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:

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.

References

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).

References

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. https://clinicaltrials.gov/ct2/show/NCT02910583
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).