Treatment strategies and outcome in relapsed peripheral T-cell lymphoma: results from the Netherlands Cancer Registry.

Optimal treatment in patients with refractory or relapsed peripheral T-cell lymphomas (R/R T-NHL) is unknown. In this population-based study, outcome in R/R PTCL not otherwise specified (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL) and ALK+ and ALK- anaplastic large cell lymphoma (ALCL) was evaluated. Patients with PTCL NOS, AITL, ALK+ ALCL and ALK- ALCL (≥18 years) diagnosed in 2014-2019 were identified using the Netherlands Cancer Registry. Endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). The 2-year PFS of 821 patients was 57%. Among 311 patients with a relapse, 243 received second-line treatment: 44% salvage chemotherapy, 20% brentuximab vedotin (BV) and 36% other treatment. In third-line, BV was most commonly used (38%). ORR following second-line treatment was 47%. Two-year PFS and OS after relapse were 25% and 34%, respectively. Risk of second relapse was negatively affected by early relapse (<12 months post-diagnosis), while BV reduced this risk compared to salvage chemotherapy (HR 0.55; 0.35-0.87; p=0.01). Reduced risk of relapse was independent of histological subtype. The best outcomes were observed for patients treated with salvage chemotherapy receiving consolidative autologous and allogeneic stem cell transplantation (SCT) (2-year OS 68%), patients treated with BV achieving a second complete remission (2-year OS 74%) and patients with allogeneic SCT (2-year OS 60%). The risk of second relapse was significantly lower for R/R T-NHL patients treated with BV compared to patients treated with salvage chemotherapy, and this was irrespective of subtype. Therefore, the use of salvage chemotherapy for R/R T-NHL patients is challenged.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Dutch Oncology COVID-19 consortium: Outcome of COVID-19 in patients with cancer in a nationwide cohort study.

AIM OF THE STUDY: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. METHODS: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. RESULTS: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). CONCLUSION: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered.

Developing a Risk Prediction Model for Long-Term Physical and Psychological Functioning after Hematopoietic Cell Transplantation.

Hematopoietic cell transplantation (HCT) is associated with impaired physical and psychological functioning for some long-term survivors. A risk prediction model would help clinicians estimate their patients' physical and psychological functioning after HCT and determine when to refer to added supportive care when appropriate. The purpose of the present study was to develop risk prediction models for physical and psychological functioning in HCT survivors. This was a secondary analysis of data from a randomized controlled trial (NCT00799461) that included 3- to 10-year HCT survivors. Risk predictions for physical and psychological functioning were developed by using backward logistic regression. The models were internally validated using bootstrapping techniques. Regression coefficients were converted into easy-to-use risk scores. Finally, the sensitivity, specificity, and positive and negative predictive values of the total risk score were calculated. The analyses included 489 survivors, with a mean age of 45.6 (SD, 12.4) years; 47% were female and with a mean of 6.1 years (SD, 2.0) after transplantation. Younger age, higher body mass index (BMI), no or part-time work, more comorbid diseases, autologous transplantation, and chronic graft-versus-host disease predicted impaired physical functioning. Female gender, younger age, higher BMI, not living with a partner, autologous transplantation, and chronic graft-versus-host disease predicted impaired psychological functioning. Although both models had predictive value for long-term functioning, diagnostic accuracy was moderate. For the physical functioning receiver operating characteristic, area under the curve (AUC) after internal validation was .74 with sensitivity 51.9 and specificity 82.8 at the optimal cut-off. For psychological functioning, AUC after internal validation was .69 with sensitivity 83.3 and specificity 42.9 at the optimal cut-off. We conclude that it is possible to predict long-term physical and psychological functioning with readily accessible, mostly pretransplantation predictors. The accuracy of the risk prediction models can be improved for use in clinical practice, potentially by adding pretransplantation patient-reported functioning and comorbidities.

Surgery in (pre)malignant celiac disease.

AIM: To report the outcome of surgery in patients with (pre)malignant conditions of celiac disease (CD) and the impact on survival. METHODS: A total of 40 patients with (pre)malignant conditions of CD, ulcerative jejunitis (n = 5) and enteropathy associated T-cell lymphoma (EATL) (n = 35), who underwent surgery between 2002 and 2013 were retrospectively evaluated. Data on indications, operative procedure, post-operative morbidity and mortality, adjuvant therapy and overall survival (OS) were collected. Eleven patients with EATL who underwent chemotherapy without resection were included as a control group for survival analysis. Patients were followed-up every three months during the first year and at 6-mo intervals thereafter. RESULTS: Mean age at resection was 62 years. The majority of patients (63%) underwent elective laparotomy. Functional stenosis (n = 13) and perforation (n = 12) were the major indications for surgery. In 70% of patients radical resection was performed. Early postoperative complications, mainly due to leakage or sepsis, occurred in 14/40 (35%) of patients. Eight patients required reoperation. More patients who underwent resection in the acute setting (n = 3, 20%) died compared to patients treated in the elective setting. With a median follow-up of 20 mo, seven patients (18%) required reoperation due to long-term complications. Significantly more patients who underwent acute surgery could not be treated with adjuvant chemotherapy. Patients who first underwent surgical resection showed significantly better OS than patients who received chemotherapy without resection. CONCLUSION: Although the complication rate is high, the preferred first step of treatment in (pre)malignant CD consists of local resection as early as possible to improve survival.

A New and Validated Clinical Prognostic Model (EPI) for Enteropathy-Associated T-cell Lymphoma.

PURPOSE: Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal non-Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high-risk patients who need more aggressive therapy. EXPERIMENTAL DESIGN: This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method. RESULTS: Three risk groups were distinguished (P < 0.0001): a high-risk group, characterized by the presence of B-symptoms [median overall survival (OS) of 2 months]; an intermediate-risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low-risk group, representing patients without B-symptoms and an IPI score of 0 to 1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast with the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome. CONCLUSIONS: Our new, validated, prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials.

Clinical validation of dried blood spot sampling in therapeutic drug monitoring of ciclosporin A in allogeneic stem cell transplant recipients: direct comparison between capillary and venous sampling.

BACKGROUND: The immunosuppressive drug ciclosporin A has a narrow therapeutic window and a large inter- and intraindividual pharmacokinetic variability. Therapeutic drug monitoring of ciclosporin is usually performed in ethylenediaminetetraacetic acid blood, obtained by venous sampling. Dried blood spot sampling (DBS) could be a useful alternative sampling method, which also easily allows multiple sampling, for example, for obtaining area under the curve. With DBS, capillary blood is obtained from a finger prick with an automatic lancet by the patients themselves, and the drop of blood is applied to sampling paper. This may limit the number and duration of hospital visits for these patients. METHODS: We describe a validation study in which venous and finger prick blood samples were collected at the same time. Venous sampling was performed by venipuncture, and the ethylenediaminetetraacetic acid blood samples were collected and stored at 4°C until analysis. Finger prick blood samples were collected using an automatic lancing device. The volume of the blood drops of patients was approximately 30 µL, and blood spots of about 10-mm diameter were produced. Paper disks with a diameter of 8 mm were punched out with an electromagnetic-driven hole puncher. DBS was compared with the routine assay in venous blood. The study population consisted of adult patients (18 years or older) who were treated with ciclosporin A and routinely monitored for adequate blood concentrations. RESULTS: Thirty-eight duplicate dried blood spots and venous samples were studied. Using weighted Deming regression, the slope was 1.01 with a standard error of 0.03 associated with an intercept of -9.0 (standard error = 5.9). These results indicate that there is no significant difference between the 2 sampling methods. For the medical decision level of 300 mcg/L, the bias was -4.7 mcg/L with a 95% confidence interval of -19.2 to 9.8 mcg/L. The Altman-Bland plot showed no difference between the 2 sampling methods. CONCLUSIONS: Our results demonstrate that DBS is a valid alternative for conventional venous sampling in allogeneic stem cell transplant recipients.

Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr-ibritumomab tiuxetan and PET.

PURPOSE: Positron emission tomography (PET) with (89)Zr-ibritumomab tiuxetan can be used to monitor biodistribution of (90)Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of (90)Y-ibritumomab tiuxetan in humans on the basis of (89)Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of (90)Y-ibritumomab tiuxetan influences biodistribution of (89)Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with (89)Zr-ibritumomab tiuxetan can be used to predict biodistribution of (90)Y-ibritumomab tiuxetan and the dose-limiting organ during therapy. METHODS: Seven patients with relapsed B-cell non-Hodgkin's lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq (89)Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg (90)Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data. RESULTS: The highest (90)Y absorbed dose was observed in liver (3.2 ± 1.8 mGy/MBq) and spleen (2.9 ± 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 ± 0.04 mGy/MBq, and the effective dose was 0.87 ± 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on (89)Zr-ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75). CONCLUSION: Biodistribution of (89)Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with (90)Y-ibritumomab tiuxetan, and (89)Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using (111)In-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.

Enteropathy associated T-cell lymphoma and its precursor lesions.

Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra-epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8-20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future.

Novel approaches in the management of refractory celiac disease.

Celiac disease is a gluten-sensitive enteropathy, which commits the patient to a life-long gluten-free diet. This is sufficient to treat the overwhelming majority of patients. However, a small group of these patients, mainly those diagnosed above 50 years of age, fails to improve histologically and clinically upon elimination of gluten from the diet. These patients are regarded as suffering from refractory celiac disease. In a subgroup of these patients a pre-malignant intraepithelial lymphocyte population can be detected in the small intestinal mucosa (type II). These patients are at a high risk of developing an enteropathy-associated T-cell lymphoma (50-60% within 4-6 years), which has a very poor prognosis and a 5-year survival of only 8%. The therapeutic challenge in these refractory celiac disease type II patients is targeting the aberrant intraepithelial lymphocytes to eventually prevent enteropathy-associated T-cell lymphoma development. Although management of these patients is difficult and therapeutic options are currently limited, novel treatment modalities are being explored.

Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells.

Autologous hematopoietic stem cell transplantation (ASCT) is an increasingly accepted treatment for refractory autoimmune diseases. Refractory celiac disease with aberrant T cells (RCD type II) is unresponsive to available therapies and carries a high risk of transition into enteropathy associated T-cell lymphoma (EATL). This study reports on the feasibility, safety, and efficacy of ASCT in patients with RCD type II. Thirteen patients with RCD type II were evaluated. Seven patients (4 men, 3 women, mean age 61.5 years [range, 51-69 years]) underwent transplantation. After conditioning with fludarabine and melphalan, ASCT was performed. Patients were monitored for response, adverse effects, and hematopoietic reconstitution. All 7 patients completed the mobilization and leukapheresis procedures successfully and subsequently underwent conditioning and transplantation. Engraftment occurred in all patients. No major nonhematologic toxicity or transplantation-related mortality was observed. There was a significant reduction in the aberrant T cells in duodenal biopsies associated with improvement in clinical well-being and normalization of hematologic and biochemical markers (mean follow-up, 15.5 months; range, 7-30 months). One patient died 8 months after transplantation from progressive neuroceliac disease. These preliminary results showed that high-dose chemotherapy followed by ASCT seems feasible and safe and might result in long-term improvement of patients with RCD type II whose condition did not respond promptly to available drugs.

Preparation and evaluation of (89)Zr-Zevalin for monitoring of (90)Y-Zevalin biodistribution with positron emission tomography.

PURPOSE: To evaluate whether (89)Zr can be used as a PET surrogate label for quantification of (90)Y-ibritumomab tiuxetan ((90)Y-Zevalin) biodistribution and dosimetry before myeloablative radioimmunotherapy. METHODS: Zevalin was labelled with (89)Zr by introducing N-succinyldesferal (N-sucDf) as a second chelate. For comparison of the in vitro stability of (89)Zr-Zevalin and (88)Y-Zevalin (as a substitute for (90)Y), samples were incubated in human serum at 37 degrees C up to 6 days. Biodistribution of (89)Zr-Zevalin and (88)Y-Zevalin was assessed at 24, 48, 72 and 144 h p.i. by co-injection in nude mice bearing the non-Hodgkin's lymphoma (NHL) xenograft line Ramos. The clinical performance of (89)Zr-Zevalin-PET was evaluated via a pilot imaging study in a patient with NHL, who had undergone [(18)F]FDG-PET 2 weeks previously. RESULTS: Modification of Zevalin with N-sucDf resulted in an N-sucDf-to-antibody molar ratio of 0.83+/-0.04. After radiolabelling and purification, the radiochemical purity and immunoreactivity of (89)Zr-Zevalin always exceeded 95% and 80%, respectively. (89)Zr-Zevalin showed the same stability in serum as (88)Y-Zevalin, with a radiochemical purity >95% during a period of 6 days. The co-injected (89)Zr-Zevalin and (88)Y-Zevalin conjugates showed a very similar biodistribution, except for liver and bone accumulation at 72 and 144 h p.i., which was significantly higher for (89)Zr than for (88)Y. PET images obtained after injection of (89)Zr-Zevalin showed clear targeting of all known tumour lesions. CONCLUSION: (89)Zr-Zevalin and (88)Y-Zevalin showed a very similar biodistribution in mice, implying that (89)Zr-Zevalin-PET might be well suited for prediction of (90)Y-Zevalin biodistribution in a myeloablative setting.

Radioimmunotherapy for indolent B-cell non-Hodgkin lymphoma in relapsed, refractory and transformed disease.

Radioimmunotherapy (RIT) is a new treatment modality that combines the benefits of radiotherapy and immunotherapy. In RIT, a radionuclide is coupled to a monoclonal antibody, directed against an antigen expressed on tumor cells. Recently, RIT has been introduced targeting the CD20 surface antigen, which is expressed on nearly all B-cell non-Hodgkin lymphomas (NHL). Clinical experience with RIT in the treatment of patients with indolent NHL is increasing. To date, two commercially available agents are used: yttrium-90 ((90)Y)-ibritumomab tiuxetan and iodine-131 ((131)I)-tositumomab. In general, there is no organ-specific non-hematologic toxicity when a standard dose of RIT is used. Bone marrow suppression is the dose-limiting RIT toxicity; therefore, bone marrow infiltration by NHL should be investigated before treatment. Treatment-related myelodysplastic syndromes and acute myeloid leukemia after RIT are being investigated but long-term data are needed for final evaluation. Results are quite encouraging with respect to complete remission and overall response, even in pretreated patients with unconjugated monoclonal antibodies. RIT induces high response rates and a significant subgroup of patients has achieved long-term durable responses. RIT is feasible in heavily pretreated patients and does not compromise future treatments in the event of progressive disease. Randomized phase III studies are in progress to evaluate the timing of RIT in the overall management of indolent NHLInvestigations of new emerging therapeutic strategies for patients with indolent NHL are underway, with research into the feasibility of RIT as first-line therapy and in advanced disease, RIT dose escalation and combined modality approaches with autologous stem cell transplantation. The encouraging results of RIT in indolent NHL have initiated studies focusing on its benefit for patients with aggressive NHL.