CHOP-21 for the treatment of post-transplant lymphoproliferative disorders following solid organ transplantation

There is no definitive treatment for post-transplant lymphoproliferative disorder (PTLD) that does not respond to reduction of immunosuppression. With a median follow-up of 8.8 years, the current retrospective analysis of standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in 26 adults with PTLD demonstrated an overall response rate of 65% and median overall and progression-free survivals of 13.9 and 42 months, respectively

Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83-98). 2-year Kaplan-Meier estimates of time to progression and overall survival were 78% (95% CI 65-90) and 68% (95% CI 55-80) - similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2-17). In the low-risk group, 2-year EFS was 66% (95% CI 45-86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

The EHA Research Roadmap : Malignant Lymphoid Diseases

Peer reviewe

Posttransplant lymphoproliferative disorders (PTLD) - treatment with chemotherapy: indications and outcome

Titelblatt und Inhaltsverzeichnis Einleitung Fragestellung Ergebnisse Diskussion LiteraturverzeichnisDie 1-Jahres-Überlebensrate von Transplantatempfängern liegt heute bei bis zu 90% bei einem stetig steigenden Anteil von Patienten mit Langzeitüberleben. Aufgrund der verbesserten Prognose nach Organtransplantation gefährden transplantationsassoziierte lymphoproliferative Erkrankungen zunehmend das Langzeitüberleben transplantierter Patienten. In Abhängigkeit des transplantierten Organs beträgt das Risiko, an einer PTLD zu erkranken, zwischen 0.5% und 20% und nimmt kumulativ mit dem Langzeitüberleben zu. Die vorliegende Arbeit stellt die die Frage der optimalen Therapie für diese aufgrund ihrer Begleiterkrankungen und immunsuppressiven Therapie oft schwer zu behandelnde Patientengruppe. Der Schwerpunkt wird hierbei auf die Evaluation verschiedener chemotherapeutischer Strategien gelegt. Die durchgeführten Studien zur Erstlinientherapie der PTLD mit CHOP, zur sequentiellen Therapie der PTLD mit Rituximab gefolgt von CHOP und zur Rezidivtherapie der PTLD haben die sequentielle Therapie mit Rituximab und CHOP in der Erstlinientherapie der CD20-positiven B-Zell PTLD als neuen Therapiestandard etabliert und zu einem besseren Verständnis der verschiedenen Therapieoptionen in der Rezidivsituation beigetragen. Die sequentielle Kombination von Rituximab und einem dreiwöchtenlich applizierten CHOP-Regime zeichnet sich im Vergleich zu historischen Daten in der Behandlung der PTLD durch eine bessere Verträglichkeit, ein überlegenes Ansprechen und eine bisher unübertroffen Remissionskontrolle aus. Die sequentielle Therapie erreicht eine CR Rate von 65% und eine Gesamtansprechrate von 90% mit einer deutlich geringeren Toxizität als sie für die Erstlinientherapie der PTLD mit CHOP beschrieben ist. Während die Therapie mit Rituximab mit keiner signifikanten Toxizität verbunden ist, kommte es in 38% der Chemotherapiezyklen zu einer schweren Neutropenie und 16% der Patienten erleiden schwere Infektionen. Die Therapie-assoziierte Mortalität der sequentiellen Therapie beträgt weniger als 10%. Das erkrankungsfreie Überleben nach 1 und 2 Jahren beträgt aktuell 81% und 64% der Patienten sind auch nach 2 Jahren noch progressionsfrei. Die Daten zur Zweitlinientherapie der PTLD nach Versagen einer initialen Rituximab- Monotherapie haben das klassische CHOP-21 Regime hier als sinnvolle Behandlungsoption mit einer Gesamtansprechrate von etwa 70% etabliert und gezeigt dass auch die Rituximabvorbehandelte PTLD grundsätzlich chemosensitiv ist. Trotz einer siginifikanten Therapie-assoziierten Toxizität von CHOP wurde in dieser Studie keine letale Infektionstoxizität beobachtet. Allerdings mussten einzelne Patienten auf weniger toxische Monotherapien umgestelt werden und haben nachfolgend eine Progression der PTLD erfahren. Die chemotherapeutischen Optionen in der Rezidivsituation chemotherapeutisch vorbehandelter Patienten werden entscheidend durch die Vorbehandlung und die Begleiterkrankungen der Patienten beeinflusst. Subgruppenanalysen belegen hier eine erhöhte therapieassoziierten Mortalität auch bei Verwendung wenig toxischer Therapieregime wie Carboplatin und Etoposid oder Bendamustin für Patienten in reduziertem Allgemeinzustand (ECOG >2) und für Patienten mit eingeschränkter Nierenfunktion (Kreatinin> 2.5 mg/dl). Allerdings kann mit beiden Regimen auch ohne nachfolgende Hochdosistherapien mit autologer Stammzelltransplantation ein Gesamtüberleben von 50% nach 1 Jahr und 17% nach 5 Jahren erzielt werden. Die herkömmlichen Salvage-Regimen wie DHAP, DexaBEAM und ICE (+/- HD-Therapie/ASZT) stellen hingegen keine geeigneten Behandlungsalternative für die Mehrzahl der Patienten dar.Post transplant lymphoproliferative disorder is the second most frequent malignancy following solid organ transplantation with an incidence of about 0.5 to 20% in the transplant population. The incidence of PTLD is greatly dependent on the type of transplant and the intensity of immunosuppression in induction and maintenance. With recent improvements in the management of immunologic and infectious complications in solid organ transplantation, PTLD is becoming a major challenge and represents a serious and often devastating complication after SOT. This is an analysis of different therapeutic options in PTLD with a strong focus on chemotherapy. Our studies using sequential treatment with rituximab and CHOP chemotherapy after patients failed to respond significantely to an upfront reduction of immunosuppression clearly demonstrate that sequential treatment is feasible in adult solid organ transplant recipients, and shows a superior efficacy rate and safety profile compared with historic data in the treatment of PTLD. Further studies have improved therapeutic options for patients with relapsed PTLD. Sequential therapy with CHOP after 4 courses rituximab therapy achieved a CR rate of 65% and an overall response rate of 90%, with a much lower toxicity than usually reported for CHOP in the literature. While there was no severe rituximab related toxicity, CHOP associated severe neutropenia occured in 38% of chemotherapy cycles and severe infections were observed in 16% of patients. However, the treatment related mortality was below 10%. Disease free survival after 1 and after 2 years is 81% in this study at the moment. Notably, of the patients that were treated according to protocol, 64% are progression-free at 2 years. The purpose of the following studies was to analyze the efficiency and safety of chemotherapy salvage therapies in adult recipients of solid organ transplant with a second progression of PTLD after 1st-line therapy. After 1st-line rituximab CHOP salvage therapy achieves a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab. Although the treatment associated toxicity for CHOP was significant, lethal infectious toxicity was not observed in this study. However, some patients had to be switched to less toxic monotherapies because CHOP was not tolerated and both patients subsequently experienced disease progression. After 1st-line CHOP-based chemotherapy protocols the effect of salvage therapy is greatly dependet on upfront treatment and comorbidity. There is a higher treatment associated toxicity even for less toxic regimens like carboplatin/etoposide or single agent bendamustin for patients with an ECOG greater than 2 or with an impaired renal function. However, both regimens do achieve an overall survival of about 50% after 1 year and 17% after 5 years without high dose therapy and autologous stem cell transplantation. Classical salvage therapy using DHAP, DexaBEAM and ICE (+/- high dose therapy and ASCT) are not suitiable for the majority of patients with PTLD

European Society of Gynaecological Oncology guidelines for the peri-operative management of advanced ovarian cancer patients undergoing debulking surgery

The European Society of Gynaecological Oncology (ESGO) developed and established for the first time in 2016, and updated in 2020, quality indicators for advanced ovarian cancer surgery to audit and improve clinical practice in Europe and beyond. As a sequela of the continuous effort to improve oncologic care in patients with ovarian cancer, ESGO issued in 2018 a consensus guidance jointly with the European Society of Medical Oncology addressing in a multidisciplinary fashion 20 selected key questions in the management of ovarian cancer, ranging from molecular pathology to palliation in primary and relapse disease. In order to complement the above achievements and consolidate the promoted systemic advances and surgical expertise with adequate peri-operative management, ESGO developed, as the next step, clinically relevant and evidence-based guidelines focusing on key aspects of peri-operative care and management of complications as part of its mission to improve the quality of care for women with advanced ovarian cancer and reduce iatrogenic morbidity. To do so, ESGO nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of ovarian cancer (18 experts across Europe). To ensure that the guidelines are evidence based, the literature published since 2015, identified from a systematic search, was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 117 independent international practitioners in cancer care delivery and patient representatives