Relapsed or Refractory Chronic Lymphocytic Leukemia - An Overview

Introduction

Notable progress has been made in treating chronic lymphocytic leukemia (CLL) within the last ten years. Beyond conventional methods, there are now more therapy choices because of novel medications such as phosphatidylinositol 3-kinase inhibitors (PI3Ki), BCL-2 inhibitors, and Bruton tyrosine kinase inhibitors (BTKi). These therapies might be ongoing or have a set period. Even though survival rates with current medications have increased, CLL is still incurable and frequently needs several treatments because of recurrence or non-response.

Refractoriness refers to not responding to treatment or progressing within six months of finishing therapy, whereas relapse occurs when CLL advances after at least six months of remission. Although frontline treatments work well, CLL patients may relapse. This calls for investigating treatment sequences in the context of relapsed or resistant patients. When choosing a treatment, one must consider several aspects, such as past medicines, illness features, patient condition, availability of clinical trials, and financial implications.

What Is the First-Line Treatment for Chronic Lymphocytic Leukemia?

The choices available to patients with active chronic lymphocytic leukemia (CLL) have significantly expanded during the past 20 years. In light of the COVID-19 pandemic, new targeted therapeutics have supplanted conventional treatments as the preferred approach. The current treatment options include Venetoclax in combination with anti-CD20 monoclonal antibodies and BTK inhibitors administered continuously, either alone or in combination. Compared to conventional medicines, these treatments have been demonstrated to be extremely effective, improving overall survival (OS) and progression-free survival (PFS).

There was originally no difference in PFS between patients treated with Ibrutinib, a BTK inhibitor, and those treated with the conventional Fludarabine-Cyclophosphamide-Rituximab combination, according to recent data, including the ECOG 1912 clinical study. Longer-term data, however, showed that Ibrutinib improved PFS in all patient subgroups, suggesting that, where available, targeted treatments should be used as the first line of treatment for CLL.

The kind of disease (standard or high risk), the patient's health and other conditions, financial concerns, and patient desire (for example., limited-time or ongoing treatment) all play a role in the treatment decision.

What Factors Predict CLL Treatment Response and Survival?

A patient's prognosis and response to chronic lymphocytic leukemia (CLL) treatment can be predicted based on key variables. These include genetic characteristics such as an unmutated IGHV gene and specific chromosomal abnormalities. Certain anomalies, such as TP53 mutation or del(17p), suggest a shorter survival time and a less favorable response to conventional treatments. A worse response to additional treatment is typically indicated if the disease recurs or advances before the end of the first course of treatment. Physicians utilize many models to forecast the course of CLL patients' treatment, and the kind of relapse during ongoing therapy or following a particular course of treatment determines the course of treatment that should be followed. It could be necessary to switch to a new medication if the disease becomes resistant to the existing course of treatment.

What Distinguishes Richter Transformation From Relapsed CLL?

When symptoms of chronic lymphocytic leukemia (CLL) patients rapidly worsen, physicians must rule out Richter transformation (RT). This is the point at which CLL develops into a more aggressive lymphoma, most commonly Hodgkin lymphoma or diffuse large B cell lymphoma. Because RT has a poor prognosis and alternative treatments are required, it is essential to differentiate between RT and relapsed CLL.

Relapsed CLL shares many symptoms with RT; however, RT symptoms are more severe and include markers such as elevated blood LDH (lactate dehydrogenase), fast enlargement of lymph nodes, and hypercalcemia (increased calcium levels in the blood). A tissue biopsy of the putatively transformed area is required to confirm RT, and this biopsy is frequently guided by enhanced FDG (Fludeoxyglucose F18) uptake on PET-CT (positron emission tomography–computed tomography) images.

Additionally, there is a phenomenon known as pseudo-Richter transformation, in which symptoms of RT are momentarily mimicked by halting a particular medication (BTKi). Still, they return when the therapy is resumed. It is critical to recognize this potential hazard. Aggressive chemotherapy is the usual treatment for RT; however, the prognosis is usually poor, and the response is usually transient. After chemo-immunotherapy produces a response, younger, healthier individuals may be evaluated for an allogeneic stem cell transplant, increasing the likelihood of long-term survival.

What Are the Current Treatment Options for Relapsed or Refractory Chronic Myeloid Leukemia?

• Ibrutinib: Ibrutinib is a covalent BTK inhibitor authorized for treating chronic lymphocytic leukemia (CLL). Approved by the US FDA (United States Food and Drug Administration) in 2014, this medication showed promise in the RESONATE research, extending median PFS to 44.1 months, a considerable improvement above Ofatumumab's 8.1 months. Notably, a longer PFS was associated with the use of Ibrutinib in earlier therapy lines. Over prolonged therapy durations, Ibrutinib's safety profile has proven to be largely acceptable despite certain toxicities, including bleeding and hypertension (high blood pressure).

• Acalabrutinib: Acalabrutinib is a covalent BTK inhibitor intended to lessen toxicity. It has better specificity than Ibrutinib. The FDA approved the ASCEND study after finding a 63 percent 36-month PFS rate. Acalabrutinib was found to have much-reduced toxicity but to be non-inferior in efficacy when compared head-to-head with Ibrutinib in a clinical trial. This implies that Acalabrutinib is the best choice for most patients.

• Zanubrutinib: This selective BTK inhibitor is notable for being approved by the FDA for several types of lymphomas. Compared to Ibrutinib, it shows less impact on platelet aggregation and shows encouraging results. When comparing Ibrutinib to Zanubrutinib for relapsed or refractory CLL, another research shows that Zanubrutinib has better overall response rates and a 12-month PFS. Additionally, the safety results indicate that Zanubrutinib is a better option for patients than Ibrutinib.

• Venetoclax: Venetoclax, a BCL2 protein inhibitor, exhibits remarkable efficacy in CLL relapses. A 53.6-month median PFS and an overall response rate of 92.3 percent were attained in the MURANO study. Venetoclax is frequently used in conjunction with a monoclonal antibody against CD20. Ongoing research on time-limited methods is necessary since their continued use is linked to resistance and clonal hematopoiesis (any stage of clonal growth within the system that forms blood).

• Therapy Sequencing: When treating relapsed or resistant CLL, several parameters are taken into account. The two main alternatives are Venetoclax and Ibrutinib, with previous treatments, adverse effect profiles, and patient preferences taken into account. Novel therapeutic approaches, like CAR-T cell treatments and reversible BTK inhibitors, are being studied and point to a changing landscape in the treatment of CLL.

Conclusion

In conclusion, these drugs offer choices with different modes of action and adverse effect profiles, which constitute major improvements in the treatment of CLL. Based on each patient's unique characteristics and responses to previous treatments, the sequencing of these therapies is carefully examined. Ongoing research and the development of new medications suggest a dynamic landscape in the management of CLL.