Initial treatment of CLL: integrating biology and functional status

Jain, Nitin; O’Brien, Susan

doi:10.1182/blood-2015-04-585067

Cited by 70 publications

(48 citation statements)

References 69 publications

(61 reference statements)

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“…2 In the United States, age is most commonly used to identify patients eligible for intensive CIT, with patients younger than 65 years of age typically offered CIT as first-line therapy. The German CLL Study Group (GCLLSG) has used comorbidity index (Cumulative Illness Rating Scale [CIRS]) and renal function to identify CIT-eligible patients (CIRS #6 and creatinine clearance $70 mL per minute).…”

Section: Learning Objectivesmentioning

confidence: 99%

“…Besides FCR and BR, several other CIT combinations have been explored; however, none of these regimens have been compared directly to the standard FCR regimen, and do not appear to be superior based on the reported phase 2 data. 2 It is important to note that the outcomes of patients with deletion 17p or TP53 mutation remain dismal with CIT, with a median PFS of ,12 months 5 ; therefore, targeted therapies (described in the next section) are the standard first-line choice for this group of patients.…”

Section: Chemoimmunotherapymentioning

confidence: 99%

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First-line therapy for young patients with CLL

Jain

O’Brien

2016

Hematology

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A 61-year-old man with a history of chronic lymphocytic leukemia (CLL) presents with complaints of worsening fatigue and night sweats. He was diagnosed with CLL 3 years ago on routine blood count testing. He has no major medical comorbidities. On examination, he has several 2-to 3-cm lymph nodes in the cervical and axillary area. Spleen is palpable 5 cm below the costal margin. Blood counts show lymphocytosis with thrombocytopenia and anemia. Prognostic markers include deletion 13q by fluorescence in situ hybridization analysis and mutated IGHV. You are asked by the hematology fellow you are supervising about the best treatment of this patient. Learning Objectives• To understand the role of chemoimmunotherapy in the management of young patients with CLL • To understand the role of novel targeted therapies in this patient population • To recognize the emerging role of IGHV mutation status in treatment selection for these patients Therapy options for patients with chronic lymphocytic leukemia (CLL) have undergone a remarkable evolution in the last several years. 1 Though chemoimmunotherapy (CIT) has been the standard first-line option for young fit patients with CLL, the overall role of CIT in the management of patients with CLL is diminishing with an increasing role for targeted therapies. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has shown remarkable clinical activity in patients with CLL, and is currently approved for patients with CLL, both for previously untreated, and for patients with relapsed disease. Idelalisib, a phosphatidylinositol 3-kinase (P13K) kinase inhibitor, is approved in combination with rituximab for patients with relapsed CLL. Venetoclax, a BCL-2 inhibitor, was recently approved for patients with relapsed CLL with deletion 17p. Several other agents are in clinical development and will likely further enhance the therapeutic armamentarium. Early trials with these targeted therapies were conducted in relapsed/refractory patients; these drugs are now being explored in the first-line setting in several trials, including in "young fit" patients (the patient in the scenario in the Abstract).The definition of "young fit" (ie, those eligible for intensive CIT) varies.2 In the United States, age is most commonly used to identify patients eligible for intensive CIT, with patients younger than 65 years of age typically offered CIT as first-line therapy. The German CLL Study Group (GCLLSG) has used comorbidity index (Cumulative Illness Rating Scale [CIRS]) and renal function to identify CIT-eligible patients (CIRS #6 and creatinine clearance $70 mL per minute).3 CIT has been the standard therapy for this group of patients; however, ibrutinib is currently approved for all patients with CLL, including young fit patients with CLL who would otherwise be eligible for CIT. This poses a question about the appropriate therapy for this group of patients. ChemoimmunotherapyCIT, such as with fludarabine, cyclophosphamide (FC), rituximab (FCR), has been the standard therapy for CLL (Table 1). In a singlec...

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Section: Learning Objectivesmentioning

confidence: 99%

Section: Chemoimmunotherapymentioning

confidence: 99%

First-line therapy for young patients with CLL

Jain

O’Brien

2016

Hematology

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“…In the United States, approximately 130,000 patients live with CLL, and approximately 15,000 new cases occur every year. 1 Although most patients with CLL have early-stage disease at the time of initial diagnosis and are recommended for watchful waiting, 2 the majority eventually require treatment, typically after a few years of observation, and often experience prolonged survival. 3,4 Chemoimmunotherapy (CIT) regimens, such as fludarabine, cyclophosphamide, and rituximab (FCR), have been the standard first-line treatment of young patients with CLL.…”

Section: Introductionmentioning

confidence: 99%

Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States

Chen

Jain

Ayer

et al. 2017

JCO

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Purpose Oral targeted therapies represent a significant advance for the treatment of patients with chronic lymphocytic leukemia (CLL); however, their high cost has raised concerns about affordability and the economic impact on society. Our objective was to project the future prevalence and cost burden of CLL in the era of oral targeted therapies in the United States. Methods We developed a simulation model that evaluated the evolving management of CLL from 2011 to 2025: chemoimmunotherapy (CIT) as the standard of care before 2014, oral targeted therapies for patients with del(17p) and relapsed CLL from 2014, and for first-line treatment from 2016 onward. A comparator scenario also was simulated where CIT remained the standard of care throughout. Disease progression and survival parameters for each therapy were based on published clinical trials. Results The number of people living with CLL in the United States is projected to increase from 128,000 in 2011 to 199,000 by 2025 (55% increase) due to improved survival; meanwhile, the annual cost of CLL management will increase from $0.74 billion to $5.13 billion (590% increase). The per-patient lifetime cost of CLL treatment will increase from $147,000 to $604,000 (310% increase) as oral targeted therapies become the first-line treatment. For patients enrolled in Medicare, the corresponding total out-of-pocket cost will increase from $9,200 to $57,000 (520% increase). Compared with the CIT scenario, oral targeted therapies resulted in an incremental cost-effectiveness ratio of $189,000 per quality-adjusted life-year. Conclusion The increased benefit and cost of oral targeted therapies is projected to enhance CLL survivorship but can impose a substantial financial burden on both patients and payers. More sustainable pricing strategies for targeted therapies are needed to avoid financial toxicity to patients.

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“…CLL typically affects the elderly population, many of whom have preexisting conditions that restrict the use of the current standard treatment, which involves the combination of chemotherapeutic agents (fludarabine and cyclophosphamide) and an antibody (rituximab) (2, 3). Therefore, combination therapy that targets distinct biological pathways in CLL pathogenesis represents a significant step outside of the conventional chemotherapy-based approach.…”

Section: Introductionmentioning

confidence: 99%

Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses

Lamothe

Wierda

Keating

et al. 2016

Clinical Cancer Research

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Purpose Carfilzomib, while active in B-cell neoplasms displayed heterogeneous response in chronic lymphocytic leukemia (CLL) samples from patients and showed interpatient variability to carfilzomib-induced cell death. To understand this variability and predict patients that would respond to carfilzomib, we investigated the mechanism by which carfilzomib induces CLL cell death. Experimental Design Using CLL patient samples and cell lines, complementary knockdown and knockout cells, and carfilzomib-resistant cell lines, we evaluated changes in intracellular networks to identify molecules responsible for carfilzomib’s cytotoxic activity. Carfilzomib-treated cells were immunoblotted for molecules involved in ubiquitin, apoptotic, and endoplasmic reticulum (ER) stress response pathways and results correlated with carfilzomib cytotoxic activity. Co-immunoprecipitation and pull down assays were performed to identify complex interactions among MCL-1, Noxa, and Bak. Results Carfilzomib triggered ER stress and activation of both the intrinsic and extrinsic apoptotic pathways through alteration of the ubiquitin proteasome pathway. Consequently, the transcription factor CCAAT/enhancer-binding protein homology protein (CHOP) accumulated in response to carfilzomib, and CHOP depletion conferred protection against cytotoxicity. Carfilzomib also induced accumulation of MCL-1 and Noxa, whereby MCL-1 preferentially formed a complex with Noxa and consequently relieved MCL-1’s protective effect on sequestering Bak. Accordingly, depletion of Noxa or both Bak and Bax conferred protection against carfilzomib-induced cell death. Conclusions Collectively, carfilzomib induced ER stress culminating in activation of intrinsic and extrinsic caspase pathways, and we identified the CHOP protein level as a biomarker that could predict sensitivity to carfilzomib in CLL.

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Initial treatment of CLL: integrating biology and functional status

Cited by 70 publications

References 69 publications

First-line therapy for young patients with CLL

First-line therapy for young patients with CLL

Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States

Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses

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