Considerations in Front-Line Treatment Selection for CLL

Welcome to this Clinical Case Series learning module!

Here's how it works:

  1. Read these 3 case studies on selecting front-line treatments in CLL and the AP's role in managing patients in this population.
  2. Answer the poll next to each case to see how your colleagues are managing this patient population. You'll see results in real time.
  3. Continue your learning by watching a recording of a webinar presented by Laura J. Zitella, MS, RN, ACNP-BC, AOCN, as she delves deeper into the 3 cases and shares clinical pearls for advanced practitioners. Download the slides from the webinar for your reference.

Patient With History of Provoked Atrial Fibrillation, Subsequently Treated With Ibrutinib Plus Obinutuzumab With No Recurrence of Atrial Fibrillation

Patients with a history of atrial fibrillation treated with ibrutinib should be monitored closely for recurrence of atrial fibrillation.

Mr. Garcia is a 68-year-old man with prostate cancer on active surveillance, with a past medical history of hypertension, obesity, obstructive sleep apnea (treated with a CPAP), and chronic kidney disease. During his last evaluation for prostate cancer, it was noted that he harbored a monoclonal B-cell population in his peripheral blood and lymphadenopathy was observed on a PET-CT scan. His absolute lymphocyte count (ALC) was 38,000 cells/μL, and peripheral blood flow cytometry showed an atypical B-cell population that was CD5+, CD19+, and CD23+. Based on these findings, he was diagnosed with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Further testing identified an IgVH mutation, trisomy 12 by fluorescence in situ hybridization (FISH), and no deletion in chromosome 17p. Since Mr. Garcia was asymptomatic, he did not require treatment.

Mr. Garcia was followed by active surveillance every 3 months for 2 years, with no indication for treatment until February 2019, when he was hospitalized for sepsis. During this hospitalization, he developed atrial fibrillation (AF) with rapid ventricular rate during a febrile episode. The AF resolved with resolution of the infection and normalization of electrolytes. Following discharge, Mr. Garcia did not require treatment for AF because it was thought to be provoked by the febrile episode in the setting of hypokalemia.

He is seen in the clinic for a follow-up visit for CLL. Mr. Garcia’s laboratory values are summarized in the table below.

Table. Laboratory Values

Laboratory Parameters Values
White blood cell count 75,000 cells/μL

Hemoglobin 10.1 g/dL

Platelets 188,000 cells/μL

ALC 62,000 cells/μL

The decision was made to treat the CLL due to worsening anemia, fatigue, and the recent severe infection. At the time, ibrutinib plus obinutuzumab was the only non-chemotherapy combination approved by the U.S. Food and Drug Administration (FDA). The approval was based on the phase III iLLUMINATE trial data, in which clinical outcomes were superior with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab.1

Ibrutinib plus obinutuzumab was initiated. Following the second cycle, Mr. Garcia developed bilateral lower extremity (BLE) edema. The differential diagnosis included left ventricular dysfunction, lymphedema, deep vein thrombosis (DVT), or ibrutinib (22% incidence of peripheral edema2). BLE ultrasound showed no DVT or enlarged inguinal lymph nodes. An echocardiogram showed normal ejection fraction. The edema was thought to be due to ibrutinib and was treated to resolution with a short course of furosemide.

Mr. Garcia has been on ibrutinib for 5 years with excellent response and has not developed any other complications including recurrent AF. He continues to see his advanced practitioner (AP) for follow-up every 3 to 4 months.


  1. Moreno C, Greil R, Emirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43-56.
  2. IMBRUVICA (ibrutinib) capsules or tablets [prescribing information]. Sunnyvale, CA: Pharmacyclics LLC. 12/2020.

Previously Untreated CLL Patient Who Presented With Evans Syndrome (Autoimmune Hemolytic Anemia and Immune Thrombocytopenia)

As the treatment recommendations for CLL continue to evolve, there is ongoing shared decision-making based on clinical evidence of expected outcomes and potential risks balanced with patient preferences and values.

Ms. Anderson is a 48-year-old woman who presented in 2016 with flu-like symptoms, several nosebleeds, bleeding gums, and blood blisters in her mouth. She went to the ED, where her WBC count was 79,000 cells/μL, Hgb 9.2 g/dL, and platelets 2,000 cells/μL. She was urgently admitted, and peripheral blood flow cytometry and bone marrow biopsy were performed. The peripheral blood flow cytometry showed a CD5-positive lymphoproliferative disorder consistent with CLL. The bone marrow biopsy showed 70% chronic lymphocytic leukemia (CLL) involvement with adequate megakaryocytes. Fluorescence in situ hybridization (FISH) identified deleted chromosome 13q. IgVH somatic hypermutation analysis showed an unmutated IgVH. A CT of the chest, abdomen, and pelvis demonstrated lymphadenopathy in multiple nodal regions. Significant laboratory findings included anemia, positive direct Coombs test, indirect hyperbilirubinemia, decreased haptoglobin, and elevated serum lactate dehydrogenase (LDH), which was consistent with autoimmune hemolytic anemia. The profound thrombocytopenia in the setting of adequate bone marrow megakaryocytes was consistent with autoimmune thrombocytopenia. She was diagnosed with Rai stage IV CLL with Evans syndrome (secondary autoimmune hemolytic anemia and immune thrombocytopenia). Ms. Anderson was treated with steroids and intravenous immune globulin (IVIG) for CLL-associated Evans syndrome.

For the treatment of the CLL, ibrutinib vs chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) were discussed as first-line therapy. Through shared decision-making, the treatment team and Ms. Anderson opted for ibrutinib based on safety and efficacy data. There are inferior outcomes for unmutated IgVH CLL with chemoimmunotherapy and a long-term risk of secondary malignancy.1-3

Ms. Andersen started ibrutinib. After 1 month there was a significant decrease in her absolute lymphocyte count (ALC). However, her platelets remained low after 2 courses of pulse steroids and IVIG, so IV rituximab was initiated, with 4 weekly doses followed by once a month (planned for 5 months). After the third cycle of rituximab, Ms. Andersen developed neutropenia. The rituximab-induced neutropenia was treated to resolution with granulocyte colony stimulating factor. The anemia and thrombocytopenia normalized and the CLL was responding to ibrutinib, so no additional doses of rituximab were administered.

At her follow-up visit 4 months after starting ibrutinib, Ms. Anderson’s platelet levels stabilized at 80,000 to 90,000 cells/μL, and her ALC was 4,000 to 5,000 cells/μL. Approximately 6 months later, a bone marrow biopsy found 5% CLL involvement. One year after initiating ibrutinib, Ms. Anderson achieved a complete response by peripheral blood cytometry and bone marrow biopsy. Her laboratory values are summarized in the table below:

Laboratory Parameters Values
White blood cell count 3,800 cells/μL

Absolute neutrophil count 2,350 cells/μL

ALC 1,160 cells/μL

Hemoglobin 12.3 g/dL

Platelets 93,000 cells/μL

At a follow-up visit 5 years later, Ms. Anderson shares that she heard about the obinutuzumab plus venetoclax combination at a CLL conference. She asks if she can switch to that, as it’s a fixed-duration therapy. The AP agrees that this combination is a very effective CLL therapy and that she’d be happy to discuss the regimen. One major advantage is that the treatment is given for a year rather than indefinitely. The AP describes the logistics of the obinutuzumab plus venetoclax regimen, which requires administration of obinutuzumab in an infusion center twice during the first week, weekly for 3 weeks, and then monthly for 5 months.4 She also discusses the risk of infection and neutropenia.

The AP reminds Ms. Anderson that she is in complete remission, so it would not make sense to start an intensive new therapy regimen at this time. If she wanted to stop ibrutinib, it would be more prudent to stop ibrutinib and monitor with active surveillance until treatment was indicated. The patient states she is tolerating ibrutinib well, and she prefers to continue it to maintain the excellent response. She also shares that understanding the logistics of the obinutuzumab plus venetoclax regimen made her feel better about her treatment choice of ibrutinib because she lives 3 hours away from an infusion center and it would be time consuming and inconvenient to undergo IV therapy. The AP reassures her that there are clinical trials underway to evaluate the impact of stopping ibrutinib after a fixed duration, so there may be a possibility of ending treatment in the future.


  1. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-215.
  2. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126:1921-1924
  3. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-309.
  4. GAZYVA (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc. 2/2022.

Patient With CLL Assessed for Clinical Trial Eligibility in Front-Line Therapy

Ongoing clinical trials are evaluating outcomes using fixed-dose regimens of BTK inhibitors.

Mr. Thompson was diagnosed 3 years ago at age 55 with Rai stage 0 chronic lymphocytic leukemia (CLL). His past medical history includes hypertriglyceridemia and obesity.

For his initial CLL diagnosis, Mr. Thompson presented to dermatology with a small nodule on his left ear. An excisional biopsy showed an atypical lymphoid infiltration that was CD20 and BCL2 positive. He was referred to the clinic, where his workup showed a white blood cell count (WBC) of 15,000 cells/μL, an absolute lymphocyte count (ALC) of 11,000 cells/μL, a hemoglobin (Hgb) of 14 g/dL, and a platelet count of 340,000 cells/μL. Peripheral blood flow cytometry showed 40% of the cells to be comprised of a CD5-positive, CD23-positive, and CD19-positive clonal lymphoproliferative disorder consistent with a diagnosis of CLL. Peripheral blood fluorescence in situ hybridization (FISH) showed a deletion at chromosome 13q-. A CT of the chest, abdomen, and pelvis showed no involved lymph nodes.

Given Mr. Thompson’s initial diagnosis of Rai stage 0 CLL, there was no indication for treatment. He was followed with active surveillance every 3 to 6 months for 3 years, when he reported fatigue, nausea, and bloating. Mr. Thompson was seen in clinic and had palpable cervical lymph nodes. His laboratory values showed that his WBC count decreased to 30,400 cells/μL and his ALC decreased to 22,900 cells/μL. His lactate dehydrogenase (LDH) was elevated at 250 U/L. A PET-CT was ordered, which showed left axillary, bilateral supraclavicular, B cervical, mesenteric, periportal, portacaval, and pelvic lymph node involvement. The majority of the lymph nodes were 2 to 3 cm in size, with the largest measuring 2.4 x 4.5 cm and all nodes had similar SUV of 5-6. A left axillary lymph node core biopsy was performed to rule out transformation and was consistent CLL without evidence of transformation. A repeat FISH showed a deletion at chromosome 13q-.

The treatment options were discussed with Mr. Thompson, including monotherapy with ibrutinib, fixed-duration obinutuzumab plus venetoclax, and clinical trials. He opted to enroll in the CAPTIVATE clinical trial.1,2 CAPTIVATE is a phase II trial of previously untreated patients with CLL age <70 (median age, 58 years; range, 28-69). Patients were randomly assigned to ibrutinib and venetoclax for a fixed duration or a minimal residual disease (MRD)-directed strategy.

As a participant in the CAPTIVATE trial, Mr. Thompson was randomly assigned to the fixed-duration arm and received ibrutinib for 3 cycles followed by ibrutinib plus venetoclax for 12 cycles. Three months after the start of therapy, he developed pain in his fingernails and loss of his curly hair (it became straight). He was referred to dermatology, who noted paronychia/excess granulation tissue and treated this with clobetasol ointment, warm soaks, and mupirocin ointment. These nail and hair changes were attributed to ibrutinib.

During month 4, Mr. Thompson developed an erythematous maculopapular pruritic rash on his chest, which was treated to resolution with topical steroids. His primary complaints of ibrutinib plus venetoclax were as follows:

  • Fatigue
  • Intermittent rash
  • Pain in his nails due to paronychia and onychorrhexis (lamellar splitting of the distal free edge portion of the nail plate) of the fingernail
  • Curly hair that had become straight (this was important to Mr. Thompson, as he felt his curly hair was his best feature)

Throughout the course of treatment, Mr. Thompson continued to have mild fatigue, mild but tolerable pain in his nails, and loss of his curly hair. He was relieved that he was assigned to fixed-duration therapy. At the end of treatment, there was no detectable MRD as assessed by 8-color flow cytometry (<104).


  1. NCT02910583. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL) (CAPTIVATE). Pharmacyclics LLC and Janssen Research & Development LLC.
  2. Ghia P, Allan JN, Siddiqi T, et al. First-line treatment with ibrutinib (Ibr) plus venetoclax (Ven) for chronic lymphocytic leukemia (CLL): 2-year post-randomization disease-free survival (DFS) results from the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE study. J Clin Oncol. 2021;39 (suppl; abstr 7501).

Meet the Faculty

Laura J. Zitella

University of California San Francisco
San Francisco, CA

Laura J. Zitella, MS, RN, ACNP-BC, AOCN, is a hematology nurse practitioner in the UCSF Hematology, Blood and Marrow Transplant, and Cellular Therapy (HBC) Program and clinical associate professor at the University of California San Francisco (UCSF). She has practiced in the field for over 25 years and has delivered hundreds of educational presentations to national/international audiences, and authored numerous peer-reviewed publications, webcourses, and book chapters. Ms. Zitella also serves on planning committees for numerous educational conferences, the editorial board for the Journal of the Advanced Practitioner in Oncology, and national committees such as the ACCC Clinical Affairs committee, ACCC Community Oncology Research Institute (ACORI), and the APSHO Research and Quality Initiative Taskforce.

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