MCL

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

On 13th 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
Follow-up

Examination

Details

Year 1–2

Year 3–5

Year >5

History

B symptoms

Every 3 months

Twice annually

Annually

Physical examination

Peripheral lymph nodes, liver, spleen

Every 3 months

Twice annually

Annually

Laboratory work-up

Blood and differential count; LDH

Every 3 months

Twice annually

Annually

Imaging

Abdominal ultrasound;

CT neck, chest, abdomen, pelvis

Optional: every 3–6 months

Optional: every 3–6 months

If progress suspected

Toxicity

Thyroid-stimulating hormone if irradiated

Annually

 

 

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
References:
  1. Dreyling M. et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017 Jul 13; 28(supplement 4):iv62–iv71. DOI:10.1093/annonc/mdx223.
  2. Klapper W. et al. Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network. Journal of Hematopathology. 2009 Jul; 2(2):103–11. DOI:10.1007/s12308-009-0036-x. [Epub 2009 Jun 16].