Kathleen A. Dorritie, MD, is a hematologist/medical oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania. 

Dr Dorritie on the Use of Pirtobrutinib Following Prior BTK Inhibition in CLL

“[Liso-cel] is a newer option for patients…. It is important to get the word out to community [oncologists] that patients do better with CAR T-cell therapy and that they should be referred to tertiary centers."

Kathleen A. Dorritie, MD, a hematologist/medical oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed data that inform the current treatment paradigm of BTK inhibitors and CAR T-cell therapy for the treatment of patients with chronic lymphocytic leukemia (CLL).

Prior data have demonstrated the activity of pirtobrutinib (Jaypirca)—the first and only noncovalent, reversible BTK inhibitor—in patients with CLL who previously developed resistance to covalent BTK inhibitors, such as acalabrutinib (Calquence), ibrutinib (Imbruvica), or zanubrutinib (Brukinsa), Dorritie began. Findings from the phase 1/2 BRUIN trial (NCT03740529) established pirtobrutinib as an important therapeutic option in this setting, she explained.

, updated data were presented regarding the efficacy of lisocabtagene maraleucel (liso-cel; Breyanzi) in patients with CLL. Notably, in ​2024, 

 for the treatment of adult patients with relapsed or refractory CLL or small lymphocytic lymphoma who have received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Importantly, real-world outcomes with liso-cel were shared at ASCO 2025, providing evidence to support the use of this agent beyond the clinical trial setting, according to Dorritie. In these analyses, liso-cel was compared with standard-of-care (SOC) chemoimmunotherapy regimens. Both progression-free survival and overall survival were superior in the liso-cel cohort relative to the SOC cohort, reinforcing the clinical benefit of CAR T-cell therapy in CLL, she said.

These real-world findings underscore the growing role of CAR T-cell therapy as a viable and effective treatment modality in CLL, Dorritie emphasized. They further highlight the importance of raising awareness among community oncologists regarding timely referral of eligible patients to tertiary centers where cellular therapy can be delivered, as patient outcomes are demonstrably improved with this approach, she concluded.

Videos

Kathleen A. Dorritie, MD, discusses data that inform the use of pirtobrutinib and liso-cel for the treatment of patients with chronic lymphocytic leukemia.

Kathleen A. Dorritie, MD, details the difference in care between the management of untreated CLL and relapsed/refractory CLL.

Dr Dorritie on the Management of Untreated and Relapsed/Refractory CLL

“In the newly diagnosed setting, [care for CLL] has really changed with the results from studies like AMPLIFY and also the ELEVATE-TN population. Essentially, at this point, we've now had evidence both from AMPLIFY and from ELEVATE-TN that directed therapies.”

Kathleen A. Dorritie, MD, a hematologist/medical oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center, detailed differing care among patients with newly diagnosed chronic lymphocytic leukemia (CLL) compared with patients with relapsed/refractory CLL who have received multiple lines of therapy.

The difference in care for patients with CLL in the newly diagnosed setting has changed following data from the phase 3 AMPLIFY trial (NCT03836261) and phase 3 ELEVATE-TN trial (NCT02475681), Dorritie began.

Of note, the AMPLIFY trial evaluated fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta) vs acalabrutinib plus venetoclax and obinutuzumab (Gazyva) vs chemoimmunotherapy for the treatment of patients with untreated CLL.

Additionally, the ELEVATE-TN study investigated acalabrutinib with or without obinutuzumab in patients with untreated CLL. In particular, the study compared acalabrutinib plus obinutuzumab with acalabrutinib monotherapy and with chlorambucil plus obinutuzumab. 

Specifically, the implementation of BTK inhibitors and venetoclax, a BCL2 inhibitor, as upfront treatment is becoming the standard of care in treatment-naive CLL, Dorritie continued. She noted that now, fewer patients are treated with only an upfront chemotherapy regimen for untreated CLL. Both the AMPLIFY and ELEVATE-TN studies have demonstrated that patients who are treated with targeted therapies showed improved outcomes vs those treated with standard chemoimmunotherapy, she added.

Furthermore, in the relapsed/refractory CLL setting, a remaining question includes how subsequent therapies should be sequenced, which requires additional information, such as what patients were previously treated with, how they responded to those therapies, and the toxicities they experienced related to a specific treatment, Dorritie emphasized. These factors ultimately and collectively guide the next treatment option for this patient population, she concluded.

Kathleen A. Dorritie, MD, discusses the role of quadruplet regimens for the treatment of patients with multiple myeloma.

Dr Dorritie on the Role of Quadruplet Regimens in Multiple Myeloma

“Any patient [with multiple myeloma] who can possibly tolerate a quadruplet [regimen] should be offered a quadruplet because we [can] improve overall response rates and rates of [minimal residual disease] negativity [with these regimens], which translate into progression-free survival benefits.”

Kathleen A. Dorritie, MD, a hematologist/medical oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the role of quadruplet regimens for the treatment of patients with multiple myeloma.

Although triplet regimens have remained the standard of care for patients with multiple myeloma for a significant amount of time, quadruplet regimens are becoming more relevant for these patients, Dorritie began. A significant amount of data have emerged, particularly in the transplant-eligible setting, from the phase 2 GRIFFIN trial (NCT02874742) and the phase 3 PERSEUS trial (NCT03710603), she noted. The studies compared quadruplet regimens with triplet regimens, she explained.

For example, in GRIFFIN, daratumumab (Darzalex) plus lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (D-RVd) was compared with lenalidomide, bortezomib, and dexamethasone (RVd) in patients with newly diagnosed multiple myeloma. At a median follow-up of 49.6 months (IQR, 47.4-52.1), the stringent complete response rate was 67% in the D-RVd arm (n = 100) compared with 48% in the RVd arm (n = 98; odds ratio, 2.18; 95% CI, 1.22-3.89; 

 = .0079). Of note, the 4-year progression-free survival (PFS) rate was 87.2% (95% CI, 77.9%-92.8%) in the investigational arm compared with 70.0% (95% CI, 55.9%-80.3%) in the control arm.

Furthermore, patients who are considered transplant-ineligible or transplant deferred were included in the phase 3 IMROZ (NCT03319667), CEPHEUS (NCT03652064), and BENEFIT (NCT04751877) trials, Dorritie continued. Data from these trials demonstrated that patients who can potentially tolerate a quadruplet regimen should be offered a quadruplet regimen instead of a triplet due to improved overall response rates, along with minimal residual disease negativity, which can lead to PFS benefits, she said.

Overall, the takeaway is that quadruplet regimens should be given to all patients with multiple myeloma if eligible, and triplet regimens to those who are ineligible for quadruplet. These regimens are more widely used in clinical practice, as doublet regimens are no longer a standard of care option, Dorritie concluded.

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.

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