Dr Dorritie on the Clinical Implications of the 5-Year Follow-Up Data From CAPTIVATE in CLL/SLL

 mutation, which is really reassuring, because we do know that patients who stay on BTK inhibitors for a longer period of time are at risk of developing those mutations.”

Kathleen A. Dorritie, MD, hematologist/medical oncologist, the University of Pittsburgh Medical Center’s Hillman Cancer Center; assistant professor, medicine, Division of Oncology, Department of Medicine, University of Pittsburgh, discusses 

5-year of follow-up data from the phase 2 CAPTIVATE trial (NCT02910583)

 in patients with chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma.

This investigation evaluated first-line, fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta), which continued to elicit clinically meaningful progression-free survival and deep remissions, according to the follow-up data, which were shared at the 

. This 5-year follow-up provides valuable insights into the combination’s efficacy and potential to mitigate resistance mechanisms associated with single-agent targeted therapies, Dorritie begins.

At up to 5.5 years of follow-up, with a median follow-up of 61.2 months (range, 0.8-66.3), the 5-year PFS rate was 67%. Most of the patients who progressed did so mostly after the 2-year treatment cutoff, she reports. Encouragingly, among patients who required retreatment, most responded effectively, she adds. This indicates that fixed-duration therapy may offer an effective approach to limit prolonged exposure to these agents, reducing toxicity and delaying the emergence of resistance mutations, Dorritie explains. The ability to achieve a robust response upon retreatment adds further support for this strategy, demonstrating that patients can still derive substantial benefit when therapy is resumed, she emphasizes.

Additionally, the development of resistance mutations was notably rare in this study, according to Dorritie. Among the cohort of patients who experienced disease progression, only one developed a 

 mutations, she continues. This is reassuring given the known risks of resistance mutations associated with prolonged use of BTK inhibitors, she says. These findings highlight the potential of fixed-duration ibrutinib plus venetoclax to maintain disease control and simultaneously minimize long-term risks, offering a balanced treatment approach for patients with CLL, Dorritie concludes.

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Kathleen A. Dorritie, MD, discusses 5-year of follow-up data from the CAPTIVATE trial in chronic lymphocytic leukemia and/or small lymphocytic lymphoma.

Dr Dorritie on Acalabrutinib With/Without Obinutuzumab in Treatment-Naive CLL

Kathleen A. Dorritie, MD, hematologist/medical oncologist at the University of Pittsburgh Medical Center’s Hillman Cancer Center and assistant professor of medicine in the Division of Oncology, Department of Medicine, University of Pittsburgh, discusses the clinical implications of the 6-year follow-up data from the phase 3 ELEVATE-TN study (NCT02475681) evaluating acalabrutinib (Calquence) with or without obinutuzumab (Gazyva) vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia (CLL).

 demonstrated that both acalabrutinib-containing regimens demonstrated an improvement in progression-free survival (PFS) compared with the control arm. The median PFS was not reached (NR) in the acalabrutinib plus obinutuzumab arm (HR, 0.14; 95% CI, 0.10-0.20; 

 < .001) and the acalabrutinib monotherapy arm (HR, 0.24; 95% CI, 0.17-0.32; 

Additionally, overall response rates (ORRs) compared with the control arm were higher for both acalabrutinib plus obinutuzumab and acalabrutinib monotherapy (difference, 6.1%; 95% CI, 0.9%-11.4%; 

 = .022). Complete response rates were also improved in the acalabrutinib arms (difference, 17.9%; 95% CI, 8.8%-27.0%; 

The safety profile of acalabrutinib was consistent with previous findings, Dorritie explains, with adverse effects largely limited to manageable cytopenias and infections, she adds. These findings reinforce acalabrutinib’s position as a frontline treatment option for patients with CLL, allowing clinicians to tailor treatment strategies based on individual patient needs.

She explains that although benefits were observed in both of the acalabrutinib-containing arms, the use of the combination was associated with deeper responses in terms of minimal residual disease negativity.

Kathleen A. Dorritie, MD, discusses acalabrutinib with or without obinutuzumab vs obinutuzumab plus chlorambucil in treatment-naïve CLL.

Kathleen A. Dorritie, MD, discusses unmet needs regarding upfront treatment selection in chronic lymphocytic leukemia.

Dr Dorritie on Unanswered Questions Regarding Upfront Treatment Selection in CLL

Kathleen A. Dorritie, MD, hematologist/medical oncologist, the University of Pittsburgh Medical Center’s Hillman Cancer Center; assistant professor of medicine, Division of Oncology, Department of Medicine, University of Pittsburgh, discusses persistent unmet needs and unanswered questions regarding upfront treatment selection in chronic lymphocytic leukemia (CLL).

A pressing question within the treatment of CLL is determining the optimal up-front treatment for patients, Dorritie begins. Ongoing debate also currently surrounds whether it is more beneficial to administer a BTK inhibitor as a fixed-duration regimen alongside a CD20 monoclonal antibody, or to opt for venetoclax plus a monoclonal antibody, she expands.

The emergence of data supporting the use of ibrutinib (Imbruvica) and venetoclax (Venclexta), adds another layer of complexity to treatment decision-making in this setting, Dorritie continues. Prior to the read out of these data, the general consensus was to administer BTK inhibitors as a continuous therapy, Dorritie says. This approach facilitated straightforward discussions with patients about their preference for long-term BTK inhibitor therapy vs a fixed-duration treatment.

However, recent data complicates this narrative by showing that administering ibrutinib in combination with venetoclax—both targeted, oral agents—can yield high response rates and allow for treatment discontinuation, with the option for patients to resume treatment upon disease progression, Dorritie explains. In light of this development, a reevaluation of treatment strategies and consideration of the benefits of continuous vs fixed-duration approaches is necessary, she emphasizes.

Another unanswered question surrounds the potential impact of using highly potent drugs in the upfront setting on future later-line treatment strategies, Dorritie states. If the strongest therapies are utilized initially, the arsenal may be depleted for later stages of the disease, potentially limiting the options available for patients who relapse or experience disease progression, Dorritie concludes.

This underscores the complexity of personalized treatment planning in CLL, and both immediate efficacy and long-term strategy must be considered when determining the most effective and sustainable approaches for each patient.

Dr Dorritie on the NCRI-FLAIR Trial of Ibrutinib Plus Venetoclax in Previously Untreated CLL

Kathleen A. Dorritie, MD, hematologist/medical oncologist, the University of Pittsburgh Medical Center’s Hillman Cancer Center; assistant professor of medicine, Division of Oncology, Department of Medicine, University of Pittsburgh, discusses the significance of results from the phase 3 National Cancer Research Institute (NCRI) FLAIR study (ISRCTN01844152) of ibrutinib (Imbruvica) plus venetoclax (Venclexta) in previously untreated chronic lymphocytic leukemia (CLL).

The NCRI-FLAIR study compared ibrutinib and venetoclax with fludarabine, cyclophosphamide, and rituximab (FCR) in untreated CLL, and assessed whether a personalized treatment duration using peripheral blood minimal residual disease (MRD) response as a measure could optimize outcomes, Dorritie details. Unlike previous trials, NCRI-FLAIR excluded the higher-risk patients with 

-mutated CLL and employed an adaptive design allowing patients to discontinue therapy upon achieving MRD negativity, she notes. The study's primary end point was investigator-assessed progression-free survival (PFS). Key secondary end points presented included overall survival (OS), IWCLL response, MRD, and safety. All appropriate end points were analyzed according to CLL prognostic sub-groups.

Results demonstrated substantially higher rates of MRD negativity with the ibrutinib plus venetoclax combination, reaching approximately 60% overall vs 40% with FCR across all MRD testing methods, Dorritie reports. Moreover, the majority of patients attained MRD negativity in peripheral blood with the ibrutinib plus venetoclax regimen, she says. This translated into superior overall response rates, prolonged PFS, and OS benefits. In the primary analysis, the PFS rate at 3 years was 97.2% in the ibrutinib plus venetoclax arm vs 76.8% in the FCR arm, for a hazard ratio of 0.13 (95% CI, 0.07-0.24; 

Notably, high PFS rates were observed among higher risk 

-unmutated patients, a subgroup historically associated with poorer outcomes, Dorritie adds. This finding suggests that the combination therapy could potentially elevate the prognosis of these patients to a level comparable to that of standard-risk individuals, she concludes.

Kathleen A. Dorritie, MD, discusses the significance of results from the phase 3 NCRI-FLAIR study in previously untreated chronic lymphocytic leukemia.

Kathleen ​A. Dorritie, MD, hematologist/medical oncologist​, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center​, discusses transplant eligibility in multiple myeloma.

Transplant eligibility criteria are continually evolving and var​y based on geographic location. For example, in Europe, age may have a more significant role in determining whether a patient is eligible for transplant, Dorritie says.

Further, it’s important to be aware of the patient's comorbidities because ​transplants are known to be quite toxic. As such, patients who have ​an extensive history of cardiac or renal disease are not eligible ​for transplant, Dorritie adds.

Notably, trials such as the ​phase 3 MAIA trial, which evaluated ​the combination of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone vs lenalidomide/dexamethasone alone in patients with transplant-ineligible multiple myeloma, will help to determine whether transplant should be included in the treatment paradigm for patients with newly diagnosed multiple myeloma, Dorritie concludes.

Kathleen ​A. Dorritie, MD, discusses transplant eligibility in multiple myeloma.

Kathleen A. Dorritie, MD

Articles

Dr Dorritie on the Clinical Implications of the 5-Year Follow-Up Data From CAPTIVATE in CLL/SLL

Dr Dorritie on Acalabrutinib With/Without Obinutuzumab in Treatment-Naive CLL

Dr Dorritie on Unanswered Questions Regarding Upfront Treatment Selection in CLL

Dr Dorritie on the NCRI-FLAIR Trial of Ibrutinib Plus Venetoclax in Previously Untreated CLL

Dr. Dorritie on Determining Transplant Eligibility in Multiple Myeloma