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23 Publications visible to you, out of a total of 23
Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: In the SMARTE-R-CHOP-14 … trial, rituximab 375 mg/m(2) was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6xR-CHOP-14), on days -4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6xR-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial. RESULTS: The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index [IPI], 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients. CONCLUSION: Extended rituximab exposure compared with eight 2-week applications in combination with 6xR-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6xR-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted.

Authors: M. Pfreundschuh, V. Poeschel, S. Zeynalova, M. Hanel, G. Held, N. Schmitz, A. Viardot, M. H. Dreyling, M. Hallek, C. Mueller, M. H. Wiesen, M. Witzens-Harig, L. Truemper, U. Keller, T. Rixecker, C. Zwick, N. Murawski

Date Published: 20th Dec 2014

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas.
GLA - German Lymphoma Alliance

Abstract (Expand)

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin … Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

Authors: N. Murawski, G. Held, M. Ziepert, B. Kempf, A. Viardot, M. Hanel, M. Witzens-Harig, R. Mahlberg, C. Rube, J. Fleckenstein, C. Zwick, B. Glass, N. Schmitz, S. Zeynalova, M. Pfreundschuh

Date Published: 31st Jul 2014

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Excellent outcome of young adults with aggressive non-Hodgkin lymphomas treated with CHOP-like regimens.
GLA - German Lymphoma Alliance

Abstract

Not specified

Authors: K. Hohloch, S. Zeynalova, G. Held, M. Ziepert, M. Loeffler, G. Wulf, N. Schmitz, M. Pfreundschuh, L. Trumper

Date Published: 10th Jul 2014

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial. PATIENTS AND METHODS: Rituximab (375 … mg/m(2)) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60. RESULTS: One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0). CONCLUSIONS: Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP.

Authors: N. Murawski, M. Pfreundschuh, S. Zeynalova, V. Poeschel, M. Hanel, G. Held, N. Schmitz, A. Viardot, C. Schmidt, M. Hallek, M. Witzens-Harig, L. Trumper, T. Rixecker, C. Zwick

Date Published: 15th Jun 2014

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Suboptimal dosing of rituximab in male and female patients with DLBCL.
GLA - German Lymphoma Alliance

Abstract (Expand)

To determine the effect of gender on outcome, the male hazard ratio for progression-free survival (HRPFS-male) was determined in patients with diffuse large B-cell lymphoma (DLBCL). In young patients … (MapThera International Trial study), HRPFS-male was 1.3 (P = .092) without and 1.1 (P = .660) with rituximab. In elderly patients (RICOVER-60 study), HRPFS-male was 1.1 (P = .348) with CHOP but increased to 1.6 (P = .004) with R-CHOP. The similar improvements of outcome in young patients were associated with similar rituximab clearances in young males and females (9.89 vs 10.38 mL/h; P = .238), whereas the greater benefit for elderly females was associated with a slower rituximab clearance (8.47 vs 10.59 mL/h; P = .005) and hence higher serum levels and longer exposure times, attributable to an age-dependent (P = .004) decrease of rituximab clearance in females but not males. Compared with elderly females, all other subgroups had significantly faster rituximab clearances and hence appear to be suboptimally dosed when rituximab is given at 375 mg/m(2). Although early results of pharmacokinetic-based prospective trials designed to exploit the full therapeutic potential of rituximab suggest that increased doses and/or prolonged exposure times can improve the outcome of elderly males with DLBCL, further studies are warranted that address the optimization of rituximab dose and schedule in all subgroups of DLBCL patients.

Authors: M. Pfreundschuh, C. Muller, S. Zeynalova, E. Kuhnt, M. H. Wiesen, G. Held, T. Rixecker, V. Poeschel, C. Zwick, M. Reiser, N. Schmitz, N. Murawski

Date Published: 30th Jan 2014

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: To study clinical presentation, outcome, and the role of radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement treated with and without rituximab. PATIENTS AND … METHODS: Outcome of patients with skeletal involvement was analyzed in a retrospective study of nine consecutive prospective trials of the German High-Grade Non-Hodgkin lymphoma Study Group. RESULTS: Of 3,840 patients, 292 (7.6%) had skeletal involvement. In the MabThera International Trial (MInT) for young good-prognosis patients and the Rituximab With CHOP Over 60 Years (RICOVER-60) study for elderly patients, the randomized addition of rituximab improved event-free survival (EFS; hazard ratio for MInT [HRMInT] = 0.4, P > 001; hazard ratio for RICOVER-60 [HRRICOVER-60] = 0.6, P > .001) and overall survival (OS; HRMInT = 0.4, P < .001; HRRICOVER-60 = 0.7, P = .002) in patients without skeletal involvement, but failed to improve the outcome of patients with skeletal involvement (EFS: HRMInT = 1.4, P = .444; HRRICOVER-60 = 0.8, P = .449; OS: HRMInT = 0.6, P = .449; HRRICOVER-60 = 1.0, P = .935). Skeletal involvement was associated with a worse outcome after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (HREFS = 1.5, P = .048; HROS = 1.1; P = .828), but not after CHOP without rituximab (HREFS = 0.8, P = .181; HROS = 0.7, P = .083). In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a decreased risk (HREFS = 0.3, P = .001; HROS = 0.5; P = .111). CONCLUSION: Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials.

Authors: G. Held, S. Zeynalova, N. Murawski, M. Ziepert, B. Kempf, A. Viardot, M. Dreyling, M. Hallek, M. Witzens-Harig, J. Fleckenstein, C. Rube, C. Zwick, B. Glass, N. Schmitz, M. Pfreundschuh

Date Published: 10th Nov 2013

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, … either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Authors: S. Zeynalova, M. Ziepert, M. Scholz, S. Schirm, C. Zwick, M. Pfreundschuh, M. Loeffler

Date Published: 30th Jul 2013

Publication Type: Not specified

Human Diseases: B-cell lymphoma

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