• Machine learning and radiomics applications in esophageal cancers using non-invasive imaging methods—a critical review of literature.

      Xie, C-Y; Pang, Chun-Lap; Chan, B; Yuen-yuen Wong, E; Du, Q; Vardanabhuti, V; Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. (2021)
      Esophageal cancer (EC) is of public health significance as one of the leading causes of cancer death worldwide. Accurate staging, treatment planning and prognostication in EC patients are of vital importance. Recent advances in machine learning (ML) techniques demonstrate their potential to provide novel quantitative imaging markers in medical imaging. Radiomics approaches that could quantify medical images into high-dimensional data have been shown to improve the imaging-based classification system in characterizing the heterogeneity of primary tumors and lymph nodes in EC patients. In this review, we aim to provide a comprehensive summary of the evidence of the most recent developments in ML application in imaging pertinent to EC patient care. According to the published results, ML models evaluating treatment response and lymph node metastasis achieve reliable predictions, ranging from acceptable to outstanding in their validation groups. Patients stratified by ML models in different risk groups have a significant or borderline significant difference in survival outcomes. Prospective large multi-center studies are suggested to improve the generalizability of ML techniques with standardized imaging protocols and harmonization between different centers.
    • Use of out-of-field contact shielding on patients in medical imaging: A review of current guidelines, recommendations and legislative documents

      Candela-Juan, C.; Ciraj-Bjelac, O.; Sans Merce, M.; Dabin, J.; Faj, D.; Gallagher, A.; de Las Heras Gala, H.; Knežević, Ž.; Malchair, F.; De Monte, F.; et al. (2021)
      The use of patient contact-shielding has become a topic of intensive scientific debate. While it has been common practice during the last decades, some studies have questioned the efficiency of using such shielding while others have highlighted the inconsistencies in its application. The objective of this work is to review current recommendations and legislative documents on the use of out-of-field shielding in X-ray imaging, including those from national authorities and from international and national organisations and professional bodies. The review, performed within the framework of the activities of EURADOS Working Group 12, covers available recommendations on use of contact shielding in adult, pregnant and paediatric patients in general radiography, fluoroscopy, computed tomography, mammography and dental radiology. It includes a comprehensive search of 83 documents from 32 countries and 6 international organisations over the last 39 years. In general, using shielding is recommended only under two conditions: if it does not compromise the diagnostic task and the performance of the procedure and/or if it reassures the patient and comforters that they are appropriately protected against potentially harmful effects of radiation. There are very few specific regulatory requirements to use shielding in a particular imaging modality, although they may consider use of shielding either as part of good radiological practice or as requirements for availability of protective or ancillary tools, without further specification of their use. There is a wide variety of positions among documents that recommend out-of-field shielding, those that do not recommend it and those that are not specific. Therefore, evidence-based consensus is still needed to ensure best and consistent practice.
    • Thoracic radiotherapy in small cell lung cancer-a narrative review

      Levy, A.; Botticella, A.; Le Péchoux, C; Faivre-Finn, Corinne; Department of Radiation Oncology, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, Villejuif, France. (2021)
      Small-cell lung cancer (SCLC) represents 10-15% of all lung cancers and has a poor prognosis. Thoracic radiotherapy plays a central role in current SCLC management. Concurrent chemoradiotherapy (CTRT) is the standard of care for localised disease (stage I-III, limited-stage, LS). Definitive thoracic radiotherapy may be offered in metastatic patients (stage IV, extensive stage, ES-SCLC) after chemotherapy. For LS-SCLC, the gold standard is early accelerated hyperfractionated twice-daily CTRT (4 cycles of cisplatin etoposide, starting with the first or second chemotherapy cycle). Modern radiation techniques should be used with involved-field radiotherapy based on baseline CT and PET/CT scans. In ES-SCLC, thoracic radiotherapy should be discussed in cases of initial bulky mediastinal disease/residual thoracic disease not progressing after induction chemotherapy. This strategy was however not assessed in recent trials establishing chemo-immunotherapy as the standard first line treatment in ES-SCLC. Future developments include technical radiotherapy advances and the incorporation of new drugs. Thoracic irradiation is delivered more precisely given technical developments (IMRT, image-guided radiotherapy, stereotactic radiotherapy), reducing the risks of severe adverse events. Stereotactic ablative radiotherapy may be discussed in rare early stage (T1 to 2, N0) inoperable patients. A number of current clinical trials are investigating immunoradiotherapy. In this review, we highlight the current role of thoracic radiotherapy and describe ongoing research in the integration of biological surrogate markers, advanced radiotherapy technologies and novel drugs in SCLC patients.
    • Reply to (20-1119.R1) Surgery for advanced intrahepatic cholangiocarcinoma warrants further investigation

      Lamarca, Angela; Santos-Laso, A.; Utpatel, K.; La Casta, A.; Stock, S.; Forner, A.; Adeva, J.; Folseraas, T.; Fabris, L.; Macias, R. I.; et al. (2021)
      We thank Jansson & Sparrelid for their Letter to the Editor(1)regarding our publication(2). We stated that "based on our results, patients with liver metastases should not be offered therapeutic strategies suitable for early stages, in view of poor survival". Jansson(1) argues that "the role of surgery in multiple intrahepatic cholangiocarcinoma (iCCA) should not be dismissed without further analysis"; similar to Zhang's views(3).
    • Challenges in the target volume definition of lung cancer radiotherapy

      Mercieca, S.; Belderbos, J. S. A; van Herk, Marcel; Faculty of Health Science, University of Malta, Msida, Malta. (2021)
      Radiotherapy, with or without systemic treatment has an important role in the management of lung cancer. In order to deliver the treatment accurately, the clinician must precisely outline the gross tumour volume (GTV), mostly on computed tomography (CT) images. However, due to the limited contrast between tumour and non-malignant changes in the lung tissue, it can be difficult to distinguish the tumour boundaries on CT images leading to large interobserver variation and differences in interpretation. Therefore the definition of the GTV has often been described as the weakest link in radiotherapy with its inaccuracy potentially leading to missing the tumour or unnecessarily irradiating normal tissue. In this article, we review the various techniques that can be used to reduce delineation uncertainties in lung cancer.
    • Correction to: Factors determining ultra-short-term survival and the commencement of active treatment in high-grade serous ovarian cancer: a case comparison study

      Hawarden, A.; Russell, B.; Gee, M. E.; Kayali, F.; Clamp, Andrew R; Crosbie, E. J; Edmondson, R. J.; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Research Floor, Oxford Road, Manchester, M13 9WL, UK (2021)
      None
    • Clinical benefit of surveillance after resection of pancreatic ductal adenocarcinoma: A systematic review and meta-analysis

      Halle-Smith, J. M.; Hall, L.; Daamen, L. A.; Hodson, J.; Pande, R.; Young, A.; Jamieson, N. B.; Lamarca, Angela; van Santvoort, H. C.; Molenaar, I. Q.; et al. (2021)
      Background: The value of routine surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear, and expert guidelines offer conflicting recommendations. This study is a systematic review of evidence for surveillance programs. Methods: A systematic review of studies evaluating different surveillance methods was undertaken. A meta-analysis was performed for those studies reporting rates of asymptomatic recurrence, treatment of recurrence and overall survival, according to different surveillance methods. Results: Ten studies were included in the literature review, with five studies appropriate for meta-analysis (1596 patients). Patients within active surveillance programs were more likely to have recurrence detected at an asymptomatic stage (Pooled Rate: 49.3% vs. 19.1%, p = 0.043). Within studies reporting these outcomes, patients with asymptomatic recurrence were more likely to receive treatment for recurrence (Odds Ratio 3.49; 95% CI: 1.73-7.07; p < 0.001) and had longer overall survival (Mean Difference: 9.5 months; 95% CI: 4.1-14.8; p < 0.001) than those with symptoms at time of recurrence. Discussion: Routine surveillance after surgery for PDAC appears to detect more patients at an asymptomatic stage. Data from these non-randomised trials also suggest that treatment rates and survival may be superior in patients were recurrence is detected when asymptomatic. As such, these data suggest that routine surveillance may improve patient outcomes, although an appropriately conducted trial would be required to address concerns that various sources of bias may be affecting these results.
    • Treatment options and outcomes for men with penile intraepithelial neoplasia: a systematic review

      Issa, Allaudin; Sebro, K.; Kwok, A.; Janisch, F.; Grossmann, N. C.; Lee, Esther; Lucky, M.; Oliveira, Pedro; Lau, Maurice W; Parnham, Arie S; et al. (2021)
      Penile intraepithelial neoplasia (PeIN) is a rare skin condition with potential to progress to invasive penile cancer. We performed a systematic review of treatment options and outcomes for PeIN. Topical agents showed response and recurrence rates of 40-100% and 20% for imiquimod, and 48-74% and 11% for 5-fluorouracil, respectively. Discontinuation of topical agents because of side effects was observed in 12% of cases. Response rates for laser therapies were 52-100%, with recurrence in 7-48% of cases and a change in penile sensitivity in 50%. Circumcision cleared preputial PeIN. Rates of recurrence after surgical treatment of glans PeIN were 25% for wide local excision, 4% for Mohs surgery, 5% for total glans resurfacing, and 10% for glansectomy. There are limited data on factors predictive of treatment response and on sequencing of treatment options. PATIENT SUMMARY: Several treatment options are available for men with precancerous lesions of the foreskin or glans. Close follow-up is necessary as lesions can recur or progress to invasive penile cancer.
    • Reframing recalcitrance for small-cell lung cancer

      Blackhall, Fiona H; Christie Hospital NHS Trust-Medical Oncology, Manchester, UK. (2021)
      None
    • Combined hepatocellular-cholangiocarcinoma - More questions than answers

      Hubner, Richard A; Reeves, H. L; Edeline, J.; Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Manchester, UK (2021)
      None
    • Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial

      Straus, D. J.; Długosz-Danecka, M.; Connors, J. M.; Alekseev, S.; Illés, Á.; Picardi, M.; Lech-Maranda, E.; Feldman, T.; Smolewski, P.; Savage, K. J.; et al. (2021)
      Background: Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population. Methods: ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing. Findings: Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50). Interpretation: With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.
    • Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study

      Hamadani, M.; Collins, G. P.; Caimi, P. F.; Samaniego, F.; Spira, A.; Davies, A.; Radford, John A; Menne, T.; Karnad, A.; Zain, J. M.; et al. (2021)
      Background: Novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population. Methods: This was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 μg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235. Findings: Between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 μg/kg and 45 μg/kg for patients with classical Hodgkin lymphoma and 80 μg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81). Interpretation: These results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma
    • A tailored radiation therapy strategy for older patients with localized bladder cancer not eligible for curative treatment

      Sargos, P.; Baumann, B. C.; Faye, M. D.; Fonteyne, V; Eccles, Cynthia L; Department of Radiation Oncology, Institut Bergonié, Bordeaux, France. (2021)
      None
    • The dawn of another new era

      Choudhury, Ananya; Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. (2021)
      None
    • Treatment outcomes of advanced digestive well-differentiated grade 3 NETs

      de Mestier, L.; Lamarca, Angela; Hernando, J.; Zandee, W.; Alonso-Gordoa, T.; Perrier, M.; Walenkamp, A. M. E.; Chakrabarty, Bipasha; Landolfi, S.; Van Velthuysen, M. F.; et al. (2021)
      There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1=74; L2=52) included alkylating-based (n=32), etoposide-platinum (n=22) or adenocarcinoma-like chemotherapy (n=20), somatostatin analogs (n=21), targeted therapies (n=22) and liver-directed therapies (n=7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI [1.5-12.2]; p=0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (p<0.001 and p=0.008, respectively). The longest median PFS were obtained with adenocarcinoma-like chemotherapy (16.5 months [9.0-24.0]) and targeted therapies (12.0 months [8.2-15.8]), while the shortest PFS were observed with somatostatin analogues (6.2 months [3.8-8.5]) and etoposide-platinum chemotherapy (7.2 months [5.2-9.1]). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 [1.61-8.44], p=0.002) and alkylating-based chemotherapies (multivariable HR 1.95 [1.01-3.78], p=0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.
    • Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

      Middleton, M. R.; Dean, Emma J; Evans, T. R. J.; Shapiro, G. I.; Pollard, J.; Hendriks, B. S.; Falk, M.; Diaz-Padilla, I; Plummer, R.; Department of Oncology, University of Oxford, Oxford, UK. (2021)
      Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.
    • Immunotherapy in older adults with cancer

      Presley, C. J.; Gomes, Fabio; Burd, C. E.; Kanesvaran, R; Wong, M. L.; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH. (2021)
      None
    • A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer

      Fung, A. S.; Graham, Donna; Chen, E. X.; Stockley, T. L.; Zhang, T.; Le, L. W.; Albaba, H.; Pisters, K. M.; Bradbury, P. A.; Trinkaus, M.; et al. (2021)
      Introduction: MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690). Methods: A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype. Results: Thirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months-NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1-mutated patients, the ORR was 42.8%. Conclusion: The addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.
    • High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency

      Ellingford, J. M.; Telford, Nicholas; Urquhart, J.; Will, A. M.; Bonney, D.; Adams, B.; Dixon, R.; Kerr, B.; Black, G. C.; Wynn, R. F; et al. (2021)
      Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
    • Systemic ALCL Treated in Routine Clinical Practice: Outcomes Following First-Line Chemotherapy from a Multicentre Cohort

      Martinez-Calle, N.; Kirkwood, A. A.; Lamb, M.; Smith, A.; Khwaja, J.; Manos, K.; Shrubsole, C.; Gray, N.; Lewis, K.; Tivey, Ann; et al. (2021)
      Introduction: Brentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice. Methods: Patients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken. Results: The median age 52 years (range 16-93), 18% ECOG ≥3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1-49.1) and 58.9% (95% CI 50.3-66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21-0.63) but not OS (0.44, 95% CI 0.18-1.07). Discussion: We present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes. Conclusion: These data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2.