Chronic Lymphocytic Leukemia (CLL)
The most prevalent type of adult leukemia in Western populations is chronic lymphocytic leukemia (CLL). It is a lymphoproliferative disorder characterized by the expansion of a monoclonal population of mature CD5 CD23 B cells in the lymphoid tissues and bone marrow. Alfa Cytology is dedicated to the field of drug development in CLL, providing high-quality solutions to our clients.
Fig. 1. The cellular origin of chronic lymphocytic leukemia. (Bosch, F.; Dalla-Favera, R., 2019)
The genetic and epigenetic events underlying CLL development are believed to occur in HSCs, although this hypothesis remains controversial. Following the acquisition of genetic and epigenetic alterations in HSCs, the cellular output of these abnormalities may manifest as a polyclonal expansion of B-cell progenitors.
Current Status of CLL
In 2022, the market size for CLL was $8.4 billion. The United States is the largest CLL market, accounting for over 70% of sales in major pharmaceutical markets including the US, France, Germany, Italy, Spain, the UK, and Japan. Currently, targeted therapies play a significant role in CLL therapy, contributing to the highest sales in the CLL market in 2022. Due to the increasing number of CLL patients and the continuous demand for innovative therapies, the global market for CLL therapy is projected to experience steady growth.
Drugs Approved for CLL
The powerful GVL effect of allogeneic HCT offers the potential for long-term remissions in an otherwise incurable malignancy. Unfortunately, the majority of patients are not suitable candidates for transplantation, and therefore, disease control and symptom management are primarily achieved through medication. There are three categories of drugs used for treating CLL, including chemotherapy agents, targeted therapies, and monoclonal antibodies.
Fig. 2. Timeline of approvals drugs for chronic lymphocytic leukemia. (Bosch, F.; Dalla-Favera, R., 2019)
Targeted Agents in CLL
After years of research, numerous drugs have been developed for CML therapy. The following table presents some medications used for CLL therapy.
| Drugs | Description |
|---|---|
| Bruton tyrosine kinase (BTK) inhibitors | Ibrutinib, a tyrosine kinase inhibitor (TKI), is employed for the management of symptomatic or progressive CLL that has recurred or proved refractory. Acalabrutinib, on the other hand, represents an alternative BTK inhibitor capable of enhancing progression-free survival. |
| BCL2 inhibitors | Venetoclax, a therapeutic agent targeting BCL2, exhibits a rapid reduction in CLL burden in lymph nodes and spleen. It has gained approval for patients with relapsed/refractory CLL accompanied by del(40p). |
| PI3K inhibitors | Idelalisib is indicated for patients who are intolerant to ibrutinib or experiencing their first relapse. |
| Monoclonal antibodies | They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Rituximab, ofatumumab, and obinutuzumab alone and in combination with chemotherapy are used to treat symptomatic or progressive, recurrent, or refractory CLL. |
Chemoimmunotherapy of CLL
Fludarabine, cyclophosphamide, and rituximab (FCR) are initial therapy options in younger patients who can tolerate chemotherapy without 17p deletion/TP53 mutation but with IGHV mutated CLL. Bendamustine plus rituximab (BR) is a therapy of choice for older patients (> 65 years of age) with IGHV-mutated CLL.
Lenalidomide, an immunomodulating agent, activates T cells to eliminate leukemia cells. It can be administered as a monotherapy or in combination with rituximab to patients experiencing symptomatic progression, recurrence, or refractory CLL.
Allogeneic hematopoietic stem cell transplantation is rarely employed in CLL; however, it has been utilized in refractory cases deemed suitable for this approach. Individuals with highly aggressive forms of the disease are recommended for bone marrow transplantation using an HLA-matched donor.
Clinical Trials for CLL
The CLL therapy landscape has shifted from chemoimmunotherapies to targeted therapies. However, resistance mechanisms, including Richter's transformation, have emerged. There is an unmet need to discover new therapy strategies and molecular pathways for CLL cure. Below is a table of drugs currently in development.
| Drug | Study Phase | Title | Trial |
|---|---|---|---|
| Zanubrutinib (second-line or later monotherapy) | I | Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. | NCT02343120 |
| Zanubrutinib (first-line monotherapy [Arm C]) | III | Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial | NCT03336333 |
| Orelabrutinib (second-line or later monotherapy) | II | Updated results from the phase II study of orelabrutinib monotherapy in Chinese patients with relapsed or refractory chronic lymphocytic leukemia/small cell leukemia. | |
| Umbralisib (second-line or later monotherapy) | II | Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kdelta inhibitor therapy. | NCT02742090 |
| Umbralisib (second-line or later combination therapy) | I | Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial. | NCT02006485 |
| ME-401 (second-line or later monotherapy or combination therapy) | I | Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies. | NCT02914938 |
| Venetoclax + obinutuzumab | III | Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. | NCT02264574 |
| Ibrutinib + obinutuzumab | III | Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. | NCT02242942 |
As an industry leader in the field of leukemia drug development, Alfa Cytology offers comprehensive research services to support your preclinical studies. Please contact us to learn more about our service offerings.
References
- Bosch, F.; Dalla-Favera, R. Chronic lymphocytic leukaemia: from genetics to treatment. Nature reviews Clinical oncology. 2019, 16(11): 684-701.
- Hampel, P.J.; Parikh, S.A. Chronic lymphocytic leukemia treatment algorithm 2022. Blood cancer journal. 2022, 12(11): 161.
- Patel, K.; Pagel, J.M. Current and future treatment strategies in chronic lymphocytic leukemia. Journal of Hematology & Oncology. 2021, 14(1): 1-20.