ASH 2020: TRANSCEND-CLL-004 Study: Results of CAR-T Monotherapy in R/R CLL or SLL

FOR YOUR REFERENCE: What Are Clinical Trials?

Clinical trials determine whether a drug works in humans and whether it is safe and effective. For a drug to be approved for use, the Food and Drug Administration (FDA) requires four phases of a clinical trial. The number of participants increases in each phase, starting from 20 to 80 people for a phase 1 trial to up to several thousand for a phase 3 trial (Figure 1).¹

• Phase 1: tests an experimental treatment on a small group of often healthy people to judge the drug’s safety and side effects and find the correct dosage.
• Phase 2: focuses on effectiveness and obtains preliminary data on whether the drug works in people who have a certain disease or condition.
• Phase 3: gathers more information about safety and effectiveness, studies different populations and dosages and examines the drug’s use in combination with other drugs.
• Phase 4: occurs after FDA approval; monitors safety and effectiveness in large, diverse populations; and collects information on long-term side effects.

FOR YOUR REFERENCE: What Is Chronic Lymphocytic Leukemia?

Chronic lymphocytic leukemia (CLL) is a form of cancer that starts in the blood-forming cells in bone marrow that become certain white blood cells, called lymphocytes. In CLL, cancer occurs in B cells, a type of lymphocyte, which defends your body against infection. These cells change and become cancer cells, or leukemia cells, that can grow out of control and spread by traveling in the blood to other parts of the body.²

Patients with CLL may experience symptoms such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes, pain and a sense of fullness in the belly. Although these signs and symptoms can point to CLL, tests are needed for a diagnosis. Many people with CLL do not have any symptoms at the time of their diagnosis; their leukemia is found during blood tests for unrelated health issues or routine checkups.³ CLL is usually recognized when blood counts performed for unrelated reasons reveal lymphocytosis, or a higher-than-normal amount of lymphocytes in the body.

Treatment options for patients with CLL include the following⁴:

• Watchful waiting.
• Radiation therapy.
• Chemotherapy.
• Immunotherapy.
• Targeted therapy.
• Clinical trials.

Patients undergoing CLL treatment often experience a complete or partial response to initial therapy — but not always. Consequently, CLL can be classified as relapsed or refractory (R/R), depending on how the disease responds to treatment. Relapsed CLL describes CLL that responded to therapy initially but stopped responding after six or more months. CLL is called refractory if treatment does not result in the total disappearance of CLL cells (though the patient may have stable disease) or if the patient experiences worsening of CLL within six months of the last treatment.⁵

FOR YOUR REFERENCE: What Agents Were Investigated in the TRANSCEND-CLL-004 Study?

Some patients who have been previously treated with CLL agents, such as Imbruvica (ibrutinib) and Venclexta (venetoclax), have disease that doesn’t respond to treatment or disease that responds initially and comes back. Doctors look to long-term safety and efficacy data from clinical trials to help make informed treatment decisions.^6-8

Lisocabtagene maraleucel (liso-cel) is a type of chimeric antigen receptor (CAR)-T cell therapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells, and given to the patient by infusion.^6,9,10

ASH 2020: TRANSCEND-CLL-004 Study: Results of CAR-T Monotherapy in R/R CLL or SLL

The TRANSCEND-CLL-004 phase 1/2 clinical trial included a group of 23 patients with R/R CLL or small lymphocytic lymphoma (SLL) who received liso-cel monotherapy, meaning they received only this one type of treatment. The study investigators aimed to assess the outcomes of treatment with liso-cel monotherapy after a median follow-up of 18 months.^9,10

Patients who had received two or more prior lines of therapy (based on risk of disease progression) were included in the study; patients with active untreated central nervous system disease were excluded.7,8 All patients (N = 23) were previously treated with ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi); 9% (n = 2) could not tolerate it.¹⁰

The patients’ median age was 66 years (range, 49-79) and the median number of prior therapies was six (range, 3-13). Eighty-three percent of patients were classified as being at high risk for disease progression, 91% (n = 21) had relapsed on or were refractory to ibrutinib and 48% (n = 11) were refractory to both a prior BTKi and venetoclax. Study participants were given liso-cel at a dose of either 50 × 106 or 100 × 106 CAR-T cells.^9,10

Figure 2 illustrates the participant eligibility and trial design.^9,10

The primary end point of this study was to assess liso-cel’s safety profile.9,10 Secondary end points were the overall response rate (ORR), minimal residual disease (MRD; meaning a very small number of cancer cells remain in the body during or after treatment) and the proportion of patients experiencing side effects at 24 months.^9,10

After a median follow-up of 18 months, all enrolled patients

(N = 23) were evaluated for treatment safety, 22 were evaluated for efficacy and 20 were evaluated for MRD.¹⁰

The key outcomes are outlined below and are also presented in Figure 3¹⁰:

• The most common side effects were thrombocytopenia (70%, n = 16), anemia (78%, n = 18), neutropenia (57%, n = 13) and leukopenia (43%, n = 10).
• Two patients (9%) experienced grade 3 cytokine release syndrome (CRS), which is severe and requires hospitalization; no grade 4 (life-threatening) or 5 (death) CRS events occurred.
  • The median time to onset of CRS was three days (range, 1-10) and the CRS lasted a median of 12 days (range, 2-50).
• Five patients (22%) experienced grade 3 or greater (severe or life-threatening) neurological events (NEs), which occurred a median of four days from the start of treatment (range, 2-21) and lasted a median of 21 days (range, 6-56).^8,9
• The ORR was 82% (n = 18) upon follow-up; 68% of patients (n = 15) obtained ORR by day 30.
• Median progression-free survival was 18 months for all 22 patients evaluated for efficacy.
• Of the 20 patients evaluated for MRD, 75% (n = 15) had undetectable MRD (uMRD), meaning CLL cell levels were so low they could not be detected in the blood; of these, 87% (n = 13) also had uMRD in the bone marrow and 60% (n = 12) achieved uMRD at day 30 of treatment with liso-cel.

Also, a subgroup analysis of patients who were refractory to prior BTKi and venetoclax treatments (n = 10) had a similar ORR to the total evaluable population, with a complete response of 60% (n = 6).¹⁰

No serious side effects (grade 3 or higher CRS or grade 3 or higher NEs) occurred after or lasted beyond the first two months of treatment.¹⁰ The rate of uMRD among study participants was high, and liso-cel was detectable for up to 18 months after infusion.

Thus far, the results of this trial indicate that liso-cel may be a rapid and durable treatment option for treatment-experienced adult patients with high-risk R/R CLL or SLL.¹⁰

Not all patients qualify for certain clinical trials. If you are interested in enrolling in a trial, ask your doctor which possible treatment options would be appropriate for you.

FOR YOUR REFERENCE:

Glossary of Terms^1-13

Anemia: a condition in which the number of red blood cells is below normal

Bruton tyrosine kinase (BTK): a protein in B cells that sends signals that help B cells survive and multiply

B cell: a type of white blood cell that is an important part of your immune system (the body’s defense against infection)

Bone marrow: spongy tissue inside bones; cells that make blood cells are found in the bone marrow

Chemotherapy: treatment that uses drugs to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. These drugs are taken by mouth or injected and enter the bloodstream so they can help fight cancers that spread throughout the body (like CLL). This can affect cancer cells and normal cells

Chimeric antigen receptor T (CAR-T) cell therapy: a type of immunotherapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells, and given to the patient by infusion. Lisocabtagene maraleucel (liso-cel) is a type of CAR-T cell therapy.

Chronic lymphocytic leukemia (CLL): a slow-growing cancer in which too many immature lymphocytes (white blood cells) are found mostly in the blood and bone marrow

Clinical trials: a research study in which one or more human patients are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the intervention(s) on health-related biomedical or behavioral outcomes

Complete response (CR): the disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission

Complete remission with incomplete count (CRi): CR with incomplete blood count recovery

Cytokine release syndrome (CRS): a condition that may occur after treatment with some types of immunotherapy in which a great number of cytokines (immune substances) are rapidly released into the blood from immune cells affected byimmunotherapy. CRS signs and symptoms include fever, nausea, headache, rash, rapid heartbeat, low blood pressure and trouble breathing

Efficacy: the ability of a therapy to produce the expected result under ideal circumstances

End point: an event or outcome that can be measured to determine whether the treatment being studied in a clinical trial is beneficial

Imbruvica (ibrutinib): an FDA-approved BTK inhibitor indicated for the treatment of adult patients with CLL or SLL with or without 17p deletion. Ibrutinib may slow the spread of CLL or SLL.

Immunotherapy: type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some types of immunotherapy target only certain cells of the immune system. Others affect the immune system in a general way.

Leukemia: cancer that starts in blood-forming tissue, such as bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream

Leukopenia: a condition marked by a decrease in the number of leukocytes (a type of white blood cell)

Lisocabtagene maraleucel (liso-cel): a type of CAR-T cell therapy in which T cells are taken from a patient’s blood, programmed in a laboratory to bind to and attack cancer cells, and given to the patient by infusion.

Lymphocytes: a type of white blood cell that is made in the bone marrow and found in the blood and lymph tissue

Lymphodepletion: prepares the immune system so that CAR-T cells can multiply and last longer. Lymphodepletion is accomplished by treating patients with the chemotherapy drugs fludarabine and cyclophosphamide before CAR T-cell therapy.

Median: the middle value of a sorted list of numbers placed in value order from highest to lowest

Median follow-up: the median time between treatment and when data outcomes are gathered

Minimal residual disease (MRD): a very small number of cancer cells that remain in the body during or after treatment

Neutropenia: a condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell) in the blood

Overall response rate (ORR): the percentage of people in a study or treatment group who have a partial or complete response to the treatment within a certain period of time

Partial response: a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

Pharmacokinetics (PK): the activity of drugs in the body over a period of time, including the processes by which drugs are absorbed, distributed in the body, localized in the tissuesand excreted

Phase 1: trial that tests an experimental treatment on a small group of often healthy people to judge its safety and side effects and to find the correct drug dosage

Phase 2: trial that focuses primarily on effectiveness of the drug and obtains preliminary data on whether it works in people who have a certain disease or condition

Phase 3: trial that gathers more information about safety and effectiveness, studies different populations and different dosages and examines use of the drug in combination with other drugs

Phase 4: trial that occurs after FDA approval; monitors safety and effectiveness in large, diverse populations; and collects information on long-term side effects

Refractory: a disease state or condition that does not respond to treatment or medication. Refers to when the lymphoma does not respond to treatment (the cancer cells continue to grow) or when the response to treatment does not last very long.

Relapsed: a return of signs and symptoms of cancer after undergoing treatment and/or taking medication. Relapsed is the disease that returns or grows again after a period of remission following one or more treatments. Marked by an initial response to treatment that is no longer present after six months or more

Side effect: an unintended reaction to, or result of, a treatment

Small lymphocytic lymphoma (SLL): a slow-growing type of lymphoma in which too many immature lymphocytes (white blood cells) are found mostly in the lymph nodes

Thrombocytopenia: a condition marked by a low number of platelet cell levels in the blood. Platelets help the blood to clot and stop bleeding

Undetectable minimal residual disease (uMRD): the presence of less than 1 CLL cell in 10,000 leukocytes in the blood and/or bone marrow

Venclexta (venetoclax): an oral prescription medicine used to treat adults with CLL/SLL. It targets specific proteins (BCL-2) on CLL cells and signals these cells to self‑destruct.

White blood cell: a type of cell that is found in the blood and lymph tissue that helps fight infections and otherdiseases. Lymphocytes (T and B cells) are a type of white blood cell.

References

1. What are clinical trials and studies? National Institute on Aging. Updated April 9, 2020. Accessed March 15, 2021. https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies

2. What is chronic lymphocytic leukemia? American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html

3. Signs and symptoms of chronic lymphocytic leukemia. American Cancer Society. Updated May 10, 2018. Accessed March 15, 2021. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html

4. Chronic lymphocytic leukemia treatment (PDQ)–patient version. National Cancer Institute. Updated November 25, 2020. Accessed March 15, 2021. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq

5. Chronic lymphocytic leukemia. Leukemia and Lymphoma Society. Updated 2014. Accessed March 15, 2021. https://www.lls.org/sites/default/files/file_assets/cll.pdf

6. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed March 22, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms

7. Imbruvica. Prescribing information. Janssen Biotech Inc; 2020. Accessed March 22, 2021. https://imbruvica.com/files/prescribing-information.pdf

8. Venclexta. Prescribing information. AbbVie Inc; 2020. Accessed March 17, 2021. https://www.rxabbvie.com/pdf/venclexta.pdf

9. Study evaluating safety and efficacy of JCAR017 in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Clinical Trials.gov. Updated August 28, 2020. Accessed March 15, 2021. https://clinicaltrials.gov/ct2/show/NCT03331198

10. Siddiqi T, Soumerai JD, Dorritie KA, et al. Updated follow-up of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma treated with lisocabtagene maraleucel in the phase 1 monotherapy cohort of Transcend CLL 004, including high-risk and ibrutinib-treated patients. Blood. 2020;136(suppl 1):40-41. doi:10.1182/blood-2020-140491

11. Maziarz RT, Schuster SJ, Romanov VV, et al. Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020;4(7):1440-1447. doi:10.1182/bloodadvances.2019001305

12. Gartlehner G, Hansen RA, Nissman D, Lohr KN, Carey TS, eds. Criteria for Distinguishing Effectiveness From Efficacy Trials in Systematic Reviews. Agency for Healthcare Research and Quality (US); 2006. Accessed March 22, 2021. https://www.ncbi.nlm.nih.gov/books/NBK44029/

13. Fürstenau M, De Silva N, Eichhorst B, Hallek M. Minimal residual disease assessment in CLL: ready for use in clinical routine? Hemasphere. 2019;3(5):e287. doi:10.1097/HS9.0000000000000287

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