Chronic Lymphocytic Leukemia (CLL)

CLL is a heterogenous disease, where on one hand there is just an increase in clonal B lymphocytes in the circulation without any other problems and an aggressive lymphoma like disease on the other end of the spectrum.

In the case of slow and indolent presentation, CLL does not need any treatment and can behave like a benign disorder for months and years. The disease on the aggressive end of the spectrum needs more urgent attention.

Most commonly, CLL is detected as an incidental finding on a simple complete blood count — noted as an isolated increase in lymphocytes. In more advanced stages, the patient might experience any or all symptoms of Non-Hodgkin's Lymphoma (NHL).

In some cases, there is an immune mediated anemia or thrombocytopenia, which is independent of the severity of the CLL itself.

Patients with advanced CLL are extremely susceptible to infections, particularly of the respiratory tract.

In about 10% of patients, CLL can transform to an aggressive form of NHL, which is termed as Richter's Transformation.

The initial diagnosis of CLL can be made by microscopic examination of a peripheral blood sample, where the otherwise normal appearing lymphocytes increase in number and get smudged in the time of processing. This particular morphological appearance is termed as 'smudge cells' and is considered characteristic of CLL.

Confirmation is made by Immunophenotyping with multicolour Flow Cytometry, where the characteristic combination of certain antigens on the surface of these cells (CD19/5/200/20/23) helps confirming the diagnosis.

We strongly recommend cytogenetic testing on peripheral blood to determine if any adverse cytogenetic features are present. In addition, two salient markers for a more serious disease, namely mutation of the TP53 gene and lack of Immunoglobulin heavy chain mutation — should be specifically tested.

In patients with fever, low blood counts, splenomegaly and/or enlarged lymph nodes, a 18FDG PET-CT scan is recommended to review the extent of the disease. Usually, the glucose uptake in affected nodes is lower in CLL than a high-grade NHL. However, areas of increased FDG uptake would suggest a Richter's Transformation.

The simplest scoring system for CLL was devised by Binet and team and is categorised as A, B or C, depending on extent of the disease as measured by presence or absence of lymph nodes, their extent and reduction in hemoglobin or platelet count. Interestingly, absolute number of lymphocytes in the peripheral blood is not an indicator of severity by itself. Only if the lymphocyte count rises rapidly to double itself in 3-6 months, is it taken into consideration.

A more recent system of scoring (CLL-IPI) incorporates all of the above with cytogenetics and molecular abnormalities and assigns points to each and grades the disease in terms of severity.

Treat or Wait?

CLL, which is Binet A or CLL-IPI low score doesn't require treatment and is monitored with periodic clinical examination and blood counts. Treatment in such patients would be indicated only if there is development of a new-onset anemia or low platelet count, or there is rapid increase in absolute count of CLL cells in blood. In all other situations, treatment is necessary.

First-line therapy

We have traditionally used a combination of Rituximab and Bendamustine in most patients with good results, apart from those with poor cytogenetics or molecular mutations. In the latter group, oral BTK inhibitors such as Ibrutinib, acalabrutinib or Zanubrutinib are added either as a single agent or in combination.

More recently, a combination of a BTK inhibitor and venetoclax (BCL2 inhibitor) has been found to be extremely effective in producing impressive disease control. As these are oral medicines, it can now be conceived that like CML, CLL can also be treated with oral therapy with excellent long term results.

Relapsed Disease

In case of an early relapse of CLL (within 2 years), particularly if adverse features are present, an allogeneic HCT is recommended. This is also recommended upfront for younger patients with adverse features.

In case of Richter's Transformation, lymphoma-like chemotherapy followed by an Autologous/Allogeneic HCT is recommended.

CAR-T cell Therapy directed at CD19+ B cells is also an option for relapsed/refractory CLL.