Martin Soekler

Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial

PURPOSE In patients with early unfavorable Hodgkins lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy. PATIENTS AND METHODS Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity. RESULTS With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies. CONCLUSION Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.

A phase II study of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas

The clinical course of peripheral T-cell lymphoma (PTCL) is usually aggressive and the prognosis unfavorable. Therefore, there is a need for improvement of treatment options. Patients with newly diagnosed (n = 27) or refractory/relapsed (n = 11) PTCL received a combination of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin. The overall response rate (ORR) was 61%, with a complete response rate of 39%. In newly diagnosed patients the ORR was 63%, the median overall survival 25.9 months, and progression-free survival 11.8 months. In relapsed/refractory patients the median OS was 6.1 months. The most frequent grade 3/4 toxicities were leukopenia (95% of patients) and thrombocytopenia (58%). Cytomegalovirus (CMV) reactivation occurred in 12 patients, but only two had CMV disease. Treatment-related deaths occurred in six newly diagnosed patients and one with relapsed/refractory disease. In conclusion, Campath-FCD is active in PTCL but is associated with significant toxicity and is, therefore, not recommended for use or further study. Further studies are warranted to investigate other approaches to combining alemtuzumab with chemotherapy for the treatment of PTCL.

PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group

BACKGROUND The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkins lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. METHODS In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkins lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. FINDINGS Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). INTERPRETATION The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkins lymphoma. FUNDING Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

Cancer-related fatigue in patients with and survivors of Hodgkin's lymphoma: a longitudinal study of the German Hodgkin Study Group

BACKGROUND Patients with Hodgkins lymphoma might have persistent fatigue even years after treatment. However, knowledge of the development of fatigue persisting long after completion of treatment is limited. Therefore, we did a detailed analysis of fatigue in our first-line clinical trials for early-stage favourable (HD13 trial), early-stage unfavourable (HD14 trial), and advanced-stage (HD15 trial) Hodgkins lymphoma. Beyond the description of fatigue from diagnosis up to 5 years after treatment, we aimed to assess any effect of patient characteristics, disease characteristics, or treatment characteristics on persistent fatigue. METHODS In this longitudinal study, we included patients with early-stage favourable, early-stage unfavourable, and advanced-stage Hodgkins lymphoma from the HD13, HD14, and HD15 trials, respectively, aged between 18 and 60 years. Eligible patients for these trials had newly diagnosed, histologically proven Hodgkins lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or lower, HIV negativity, and absence of comorbidity disallowing protocol treatment. We used the fatigue scale of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire to assess fatigue from diagnosis up to 5 years after the end of treatment. The primary outcomes of interest in this study were fatigue scores in the second and fifth year after end of treatment. We estimated the effect of different disease, patient, and treatment characteristics on fatigue with multiple regression analyses and identified fatigue trajectories with growth mixture models. The regression analyses and growth mixture models used robust and full information maximum likelihood estimates to account for missing data. The HD13, HD14, and HD15 trials are registered as international standard randomised controlled trials, ISRCTN63474366, ISRCTN04761296, and ISRCTN32443041, respectively. FINDINGS The HD13 trial enrolled patients with early-stage favourable disease from Jan 28, 2003, to Sept 30, 2009; the HD14 trial enrolled patients with early-stage unfavourable disease from Jan 28, 2003, to Dec 23, 2009; and the HD15 trial enrolled patients with advanced-stage disease from Jan 28, 2003, to April 18, 2008. 5306 patients were enrolled in these trials. We analysed 4215 patients with any valid fatigue assessment up to 5 years after the end of treatment. Patients with higher tumour burden at diagnosis had more fatigue at baseline (mean fatigue score in HD13: 30·8 [SD 28·0]; in HD14: 39·8 [29·4], and in HD15: 49·0 [30·2]). Fatigue scores (FA) in the second year after the end of treatment were 28·5 (24·7) in HD13, 28·8 (24·4) in HD14, and 30·7 (24·4) in HD15; in the fifth year after the end of treatment FA was 30·8 (26·0) in HD13, 27·1 (24·8) in HD14, and 28·2 (24·9) in HD15. Predictors of fatigue in the second and fifth year after end of treatment were baseline fatigue (p<0·0001) and age as a continuous variable (p<0·0001). In addition to preceding fatigue and age, patient sex and Hodgkins lymphoma specific risk factors at baseline did not consistently and significantly improve the prognosis of fatigue in the first, second, and fifth year after end of treatment. There was no significant effect of treatment on fatigue scores in the second and fifth year after treatment. INTERPRETATION Our findings show a high incidence of severe acute and persistent fatigue in Hodgkins lymphoma survivors, which is largely independent of tumour stage and treatment. Our results contribute to a better understanding of fatigue in patients with Hodgkins lymphoma and Hodgkins lymphoma survivors and could inform development of urgently needed intervention strategies. FUNDING Deutsche Krebshilfe.

Advanced-stage III/IV follicular lymphoma: treatment strategies for individual patients.

Background:In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient.Methods:The literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank.Results:In advanced-stage III/IV FL, median survival may approach 8–10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and – as an experimental approach so far – radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response.Conclusion:In case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab ± single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/ relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes.ZusammenfassungHintergrund:Für Patienten mit follikulärem Lymphom (FL) fortgeschrittener Stadien III/IV liegen mehrere etablierte Therapieoptionen vor. Die Herausforderung besteht darin, eine optimale Behandlungsstrategie für den einzelnen Patienten auszuwählen.Methodik:Es wurde eine Literaturrecherche unter Verwendung der PubMed-Datenbank zu Therapiestrategien bei Patienten mit fortgeschrittenen Stadien eines FL durchgeführt.Ergebnisse:Für fortgeschrittene Stadien III/IV eines FL beträgt das mediane Überleben 8–10 Jahre. Aktuelle Behandlungs optionen umfassen eine „watch and wait“-Strategie, eine kombinierte Chemoimmuntherapie, eine Monotherapie mit Rituximab sowie – als bislang experimentellem Ansatz – die Radioimmuntherapie. Die Anwendung der autologen Transplantation in erster Remission oder bei chemosensitivem Rezidiv kann im Vergleich zur konventionellen Chemotherapie das progressionsfreie Überleben verlängern, der Einfluss auf das Gesamtüberleben ist noch ungeklärt. Die Langzeitergebnisse werden durch hohe Rückfallraten und das Auftreten von Sekundärmalignomen beeinträchtigt. Bei Patienten im Rezidiv oder bei chemoresistenter Erkrankung ist die allogene Transplantation die einzige kurative Behandlungsoption mit allerdings hoher therapiebedingter Mortalität. Im Rahmen der Palliation stellt eine niedrigdosierte Involved-Field-Strahlentherapie eine effektive lokale Behandlungsoption mit potentiell lang anhaltender Remission dar.Schlussfolgerung:In fortgeschrittenen Stadien eines FL ist bei asymptomatischer Erkrankung ein abwartendes Verhalten gerechtfertigt. Bei Patienten mit symptomatischer Erkrankung wird die Chemoimmuntherapie als Standard erachtet. Bei symptomatischen älteren Patienten mit relevanter Komorbidität scheint eine Rituximabgabe ± Monochemotherapie bzw. niedrigdosierte Involved-Field-Radiotherapie angemessen. Bei jüngeren Patienten mit chemoresistenter Erkrankung oder Rezidiv eines FL kann eine allogene Transplantation erwogen werden, da ein optimales Management die Mortalitätsrate der allogenen Stammzelltransplantation gesenkt hat.

Advanced-Stage III/IV Follicular Lymphoma

Background:In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient.Methods:The literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank.Results:In advanced-stage III/IV FL, median survival may approach 8–10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and – as an experimental approach so far – radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response.Conclusion:In case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab ± single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/ relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes.ZusammenfassungHintergrund:Für Patienten mit follikulärem Lymphom (FL) fortgeschrittener Stadien III/IV liegen mehrere etablierte Therapieoptionen vor. Die Herausforderung besteht darin, eine optimale Behandlungsstrategie für den einzelnen Patienten auszuwählen.Methodik:Es wurde eine Literaturrecherche unter Verwendung der PubMed-Datenbank zu Therapiestrategien bei Patienten mit fortgeschrittenen Stadien eines FL durchgeführt.Ergebnisse:Für fortgeschrittene Stadien III/IV eines FL beträgt das mediane Überleben 8–10 Jahre. Aktuelle Behandlungs optionen umfassen eine „watch and wait“-Strategie, eine kombinierte Chemoimmuntherapie, eine Monotherapie mit Rituximab sowie – als bislang experimentellem Ansatz – die Radioimmuntherapie. Die Anwendung der autologen Transplantation in erster Remission oder bei chemosensitivem Rezidiv kann im Vergleich zur konventionellen Chemotherapie das progressionsfreie Überleben verlängern, der Einfluss auf das Gesamtüberleben ist noch ungeklärt. Die Langzeitergebnisse werden durch hohe Rückfallraten und das Auftreten von Sekundärmalignomen beeinträchtigt. Bei Patienten im Rezidiv oder bei chemoresistenter Erkrankung ist die allogene Transplantation die einzige kurative Behandlungsoption mit allerdings hoher therapiebedingter Mortalität. Im Rahmen der Palliation stellt eine niedrigdosierte Involved-Field-Strahlentherapie eine effektive lokale Behandlungsoption mit potentiell lang anhaltender Remission dar.Schlussfolgerung:In fortgeschrittenen Stadien eines FL ist bei asymptomatischer Erkrankung ein abwartendes Verhalten gerechtfertigt. Bei Patienten mit symptomatischer Erkrankung wird die Chemoimmuntherapie als Standard erachtet. Bei symptomatischen älteren Patienten mit relevanter Komorbidität scheint eine Rituximabgabe ± Monochemotherapie bzw. niedrigdosierte Involved-Field-Radiotherapie angemessen. Bei jüngeren Patienten mit chemoresistenter Erkrankung oder Rezidiv eines FL kann eine allogene Transplantation erwogen werden, da ein optimales Management die Mortalitätsrate der allogenen Stammzelltransplantation gesenkt hat.

Fertility preservation in young female lymphoma patients: review of available options and initial experiences with their implementation in clinical routine.

Background: High cure rates in women suffering from Hodgkin’s disease or aggressive non-Hodgkin’s lymphoma are often achieved at the cost of impaired ovarian function or infertility. Different strategies can be offered to protect fertility. Early experiences with the implementation of a specialised fertility preservation clinic are analysed with the aim to assess the need for and acceptance of the clinic, as well as the delay of treatment caused by the different approaches. Available options are reviewed. Patients and Methods: Data on underlying malignancy and fertility preservation measures in women of childbearing age treated for aggressive lymphoma and Hodgkin’s disease with curative intent between November 2006 and January 2010 were retrospectively analysed. Results: Among 111 female lymphoma patients, 30 were eligible for counselling. Nineteen accepted the offer. The main reason for declining was completed family planning. Eight further patients were referred from elsewhere. Of the counselled patients, 96% decided to pursue at least 1 protective strategy, 39% chose an invasive procedure (cryopreservation of ovarian tissue or oocyte aspiration following hormonal stimulation). These procedures deferred the start of systemic treatment within the expected range, no undue delays were observed. Conclusions: Female lymphoma patients have a large demand for counselling about measures to protect fertility. In a proper setting, counselling and intervention can be offered without undue delays menacing the chance for cure.

Dasatinib overrides the differentiation blockage in a patient with mutant- KIT D816V positive CBFβ-MYH11 leukemia

Activating KIT D816V mutations are frequently found in CBF AML, which predicts for an unfavorable outcome. Dasatinib is a potent inhibitor of wildtype and mutant-KIT isoforms – including D816V. We now provide proof of antileukemic efficacy in a patient with relapsing mutant-KIT D816V CBF AML. Importantly, this effect is mediated via overriding the differentiation blockage of the leukemia clone. In addition, we show that dasatinib is capable to induce pulmonary differentiation syndrome – and therefore needs close monitoring of patients under therapy.

Advanced-Stage III/IV Follicular Lymphoma@@@Follikuläre Lymphome in fortgeschrittenen Stadien III/IV. Behandlungsstrategien für den einzelnen Patienten: Treatment Strategies for Individual Patients

Background:In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient.Methods:The literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank.Results:In advanced-stage III/IV FL, median survival may approach 8–10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and – as an experimental approach so far – radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response.Conclusion:In case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab ± single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/ relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes.ZusammenfassungHintergrund:Für Patienten mit follikulärem Lymphom (FL) fortgeschrittener Stadien III/IV liegen mehrere etablierte Therapieoptionen vor. Die Herausforderung besteht darin, eine optimale Behandlungsstrategie für den einzelnen Patienten auszuwählen.Methodik:Es wurde eine Literaturrecherche unter Verwendung der PubMed-Datenbank zu Therapiestrategien bei Patienten mit fortgeschrittenen Stadien eines FL durchgeführt.Ergebnisse:Für fortgeschrittene Stadien III/IV eines FL beträgt das mediane Überleben 8–10 Jahre. Aktuelle Behandlungs optionen umfassen eine „watch and wait“-Strategie, eine kombinierte Chemoimmuntherapie, eine Monotherapie mit Rituximab sowie – als bislang experimentellem Ansatz – die Radioimmuntherapie. Die Anwendung der autologen Transplantation in erster Remission oder bei chemosensitivem Rezidiv kann im Vergleich zur konventionellen Chemotherapie das progressionsfreie Überleben verlängern, der Einfluss auf das Gesamtüberleben ist noch ungeklärt. Die Langzeitergebnisse werden durch hohe Rückfallraten und das Auftreten von Sekundärmalignomen beeinträchtigt. Bei Patienten im Rezidiv oder bei chemoresistenter Erkrankung ist die allogene Transplantation die einzige kurative Behandlungsoption mit allerdings hoher therapiebedingter Mortalität. Im Rahmen der Palliation stellt eine niedrigdosierte Involved-Field-Strahlentherapie eine effektive lokale Behandlungsoption mit potentiell lang anhaltender Remission dar.Schlussfolgerung:In fortgeschrittenen Stadien eines FL ist bei asymptomatischer Erkrankung ein abwartendes Verhalten gerechtfertigt. Bei Patienten mit symptomatischer Erkrankung wird die Chemoimmuntherapie als Standard erachtet. Bei symptomatischen älteren Patienten mit relevanter Komorbidität scheint eine Rituximabgabe ± Monochemotherapie bzw. niedrigdosierte Involved-Field-Radiotherapie angemessen. Bei jüngeren Patienten mit chemoresistenter Erkrankung oder Rezidiv eines FL kann eine allogene Transplantation erwogen werden, da ein optimales Management die Mortalitätsrate der allogenen Stammzelltransplantation gesenkt hat.