The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Novel Comorbidity Score Derived from a Large Multicenter Retrospective Cohort Study of Patients Treated with Ibrutinib and/or Chemo-Immunotherapy (CIT)

Gordon, Max J.; Kaempf, Andy; Sitlinger, Andrea; Salous, Tareq; Alqahtani, Hamood; Churnetski, Michael C.; Wisniewski, Paul; Rivera, Xavier; Patel, Krish; Persky, Daniel O.; Cohen, Jonathon B.; Choi, Michael Y.; Hill, Brian T.; Shadman, Mazyar; Stephens, Deborah M.; Brander, Danielle M.; Park, Byung; Danilov, Alexey V.

doi:10.1182/blood-2019-124631

Cited by 3 publications

(4 citation statements)

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“…They also found that hypertension and cardiac comorbidities did not improve CLL-CI’s discriminatory power. 48 Even in our series, cardio-comorbidities did not affect survival outcomes, possibly because of an a priori exclusion and accurate selection of patients before starting ibrutinib treatment.…”

Section: Discussionmentioning

confidence: 56%

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

et al. 2021

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Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In ibrutinib era it is still unclear whether age, CIRS and ECOG-PS retain their predictive role on treatment vulnerability. In this 712 CLL patients series treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia, resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions may affect drug management. We confirmed the role of CIRS>6 as a predictor of a poorer progression and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDR), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A-inhibitors with ibrutinib. In our series, these factors had no impact, though CYP3A4 inhibitors use correlated at Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes and importantly neutropenia emerged as a relevant tool influencing patients vulnerability. Although CIRS>6 retained a significant impact on PFS and EFS its value should be confirmed by prospective studies.

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Section: Discussionmentioning

confidence: 56%

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

et al. 2021

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“…Generally, patients with comorbidities do not respond as well to treatment as those without, and comorbidities, including musculoskeletal and endocrine problems, confer inferior outcomes in patients treated with ibrutinib. 44,77 However, this is yet to be evaluated in patients treated with acalabrutinib.…”

Section: Considerations For Treating Patientsmentioning

confidence: 99%

“…Before administration, a baseline medical history must be taken, including recent surgery/plans for surgery; history of cardiac arrhythmias; hypertension; infections (including history of hepatitis B virus infection); and current medications, including prescription, over‐the‐counter medicines and, importantly, herbs and supplements. Generally, patients with comorbidities do not respond as well to treatment as those without, and comorbidities, including musculoskeletal and endocrine problems, confer inferior outcomes in patients treated with ibrutinib 44,77 . However, this is yet to be evaluated in patients treated with acalabrutinib.…”

Section: Acalabrutinib: Clinical Usementioning

confidence: 99%

Incorporating acalabrutinib, a selective next‐generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies

Danilov

Persky

2020

Br J Haematol

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Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/ small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a firstin-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.

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“…Interestingly, neither cardiac disease nor hypertension were factors strongly associated with shortened survival in these patients. 60 While it may be intuitive that patients with comorbidities have worse outcomes with oncologic drug treatments, we have also shown that comorbidities have minimal impact on idelalisib therapy. 61 This further justifies exploration of the role of comorbidities in patients treated with second-generation BTK inhibitors.…”

Section: Something Blue: Challenges With Btk Inhibitionmentioning

confidence: 81%

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

Gordon

Danilov

2021

Therapeutic Advances in Hematology

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Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.

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The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Novel Comorbidity Score Derived from a Large Multicenter Retrospective Cohort Study of Patients Treated with Ibrutinib and/or Chemo-Immunotherapy (CIT)

Cited by 3 publications

References 0 publications

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Incorporating acalabrutinib, a selective next‐generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

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