CLL Treatment

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Chronic Lymphocytic Leukemia is the most common leukemia in the US and western hemisphere accounting for about one-quarter of all leukemia cases. The overall incidence and mortality rate of CLL has been slightly declining during the last decade. Chronic Lymphocytic Leukemia more commonly affects older age individuals with highest incidence observed in individuals aged between 65 to 74 years. The incidence rate of CLL is slightly higher in males than in females. CLL is a disorder in which abnormal B lymphocytes (leukemia cells in CLL look like mature B lymphocytes) start dividing without control. The abnormal B lymphocytes slowly get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal RBCs, WBCs, and platelets. The CLL cells can spread to different organs like liver, spleen, and lymph nodes. Pathologically, CLL is defined as the presence of >/=5 x 10^9/L malignant monoclonal B cells in the blood. CLL cells express the B-cell markers CD19, CD20, CD21, CD23; and T-cell marker CD5.

Staging of CLL

Before discussing the treatment, let’s have a look at the staging of CLL. The staging system is used to describe the severity of Chronic Lymphocytic Leukemia based on various clinical parameters such as lymphocytosis; involvement of lymph nodes; enlargement of the spleen and/or liver; hemoglobin level; and platelets count. Staging helps to determine the disease prognosis, and thus, to select an appropriate treatment strategy. “Rai” and “Binet” are the two most commonly used staging system for CLL by the medical community. The Rai system is mostly used in the US and the Binet system is mainly used in Europe. The Rai system assigns 5 stages (from 0 to IV) to the disease while the Binet system assigns 3 stages (A, B, and C) to the disease. Following table describes the characteristics of CLL according to different stages and different systems:

Rai Staging

RAI STAGE RISK GROUP DESCRIPTION
0 Low Lymphocytosis (>/=5*10^9/L leukemia cells in the blood and >40% leukemia cells in the bone marrow); no enlargement of the lymph nodes, spleen, or liver; RBCs and platelet counts are near normal
I Intermediate Lymphocytosis with enlarged lymph node(s)
II Intermediate Lymphocytosis with splenomegaly and/or hepatomegaly
III High Lymphocytosis with hemoglobin <11.0 g/dL or hematocrit <33%
IV High Lymphocytosis with platelets <100,000/microliter

Binet Staging

BINET STAGE DESCRIPTION
A Hemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and <3 enlarged nodal areas
B Hemoglobin >/=10 g/dL, Platelets >/=100,000/mm^3 and >/=3 enlarged nodal areas
C Hemoglobin <10 g/dL and/or Platelets <100,000/mm^3
Many other factors have been identified in different clinical research studies, which can predict the outcome of Chronic Lymphocytic Leukemia. These factors are not included in the staging system but are taken into account before starting the treatment for CLL. Following are examples of such prognostic factors: Adverse prognostic factors: Examples of adverse prognostic factors include
  • Cytogenetic abnormalities (deletions of parts of chromosomes 17 or 11, trisomy 12, mutation in TP53 gene, and >/=3 unrelated chromosomal abnormalities);
  • flow cytometry-based parameters (CD38, CD49d and ZAP-70); elevated level of serum beta-2 microglobulin;
  • Increased fraction of prolymphocytes;
  • short lymphocyte doubling time;
  • diffuse pattern of bone marrow involvement; and
  • advanced age.
Favorable prognostic factors: Examples of favourable prognostic factors include a mutated gene for IGHV; deletion of part of chromosome 13; and nodular pattern of bone marrow involvement.

Treatment of CLL

The treatment of Chronic Lymphocytic Leukemia depends on many factors, including but not limited to, patient’s age, overall health or comorbidities, stage/risk group, immunophenotypic/cytogenetic abnormality involved, etc. Decision for whether to treat the patient or to observe is taken on the basis of – disease related symptoms (fever, night sweats, weight loss, etc), threatened end organ function, progressive bulky disease, progressive anemia or thrombocytopenia, lymphocyte doubling time, etc. If none is present, patient may be observed closely, but the final decision is taken after clinical assessment of the patient by an oncologist.

Treatment of CLL without del(17p) or TP53 mutation

Chemoimmunotherapy (chemotherapy plus monoclonal antibody) or targeted therapy is considered as the preferred treatment for both elderly and young patients with significant comorbidities. In patients <65 years of age and without significant comorbidities, Chemoimmunotherapy is considered as the preferred treatment approach.

Treatment of CLL with del(17p) or TP53 mutation

Targeted therapy is considered the preferred treatment for both elderly and young patients with or without any significant comorbidities.

Role of Chemotherapy

chemotherapy for cancer treatment Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. Purine analogs and alkylating agents are the most commonly used chemotherapeutic agents for the treatment of CLL. Chemotherapy is generally employed in combination with immunotherapy (monoclonal antibodies) for the management of CLL. It may be associated with side effects like  nausea/vomitinghair lossfatigue, cytopenias, etc due to its effect on normal body cells apart from cancerous cells.

Corticosteroids

Corticosteroids These are a category of drugs which are structurally similar to cortisone, a hormone produced by the adrenal cortex. Examples of corticosteroids include dexamethasone and prednisone that are generally employed in the treatment CLL. These may have their own side effects like hyperglycemia, weight gain, mood changes, weakness in bones etc.

Role of Monoclonal Antibodies

Monoclonal Antibodies Monoclonal antibodies are man-made antibodies which can be directed to certain protein characteristic of cancer cells. These drugs activate the immune system to act against the cancer cells. For the treatment of CLL, Obinutuzumab gets attached to the CD20 protein on CLL cells and helps immune cells to identify and destroy the leukemia cells. Rituximab and ofatumumab are other monoclonal antibodies are generally employed for the treatment of CLL. Following monoclonal antibodies are used for the treatment of CLL:

Rituximab

Rituximab   Rituximab is a CD20 targeted monoclonal antibody that binds to and inactivates CD20, a protein expressed on the surface of B cells. It is approved as the first-line treatment for CLL in combination with chemotherapy. Since then, rituximab in combination with chemotherapy has become standard of care for the management of patients with CLL. It has also been approved for the treatment patients with relapsed or refractory disease in combination with targeted agents or chemotherapeutic agents.

Obinutuzumab

Obinutuzumab Obinutuzumab is a type II monoclonal antibody that works differently than rituximab for blocking CD20 receptor expressed on the surface of B-cells resulting in greater destruction of CLL cells. It is approved in combination with chemotherapy for the first-line treatment of patients with CLL. Also, it may be used as a single-agent treatment for selected patients who cannot tolerate chemotherapy in both first-line or second-line therapy.

Ofatumumab

Ofatumumab   Ofatumumab is a second generation, type I anti-CD20 monoclonal antibody with increased efficacy (compared to rituximab) in some patients who have not responded to rituximab. Similar to rituximab and obinutuzumab, it can be employed (in combination with chemotherapy) for the first-line treatment of patients with CLL, or as a single-agent treatment for the management of relapsed or refractory disease. It can also be used as the maintenance treatment for patients with relapsed or refractory CLL who achieved complete or partial response after at least two prior lines of therapy.

Alemtuzumab

Alemtuzumab   Alemtuzumab is a monoclonal antibody that targets the CD52 antigen found on the surface of B-cells, T-cells, natural killer cells, eosinophils, dendritic cells, and macrophages. Alemtuzumab may be employed as a single agent or in combination with rituximab for the treatment of relapsed or refractory CLL with or without del(17p)/TP53 mutation. In combination with rituximab, it can be employed for the treatment of del(17p)/TP53 mutation-positive CLL in the first-line setting.

Role of Targeted Therapy

Targeted drugs are designed to target a specific gene or protein characteristic of the CLL cells. Following targeted drugs are used for the treatment of CLL

Ibrutinib

Ibrutinib Ibrutinib is an orally active, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an enzyme involved in the B-cell receptor (BCR) signaling that supports the B-cell survival and proliferation. Ibrutinib was initially approved for the treatment of patients with relapsed or refractory CLL, but it has now gained approval to be used in first-line settings, especially for patients with del(17p) or TP53 mutation. Single-agent therapy with Ibrutinib is recommended to be employed for the treatment of patients with significant comorbidity, those who are frail (cannot tolerate chemotherapy), and for patients with age >/=65 years or younger with significant comorbidities. It is also recommended for the treatment of patients with the relapsed or refractory disease. It is now considered a standard treatment for patients with del(17p) or TP53 mutation-positive CLL both as first-line therapy or for the relapsed/refractory disease. Ibrutinib may cause an initial transient increase in absolute lymphocyte count that does not indicate a disease progression and may persist for several weeks.

Acalabrutinib

Acalabrutinib   Acalabrutinib is a second-generation BTK inhibitor that has been approved for the treatment of patients with relapsed or refractory CLL regardless of age. Of note, acalabrutinib is not helpful in the treatment of ibrutinib-resistant CLL with BTK C481S mutations, one of the common reasons for the development of resistance against ibrutinib treatment.

Idelalisib

Idelalisib is an orally active, p110 delta (δ) isoform-selective inhibitor of phosphoinositide-3 kinase (PI3K), an enzyme involved in B-cell activation, proliferation, and survival. Idelalisib, in combination with rituximab, has been approved by US FDA for the treatment of patients with relapsed or refractory CLL. Idelalsib with  rituximab is also effective for the treatment of patients with adverse prognostic factors, like del(17p) or TP53 mutations, ZAP70, CD38 expression, unmutated IGHV, and elevated beta-2 microglobulin (>4 mg/L). Single-agent therapy with Idelalisib may be helpful for some patients with relapsed/refractory disease.

Duvelisib

Duvelisib is an orally active, selective inhibitor of PI3K3γ and PI3Kδ isoforms that suppress B-cell proliferation and promotes apoptosis in CLL cells. Single-agent therapy with Duvelisib is recommended for the patients with relapsed or refractory CLL.

Venetoclax

Venetoclax Venetoclax is an orally active, selective inhibitor of B-cell leukemia/lymphoma-2 (BCL2) protein, a protein found to be involved in the B-cell apoptosis and cancer development. Venetoclax has been approved as a single-agent therapy or in combination with rituximab for the treatment of patients with relapsed or refractory CLL who have received prior treatment with ibrutinib or idelalisib. Tumor lysis syndrome (TLS), a syndrome caused by the mass destruction of leukemia cells that release their constituents in the blood leading to kidney failure, was observed in some patients treated with venetoclax.

Immune Checkpoint Inhibitors

Immune Checkpoint Inhibitors like pembrolizumab and nivolumab have shown activity in patients with Richter’s transformation refractory to chemotherapy or targeted therapy.

Adoptive T-cell Therapy

Similarly, adoptive T-cell therapy, directed towards CD19-surface protein and/or other proteins expressed on the surface of CLL cells, have demonstrated exciting results in different clinical trials. Additionally, the genetically modified CART cells persist for many years that is advantageous to eradicate the minimum residual disease (MRD) in patients with high-risk features. Considering the potential clinical application of CART therapy for the treatment of leukemia it may soon be incorporated into clinical practice for the treatment of CLL.

Assessment of Response to Treatment

Complete response (CR)

A CR means meeting following criteria : peripheral blood lymphocyte counts <4 x 10^9/L; absence of lymphadenopathy (that is, palpable nodes must be </=1.5 cm in diameter); absence of splenomegaly or hepatomegaly; absence of constitutional symptoms (that is, weight loss, significant fatigue, fevers, night sweats); and normalization of blood counts without growth factor support (that is, neutrophils >1.5 x 10^9/L, platelets >100 x 10^9/L, hemoglobin >11 g/dL). Confirmation of CR requires bone marrow evaluation with aspirate and core biopsy, demonstrating <30% lymphocytes, with no B lymphoid nodules.

Partial response (PR)

PR means meeting at least 2 of the following criteria for at least 2 months: at least 50% reductions in – peripheral blood lymphocyte counts (from baseline), lymphadenopathy (based on the sum of the products of multiple affected nodes), hepatomegaly, and/or splenomegaly. In addition, at least 1 of the blood counts should be normalized or increase by >/=50% from baseline, for at least 2 months duration.

Progressive Disease

Progressive disease means any of the following: at least 50% increase from baseline in – lymphocyte counts, lymphadenopathy, hepatomegaly, or splenomegaly; appearance of any new lesions; or occurrence of cytopenia attributable to disease (that is, >/=50% decrease from baseline in platelet count, >2 g/dL decrease from baseline in hemoglobin levels).

Stable disease

Patients who do not have a progressive disease but do not meet the criteria for a CR or PR are considered to have stable disease.

Refractory Disease

A failure to achieve a response or having disease progression within 6 months of the last treatment is termed as the refractory disease.

Disease Relapse

An evidence of disease progression after a period of 6 months or more following an initial CR or PR is known as disease relapse.

Minimal Residual Disease (MRD)

When leukemia cells are undetectable with conventional diagnostic technique after treatment but leukemia cells are detectable with a more sensitive technique such as PCR, it is known as MRD. Patients with MRD after treatment are more likely to have disease relapse.

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