Updated ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of newly diagnosed and R/R Mantle Cell Lymphoma

On 13^th July 2017, on behalf of the European Society for Medical Oncology (ESMO) Guidelines Committee, M. Dreyling from the Hospital of the Ludwig-Maximilians-University, Munich, Germany, et al. published updated clinical practice guidelines for newly diagnosed and Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) in the Annals of Oncology.¹

This article highlights the key recommendations given by the ESMO Guidelines Committee in terms of diagnosis, staging, treatment, response evaluation, and follow-up.

Diagnosis and pathology/molecular biology

• Surgical specimens, preferably lymph node biopsy, should be used for diagnosis
• Core biopsies should only be undertaken in patients without easily accessible lymph nodes
• Bone Marrow (BM) biopsy may be relevant only in rare patients with leukemic manifestations
• Besides histomorphology, additional diagnostic measures include immunophenotype (CD5+, CD19/20+), presence of t(11;14)(q13;q32), and cyclin D1 overexpression
• The histological report should state the diagnosis in accordance with the WHO classification; Ki67 is the most established histomorphological risk factor
• Most cases display classic morphology of small-median sized cells containing irregular nuclei
• Few cases of leukemic non-nodal subtype are diagnosed correctly based on histology alone, therefore review by an expert hematopathologist is advised and additional immunohistochemical detection of cyclin D1 overexpression is mandatory
• Identification of SOX11 may assist in making a diagnosis in rare cyclin D1-negative cases

Staging and risk assessment

• Initial work-up: CT scan of neck, thorax, abdomen, and pelvis, and BM aspirate and biopsy
• PET-CT is recommended for patients with rare limited stages I/II before localized radiotherapy
• In these rare cases, gastrointestinal endoscopy is recommended to detect asymptomatic involvement but otherwise is only required in symptomatic patients; most patients will have gastrointestinal involvement
• A lumbar puncture to detect CNS involvement may be considered in high-risk cases that have 2 or more of the following risk factors: blastoid variant, elevated LDH, impaired performance status, or neurological symptoms
• Also required is full blood count, bloody chemistry (LDH and uric acid), and screening for HIV, Hepatitis B, and Hepatitis C viruses
• The Lugano classification system is referred to for staging; it is important to mention bulky disease >5cm as appropriate
• Evaluation of Ki67 has been found to vary between pathologists in terms of reproducibility; a standardized method has been proposed²
• A combined MCL International Prognostic Index (MIPI-c) has been established (web-based calculator: www.european-mcl.net/de/clinical_mipi.php) and should be applied in routine practice to estimate the clinical behavior
• No markers have thus far been defined to predict indolent disease course

Treatment

• Indolent: Short period of ‘watch and wait’ under close observation; if therapy is needed then the recommendations for classical MCL apply
• Localized stages (I–II): discuss conventional chemotherapy followed by radiotherapy (30–36 Gy)
• Advanced stages (III–IV):
  • Younger patients (≤65 years): high dose-AraC containing regimens plus rituximab followed by Autologous Stem Cell Transplant (ASCT) and rituximab maintenance
  • Elderly patients (>65 years): conventional immunochemotherapy (e.g. R-CHOP, VR-CAP, BR, R-BAC) followed by rituximab maintenance
• Relapse:
  • Targeted approaches (ibrutinib, lenalidomide) should be considered; temsirolimus and bortezomib should be considered preferably combined with chemotherapy
  • For younger patients, an Allogeneic Stem Cell Transplant (allo-SCT) should be considered
  • Consider enrollment in clinical trials

Response evaluation

• PET-CT according to the Lugano classification system is optional
• Radiological tests should be undertaken mid- and post-chemotherapy
• Assessment of Minimal Residual Disease (MRD) is advised for clinical trials but not in routine practice, except in the setting of donor lymphocyte infusion post-allograft

Personalized medicine

• Currently, more research is required to determine molecular markers that could potentially become targets for more personalized approaches
• Novel agents, in particular those that target the BCR pathway, BCL-2, or cyclin dependent kinases, are presently being explored