Consensus recommendations for CLL/SLL treatment selection and sequencing in the US

[CLLerinOz]

In the past ten years, there has been a shift away from treating CLL/SLL with chemoimmunotherapy to treating it with more targeted therapies. To support practitioners in real world settings in the US, the Leukemia Research Foundation convened a panel of CLL/SLL specialists to write a consensus statement that complements existing guidelines and provides recommendations for the care of patients with CLL/SLL.

"Over the past decade, treatment recommendations for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) have shifted from traditional chemoimmunotherapy to targeted therapies. Multiple new therapies are commercially available, and in many cases a lack of randomized clinical trial data makes selection of the optimal treatment for each patient challenging. Additionally, many patients continue to receive chemoimmunotherapy in the US, suggesting a gap between guidelines and real-world practice. The Lymphoma Research Foundation convened a workshop comprised of a panel of CLL/SLL experts in the US to develop consensus recommendations for selection and sequencing of therapies for patients with CLL/SLL in the US. Herein, the recommendations are compiled for use as a practical clinical guide for treating providers caring for patients with CLL/SLL, which complement existing guidelines by providing a nuanced discussion relating how our panel of CLL/SLL experts in the US care for patients in a real-world environment."

The statement covers the following topics:

Decision to initiate therapy

Recommended frontline therapeutic options

Choice of cBTKi in CLL/SLL

Selection of initial therapy

Second-line therapy after a frontline cBTKi

Second-line therapy after frontline Ven-O

Second-line therapy after other therapies - Prior cytotoxic chemotherapy

Second-line therapy after other therapies - Prior therapy with a cBTKi and BCL2i with or without obinutuzumab

Treatment sequencing after ≥2 therapies including venetoclax and a cBTKi - For patients with CLL/SLL and two or more prior therapies including a cBTKi and venetoclax, when retreatment with venetoclax ± an anti-CD20 mAb or transitioning to an alternate cBTKi is not preferred, we recommend pirtobrutinib in most cases. In patients who are deemed good candidates, lisocabtagene maraleucel (liso-cel) should also be considered for this line or subsequent lines of therapy.

Treatment sequencing after ≥2 therapies including venetoclax and a cBTKi - For patients with CLL/SLL that is refractory to three prior therapies including venetoclax, a cBTKi, and pirtobrutinib, when treatment with liso-cel or participation in a clinical trial is not feasible or preferred, a PI3K𝛿 inhibitor should be considered.

Treatment sequencing after ≥2 therapies including venetoclax and a cBTKi - Referral to a CLL expert to discuss whether to pursue allogeneic stem cell transplant (alloSCT) may be considered for patients with CLL/SLL who are refractory to at least 2 prior therapies including venetoclax and a cBTKi and who obtained a remission to a subsequent therapy.

Clinical trials

MRD

Resistance mutations

Figure 1: When to use a covalent BTK inhibitor vs venetoclax plus obinutuzumab in CLL or SLL.

Figure 2: Treatment algorithms for CLL or SLL.

Table 1: Pretreatment patient and disease assessments in CLL or SLL

Table 2: Past medical history, active co-morbidities and concomitant medications, and therapy selection

Table 3: Special treatment situations

Table 4: MRD assessment

Table 5: Future directions

CONCLUSION: "Treatment selection should be individualized for patients with CLL/SLL. Pretreatment assessment should include clinical evaluation and testing of cytogenetic and molecular features. Line of treatment, previous treatments, comorbidities, and concomitant medications should be considered when selecting treatment, and shared decision-making used to incorporate patient preferences. Much research remains ongoing (Table 5), and we will reconvene the LRF CLL Working Group as the treatment landscape evolves for patients with CLL/SLL."

Jacob D Soumerai, Jacqueline Claudia Barrientos, Inhye E. Ahn, Catherine C. Coombs, Douglas E Gladstone, Marc S Hoffmann, Adam S Kittai, Ryan W Jacobs, Andrew Lipsky, Krish Patel, Joanna M Rhodes, Alan P Skarbnik, Meghan C. Thompson, Daniel A. Ermann, Patrick K Reville, Harsh R. Shah, Jennifer R Brown, Deborah M Stephens; Consensus Recommendations from the 2024 Lymphoma Research Foundation Workshop on Treatment Selection and Sequencing in CLL or SLL. Blood Adv 2024; bloodadvances.2024014474. doi: doi.org/10.1182/bloodadvanc...

To read the full document, select the 'PDF' option after opening the link above.

As it makes clear, it's a document for those in the US and some of the treatments it includes may not yet be available everywhere else.

(Note: this is an unlocked post. - if you have a question about your own situation, you may wish to start your own locked post. You can read more about that here: healthunlocked.com/cllsuppo... )

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[joed1rt]

I'm pretty sure that FCR is still the preferred initial first treatment for patients under 65 (like myself) here in Canada. I understand that the latest long term data on FCR shows it can produce a very long remission in some mutated patients (20+ years). Is it being dropped in other countries because of the potential side effects like secondary cancers, mutations etc. and the ease of the new treatments on older patients?

Thanks

[Emgeegee in reply to joed1rt]

In my province of Saskatchewan, a BTKi was recommended to me (4 years ago) as a first line treatment, as I am unmutated (and 13q deleted - no other mutations). If I had refused that, I could have done obinituzimab plus clorambucil. FCR was not even suggested. I am under 65.

[New-bee-cell in reply to joed1rt]

My experience here in Ontario is that one would only be offered FCR if IVIG mutated (and younger/fit). Although I am younger than 65, mutated and considered fit, my hematologist heard my discomfort with the post-FCR increased risk for Acute Myeloid Leukaemia, and is treating me with O + V. If I had wanted FCR, I think he would have provided it. Not sure whether this choice is provided in all provinces or by all Canadian doctors though.

[SFF95]

Great information. Thanks for posting

[CLLerinOz Administrator]

On 11 March 2025, the journal Blood Advances again featured the consensus guidelines for the treatment of CLL that were shared in this post late last year (link is in parent post).

Accompanying that article is a commentary article written by Mazyar Shadman, Bita Fakhri and Nitin Jain who discuss:

- the paradigm shift in CLL treatment in the past decade with the advent of targeted therapies

"Although the phrase “paradigm shift” is often used in oncology, its use is truly justified when describing the transformation of the CLL treatment landscape after the introduction of targeted agents."

- The need to engage expert advice and make shared treatment decisions, weighing up disease, treatment and patient related factors

"In conversation with patients, in-depth discussions are essential to highlight the differences, pros, and cons of each approach. These shared decisions are made by considering disease-related factors (molecular and cytogenetic markers), treatment-related factors (duration, adverse event profiles), and patient-related factors (age, comorbidities, social support, and patient preferences). Consensus guidelines are valuable in highlighting the discussion points to facilitate these nuanced conversations by incorporating updated data from long-term follow-up of the trials and the cumulative safety information. ³ "

- the scope of the consensus guidelines

"As is inherent to any consensus guidelines, the panel was understandably cautious to remain inclusive, unbiased, and evidence based. At the same time, they have done an exceptional work in sharing their expert opinions in areas where published data are either lacking or unclear."

- current clinical trials and investigations that may lead to further recommendations

First line therapy:

SWOG S1925 (NCT04269902) - does early intervention with time-limited venetoclax and obinutuzumab improve survival in patients with high-risk CLL

CLL17 study (NCT04608318) - compares ibrutinib (indefinite), venetoclax and obinutuzumab (time limited), and ibrutinib and venetoclax (time limited)

MAJIC trial (NCT05057494) - acalabrutinib, in combination with venetoclax vs the current standard of care, venetoclax and obinutuzumab

CELESTIAL TNCLL study (NCT06073821) - time-limited zanubrutinib and sonrotoclax vs venetoclax and obinutuzumab

BRUIN CLL-314 (NCT05254743) - pirtobrutinib vs ibrutinib

BELLWAVE-011 (NCT06136559) - nemtabrutinib vs BTK inhibitor of choice

BRUIN-CLL-322 (NCT04965493) - explores potential added benefit of pirtobrutinib in combination iwth ventoclax and rituximab

BELLWAVE-010 (NCT05947851) - venetoclax and nemtabrutinib vs venetoclax and rituximab

Relapsed/Refractory therapy:

BTK degraders, T-cell engagers, novel cellular immunotherapies, and new targeted agents along with a number of both industry-sponsored and investigation initiated studies that "explore different combination and sequencing strategies for treatment of CLL and may make it to the next versions of the guidelines" including those that "may illuminate and guide the use of measurable residual disease testing in clinical practice."

"Furthermore, the integration of information about resistance mutations that may arise in patients treated with BTK inhibitors or B-cell lymphoma 2 inhibitors is likely to shape future management strategies and could potentially make it to future practice guidelines."

- the challenge of providing equitable access to recommended therapies and the need for guidelines that are tailored to local resources and accommodate different tiers of access

"Unfortunately, availability, accessibility, and affordability are only true in a small number of countries, as access to nonchemotherapy CLL therapies remains very limited globally. Even when available, patients in many areas of the world may only have access to a limited selection of options, and the high cost of these drugs remains prohibitive.⁴ Systematic research is needed to better understand the details of practice in the global context, where deviation from approved treatment schedules and dosing may occur due to cost and access issues . . . there is an unmet need for developing CLL practice guidelines tailored to the available local resources and designed to accommodate different tiers of access. Such guidelines must consider both diagnostic limitations and availability of therapeutic agents. For example, recommendations for a setting where only ibrutinib is accessible must differ from those for a setting with broader access to diagnostics and CLL therapeutics."

"We sincerely hope that these recommendations are updated, balancing access and excess, regularly given the rapidly evolving landscape of CLL treatment. As we collectively strive for universal access to novel diagnostic and therapeutic resources globally, we call on the CLL expert community and professional organizations to take action in developing practice guidelines that are customized and resource specific. This effort is essential to ensure that all patients living with a diagnosis of CLL receive the best possible care to overcome geographic health disparities."

Mazyar Shadman, Bita Fakhri, Nitin Jain; Consensus in CLL: global needs matter. Blood Adv 2025; 9 (5): 1210–1212. doi: doi.org/10.1182/bloodadvanc...

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