Table 3. Special treatment situations... | American Society of Hematology

Table 3.

Special treatment situations

Topic	Consensus statement	Justification and supporting literature
When to consider a treatment holiday	For patients with CLL/SLL who discontinue therapy for intolerance, a treatment holiday can be considered.	This recommendation is based on the observation that among patients with CLL/SLL whose disease is responding to therapy, and who discontinue therapy for intolerance, some have durable treatment-free remissions. Little data exist to guide selection of patients for a treatment holiday. Our panel considers several factors, for example, duration of therapy and quality of response, in an effort to predict which patients will remain progression-free off therapy. In a single-arm study of elective ibrutinib discontinuation after ≥6 y of continuous therapy, most had decreased or stable disease after a ≥1-y treatment-free interval.⁷⁸ The panel is also more inclined to consider a treatment holiday in patients without high-risk molecular features, based on posttreatment MRD kinetics data from MURANO suggesting faster MRD doubling in the presence of high-risk molecular features.⁷⁹
How to transition from a cBTKi to Ven w/wo anti-CD20 mAb	In patients with progressive disease on a cBTKi who are recommended Ven w/wo an anti-CD20 mAb, the panel recommends a period of overlapping therapy, with the cBTKi generally stopped once there is evidence of disease control, which can range from 1 wk to 2 mo.	When CLL becomes resistant to a cBTKi, there are often subclones of resistant CLL cells and subclones of cells that are still responsive to the cBTKi. As such, abrupt discontinuation of a cBTKi without transition to another therapy can lead to rapid progression of CLL.⁷⁷ Safety data are available for each approved cBTKi combined with Ven and an anti-CD20 mAb.^80-82 We recommend initiating Ven w/wo an anti-CD20 mAb before stopping the cBTKi, as a period of overlap can prevent rapid progression of disease. The cBTKi can be stopped once there is evidence of disease control (eg, reduction of lymphocyte count, lymphadenopathy, splenomegaly, and/or CLL-related symptoms). This period of time can range from 1 wk to 2 mo.
How to administer Ven w/wo an anti-CD20 mAb in the retreatment setting	When retreatment with Ven w/wo anti-CD20 mAb is recommended, the decision to add anti-CD20 and the optimal treatment length should be individualized to each patient.	Data are lacking regarding the best approach for Ven retreatment (Ven monotherapy or Ven combined with rituximab or obinutuzumab). In the largest series of Ven retreatment, Ven was administered as monotherapy (45.7%) or in combination with rituximab (28.2%), obinutuzumab (10.9%), ibrutinib (4.4%), or another agent (10.9%).⁸³ When an anti-CD20 mAb is combined with Ven in the retreatment setting, the majority of the panel recommends obinutuzumab with Ven, which is initiated using a modified CLL14 schedule (refer to Section 5.2). Whether Ven should be stopped after 24 mo as in the MURANO trial or until progression or intolerance is unknown.⁶⁹^,⁷⁰ An ongoing prospective study evaluating retreatment with Ven plus obinutuzumab after frontline treatment with the same regimen will provide prospective data using this strategy (ReVenG; ClinicalTrials.gov identifier: NCT04895436).
When to consider off-label pirtobrutinib in Ven-naïve patients after a cBTKi	In a patient with a medical contraindication to Ven-based therapy, pirtobrutinib (off-label) may be considered in Ven-naïve patients after a cBTKi.	Pirtobrutinib is FDA approved for patients with CLL/SLL and ≥2 prior therapies including a cBTKi and Ven based on the BRUIN study.⁸⁴^,⁸⁵ Importantly, the BRUIN study included Ven-naïve patients (n = 154) and a post hoc analysis demonstrated a 2-y PFS of 83.1%. Therefore, in the setting of a medical contraindication to Ven-based therapy, pirtobrutinib may be considered in Ven-naïve patients after a cBTKi.

Topic	Consensus statement	Justification and supporting literature
When to consider a treatment holiday	For patients with CLL/SLL who discontinue therapy for intolerance, a treatment holiday can be considered.	This recommendation is based on the observation that among patients with CLL/SLL whose disease is responding to therapy, and who discontinue therapy for intolerance, some have durable treatment-free remissions. Little data exist to guide selection of patients for a treatment holiday. Our panel considers several factors, for example, duration of therapy and quality of response, in an effort to predict which patients will remain progression-free off therapy. In a single-arm study of elective ibrutinib discontinuation after ≥6 y of continuous therapy, most had decreased or stable disease after a ≥1-y treatment-free interval.⁷⁸ The panel is also more inclined to consider a treatment holiday in patients without high-risk molecular features, based on posttreatment MRD kinetics data from MURANO suggesting faster MRD doubling in the presence of high-risk molecular features.⁷⁹
How to transition from a cBTKi to Ven w/wo anti-CD20 mAb	In patients with progressive disease on a cBTKi who are recommended Ven w/wo an anti-CD20 mAb, the panel recommends a period of overlapping therapy, with the cBTKi generally stopped once there is evidence of disease control, which can range from 1 wk to 2 mo.	When CLL becomes resistant to a cBTKi, there are often subclones of resistant CLL cells and subclones of cells that are still responsive to the cBTKi. As such, abrupt discontinuation of a cBTKi without transition to another therapy can lead to rapid progression of CLL.⁷⁷ Safety data are available for each approved cBTKi combined with Ven and an anti-CD20 mAb.^80-82 We recommend initiating Ven w/wo an anti-CD20 mAb before stopping the cBTKi, as a period of overlap can prevent rapid progression of disease. The cBTKi can be stopped once there is evidence of disease control (eg, reduction of lymphocyte count, lymphadenopathy, splenomegaly, and/or CLL-related symptoms). This period of time can range from 1 wk to 2 mo.
How to administer Ven w/wo an anti-CD20 mAb in the retreatment setting	When retreatment with Ven w/wo anti-CD20 mAb is recommended, the decision to add anti-CD20 and the optimal treatment length should be individualized to each patient.	Data are lacking regarding the best approach for Ven retreatment (Ven monotherapy or Ven combined with rituximab or obinutuzumab). In the largest series of Ven retreatment, Ven was administered as monotherapy (45.7%) or in combination with rituximab (28.2%), obinutuzumab (10.9%), ibrutinib (4.4%), or another agent (10.9%).⁸³ When an anti-CD20 mAb is combined with Ven in the retreatment setting, the majority of the panel recommends obinutuzumab with Ven, which is initiated using a modified CLL14 schedule (refer to Section 5.2). Whether Ven should be stopped after 24 mo as in the MURANO trial or until progression or intolerance is unknown.⁶⁹^,⁷⁰ An ongoing prospective study evaluating retreatment with Ven plus obinutuzumab after frontline treatment with the same regimen will provide prospective data using this strategy (ReVenG; ClinicalTrials.gov identifier: NCT04895436).
When to consider off-label pirtobrutinib in Ven-naïve patients after a cBTKi	In a patient with a medical contraindication to Ven-based therapy, pirtobrutinib (off-label) may be considered in Ven-naïve patients after a cBTKi.	Pirtobrutinib is FDA approved for patients with CLL/SLL and ≥2 prior therapies including a cBTKi and Ven based on the BRUIN study.⁸⁴^,⁸⁵ Importantly, the BRUIN study included Ven-naïve patients (n = 154) and a post hoc analysis demonstrated a 2-y PFS of 83.1%. Therefore, in the setting of a medical contraindication to Ven-based therapy, pirtobrutinib may be considered in Ven-naïve patients after a cBTKi.