, MMR; p=0.0016) after 18 mo of imatinib based therapies. In order to investigate the reasons for unsatisfying responses BCR-ABL kinase domain mutations were assessed in 175 pts. 30 pts (17%) harbored 35 mutations affecting 18 different aminoacids. In conclusion, prospective molecular surveillance of CML shows that early response predicts stable remissions on first line imatinib therapy. After 6 mo of treatment, PCR data start to be predictive for EFS. In pts with unsatisfactory response or molecular, cytogenetic and hematologic relapse, BCR-ABL mutations have been detected in only 17% of pts. Calculation of molecular response rates dependent on the various imatinib based therapies will be performed after stop of randomization which is expected by the end of 2009.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.333.333
    RVK:
    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 4
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    Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with a Related Donor in Chronic Myeloid Leukemia (CML): An Explanation for Fast Improvement of Survival in Two Consecutive German CML Studies.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3281-3281
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3281-3281
    Abstract: Abstract 3281 Poster Board III-1 Introduction: In the two consecutive German CML studies III and IIIA (recruitment periods from 1995 to 2001 and 1997 to 2004), eligible patients were assigned to early HSCT by genetic randomization according to availability of a matched related donor. After randomization, 113 patients of study III (84% of 135) and 144 of study IIIA (87% of 166) were eventually transplanted in first chronic phase (CP) using a related donor. Despite comparable transplantation protocols and most centers participating in both studies, survival probabilities in study IIIA were significantly better, even when adjusted for the established EBMT risk score (Gratwohl et al., Lancet 1998 [1]), p + 0.0097. For further explanation, the German Registry for Stem Cell Transplantation (DRST) and the Swiss Transplant Working Group for Blood and Marrow Transplantation (STABMT) were asked for data support. Patients and Methods: The main sample characteristics of the 257 transplanted CML study patients were also applied to the registry patients: diagnosis of CML between 1994 and 2004, first HSCT with a related donor performed in first CP between 1995 and 2004 at an age between 12 and 65 years, and blood or bone marrow as stem cell sources. Thus, additional data of 582 HSCT patients were retrieved from the two registries. Age, recipient sex, donor sex, time between diagnosis and HSCT, calendar year of HSCT, stem cell source, and HLA matching were investigated as potential predictive factors for survival. Then, a sample of patients with the same risk distribution as the 113 patients of study III was randomly drawn from the registry patients. By application of repeated resampling to this new patient group, bootstrap confidence intervals for survival probabilities at various times after HSCT were extractable. This provided the basis to judge whether the survival in study III could be seen as a typical random representation of a sample with an equivalent risk structure or not. The same method was applied to the 144 patients of study IIIA. Results: The 5-year survival probability of all 839 patients resulted in 73% (229 died). Median follow-up time of living patients was 6.7 years. Due to the characteristic plateau of post-transplant survival probabilities, the predictive influence was judged by the Kaplan-Meier method and the log rank statistic. Also consideration of age and time between diagnosis and HSCT as continuous variables seemed less appropriate than working with categorizations. Furthermore, the previously published cut-points “1 year” for time from diagnosis to HSCT ([1] ) and “44 years” for age at HSCT (Maywald et al., Leukemia 2006) were independently confirmed to be the best. Cox model and logistic regression with survival status after 3 years both indicated that age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT had independent statistically significant predictive influence on survival (p 〈 0.05). The first two factors had the strongest effects. Calendar year was only influential when distinction was made between HSCT until and after 1999. All possible combinations of the 4 factors could be summarized in 4 risk groups with significantly different survival probabilities (at 5 years: 87%, 76%, 63%, and 24%). Matched for the risk group distribution of study III [study IIIA], a maximum of 290 [428] registry patients could be drawn. For the 290 [428] patients, 5-year survival was 69% [77%] with a 95% bootstrap confidence interval from 63% to 74% [72% to 81%]. Thus, as for all yearly intervals within the first 5 years, the 5-year survival probabilities of studies III: 65% and IIIA: 79% lied within the corresponding confidence intervals. Conclusions: Along with the registry patients, the study data enabled the identification of age at HSCT, HLA matching, time between diagnosis and HSCT, and calendar year of HSCT as factors with independent predictive impact on survival which led to 4 risk groups with statistically significantly different survival probabilities. More favorable-risk patients in study IIIA stood for a better transplantation strategy. In consideration of these different risks, the survival probabilities in both studies did not significantly vary from those of registry samples with matched risk structures. Accordingly, an improved transplantation strategy along with random variation could be considered as an explanation of the significantly different survival probabilities between the two studies. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Gratwohl:AMGEN, Roche, Bristol-Myers Squibb, Novartis, Pfizer: Research Funding; Novartis: Consultancy. German CML Study Group:Kompetenznetz Leukämie, European Leukemia Net, Roche, Essex, AMGEN: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3281.3281
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
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    Multicenter Phase II Trial of Patients with Refractory or Recurrent Multiple Myeloma with Oral Treatment of Thalidomide Combined with Oral Cyclophosphamide, Idarubicin and Dexamethasone.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4825-4825
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4825-4825
    Abstract: Introduction and rationale: The aim of our study is to evaluate the role of thalidomide in combination with oral CID therapy in order to improve treatment wit an all oral regime. Patients and methods: Patients with refractory or relapsed myeloma were included into this trial. Concerning inclusion criteria, 10 patients had progressive disease after standard chemotherapy, 12 no change after standard chemotherapy and required further therapy, 6 recurrent disease after standard therapy and 22 recurrence after high dose chemotherapy. At start of the treatment patients were in stages IIA (16 patients), IIB (1), IIIA (34) and IIIB (1). Idarubicin was given in capsules at 8–10 mg/m2/day for days 1–4, 40 mg dexamethasone were given on days 1–4 and 15–18, cyclophosphamide at 200 mg/m2/d d1–4 and thalidomide 100mg daily with scheduled increase to 400mg. Treatment cycles were repeated every 28 days. 3–8 cycles were applied. Supportive therapy consisted of PEG-filgrastim, cotrimoxazol, dalteparin and ibandronate. In addition, after the induction phase patients were randomized between thalidomide and thalidomide / idarubicin maintenance treatment. Results: At this interim analysis, 66 patients have been entered into the ongoing trial; 6 patients had to be excluded for violation of unclusion criteria. Of the 60 included patients, 52 patients have been documented so far and are evaluable for toxicity. In total, 187 cycles have been applied. Median cycle number was 3 (1–8). There was one death during treatment due to progressive myeloma at cycle 1. The median age was 62 years (interquartile range 57–67). The following toxicities were observed: FUO (2 patients), pneumonia (4), pulmonary embolism (1), exsiccosis after diarrhea (1), constipation (1), sepsis (1), severe nausea (2), syncope (1), collaps after bleeding (1, not related to TCID treatment) and mucositis grade 4 (1). Hematologic toxicity grade IV was reported in 35% of the patients, mainly in cycles 1 and 2. Concerning response to treatment 41 patients are evaluable for response so far. Of these 31 (76%) achieved a PR (24 patients) or MR (7 patients) according to EBMT criteria, 4 patients a stable disease and 3 patients a PD. Three patients were not evaluable and scorded as failures. Conclusions: T-CID is feasible and highly effective in relapsed or refractory myeloma patients. Toxicity seems to be acceptable and mainly hematologic and infectiologic. The remission rate of 76% is encouraging.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4825.4825
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    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 6
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    Monitoring of Phosphorylated CRKL in Imatinib Resistant Patients with BCR-ABL Positive Leukemias Expressing BCR-ABL Mutants Treated with AMN107.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 497-497
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 497-497
    Abstract: AMN107 is a new, highly potent and selective BCR-ABL inhibitor currently in clinical development for the treatment of imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia positive acute lymphoblastic leukemia ALL (Ph+ALL). Pre-clinical testing has revealed AMN107 to inhibit all but one (T315I) BCR-ABL mutants which have been associated with imatinib resistance. We sought to determine the pharmacodynamic activity of AMN107 by measuring the proportion of phosphorylated CrkL (CrkL-P) as a surrogate of BCR-ABL activity in vivo. Assay validation revealed a CV-value of 13%, which was defined as cut-off value for significant modulation of the Crkl-P/CrkL ratio. A total of 34 patients (median age 61 years, range 35–80) diagnosed with imatinib resistant Ph+ ALL (n=10), CML in chronic phase (n=1), accelerated phase (n=13), myeloid (n=7), or lymphoid blast crisis (n=3) were investigated in a phase I study permitting individual dose escalation (50–1200 mg/day). Proportion of CrkL-P (Crkl-P/total Crkl) was determined by Western blot, ratio BCR-ABL/ABL by quantitative RT-PCR, and mutation status by direct sequencing in 73 peripheral blood or bone marrow samples from baseline and during treatment with AMN107. Median follow up was 89 days (range 13–386). Patients expressed e1a2 (n=7), b2a2 (n=12), b3a2 (n=14), and b2a2 & b3a2 (n=1) BCR-ABL transcripts. At baseline, 18 pts exhibited BCR-ABL mutations (P-loop, n=4; T315I, n=3; others, n=11), in 4 pts two different mutations were found in parallel. Prior to treatment with AMN107, the median proportion of CrkL-P indicating BCR-ABL activity was 47% (range 0–69%). Significant reductions of the proportion of CrkL-P were observed from a dose level of 200 mg AMN107/day. CRKL-P (0%) became undetectable during treatment with AMN107 indicating complete suppression of BCR-ABL in 16 pts starting at AMN107 dose levels of 200 (n=1), 400 (n=2), 600 (n=4), 800 (n=8) or 1200 mg/d (n=1). At baseline, patients had unmutated BCR-ABL (n=8), M244V, Y253H, E255K, T315I, M351T, L384M/H396P, A217V/F311L, L324Q/A350V (n=1 each). Undetectability of CrkL-P, correlated with a good molecular response (ratio BCR-ABL/ABL & lt;2%) in 3 pts. We conclude that a minimum of 200 mg of AMN107 is required to induce effective BCR-ABL inhibition in patients. Effectively repressed CrkL phosphorylation in patients lacking molecular response indicates multifactorial resistance mechanisms. Even in patients with BCR-ABL mutations, BCR-ABL may be inactive suggesting alternative signaling pathways that stimulate proliferation. However, treatment with AMN107 is associated with a reduction of the proportion of CrkL-P indicating suppression of BCR-ABL activity in a significant proportion of patients after imatinib resistance. The CrkL phosphorylation status may help to determine alternative treatment strategies including dose optimization in phase I studies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.497.497
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    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 7
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    Multicenter Phase II Trial of Patients with Refractory or Recurrent Multiple Myeloma with Oral Treatment of Thalidomide Combined with Oral Cyclophosphamide, Idarubicin and Dexamethasone.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3559-3559
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3559-3559
    Abstract: Introduction and rationale: The aim of our study is to evaluate the role of thalidomide in combination with oral CID therapy in order to replace the central venous line necessary for continuous infusion of chemotherapy and to avoid hospitalization. Patients and methods: Patients with refractory or recurrent myeloma were included into this trial. Concerning inclusion criteria, 9 patients had progressive disease after standard chemotherapy, 12 no change after standard chemotherapy, 6 recurrent disease after standard therapy and 21 recurrence after high dose chemotherapy. At start of the treatment patients were in stages IIA (15 patients), IIB (1) and IIIA (34). Idarubicin was given in capsules at 8–10 mg/m2/day for days 1–4, 40 mg dexamethasone were given on days 1–4 and 15–18, cyclophosphamide at 200 mg/m2/d d1–4 and thalidomide 100mg daily with scheduled increase to 400mg. Treatment cycles were repeated every 28 days. 3–8 cycles were applied. Supportive therapy consisted of PEG-filgrastim, cotrimoxazol, dalteparin and ibandronate. In addition, patients were randomized between thalidomide and thalidomide / idarubicin maintenance treatment. Results: At this interim analysis, 64 patients have been entered into the ongoing trial; 8 patients had to be excluded. Of the 56 included patients, 50 patients have been documented so far and are evaluable for toxicity. In total, 182 cycles have been applied. Median cycle number was 3 (1–8). There was one death during treatment due to progressive myeloma at cycle 1. The median age was 62 years (interquartile range 57–67). The following toxicities were observed: FUO (2 patients), pneumonia (4), pulmonary embolism (1), exsiccosis after diarrhea (1), constipation (1), sepsis (1), severe nausea (2), syncope (1), collaps after bleeding (1) and mucositis grade 4 (1). Hematologic toxicity was reported in 34% of the patients, mainly in cycles 1 and 2. Concerning response to treatment 39 patients are evaluable so far. Of these 30 (77%) achieved a PR or MR according to EBMT criteria, 4 patients a stable disease and 2 patients a PD. Three patients were not evaluable and scorded as failures. Conclusions: T-CID is feasible and seems to be highly effective in relapsed or refractory myeloma patients. Toxicity seems to be acceptable and mainly hematologic and infectiologic. The remission rate of 77% is encouraging. The trial is still ongoing. At the meeting a follow-up of the trial will be presented. Further information can be obtained at www.myelom.net.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3559.3559
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 8
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    Frequent Loss of the SLP-65 Adapter Protein in Childhood Acute B-Precursor Lymphoblastic Leukemia (ALL) with TEL/AML1 Rearrangement.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 741-741
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 741-741
    Abstract: The adaptor protein SLP-65 plays an essential role during B cell differentiation. A crucial consequence of SLP-65 deficiency in mice is a high incidence of pre-B-cell leukemia, suggesting a tumor suppressor role for SLP-65 in pre-B-cells. While the link between SLP-65 deficiency and leukemia development is established in mice, experiments mainly using microarrays for gene expression profiling suggested normal expression of SLP-65 in human precursor B-cell ALL. This analysis however does not discriminate between normal and aberrant SLP-65 transcripts with the latter being unable to generate functional protein. To examine the correlation between SLP-65 deficiency and childhood precursor B-cell ALL, we determined SLP-65 expression in 119 precursor B-cell ALL samples by both RNA and protein methods. The expression of SLP-65 was compared to clinical and laboratory findings, cytogenetics as well as to the outcome data within this uniformly treated cohort of patients. Loss of slp-65 protein was significantly associated with the occurrence of the TEL/AML1 rearrangement (p=0.026) but not with any other clinical or cytogenetic feature. We found a profound disconnection between slp-65 mRNA and protein expression in 38 out of the 119 leukemic samples pointing to a posttranscriptional regulation of slp-65 (Table). To confirm that SLP-65 transcript expression does not automatically correlate with its protein expression, we analyzed a panel of human cell lines derived from precursor B-cell ALL patients. The cell lines HPB-NULL and BV-173 showed a deficiency in SLP-65 protein expression, although SLP-65 transcripts can easily be detected in both lines. Together, the data suggest that SLP-65 expression might be regulated at the posttranscriptional level and that the presence of SLP-65 transcripts does not necessarily lead to SLP-65 protein and function. In one particular patient, we found a truncated slp-65 transcript and the predicted slp-65 protein lacks its SH2 domain. We tested whether this SLP-65 protein lacking the SH2 domain is functional in pre-B cells. To this end, we transfected murine SLP-65 −/− pre-B cells with retroviral constructs for either wild-type (wt SLP-65) or truncated SLP-65 (SLP-65delSH2) and analysed pre-BCR downregulation, Ca2+ release and pre-B cell differentiation. The results showed that, in contrast to wt SLP-65, SLP-65delSH2 failed to induce any effects in the performed experiments. Together with previous findings showing that SLP-65-deficient mice develop pre-B cell leukemia, the data suggest that SLP-65 acts as a tumor suppressor that limits pre-B cell proliferation by inducing differentiation. Disconnection between slp-65 transcripts and protein expression total slp-65 protein+ (51 patients) slp-65 protein weak (19 patients) slp-65 protein- (49 patients) PCR+ 108 51(9 TEL/AML+, 42 TEL/AML-) 19 (9 TEL/AML+, 10 TEL/AML-) 38 (15 TEL/AML+, 23 TEL/AML-) PCR- 11 0 0 11 (T-ALL)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.741.741
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 9
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    Detection of JAK2 Exon 12 Mutations in 10 Patients (10.1%) of V617F Negative PV: A Study of 211 Cases with PV or Suspected PV.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2541-2541
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2541-2541
    Abstract: Up to 95% of all patients (pts) with polycythemia vera (PV) carry JAK2V617F mutations (V617Fmut). The underlying pathophysiologic event in the remaining 5% remained unclear. Recently, novel mutations in exon12 (exon12mut) of the JAK2 gene have been described. Thus far, 16 pts with 4 different mutation types (F537-K39delinsL, H538QK539L, N542-E543del, and K539L) have been identidied by two groups. A specific phenotype of isolated erythrocytosis and young age has been suggested by one group while another group found that besides pts with isolated erythrocythosis around 50% may present with typical criteria for PV. Thus, exon12mut are scarce with still unclear frequency. Therefore, we have applied melting curve screening covering codons 535-555 of exon12 on 211 pts with PV or suspected PV. DNA of all pts with aberrant curve was sequenced. We detected exon12mut in 10/211 (4.7%) of all pts. Of these 99 pts fulfilled diagnostic criteria of PV whereas 112 were suspected PV due to unclear polyglobulia. The frequency of exon12mut in V617Funmut (V617wt) PV was 10/99 pts (10.1%). No exon12mut was detected in pts with polyglobulia. In addition, 10 V617wt ET and 50 CMPD with elevated red blood cell counts were analyzed but turned out to be exon12 unmutated (exon12wt). 3 of the exon12mut pts had the previously described F537-K39delinsL, 2 the N542-E543del, 1 H538QK539K, 1 K539L. In addition, 2 new mutations were detected: a E543-D544del (2 pts) and a K539S mutation (1 pt). Quantification showed exon12mut in 10–30% of all PBC (7 pts) or BM cells (3 pts). 5 pts were analyzed at diagnoses and 5 pts 2–8 years (y) (median 4y) after initial diagnosis of PV. Treatment was phlebotomy and ASS only in all pts. In 1 pt a homozygous K539L mutation was found. Thus, unlike previously reported, the exon12mut like the V617F mutations can occur in a homozygous state. This pt was at advanced stage near to transformation to AML. While in PV overall the female/male ratio was 225/231 in the exon12 mutated cohort the female/male ratio was higher with 7/3. Age of onset was 16–75 y (median: 57.5 y). This is the same range as the exon12wt/V617wt pts (57.3 y) but younger than the V617Fmut PV (66.5 y). Hematocrit of the exon12mut pts was elevated with a median of 61% in males and 55% in females. Erythropoietin levels were very low with a median of 3.8 U/L. Other parameters were less conspicuous in exon12mut than in V617Fmut (given in medians): WBC: 6,100 vs. 12,200/μl; Hb: 150 vs. 158 g/l; platelets 282,000 vs. 483,000/μl. In detail, four pts had elevated WBC and platelets in addition to erythrocytosis whereas 6 pts had isolated erythrocytosis. Thus, exon12mut pts frequently show isolated polyglobulia (60%) which is rare in V617Fmut PV. In addition, none of the exon12mut pts had hepatomegaly, three pts had borderline splenomegaly. In conclusion, analysis for JAK2 exon 12 mutations is a new tool for diagnostics of PV. Based on this still small cohort it can be speculated that exon12mut in comparison to V617Fmut pts tend to occur more frequently in women, at younger age, have lower WBC and platelet counts and frequently isolated erythrocytosis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2541.2541
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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    detail.hit.zdb_id: 80069-7
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  • 10
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    FLT3-ITD but Not FLT3-TKD Mutations Have Major Prognostic Impact in Normal Karyotype AML.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 3486-3486
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3486-3486
    Abstract: Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (TKD) are the second most common abnormalties in AML patients. For FLT3-ITD it is well known that patients have an unfavourable prognosis. Up to now there are not enough reliable data to determine the prognostic impact of FLT3-TKD mutations. Patients and Methods: We have investigated the prevalence of FLT3-TKD mutations in a cohort of 803 cytogenetically normal AML (NK-AML) patients and its possible prognostic significance. At diagnosis the mutation status of FLT3 (ITD and TKD) and the NPM1 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time of survivors 23.2 months. Results of the mutation status’ of FLT3-ITD, FLT3-TKD and NPM1 were available in 757/803 (94.3%), 683/803 (85.1%) and 696/803 (86.7%) patients, respectively. FLT3-ITD, FLT3-TKD and NPM1 mutations were found in 222 (29.3%), 46 (6.7%) and 354 (50.9%) of all analyzed patients, respectively. We could not detect any influence of the FLT3-TKD mutation on OS (p= 0.753), RFS (p= 0.229), EFS (p= 0.835), CR (p= 0.168) and on d16 blast count (p= 0.696). In most patients FLT3-ITD and TKD mutations were mutually exclusive, although a minority of 8/674 patients (1.2%) carried both mutations. FLT3-TKD mutations were more frequently found in patients with NPM1 mutations compared to NPM1-negative patients (9.04% vs. 3.74%; p= 0.008). In contrast to FLT3-ITD mutations FLT3-TKD mutation had no prognostic impact in NPM1 positive AML cases. Conclusions: In our study in a large cohort of 803 NK-AML patients we could not detect any prognostic impact of FLT3-TKD mutations. Although FLT3-ITD and TKD mutations have both transforming potential in vitro and in vivo mouse models, the clinical impact of both mutations shows striking differences. Further studies with FLT3-PTK inhibitors will clarify the pathogenetic relevance of these mutations in AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.3486.3486
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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    detail.hit.zdb_id: 80069-7
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