MedPath

OPTIMAL>60 / DR. CHOP, Improvement of Therapy of Elderly Patients with CD20+ DLBCL Using Rituximab Optimized and Liposomal Vincristine

Phase 3
Completed
Conditions
CD20+ Aggressive B-Cell Lymphoma
Interventions
Drug: Conventional Vincristine
Drug: Liposomal Vincristine
Drug: optimised rituximab-schedule
Drug: Ricover-scheme rituximab
Registration Number
NCT01478542
Lead Sponsor
Universität des Saarlandes
Brief Summary

The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided reduction of therapy in Combination with Vitamin D Substitution.

Detailed Description

Primary objective of study:

"OPTIMAL\>60 Less Favourable" Patients with less favourable prognosis: To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine; To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab.

"OPTIMAL\>60 Favourable": Patients with favourable prognosis: Comparison of neurotoxicity of conventional and liposomal vincristine; Determination of PFS for the treatment strategy of reducing treatment in patients with negative FDG-PET after 4 x R-CHOP/CHLIP-14 (PET-4) and comparison with the corresponding patient population in RICOVER-60.

Secondary objectives: "OPTIMAL\>60 Favourable" and "OPTIMAL\>60 Less Favourable":

Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.

Prospective evaluation on the role of (metabolic) tumor volume to confirm or refuse the hypothesis that optimized rituximab should improve the outcome of patients with a high (metabolic) tumor volume more than that of patients with low MTV and to analyse the substitution of conventional vincristine by liposomal. • Estimation of the vincristine-related neurotoxicity ("OPTIMAL\>60 Less Favourable only, since vincristine related neurotoxicity is primary objective of the study in favourable patients") and other toxicities (all patients).

Determination of the therapeutic efficacy of a vitamin D substitution.

Comparison of the FDG-PET-based individualised treatment strategy in OPTIMAL\>60 with the fixed (pre-defined) treatment strategy in RICOVER\>60.

Investigation of the prognostic value of different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG).

Comparison of the vincristine related neurotoxicity before and after amendment 4.

Comparison of CNS events before and after amendment 4. Comparison of the Cheson, Lugano and RECIL response criteria. Prospective evaluation of the improvement of the prognostic value of ECOG performance status during prephase treatment.

Prospective evaluation of reference pathology biomarkes. Prospective evaluation of circulating tumor DNA (ctDNA), correlation and comparison with PET.

Prospective evaluation of the role of 2 additional cycles of CHOP/CHLIP-14 and involved node radiotherapy in PET-positive patients after 4xR-CHOP/CHLIP-14 in favourable patients.

Evaluation of the role of radiotherapy to PET-positive bulky disease patients after 6xR-CHOP/CHLIP-14 in less favourable patients.

Quality assurance of the performed radiotherapy, including in in-field and outfield relapses.

Investigation of the effect of cross-site ComBat harmonization. Analysis of FDG-PET derived biomarkers in combination with clinical and laboratory variables as distance of lesions and Ann-Arbor stage.

Estimation of the prognostic value of a pre-treatment FDG-PET (PET-0) compared to conventional imaging with CT/MRT.

Prospective evaluation of the prediction of the probability of time-to-progression (TTP) within 2 years by a convolutional neural network trained to analyze maximum intensity projection images from baseline PET.

Analysis regarding molecular subtype, transcriptomics, methylome analysis, spatious analysis of interaction of tumor cells and microenvironment by cyTOF, 3D-morphology (AI-based) or similar techniques, viruses (EBV, HHV6, HHV7), micro-RNA in tumor samples.

Analysis of ctDNA analysis by i) digital droplet PCR, ii) e.g. CAPP or similar methods and iii) methylome analysis as prognostic and predictive marker and comparison with imaging biomarkers.

Analysis special focus on refractory, relapsed courses (including specific patterns of relapse regarding location and time) compared to matched controls and regarding comparison with imaging biomarkers.

Analysis of specific BCR-antigens of aggressive B-NHL as Ars2, SAMD14/neurabin-I in tissue and blood. of initial samples of cases with refractory, relapsing course (including specific patterns of relapse regarding location and time).

Analysis of factors influencing immune effector cells e.g.KIR2DS1 and homozygous HLA-C2, PRF1 A91V or other fHLH variants and prognostic and predictive markers in comparison to RICOVER-60.

Investigation of possible prognostic, or predictive markers of treatment related toxicity as: Neurofilament light chain (NfL) to estimate vincristine-related neurotoxicity, or as clonal hematopoiesis with indeterminate potential (CHIP) and association with cardiovascular events.

Investigation of specific concomitant medication and possible impact on outcome.

Investigation of the efficacy of the modified mandatory infectious prophylaxis OPTIMAL compared to the RICOVER trial with a focus on mandatory chinolon prophylaxis.

Investigation of COVID-19-reated events Impact of interval of diagnosis to time to treatment. Comparison with similar patient populations treated in real-world or prospective clinical trials.

Analysis of EFS and PFS at 24 months (EFS24/PFS24) and its impact on subsequent outcome.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
1152
Inclusion Criteria

  1. Age: 61-80 years

  2. All risk groups (IPI 1-5)

  3. Diagnosis of aggressive CD20+ B-NHL, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement. It will be possible to treat the following entities in this study as defined by the new WHO classification of 200870:

    B-NHL:

    • Foll. lymphoma grade IIIb

    • DLBCL, not otherwise specified (NOS)

      • common morphologic variants:

        • centroblastic
        • immunoblastic
        • anaplastic

      • rare morphologic variants

    • DLBCL subtypes/entities:

      • T-cell/histiocyte-rich large B-cell lymphoma
      • primary cutaneous DLBCL, leg type
      • EBV-pos. DLBCL of the elderly

    • DLBCL associated with chronic inflammation

    • primary mediastinal (thymic) LBCL

    • intravascular large B-cell-lymphoma

    • ALK-positive large B-cell-lymphoma

    • plasmoblastic lymphoma

    • primary effusion lymphoma

    • transformed indolent lymphoma secondary or simultaneous high grade B-cell-lymphoma

    • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma

    • B-cell lymphoma, unclassifiable, with features intermediate between DLCBL and Hodgkin lymphoma

  4. Performance status ECOG 0 - 2 after prephase treatment. The performance status of each patient must be assessed before the initiation and after the end of prephase treatment which, as experience has shown, can result in a significant improvement of the patient's performance status. The pre-treatment performance status which can range from ECOG 0 to ECOG 4 must be documented in the Staging CRF (see ISF); the performance status after the prephase treatment must be documented in the respective Prephase Treatment CRF (PT form: see ISF). A definition of the performance status is provided in Appendix 28.10.

  5. Written informed consent of the patient

  6. Contract of participation signed by the study centre and sponsor

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Exclusion Criteria

  1. Already initiated lymphoma therapy (except for the prephase treatment)

  2. Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular:

    • heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2 and/or EF <50% or FS<25% in nuclear medicine examination/echocardiography
    • lungs: if respiratory problems are suspected the patient is to be excluded if the resultant pulmonary function test shows FeV1<50% or a diffusion capacity <50% of the reference values
    • kidneys: creatinine >2 times the upper reference limit
    • liver: bilirubin >2 times the upper reference limit, aspartate transaminase (AST, SGOT) or alanine transaminase (ALT, SGPT) >3 x institutional upper reference limit
    • uncontrollable diabetes mellitus (prephase treatment with predniso[lo]ne!)

  3. Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)

  4. Known hypersensitivity to the medications to be used

  5. Known HIV-positivity

  6. Patients with severe impairment of immune defense

  7. Patients with constipation with imminent risk of ileus

  8. Chronic active hepatitis

  9. Poor patient compliance

  10. Simultaneous participation in other treatment studies or in another clinical trial within the last 6 months

  11. Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder

  12. Other concomitant tumour disease and/or tumour disease in the past 5 years (except for localised skin tumors other than melanoma and carcinomas in situ of any other origin)

  13. CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma

  14. Persistent neuropathy grade ≥2 (NCI CTC-AE v4.03) (unless due to lymphoma involvement)

  15. History of persistent active neurologic disorders grade >2 including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition

  16. Pregnancy or breast-feeding women

  17. Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication

  18. Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.

  19. MALT lymphoma

  20. Non-conformity to eligibility criteria

  21. Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)

  22. Persons not agreeing to the transmission of their pseudonymous data

  23. Persons depending on sponsor or investigator

  24. Persons from highly protected groups. Pts. with CNS lymphoma should not be included in this study.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
FACTORIAL
Arm && Interventions
GroupInterventionDescription
Favourable Prognosis F-A - Recruitment completedConventional VincristineInduction therapy with 4 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm \[max. 2mg absolute\], Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHOP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy.
Less Favourable LF-C - Recruitment completedoptimised rituximab-scheduleInduction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm \[max. 2mg absolute\], Predniso\[lo\]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed.
Favourable F-B - Arm ClosedLiposomal VincristineInduction therapy with 4 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,4 mg/sqm (max. 2mg absolute), Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHLIP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy.
Less Favourable LF-D - Recruitment completedoptimised rituximab-scheduleInduction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm \[uncapped\], , Predniso\[lo\]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed.
Less Favourable LF-A - Recruitment completedConventional VincristineInduction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm \[max. 2mg absolute\], Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed.
Less Favourable LF-D - Recruitment completedLiposomal VincristineInduction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm \[uncapped\], , Predniso\[lo\]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed.
Less Favourable LF-A - Recruitment completedRicover-scheme rituximabInduction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm \[max. 2mg absolute\], Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed.
Less Favourable LF-B - Recruitment completedLiposomal VincristineInduction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm \[uncapped\], , Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed.
Less Favourable LF-C - Recruitment completedConventional VincristineInduction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm \[max. 2mg absolute\], Predniso\[lo\]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed.
Less Favourable LF-B - Recruitment completedRicover-scheme rituximabInduction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm \[uncapped\], , Predniso\[lo\]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed.
Primary Outcome Measures
NameTimeMethod
Progression-free survival9 years

"OPTIMAL\>60 Less Favourable": To test the effects of substitution of conventional by liposomal vincristine and of a 2-week applications of 8x rituximab by an optimised application of 12 x rituximab stratified log rank tests will be performed for each question (stratified for IPI-factors). Proportional hazard models will be used to investigate treatment interaction and to obtain estimates for the single treatment effects (HR) adjusting for the IPI-factors.

"OPTIMAL\>60 Favourable" Grade of neurotoxicity will be estimated and indicated with a 95% confidence interval (CI) separated to each type of vincristine. To investigate the 3-year PFS with 95% CI the Kaplan-Meier estimator will be used.

Secondary Outcome Measures
NameTimeMethod
for efficacy: CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS and OS; rate and CTC grades of PNP. Prognostic value of the FDG-PET derived imaging biomarkers for lymphoma load: SUV, MTV, TLG.9 years

Secondary endpoints: To analyze how (i. e. in which direction) and how often a pre-treatment FDG-PET-based assignment (PET-0) would have affected the assignment of a patient to a different stage, IPI risk group or treatment, respectively. The different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG) will be analyzed for their relationship with CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS, PFS and OS.

To compare the efficacy and side effects of the (post-induction therapy FDG-PET-based) individualised treatment strategy in OPTIMAL\>60 with the fixed (pre-defined) treatment strategy in RICOVER-60.

Rates and grades of polyneuropathy will be determined according to CTC-v4.03. Comparison of the patients without vitamin-D-substitution with patients receiving a vitamin-D-substitution.

Trial Locations

Locations (127)

Innklinikum Altötting

🇩🇪

Altötting, Germany

Saarland University Hospital

🇩🇪

Homburg, Saarland, Germany

Evangelisches Krankenhaus Paul Gerhardt Stift, Klinik für Innere Medizin II

🇩🇪

Wittenberg, Sachsen-Anhalt, Germany

Klinik für Hämatologie und Onkologie

🇩🇪

Aachen, Germany

Klinikum St. Marien Amberg, MVZ

🇩🇪

Amberg, Germany

Klinikum Augsburg, Medizinische Klinik II

🇩🇪

Augsburg, Germany

Praxis Dres. med. Brudler, Heinrich, Bangerter

🇩🇪

Augsburg, Germany

Gemeinschaftspraxis Dres. Reichert, Janssen

🇩🇪

Aurich, Germany

Helios Klinikum Bad Saarow, Klinik für Innere Medizin III

🇩🇪

Bad Saarow, Germany

Sozialstiftung Bamberg, Med. Klinik V

🇩🇪

Bamberg, Germany

Klinikum Bayreuth, Medizinische Klinik IV

🇩🇪

Bayreuth, Germany

Charité- Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik III

🇩🇪

Berlin, Germany

Knappschaftskrankenhaus Bochum

🇩🇪

Bochum, Germany

Johanniter Krankenhaus Bonn, Abteilung für Innere Medizin I

🇩🇪

Bonn, Germany

Universitätsklinikum Bonn, Med. Klinik III

🇩🇪

Bonn, Germany

Städt. Klinikum Brandenburg, Med. Klinik II

🇩🇪

Brandenburg, Germany

Evangelisches Diakonie-Krankenhaus Bremen

🇩🇪

Bremen, Germany

Praxis Dr. Obst

🇩🇪

Burgwedel, Germany

Praxis Dr. Marquard

🇩🇪

Celle, Germany

Klinikum Chemnitz, Innere Medizin III

🇩🇪

Chemnitz, Germany

Klinikum Coburg, V. Med. Klinik

🇩🇪

Coburg, Germany

Schwerpunktpraxis Dres. Glados/Retzlaff/Zühlsdorf/Deuticke

🇩🇪

Coesfeld, Germany

St. Johannes Hospital Dortmund, Med. Klinik II

🇩🇪

Dortmund, Germany

BAG Freiberg-Richter, Jacobasch, Wolf, Illmer

🇩🇪

Dresden, Germany

Gemeinschaftspraxis Dres. Mohm, Prange-Krex

🇩🇪

Dresden, Germany

Universitätsklinikum Erlangen, Med. Klinik 5

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Erlangen, Germany

St.-Antonius-Hospital Eschweiler, Hämatologie und Onkologie

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Eschweiler, Germany

Klinikum Esslingen, Klinik für Gastroenterologie, Onkologie und Innere Medizin

🇩🇪

Esslingen, Germany

Klinikum Frankfurt (Oder), Abteilung f. Innere Medizin

🇩🇪

Frankfurt (Oder), Germany

Klinikum der J.W. Goethe-Universität Frankfurt, Hämatologie/Onkologie

🇩🇪

Frankfurt, Germany

Krankenhaus Nordwest Frankfurt, II. Med. Klinik

🇩🇪

Frankfurt, Germany

Praxis Dr. med. Reiber

🇩🇪

Freiburg, Germany

Universitätsklinikum Freiburg, Innere Medizin I

🇩🇪

Freiburg, Germany

Klinikum Fulda, Med. Klinik III

🇩🇪

Fulda, Germany

St. Josef-Hospital Gelsenkirchen, Onkologie und Hämatologie

🇩🇪

Gelsenkirchen, Germany

Praxis Dr. med. Schliesser

🇩🇪

Gießen, Germany

Wilhelm-Anton-Hospital Goch, Innere Medizin

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Goch, Germany

Onkologische Kooperation Harz, Onkologische Schwerpunktpraxis

🇩🇪

Goslar, Germany

Universitätsmedizin Greifswald, Medizinische Universitätsklinik C, Hämatologie und Onkologie

🇩🇪

Greifswald, Germany

Kreiskrankenhaus Gummersbach

🇩🇪

Gummersbach, Germany

Universitätsmedizin Göttingen, Hämatologie und Onkologie

🇩🇪

Göttingen, Germany

Klinikum Gütersloh

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Gütersloh, Germany

Kath. Krankenhaus Hagen, St.-Marien-Hospital

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Hagen, Germany

Gemeinschaftspraxis Rohrberg, Hurtz, Schmidt, Frank-Gleich

🇩🇪

Halle (Saale), Germany

Asklepios Klinik St. Georg, Hämatologie/Onkologie

🇩🇪

Hamburg, Germany

Hämatolog.-onkolog. Praxis Dres. Müller-Hagen, Bertram, Albertinen-Krankenhaus

🇩🇪

Hamburg, Germany

Hämatologisch-onkologische Praxis Altona (HOPA)

🇩🇪

Hamburg, Germany

Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik und Poliklinik, Onkologie und Hämatologie

🇩🇪

Hamburg, Germany

Klinikum Hannover-Siloah, Klinik für Hämatologie

🇩🇪

Hannover, Germany

Medizinische Hochschule Hannover (MHH), Zentrum für Innere Medizin, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

🇩🇪

Hannover, Germany

Praxis MediProjekt

🇩🇪

Hannover, Germany

Universitätsklinikum Heidelberg, Innere Medizin V

🇩🇪

Heidelberg, Germany

Klinikum Kreis Herford, Med. Klinik II

🇩🇪

Herford, Germany

Onkologische Schwerpunktpraxis Dres. Freier, Sievers

🇩🇪

Hildesheim, Germany

St. Bernward Krankenhaus Hildesheim, Med. Klinik II

🇩🇪

Hildesheim, Germany

KMT Klinik Idar-Oberstein

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Idar-Oberstein, Germany

Universitätsklinikum Jena, Klinik für Innere Medizin II

🇩🇪

Jena, Germany

Westpfalz-Klinikum, Klinik für Innere Medizin I

🇩🇪

Kaiserslautern, Germany

Praxis Dres Hansen, Reeb

🇩🇪

Kaiserslautern, Germany

St. Vincentius Kliniken Karlsruhe, Med. Klinik Abt. 2

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Karlsruhe, Germany

Städtisches Klinikum Karlsruhe, II. Med. Klinik, Hämatologie/Onkologie/Infektionskrankheiten

🇩🇪

Karlsruhe, Germany

GMP Dres Siehl, Söling

🇩🇪

Kassel, Germany

Rotes Kreuz Krankenhaus Kassel, Klinik für Interdisziplinäre Onkologie

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Kassel, Germany

Klinikum Kempten-Oberallgäu, Hämatologie, Onkologie und Palliativmedizin

🇩🇪

Kempten, Germany

Gemeinschaftsklinikum Mittelrhein, Ev. Stift St. Martin, Innere Medizin

🇩🇪

Koblenz, Germany

Gemeinschaftspraxis Dres. Neise, Lollert

🇩🇪

Krefeld, Germany

Praxis Dr. Strauch

🇩🇪

Kronach, Germany

Gemeinschaftspraxis Dres. Schmitz, Steinmetz, Severin

🇩🇪

Köln, Germany

Klinikum der Universität zu Köln, Klinik I für Innere Medizin

🇩🇪

Köln, Germany

Krankenhaus Holweide

🇩🇪

Köln, Germany

Klinikum Landshut, Med. Klinik I

🇩🇪

Landshut, Germany

Caritas Krankenhaus Lebach

🇩🇪

Lebach, Germany

Onkologische Schwerpunktpraxis

🇩🇪

Leer, Germany

Klinikum St. Georg Leipzig, Abteilung für internistische Onkologie/Hämatologie

🇩🇪

Leipzig, Germany

Klinikum Lippe-Lemgo, Med. Klinik II

🇩🇪

Lemgo, Germany

Onkologische Schwerpunktpraxis Lörrach

🇩🇪

Lörrach, Germany

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

🇩🇪

Lübeck, Germany

Klinikum Magdeburg, Hämatologie/Onkologie

🇩🇪

Magdeburg, Germany

Universitätsmedizin Mainz, III. Med. Klinik und Poliklinik

🇩🇪

Mainz, Germany

Mannheimer Onkologie Praxis, Dres. Brust, Plöger, Schuster, Hensel

🇩🇪

Mannheim, Germany

Universitätsklinikum Gießen und Marburg

🇩🇪

Marburg, Germany

Johannes Wesling Klinikum, Klinik für Hämatologie, Onkologie und Palliativmedizin

🇩🇪

Minden, Germany

Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin

🇩🇪

Mutlangen, Germany

Kliniken Maria-Hilf Mönchengladbach, Innere Medizin I

🇩🇪

Mönchengladbach, Germany

GMP Dres Schröder/Sieg

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Mülheim an der Ruhr, Germany

Praxis Dres. Schmidt, Fromm, Wiesmeier, Seufert, Klapthor, Zingerle

🇩🇪

München Pasing, Germany

Klinikum Großhadern, Med. Klinik 3

🇩🇪

München, Germany

Klinikum rechts der Isar der Technischen Universität München, III. Med.Klinik

🇩🇪

München, Germany

Städtisches Klinikum München Harlaching

🇩🇪

München, Germany

Universitätsklinikum Münster, Med. Klinik A

🇩🇪

Münster, Germany

Onkologische Praxis Dr. Ladda

🇩🇪

Neumarkt, Germany

Lukaskrankenhaus Neuss, Med. Klinik II

🇩🇪

Neuss, Germany

Kreiskliniken Esslingen, Klinikum Kirchheim-Nürtingen, Hämatologie, Internist. Onkologie und Palliativmedizin

🇩🇪

Nürtingen, Germany

Gemeinschaftspraxis Dres. Balló, Böck

🇩🇪

Offenbach, Germany

Ortenau Klinikum Offenburg-Gegenbach, Medizinische Klinik II

🇩🇪

Offenburg, Germany

Klinikum Oldenburg, Hämatologie/Onkologie

🇩🇪

Oldenburg, Germany

Onkologische Schwerpunktpraxis Dr. Hübner

🇩🇪

Oldenburg, Germany

Pius Hospital Oldenburg, Klinik für Strahlentherapie und Internistische Onkologie

🇩🇪

Oldenburg, Germany

Onkologische Schwerpunktpraxis im MVZ 2 GmbH, Dr. H. Eimermacher

🇩🇪

Olpe, Germany

Klinikum Osnabrück, Med. Klinik III

🇩🇪

Osnabrück, Germany

Paracelsus Krankenhaus Ruit, Kreiskliniken Esslingen gGmbH, Zentrum für Allgemeine Innere Medizin

🇩🇪

Ostfildern, Germany

Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie

🇩🇪

Paderborn, Germany

Gemeinschaftspraxis Dres. Baake, Leonhardt, Moegling, am Regio Klinikum Pinneberg

🇩🇪

Pinneberg, Germany

Klinikum Ernst von Bergmann, Klinik für Hämatologie, Onkologie und Palliativmedizin

🇩🇪

Potsdam, Germany

Gemeinschaftspraxis Dres. Decker, Nonnenbroich, Herbrik-Zipp

🇩🇪

Ravensburg, Germany

Prosper-Hospital Recklinghausen, Med. Klinik I

🇩🇪

Recklinghausen, Germany

Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie

🇩🇪

Regensburg, Germany

Klinikum am Steinenberg, Kreiskliniken Reutlingen GmbH

🇩🇪

Reutlingen, Germany

Elblandklinikum Riesa, Klinik für Innere Medizin II

🇩🇪

Riesa, Germany

Klinikum Südstadt Rostock, Innere Medizin

🇩🇪

Rostock, Germany

Universitätsklinikum Rostock, Abteilung Hämatologie/Onkologie, Klinik u. Poliklinik für Innere Medizin

🇩🇪

Rostock, Germany

GMP Dres Jacobs, Daus, Schmits

🇩🇪

Saarbrücken, Germany

ZAHO-Siegburg, Zentrum für ambulante Hämatologie und Onkologie Siegburg

🇩🇪

Siegburg, Germany

Diakonie-Klinikum Stuttgart, Med. Klinik II

🇩🇪

Stuttgart, Germany

Klinikum Traunstein, Hämatologie/Onkologie

🇩🇪

Traunstein, Germany

Klinikum Mutterhaus der Borromäerinnen, Med. Abteilung I

🇩🇪

Trier, Germany

Krankenhaus der Barmherzigen Brüder Trier, I. Med. Abteilung

🇩🇪

Trier, Germany

Universitätsklinikum Tübingen, Medizinische Klinik und Poliklinik, Onkologie, Hämatologie, Immunologie und Rheumatologie

🇩🇪

Tübingen, Germany

Universitätsklinikum Ulm, Innere Medizin III

🇩🇪

Ulm, Germany

Katharinen Hospital Unna

🇩🇪

Unna, Germany

Schwarzwald-Baar-Klinikum - Innere Medizin II

🇩🇪

Villingen-Schwenningen, Germany

Praxis Onkologie Schwarzwald - Alb

🇩🇪

Villingen-Schwenningen, Germany

Med. Versorgungszentrum Weiden, Abteilung für Onkologie

🇩🇪

Weiden, Germany

Praxis Dres med. Perker, Sandherr

🇩🇪

Weilheim, Germany

HSK Wiesbaden, Innere Medizin III

🇩🇪

Wiesbaden, Germany

Helios Klinkum Wuppertal, Med. Klinik I

🇩🇪

Wuppertal, Germany

Hämatologisch-Onkologische Praxis Würselen

🇩🇪

Würselen, Germany

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