HCT: hematopoietic cell transplantation; IGHV: immunoglobulin heavy chain variable region; FCR: fludarabine, cyclophosphamide, and rituximab; BR: bendamustine, rituximab; MRD: measurable residual disease, also called minimal residual disease; PFS: progression-free survival; CIRS: cumulative illness rating scale; ECOG PS: Eastern Cooperative Oncology Group performance status; CrCl: creatinine clearance.
* Lymphocytosis itself, even if extreme, is not a strict indication for treatment. Likewise, treatment is not indicated solely on the basis of hypogammaglobulinemia or the presence of a monoclonal or oligoclonal paraproteinemia.
¶ Treatment is indicated if the patient develops significant disease-related complications at any time. During observation, we perform blood counts at 3-month intervals along with a clinical examination. At the end of 12 months, these evaluations can determine disease aggressiveness. The interval of examination may be lengthened for those with clinically stable disease.
Δ Among the targeted agents, we have the longest efficacy and safety data for ibrutinib. Initial reports suggest that venetoclax-based regimens are able to achieve MRD negativity in the majority of patients whereas ibrutinib and acalabrutinib rarely achieve MRD negativity. Longer follow-up is needed to determine whether this will translate into a PFS or overall survival difference. The trial that evaluated a time-limited course of venetoclax plus obinutuzumab was performed in patients who were older or had significant comorbidity; use in younger, fitter patients is extrapolated. The decision to add a monoclonal antibody to ibrutinib or acalabrutinib is individualized. The addition of obinutuzumab may improve PFS, but with added toxicity.
◊ Experts vary in the tools they use to assess fitness. This evaluation usually includes an assessment of comorbidities and their impact on function (eg, CIRS, ECOG PS, Geriatric assessment tools), kidney function, and liver function. Patients with 1 or more of the following findings are considered unfit for intensive cytotoxic chemotherapy regimens: CIRS >6, CrCl <70 mL/min, significant hepatic impairment (Child-Pugh class B or C), ECOG PS of 2 or greater.
§ Targeted therapy has demonstrated a PFS advantage over chemoimmunotherapy in patients with IGHV unmutated CLL.
¥ All of these options have demonstrated efficacy in patients with IGHV mutated CLL. We have the longest efficacy and safety data for chemoimmunotherapy and the shortest term data for venetoclax-based therapy and acalabrutinib. Subgroup analyses of this population have not demonstrated a PFS benefit for targeted therapy over chemoimmunotherapy and some studies suggest prolonged durable remissions with FCR. Clinicians often have concerns about the ability of older adults (eg, over age 70 years) to tolerate FCR. This decision can be complicated by an increased number of comorbidities.