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Paula Cramer,
Anna-Maria Fink,
Raymonde Busch,
Barbara Eichhorst,
Clemens Wendtner,
Natali Pflug,
Petra Langerbeins,
Jasmin Bahlo,
Valentin Goede,
Friederike Schubert,
Hartmut Döhner,
Stephan Stigenbauer,
Peter Dreger, Michael Kneba,
Sebastian Böttcher,
Jiri Mayer,
Michael Hallek,
Kirsten Fischer
[show abstract]
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ABSTRACT: Abstract Updated results of the CLL8-trial confirm that the addition of rituximab to chemotherapy with fludarabine and cyclophosphamide (FC) leads to a prolongation of progression-free and overall survival in first-line treatment of physically fit patients. After a median observation time of 47 months, median PFS was 57.9 months for patients treated with FC and rituximab (FCR) and 32.9 months for patients treated with FC alone (HR 0.56, CI 0.465-0.673; p<0.001). 232 patients were treated for relapse, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. The drugs most frequently used either alone or in combination were rituximab (52% of all 2nd-line therapies), fludarabine (21%), bendamustine (21%), and alemtuzumab (12%). The regimens chosen for 2nd-line treatment after FC or FCR were heterogeneous, which underlines a need for further trials in order to define treatment recommendations for patients with relapsed CLL.
Leukemia & lymphoma 04/2013; · 2.40 Impact Factor
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ABSTRACT: With the advent of multiple highly effective treatment options, minimal residual disease (MRD) measurements gained interest as a prognostic marker in chronic lymphocytic leukemia. This article provides a model explaining the clinical significance of MRD in different clinical situations and reviews available data to support that model. Factors with a possible impact on the clinical significance of MRD are discussed: technique for MRD quantification, treatment regimen, clinical response, time-point for sampling, and the additional impact of molecular risk features. Also described are data supporting the use of MRD assessments as a surrogate end-point in randomized clinical trials.
Hematology/oncology clinics of North America 04/2013; 27(2):267-88. · 2.05 Impact Factor
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Peter Dreger,
Andrea Schnaiter,
Thorsten Zenz,
Sebastian Böttcher,
Marianna Rossi,
Peter Paschka,
Andreas Bühler,
Sascha Dietrich,
Raymonde Busch,
Matthias Ritgen, [......],
Matthias Zeis,
Michael Stadler,
Lutz Uharek,
Christof Scheid,
Ute Hegenbart,
Michael Hallek, Michael Kneba,
Norbert Schmitz,
Hartmut Döhner,
Stephan Stilgenbauer
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this analysis was to provide six-year follow-up of the GCLLSG CLL3X trial which studied reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) in patients with poor-risk chronic lymphocytic leukemia (CLL), and to investigate the impact of TP53, SF3B1, and NOTCH1 mutations on HSCT outcome. Six-year overall survival (OS) and event-free survival (EFS) of 90 allografted patients was 58% and 38%, respectively. TP53, SF3B1, and NOTCH1 mutations were found in 30%, 26%, and 14% of the trial population. By univariate and multivariate analyses, the mutational status of the TP53, SF3B1, and NOTCH1 genes had no significant impact on OS and EFS. Studies of minimal residual disease confirmed durability of CLL eradication in mutated patients. We conclude that HSCT can provide long-term disease control in patients with poor-risk CLL independent of the presence of TP53, SF3B1, and NOTCH1 mutations. The trial has been registered at the US National Cancer Institute (Protocol Identity # EU-20554, NCT00281983).
Blood 02/2013; · 9.90 Impact Factor
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ABSTRACT: The quantification of submicroscopic minimal residual disease (MRD) after therapy proved to have independent prognostic significance in many mature B-cell malignancies. With the advent of routine bench-top cytometers capable of simultaneously analyzing ≥4 colors and with improved standardization, flow cytometry has become the method of choice for MRD assessments in some lymphoma entities. Herein we describe general aspects of flow cytometric standardization. Using chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) as examples we explain in detail the application of flow cytometry for MRD detection.
Methods in molecular biology (Clifton, N.J.) 01/2013; 971:149-74.
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ABSTRACT: Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell Non-Hodgkin lymphomas (B-NHL) and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. MRD diagnostics performed by real-time quantitative PCR (RQ-PCR) is the gold-standard and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). RQ-PCR analysis of the junctional regions of the rearranged immunoglobulin heavy-chain gene (IgH) serves as the most broadly applicable MRD target in B-NHL (∼80%). Chromosomal translocations as t(14;18) translocation in FL and t(11;14) translocation in MCL can be used in selected lymphoma subtypes. In patients with B-cell chronic lymphocytic leukemia, both flow-cytometry as well as RQ-PCR are equally suitable for MRD assessment as long as a sensitivity of ≤10(-4) shall be achieved.MRD diagnostics targeting the IgH gene is complex and requires extensive knowledge and experience because the junctional regions of each lymphoma have to be identified before the patient-specific RQ-PCR assays can be designed for MRD monitoring. Furthermore, somatic mutations of the IgH region occurring during B-cell development of germinal center and post-germinal center lymphomas may hamper appropriate primer binding leading to false negative results. The translocations mentioned above have the advantage that consensus forward primers and probes, both placed in the breakpoint regions of chromosome 18 in FL and chromosome 11 in MCL, can be used in combination with a reverse primer placed in the IgH joining region of chromosome 14. RQ-PCR-based methods can reach a good sensitivity (≤10(-4)). This chapter provides all relevant background information and technical aspects for the complete laboratory process from detection of the clonal IgH gene rearrangement and the chromosomal translocations at diagnosis to the actual MRD measurements in clinical follow-up samples of B-NHL. However, it should be noted that MRD diagnostics for clinical treatment protocols has to be accompanied by regular international quality control rounds to ensure the reproducibility and reliability of the MRD results.
Methods in molecular biology (Clifton, N.J.) 01/2013; 971:175-200.
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ABSTRACT: Significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL) during the past two decades, and measurement of submicroscopic (minimal) levels of residual disease (MRD) is increasingly used to monitor treatment efficacy. For a better comparability of MRD data there are ongoing efforts to standardize MRD quantification using real-time quantitative polymerase chain reaction (RQ-PCR) of clonal immunoglobulin and T-cell receptor gene rearrangements, RQ-PCR-based detection of fusion gene transcripts or breakpoints, and multiparameter flow cytometric immunophenotyping. Several studies have demonstrated that MRD assessment in childhood and adult ALL significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of treatment response, but also for early assessment of an impending relapse. Therefore MRD has gained a prominent position in many ALL treatment studies as tool for tailoring therapy with growing evidence that MRD supersedes most conventional stratification criteria at least for Ph-negative ALL. Most study protocols on adult ALL follow a two step approach with a first classical pretherapeutic and a second MRD-based risk stratification. Here we discuss whether and how MRD is ready to be used as main decisive marker and whether pretherapeutic factors and MRD are really competing or complementary tools to individualize treatment.
Blood 10/2012; · 9.90 Impact Factor
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Max S Topp,
Nicola Gökbuget,
Gerhard Zugmaier,
Evelyn Degenhardt,
Marie-Elisabeth Goebeler,
Matthias Klinger,
Svenja A Neumann Md,
Heinz A Horst,
Thorsten Raff,
Andreas Viardot, [......],
Thomas Burmeister,
Patrick Alexander Baeuerle,
Dirk Nagorsen,
Margit Schmidt,
Hermann Einsele,
Gert Riethmüller, Michael Kneba,
Dieter Hoelzer,
Peter Kufer,
Ralf C Bargou
[show abstract]
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ABSTRACT: Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase II trial in B-lineage ALL patients with persistent or relapsed MRD, a T-cell engaging bispecific antibody construct, induced an 80% MRD response rate. In this report, we show that after a median follow up of 33 months the hematological relapse free survival (RFS) of the whole evaluable study cohort of 20 patients is 61% (Kaplan-Meier estimate). The hematological RFS rate of a subgroup of 9 patients, who received allogeneic hematopoietic stem cell transplantation (HSCT) after blinatumomab treatment, was 65% (Kaplan-Meier estimate). In the subgroup of 6 Ph - negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. Blinatumomab can induce long-lasting CRs in B-lineage ALL patients with persistent or recurrent MRD. (ClinicalTrials.gov identifier: NCT00198991, NCT00198978).
Blood 09/2012; · 9.90 Impact Factor
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Kirsten Fischer,
Paula Cramer,
Raymonde Busch,
Sebastian Böttcher,
Jasmin Bahlo,
Jöerg Schubert,
Karl H Pflüger,
Silke Schott,
Valentin Goede,
Susanne Isfort, [......],
Dirk Winkler,
Karl-Anton Kreuzer,
Peter Staib,
Matthias Ritgen, Michael Kneba,
Hartmut Döhner,
Barbara F Eichhorst,
Michael Hallek,
Stephan Stilgenbauer,
Clemens-Martin Wendtner
[show abstract]
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ABSTRACT: PURPOSE We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. Results Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively. CONCLUSION Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.
Journal of Clinical Oncology 08/2012; 30(26):3209-16. · 18.37 Impact Factor
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Peter Dreger,
Hartmut Döhner,
Fabienne McClanahan,
Raymonde Busch,
Matthias Ritgen,
Hildegard Greinix,
Anna-Maria Fink,
Wolfgang Knauf,
Michael Stadler,
Michael Pfreundschuh,
Ulrich Dührsen,
Günter Brittinger,
Manfred Hensel,
Johannes Schetelig,
Dirk Winkler,
Andreas Bühler, Michael Kneba,
Norbert Schmitz,
Michael Hallek,
Stephan Stilgenbauer
[show abstract]
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ABSTRACT: The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.
Blood 04/2012; 119(21):4851-9. · 9.90 Impact Factor
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Nicola Gökbuget, Michael Kneba,
Thorsten Raff,
Heiko Trautmann,
Claus-Rainer Bartram,
Renate Arnold,
Rainer Fietkau,
Mathias Freund,
Arnold Ganser,
Wolf-Dieter Ludwig,
Georg Maschmeyer,
Harald Rieder,
Stefan Schwartz,
Hubert Serve,
Eckhard Thiel,
Monika Brüggemann,
Dieter Hoelzer
[show abstract]
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ABSTRACT: Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
Blood 03/2012; 120(9):1868-76. · 9.90 Impact Factor
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Sebastian Böttcher,
Matthias Ritgen,
Kirsten Fischer,
Stephan Stilgenbauer,
Raymonde M Busch,
Günter Fingerle-Rowson,
Anna Maria Fink,
Andreas Bühler,
Thorsten Zenz,
Michael Karl Wenger,
Myriam Mendila,
Clemens-Martin Wendtner,
Barbara F Eichhorst,
Hartmut Döhner,
Michael J Hallek, Michael Kneba
[show abstract]
[hide abstract]
ABSTRACT: To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial.
MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups.
Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC.
MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
Journal of Clinical Oncology 02/2012; 30(9):980-8. · 18.37 Impact Factor
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ABSTRACT: Measurement of submicroscopic (minimal) levels of residual disease (MRD) can be used to monitor treatment response much more precisely than morphological screening of bone marrow slides. Several studies have demonstrated that MRD assessment in childhood and adult acute lymphoblastic leukemia (ALL) significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of early treatment response, but also to monitor disease before and after stem cell transplantation, for early assessment of an impending relapse and in the setting of salvage treatment. Currently, three highly specific and sensitive methodologies for MRD detection are available, namely, real-time quantitative polymerase chain reaction (RQ-PCR) of fusion gene transcripts or breakpoints, RQ-PCR-based detection of clonal immunoglobulin and T-cell receptor (TCR) gene rearrangements, and multiparameter flow cytometric immunophenotyping. Assessment of MRD has gained a prominent position in many ALL treatment studies as a tool for tailoring therapy. Only the results of these studies will answer the question of whether MRD-based treatment intervention is associated with improved outcome.
Seminars in Oncology 02/2012; 39(1):47-57. · 3.50 Impact Factor
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Alice Fabarius,
Armin Leitner,
Andreas Hochhaus,
Martin C Müller,
Benjamin Hanfstein,
Claudia Haferlach,
Gudrun Göhring,
Brigitte Schlegelberger,
Martine Jotterand,
Andreas Reiter, [......],
Frank Stegelmann,
Michael Pfreundschuh,
Cornelius F Waller,
Karsten Spiekermann,
Gabriela M Baerlocher,
Michael Lauseker,
Markus Pfirrmann,
Joerg Hasford,
Susanne Saussele,
Rüdiger Hehlmann
[show abstract]
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ABSTRACT: The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome-positive (Ph(+)) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACAs except -Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.
Blood 12/2011; 118(26):6760-8. · 9.90 Impact Factor
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Kirsten Fischer,
Paula Cramer,
Raymonde Busch,
Stephan Stilgenbauer,
Jasmin Bahlo,
Carmen D Schweighofer,
Sebastian Böttcher,
Peter Staib,
Michael Kiehl,
Michael J Eckart,
Gabriele Kranz,
Valentin Goede,
Thomas Elter,
Andreas Bühler,
Dirk Winkler, Michael Kneba,
Hartmut Döhner,
Barbara F Eichhorst,
Michael Hallek,
Clemens-Martin Wendtner
[show abstract]
[hide abstract]
ABSTRACT: The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL).
Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses.
On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively.
Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.
Journal of Clinical Oncology 08/2011; 29(26):3559-66. · 18.37 Impact Factor
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Max S Topp,
Peter Kufer,
Nicola Gökbuget,
Mariele Goebeler,
Matthias Klinger,
Svenja Neumann,
Heinz-A Horst,
Thorsten Raff,
Andreas Viardot,
Mathias Schmid, [......],
Margit Schmidt,
Ralf Lutterbuese,
Carsten Reinhardt,
Patrick A Baeuerle, Michael Kneba,
Hermann Einsele,
Gert Riethmüller,
Dieter Hoelzer,
Gerhard Zugmaier,
Ralf C Bargou
[show abstract]
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ABSTRACT: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.
Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.
Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
Journal of Clinical Oncology 06/2011; 29(18):2493-8. · 18.37 Impact Factor
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ABSTRACT: Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT.
The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany.
Fifty-two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation-based, high-dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long-term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse.
The current results indicated that autoSCT was capable of inducing long-term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long-term survival after relapse even without undergoing alloSCT.
Cancer 05/2011; 117(9):1901-10. · 4.77 Impact Factor
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Peter Dreger,
Hartmut Döhner,
Matthias Ritgen,
Sebastian Böttcher,
Raymonde Busch,
Sascha Dietrich,
Donald Bunjes,
Sandra Cohen,
Jörg Schubert,
Ute Hegenbart, [......],
Justin Hasenkamp,
Lutz Uharek,
Christof Scheid,
Andreas Humpe,
Thorsten Zenz,
Dirk Winkler,
Michael Hallek, Michael Kneba,
Norbert Schmitz,
Stephan Stilgenbauer
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this prospective multicenter phase 2 trial was to investigate the long-term outcome of reduced-intensity conditioning allogeneic stem cell transplantation (alloSCT) in patients with poor-risk chronic lymphocytic leukemia. Conditioning was fludarabine/ cyclophosphamide-based. Longitudinal quantitative monitoring of minimal residual disease (MRD) was performed centrally by MRD-flow or real-time quantitative polymerase chain reaction. One hundred eligible patients were enrolled, and 90 patients proceeded to alloSCT. With a median follow-up of 46 months (7-102 months), 4-year nonrelapse mortality, event-free survival (EFS) and overall survival (OS) were 23%, 42%, and 65%, respectively. Of 52 patients with MRD monitoring available, 27 (52%) were alive and MRD negative at 12 months after transplant. Four-year EFS of this subset was 89% with all event-free patients except for 2 being MRD negative at the most recent assessment. EFS was similar for all genetic subsets, including 17p deletion (17p-). In multivariate analyses, uncontrolled disease at alloSCT and in vivo T-cell depletion with alemtuzumab, but not 17p-, previous purine analogue refractoriness, or donor source (human leukocyte antigen-identical siblings or unrelated donors) had an adverse impact on EFS and OS. In conclusion, alloSCT for poor-risk chronic lymphocytic leukemia can result in long-term MRD-negative survival in up to one-half of the patients independent of the underlying genomic risk profile. This trial is registered at http://clinicaltrials.gov as NCT00281983.
Blood 10/2010; 116(14):2438-47. · 9.90 Impact Factor
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Christiane Pott,
Eva Hoster,
Marie-Helene Delfau-Larue,
Kheira Beldjord,
Sebastian Böttcher,
Vahid Asnafi,
Anne Plonquet,
Reiner Siebert,
Evelyne Callet-Bauchu,
Niels Andersen, [......],
Marek Trneny,
Jan Walewski,
Peter Dreger,
Michael Unterhalt,
Wolfgang Hiddemann, Michael Kneba,
Hanneke C Kluin-Nelemans,
Olivier Hermine,
Elizabeth Macintyre,
Martin Dreyling
[show abstract]
[hide abstract]
ABSTRACT: The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.
Blood 04/2010; 115(16):3215-23. · 9.90 Impact Factor
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Blood 12/2009; 114(26):5400-1; author reply 5401-2. · 9.90 Impact Factor
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Stephan Stilgenbauer,
Thorsten Zenz,
Dirk Winkler,
Andreas Bühler,
Richard F Schlenk,
Silja Groner,
Raymonde Busch,
Manfred Hensel,
Ulrich Dührsen,
Jürgen Finke,
Peter Dreger,
Ulrich Jäger,
Eva Lengfelder,
Karin Hohloch,
Ulrike Söling,
Rudolf Schlag, Michael Kneba,
Michael Hallek,
Hartmut Döhner
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ABSTRACT: The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome.
One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter.
The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased beta2-microglobulin (beta2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, beta2-MG, and TK were independent prognostic factors for OS.
Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.
Journal of Clinical Oncology 08/2009; 27(24):3994-4001. · 18.37 Impact Factor
