Pamela McKay

Guidelines for the investigation and management of mantle cell lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients representatives. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2011 using the MeSH subheading lymphoma, mantle cell and lymphoma, mantle cell as a keyword, as well as all subheadings. In addition, all references to mantle cell lymphoma in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue (Swerdlow et al, 2008) and the British Committee for Standards in Haematology (BCSH) Guideline: Best Practice in Lymphoma Diagnosis and Reporting (Parker et al, 2010) have been included. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The GRADE system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of patients with mantle cell lymphoma. The guidance may not be appropriate to patients with other lymphoma sub-types and in all cases individual patient circumstances may dictate an alternative approach.

Nodular lymphocyte predominant Hodgkin lymphoma behaves as a distinct clinical entity with good outcome: evidence from 14-year follow-up in the West of Scotland Cancer Network

Clinically and biologically, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has much more in common with germinal-center derived B-cell non-Hodgkin lymphoma (NHL) than with classical Hodgkin lymphoma (cHL). Management of NLPHL remains controversial. In a 14-year multicenter series, 69 cases were analyzed, and the median follow-up was 53 months (range 11–165.) B-symptoms were present in only 4.3% of patients, and 81.1% of patients had stage I/II disease. Treatment was with radiotherapy (53.6%), chemotherapy (21.7%), combined modality (17.4%), and observation (7.2%). In all, 10.1% of patients relapsed and 2.9% of patients developed high-grade transformation to DLBCL. All relapses and transformations were salvageable. No patient died of their disease. The 5-year relapse-free survival was 92%, transformation-free survival 98.4%, and overall survival 100%. We conclude that NLPHL behaves as a distinct clinical entity, often presenting at an early stage without risk factors. It has an excellent outcome. It may be possible, in early-stage disease, to reduce the intensity of therapy in NLPHL, to single-modality radiotherapy, without affecting OS.

Loss of utility of bone marrow biopsy as a staging evaluation for Hodgkin lymphoma in the positron emission tomography–computed tomography era: a West of Scotland study

Abstract Positron emission tomography–computed tomography (PET-CT) scanning has been shown to be more sensitive than bone marrow biopsy (BMB) in detecting bone marrow involvement (BMI) in classical Hodgkin lymphoma (cHL). In this 5-year retrospective series, 93 (54%) of all new cases of cHL were staged using PET-CT and BMB. PET-CT identified focal bone marrow uptake in 17/93 (18.3%), whilst only five of these (29.4%) were confirmed by BMB. Abnormal pelvic uptake was seen on PET-CT in these five cases. The other 12 cases were missed, giving BMB a sensitivity of 29.4% and a specificity of 100%. PET-CT upstaged 9.7% of patients compared to CT alone. BMB upstaged only one patient; however, this patient was already stage IV on PET-CT. BMB did not alter clinical management in any case. Bone positivity on PET-CT appeared to correlate with anemia, raised lactate dehydrogenase (LDH) and B symptoms. BMB has little or nothing to offer staging cHL in the PET-CT era.

Guidelines for the investigation and management of nodular lymphocyte predominant Hodgkin lymphoma.

Department of Haematology, Beatson West of Scotland Cancer Centre, Gartnavel Hospital, Glasgow, PETIC, Department of Radiology, University Hospital of Wales, Department of Clinical Oncology, Velindre Cancer Centre, Cardiff, UK, Paediatric Haematology/Oncology Unit, Children’s Hospital, John Radcliffe Hospital, Headington, Oxford, Department of Haematology, University College London Hospitals, Department of Pathology, University College London Hospitals, and Department of Haematology, The Royal Free London NHS Trust, London, UK

Possible significance of cup-like blasts in acute myeloid leukaemia

A 73-year-old woman presented with a short history of spontaneous bruising, petechiae and rectal bleeding. Full blood count showed haemoglobin of 92 g/l, white cell count of 148 · 10/l and platelet count of 27 · 10/l. Coagulation studies showed prothrombin time 16 s, activated partial thromboplastin time 25 s, thrombin time 13AE1 s, fibrinogen 2AE81 g/l and D-dimer 61 608 ng/ml fibrinogen equivalent units. The blood film showed numerous granular myeloblasts with large nuclear indentations and invaginations – cup-like blasts (figures). Bone marrow examination showed similar blasts accounting for >90% of nucleated cells, with minimal maturation. Immunophenotyping confirmed acute myeloid leukaemia (CD117, CD13, CD33 and myeloperoxidase positive) but surprisingly the blasts were negative for CD34 and HLA-DR, a finding that is more characteristic of acute promyelocytic leukaemia [M3 acute myeloid leukaemia (AML)]. Cytogenetics studies showed a normal karyotype. Screening for FLT3 internal tandem duplication (ITD) and NPM1 mutations were both positive. Acute myeloid leukaemia with cup-like blasts is defined by characteristic cup-like indentations of the nuclei in myeloid blasts. This feature appears more prominent in peripheral blood than bone marrow smears. On electron microscopy, the nuclear invagination has been shown to be filled with cytoplasmic organelles. These blasts are typically negative for CD34 and HLA-DR on immunophenotyping, which in the presence of bleeding and laboratory evidence of disseminated intravascular coagulation may cause confusion with acute promyelocytic leukaemia. However, the karyotype associated with AML with cup-like blasts is usually normal but with molecular studies showing mutations in FLT3 and NPM1, either alone or in combination. AML with cup-like blasts may be a distinct biological entity. Its characteristic morphology and immunophenotype may be a clue to the associated FLT3 ITD and NPM1 mutation profile in normal karyotype AML.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial

Summary Background Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. Methods We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0–3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1–5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1–5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). Findings Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21–1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. Interpretation The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. Funding Bloodwise and the UK National Institute of Health Research.

A British Society for Haematology Good Practice Paper on the Diagnosis and Investigation of Patients with Mantle Cell Lymphoma

Pamela McKay, Mike Leach, Bob Jackson, Stephen Robinson and Simon Rule Department of Haematology, Beatson West of Scotland Cancer Centre, Gartnavel Hospital, Department of Pathology, Queen Elizabeth University Hospital, Glasgow, Department of Haematology, University Hospitals Bristol, Bristol, and Department of Haematology, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK

Guideline for the Management of Mantle Cell Lymphoma

This guideline was compiled according to the British Society for Haematology (BSH) process at www.b-s-h.org.uk. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http:// www.gradeworkinggroup.org. MEDLINE, EMBASE, DYNAMED, TRIP and NHS EVIDENCE were searched systematically for publications in English from 1980 to 2017 using the

THE ROLE OF 18F FDG-PET/CT IN PERIPHERAL T-CELL LYMPHOMA (PTCL): INITIAL RESULTS OF THE UK NCRI MULTICENTRE PHASE II RANDOMISED CHEMO-T TRIAL PET/CT SUBSTUDY

ent from score 2 (21/47, 45%; P = 0.023) and 4 (24/27, 89%; P = 0.030), we categorized patients into 3 groups: Deauville score 1– 2, 3, and 4–5. With a median follow‐up of 54.7 months (IQR, 30.2–84.5), 5‐year PFS rate was 35.7% (95% CI, 30.0–41.4), and OS rate was 47.1% (95% CI, 40.8–53.4). NCCN‐IPI risk and post‐treatment PET‐CT scan were independently associated with PFS in multivariate analysis (for LI NCCN‐IPI, hazard ratio [HR] 1.615, 95% CI 0.838–3.113; HI NCCN‐ IPI, HR 3.063, 95% CI 1.626–5.769; high NCCN‐IPI 4.475, 95% CI 2.231–8.977; P < 0.001: for post‐treatment Deauville score 3, HR 1.895, 95% CI 1.281–2.801; score 4–5, HR 6.916, 95% CI 4.948– 9.667; P < 0.001). We stratified patients into 5 groups based on risk of progression: low (low NCCN‐IPI and Deauville score 1–2), INT‐1 (low NCCN‐IPI and score 3, or LI NCCN‐IPI and score 1–2), INT‐2 (HI NCCN‐IPI and score 1–2), high (high NCCN‐IPI and score 1–2, or LI to high NCCN‐IPI and score 3), and very high (score 4–5). The risk model showed a strong association with PFS and OS (Figure 1). Conclusion: This study proposes a new risk stratification model incorporating baseline NCCN‐IPI in combination with post‐treatment Deauville score on PET‐CT scan in patients with newly diagnosed nodal PTCL.

High-dose chemotherapy and autologous stem cell transplantation for primary central nervous system lymphoma: a multi-centre retrospective analysis from the United Kingdom.

The prognosis of patients with primary central nervous system lymphoma (PCNSL) has improved in recent years. This has partly been achieved by remission induction protocols incorporating high-dose methotrexate (HD-MTX) and rituximab. Given the high rates of relapse, consolidation therapy is usually considered in first response. Whole brain radiotherapy may prolong PFS but appears to confer no long-term survival advantage and is associated with significant neurocognitive dysfunction. Attempts to improve efficacy and reduce neurotoxicity of consolidation therapy have included thiotepa-based high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT). This multi-centre, retrospective study reports the outcome of 70 patients undergoing HDC-ASCT for PCNSL in the United Kingdom. The median age at diagnosis was 56 years and all patients received HD-MTX-containing induction regimens. All patients underwent HDC-ASCT in first response. The rate of complete response increased from 50% before HDC-ASCT to 77% following HDC-ASCT. Treatment-related mortality was 6%. At a median follow-up of 12 months from HDC-ASCT, the estimated 1- and 2-year PFS rates were 71.5% and overall survival 86.4% and 83.3%, respectively. These data are comparable to published studies of HDC-ASCT for PCNSL, supporting its feasibility and efficacy.