Dieter Körholz

Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study

PURPOSE Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkins lymphoma (HL). PATIENTS AND METHODS Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkins Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission. RESULTS Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12). CONCLUSION In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.

qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma

BackgroundInterim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions.ObjectivesWith a novel semi-automatic quantification tool we eliminate optical illusions and extend the Deauville score to a continuous scale.Patients and methodsSUVpeak of residual tumors and average uptake of the liver is measured with standardized volumes of interest. The qPET value is the quotient of these measurements. Deauville scores and qPET-values were determined in 898 pediatric Hodgkin’s lymphoma patients after two OEPA chemotherapy cycles.ResultsDeauville categories translate to thresholds on the qPET scale: Categories 3, 4, 5 correspond to qPET values of 0.95, 1.3 and 2.0, respectively. The distribution of qPET values is unimodal with a peak representing metabolically normal responses and a tail of clearly abnormal outliers. In our patients, the peak is at qPET = 0.95 coinciding with the border between Deauville 2 and 3. qPET cut values of 1.3 or 2 (determined by fitting mixture models) select abnormal metabolic responses with high sensitivity, respectively, specificity.ConclusionsqPET methodology provides semi-automatic quantification for interim FDG-PET response in lymphoma extending ordinal Deauville scoring to a continuous scale. Deauville categories correspond to certain qPET cut values. Thresholds between normal and abnormal response can be derived from the qPET-distribution without need for follow-up data. In our patients, qPET < 1.3 excludes abnormal response with high sensitivity.

Importance of F18-fluorodeoxy-D-2-glucose positron emission tomography (FDG-PET) for staging and therapy control of Hodgkin's lymphoma in childhood and adolescence - consequences for the GPOH-HD 2003 protocol.

The prognosis for children and adolescents with Hodgkin’s lymphoma is excellent. However, many patients will show secondary malignancies 15–30 years after the initial diagnosis, which appears to be connected with the intensity of treatment during primary disease. In the GPOH-HD 95 trial, the indication for radiotherapy was limited to patients who did not show a complete remission after chemotherapy, as determined radiographically. In the future protocol, the indication for radiotherapy in patients with early-stage Hodgkin’s lymphoma should be further refined by using FDG-PET for evaluating the response to chemotherapy. Furthermore, in patients at an advanced stage of the disease, it should be determined if sequential FDG-PET research during chemotherapy can separate patients into subgroups with an excellent or a poor prognosis. This article gives a review of the current literature on FDG-PET in patients with Hodgkin’s lymphoma and outlines the consequences for future protocols.

Efficacy and outcome of intensive care in pediatric oncologic patients.

Objective Because the long-term survival of children with cancer has dramatically improved because of multimodal treatment strategies, intensive care medicine has become more relevant for these patients. This study was performed to assess the efficacy of intensive care medicine in newly diagnosed pediatric oncologic patients and in patients under ongoing oncologic treatment. Design A retrospective analysis of children admitted to the pediatric intensive care unit (PICU) of the University Hospital Duesseldorf for life-threatening conditions between 1995 and 1999 was performed to identify those patients with an oncologic condition. Setting University hospital. Patients A total of 123 patients were identified. Children admitted for uncomplicated postoperative care and children admitted after bone marrow transplantation were excluded from this analysis. Forty-eight patients could be divided into two groups. Group A contained children admitted to the PICU at the time of cancer diagnosis and group B children receiving ongoing oncologic treatment. Interventions The evaluation included diagnosis, risk factors, complications leading to PICU admission, PICU therapy, and outcome. Statistical analysis included evaluation of Pediatric Risk of Mortality (PRISM) and Therapeutic Intervention Scoring System (TISS) scores. Measurements and Main Results Respiratory insufficiency was the leading diagnosis for PICU admission, whereas in the remaining children cardiovascular insufficiency, renal failure, neurologic impairment, ileus, and tumor-associated complications led to PICU admission. The number of organ failures was correlated to outcome. All children but one of group A could be discharged from the PICU, whereas 12 of 35 children in group B died, despite intensive care treatment attempts. The PRISM and TISS scores at admission to the PICU were significantly higher in children who did not survive the period of intensive care treatment in group B. However, all patients with a PRISM score of >20 died. Conclusions Diagnosis of cancer does not exclude potential benefit from intensive care medicine in these children, although severe complications might affect the prognosis.

Anticipatory Symptoms and Anticipatory Immune Responses in Pediatric Cancer Patients Receiving Chemotherapy: Features of a Classically Conditioned Response?

UNLABELLED There is considerable evidence from studies in adult patients that classical conditioning contributes to anticipatory nausea and/or vomiting (ANV) in cancer chemotherapy: The stimuli predicting the infusion serve as conditioned stimuli (CS). When reexposed to the CS, some patients experience ANV prior to infusion onset. In adult patients, anticipatory immunomodulation (AIM) has also been observed. The present study examines whether ANV and AIM occur in pediatric cancer patients and whether they show features of a conditioned response. METHODS Nineteen pediatric cancer patients (M = 10.1 years, > 2 previous chemotherapies) were studied over two consecutive cycles (A, B). In both cycles, self-reported symptoms, for example nausea and vomiting, were recorded from two days prior to the onset (Day -2), during infusion, and two days after the end of the infusion (Day +2). In Cycle B, blood was drawn at home at Day -2, and at Day 0 in the hospital prior to infusion onset, thus using a quasi-experimental variation of the CS content of the environment. Immune parameters valid for tumor defense and cytotoxic competence (natural killer cell activity [NKCA], plasma interleukin [IL]-1beta, IL-2, IL-10, interferon [IFN]-gamma, tumor necrosis factor [TNF]-alpha) and cortisol were measured. RESULTS ANV was reported by 7 patients in at least one cycle. In Cycle A, ANV was positively associated with emetogenity of chemotherapy. Features of ANV-duration and occurrence-tended to be positively associated with those of posttreatment nausea and vomiting. AN increased as infusion onset time approached. NKCA and IFN-gamma increased from home to hospital, independent from cortisol level. The NKCA increase was predominantly observed in patients with ANV. CONCLUSIONS ANV in pediatric patients showed features of a CR. Immune parameters were sensitive to the CS content of the environment, predominantly in patients with ANV. This is consistent with the manifestation of multiple CRs.

Infectious complications in children with acute lymphoblastic leukemia and T-cell lymphoma – a rationale for tailored supportive care

Infections still remain a major cause of therapy-associated morbidity and death in patients with malignant diseases. To further lower the risk of serious and long-lasting infections by additional supportive measures, detailed information on the frequency and characteristic features of infections is needed. Therefore, patient data from 112 children with acute lymphoblastic leukemia and T-cell lymphoma who were treated according to the COALL-05-92 protocol in our department were analyzed for differences in the frequency and origin of febrile episodes in relation to age, immunological type of leukemia, treatment in group assessed as being at high or low risk of relapse, actual occurrence of relapse, and course of chemotherapy. At the time of diagnosis, low-risk patients more commonly presented with febrile episodes than high-risk patients. In total, patients developed a fever in 313 (24%) of 1,307 evaluated chemotherapy cycles. Febrile episodes were associated with microbiologically or clinically documented infections in 60% of all cases, while in 40% the fever was of unknown origin. Gram-positive pathogens had a markedly higher incidence than gram-negative or fungal ones. The incidence of febrile episodes during therapy appeared to be correlated with certain chemotherapeutic drug combinations. The highest rate was found after high-dose cytarabine and asparaginase causing a long period of leukopenia. However, after other chemotherapy courses with a similar duration of leukopenia the incidence of febrile episodes was significantly lower, suggesting that specific interactions of different chemotherapeutic agents with the immune response might be an important factor in development of infections. Individual factors might also account for an increased incidence of infections, since the number of high-risk patients with recurrent infections was significantly higher than expected on the basis of statistical evaluation. In conclusion, our findings suggest that the risk of infections during chemotherapy may not only be influenced by leukopenia, but that drug-specific effects of the various chemotherapeutic agents and individual factors may also be important contributory factors. These observations must be further expanded in prospective studies so that new tailored supportive care protocols can be elaborated.

Temporary diabetes mellitus secondary to a primary pancreatic Burkitt lymphoma

Primary pancreatic lymphoma (PPL) is a rare form of extranodal lymphoma. So far, only in adults has a coincidence with diabetes mellitus (DM) been described. We report a nearly 9‐year‐old German boy presenting with a Burkitt lymphoma associated with a temporary insulin‐dependent DM and exocrine insufficiency of the pancreas. After the patient went into remission, a spontaneous recovery of the endocrine pancreatic function was observed. On immunophenotyping, the lymphoma cells revealed expression of FasL suggesting a potentially apoptotic effect on pancreatic tissue. Beta cell impairment may have been caused by FasL resembling autoimmune diabetes. Pediatr Blood Cancer

The role of IL-4 and IL-12 in the regulation of collagen synthesis by fibroblasts

Chronic sclerodermifomic graft versus host disease is a rare but important complication of allogeneic hematopoietic stem cell transplantation that especially occurs in patients who are treated with donor lymphocyte infusions for relapse of a malignant disease. Today most knowledge about the pathogenesis of chronic Graft-versus-Host Disease is based on mice models. In this report we describe the development of an allogeneic in vitro model that allows studying the pathogenesis of chronic sclerodermifomic Graft-versus-Host Disease in the human setting. We report that priming of mononuclear cells in the presence of allogeneic fibroblasts and Interleukin (IL)-4 induces fibroblast collagen synthesis, whereas priming in the presence of IL-12 suppresses collagen synthesis during subsequent coculture of primed mononuclear cells with allogeneic fibroblasts. Since IL-12 is also known to mediate anti-tumor effects by stimulation of Natural Killer cell and Lymphokine Activated Killer cell activity, these findings indicate that treatment of patients with IL-12 or pretreatment of donor lymphocytes with IL-12 might strengthen a graft versus leukemia effect and at the same time decrease the risk of chronic sclerodermifomic Graft-versus-Host Disease development.

Heat- and 4-hydroperoxy-ifosfamide-induced apoptosis in B cell precursor leukaemias

In the group of high risk childhood acute lymphoblastic leukaemia (ALL), very early and early relapses have a very poor prognosis with conventional chemotherapy alone. Remission induction in these patients is often hindered by drug resistance. Thus, intensifying chemotherapy strategies are required. Application of hyperthermia enhances efficacy of certain anti-neoplastic drugs such as ifosfamide. In this study, effects and molecular mechanisms of ifosfamide - and hyperthermia-induced apoptosis are investigated in a B cell precursor leukaemia cell line (REH) and in primary patient-derived B cell progenitor leukaemic blasts. Both 4OOH-IFA and hyperthermia are able to induce cell death in leukaemic cells, mainly by induction of caspase-dependent apoptosis. However, completely different kinetics of caspase-3, -8 and -9 activation are found for both stimuli. In addition, activation of caspase-1 is only observed following stimulation with hyperthermia. Combined application of ifosfamide and hyperthermia reveals increased cytotoxicity in both the leukaemia cell line and in 5/8 of the patient-derived leukaemic blast samples. In conclusion, hyperthermia and ifosfamide mediate cytotoxicity in B precursor leukaemic blasts by different kinetics of caspase activation. This might explain the additive effects of 4OOH-IFA and heat on leukaemic cell death. Therefore, whole body thermochemotherapy could be considered as a treatment option in relapsed leukaemic patients.

Effect of drug-induced cytotoxicity on glucose uptake in Hodgkin's lymphoma cells

Abstract:  Background: In Hodgkins lymphoma, F‐18‐fluoro‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) is used for staging and response evaluation after chemotherapy. However, drug‐mediated downregulation of glucose uptake in viable Hodgkins lymphoma cells might limit the use of FDG‐PET. Methods: We analyzed the effect of etoposide on cell viability and uptake of F‐18‐fluoro‐deoxy‐d‐glucose or the glucose analog 2‐[N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)amino]‐2‐deoxyglucose (2‐NBDG) in vitro. Results: Etoposide induced a dose‐dependent cytotoxicity in HDLM‐2 cells which was significantly correlated with reduced FDG uptake. However, it also significantly increased the portion of viable cells which did not take up 2‐NBDG. Interestingly, etoposide‐induced cytotoxicity was mainly mediated via caspase‐dependent mechanisms, whereas the cell death induced by deprivation of glucose was mediated via caspase‐independent mechanisms. Conclusion: Etoposide‐mediated reduction of glucose uptake by Hodgkins lymphoma cells is mainly caused by cell death. In a small fraction of viable cells, etoposide might downregulate glucose transporters and/or hexokinase activity and by that inhibit glucose uptake. This, however, might not lead to false‐negative results of response evaluation in Hodgkins lymphoma patients after chemotherapy, because inhibition of glucose uptake itself seems to be a strong inducer of cell death. Altogether, this study provides important in vitro evidence to clarify the mechanisms by which FDG‐PET monitors the effect of anti‐cancer treatment in Hodgkins lymphoma patients.