Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is manifested by progressive accumulation of B lymphocytes in the blood, bone marrow, and lymphatic tissues. The disease displays a highly variable clinical course. It is preceded by a pre-leukemic phase (monoclonal B-cell lymphocytosis, MBL) that occurs in up to 12% of healthy elderly persons.

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In some individuals, MBL progresses to overt CLL, which may be characterized by lymphatic enlargement with reduced numbers of platelets and red & white blood cells. Recent discoveries in biology, therapy, and their interrelationship have resulted in groundbreaking advances in the treatment of CLL. At present, five-year survival after diagnosis is approximately 70-80%, with substantial individual variation. Primarily affecting middle-aged and elderly adults, CLL is the most common form of adult leukemia in Europe.

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Key questions

By combining data of thousands of CLL patients, HARMONY aspires to identify robust prognostic markers for clinical course and drug response. These markers may constitute patient characteristics (e.g., age, fitness), genetic variables (e.g., TP53 mutation status), and other molecular data (e.g., minimal residual disease, MRD). In the future, this will improve CLL management by facilitating personalized treatment choices. Examples of key questions that HARMONY will address for CLL are:

Why does MBL evolve to overt CLL in some individuals and not in others?

• While some patients will never require treatment, others do so within a few months after diagnosis. HARMONY will study the path from MBL to CLL, with the ultimate goal to tailor treatments to patients’ risk profiles.

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Which genetic markers can predict drug response and clinical evolution?

• CLL is characterized by a marked genetic heterogeneity, with a relatively large number of genes recurrently mutated at low frequency and only a few genes mutated in up to 10-15 % of the patients. Examples of high risk genetic defects are 17p deletion and TP53 mutation. HARMONY intends to study the relationship between various genetic defects and patient outcomes.

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How should novel drugs be applied in CLL treatment?

• The current gold standard for CLL treatment is immunochemotherapy. Novel drugs have recently been introduced (ibrutinib, idelalisib, and venetoclax). HARMONY will investigate if these novel drugs should substitute immunochemotherapy, or if they should be administered in combination with chemotherapy.

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Which patient subgroups benefit most from specific therapeutic strategies? Is any particular treatment superior to another in a particular patient?

• As CLL is a heterogeneous disease, it is key to match subgroups of patients with therapeutic objectives, such as aiming for symptom control & palliation versus MRD eradication & cure.

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How can we improve the measurement of certain outcomes and what do these outcomes mean?

• Progression-free survival traditionally is the most important outcome measure for CLL. HARMONY will investigate additional outcome measures, including MRD. HARMONY wants to improve the measurement of these outcomes and deduce the meaning for subgroups of patients (e.g., define how to use the information on MRD).

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CLL Features

• Type of malignant cells: CD5+ B lymphocytes.
• Tissue of origin: unknown: probably lymph nodes; bone marrow is virtually always involved.
• Clinical symptoms: lymph node swelling, low grade fever, night sweats, and fatigue.
• Five-year survival in Europe: ~70-80% with highly heterogeneous clinical course.
• Incidence in Europe: overall crude incidence of 4.9 per 100,000 (>40,000 new cases each year).
• Age at diagnosis: primarily in middle-aged and elderly adults: median age at diagnosis is 72.
• Relevant outcomes: progression-free survival, MRD.

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HARMONY Leadership: CLL

• Paolo Ghia, European research Initiative on CLL, Italy
• Sarka Popisilova, Masarykova Univerzita, Czech Republic
• Francesc Bosch, Fundacio Privada Institut D'Investigacio Oncologica de Vall d'Hebron, Spain