Part 1: BTK Inhibitors for CLL in the Second Line

Danielle Brander, MD

Assistant Professor of Medicine

Duke Cancer Institute

Durham, NC

CASE SUMMARY

• A 53-year-old woman presented with an elevated white blood cell (WBC) count found incidentally.
• Medical history: hypertension managed with losartan
• Physical examination: left axillary lymph node, 1 cm × 1 cm
• Laboratory results:
  • WBCs: 117.3 × 10⁹/L
  • Lymphocytes: 109.2 × 10⁹/L
  • Hemoglobin: 12.6 g/dL
  • Platelets: 174 × 10⁹/L
  • Lactate dehydrogenase: 160 U/L
• Molecular testing:
  • Flow cytometry: CD19+, CD5+, CD20+, CD23+, and k-restricted monoclonal B-cell population
  • IGHV unmutated
  • Fluorescence in situ hybridization (FISH): normal
• Bone marrow: chronic lymphocytic leukemia (CLL) in 86% of cells
• The patient was monitored for 5 years, at which point she developed symptoms:
  • WBCs: 250 × 10⁹/L
  • Hemoglobin: 9.6 g/dL
  • Platelets: 105 × 10⁹/L
• Lymph node, now 4 × 3 cm
• The patient was treated with 6 cycles of fludarabine, cyclophosphamide, and rituximab (Rituxan) and achieved complete remission.
• Four years later (at aged 62 years), she had a relapse.
  • WBCs: 80 × 10⁹/L
  • Hemoglobin: 9.5 g/dL
  • Platelets: 60 × 10⁹/L
  • FISH: del(17p)

Targeted Oncology™: What are the guideline-recommended regimens to treat a patient with CLL such as this one?

BRANDER: The [National Comprehensive Cancer Network] guidelines for regimens in the relapsed/refractory setting include acalabrutinib [Calquence] and venetoclax [Venclexta], which are approved in all lines of therapy. In the relapsed/refractory setting, there’s also approval of duvelisib [Copiktra] and idelalisib [Zydelig], which are PI3K inhibitors.¹

What data support the use of ibrutinib (Imbruvica), which is another guideline-recommended agent for the treatment of this patient?

The data that led to the initial approval of ibrutinib was the RESONATE trial [NCT01578707]. [The trial] randomized patients 1:1 to either ibrutinib or the anti-CD20 antibody standard-of-care agent in the relapsed/refractory setting, ofatumumab. Patients were allowed to cross over on this study.²

There are now 6-year follow-up data [showing that the] median progression-free survival [PFS] for the ibrutinib arm was not reached but was short [8.1 months] for the ofatumumab alone [HR, 0.133; 95% CI, 0.099-0.178]. Markers [of prognosis] that would indicate inferior response to chemoimmunotherapy are either the patients with IGHV unmutated or del(17p) or del(11q), who are still having good responses. This is in the relapsed/refractory setting with novel agents.

The grade 3 or greater AEs [adverse effects] that you’ll see are infectious complications. Infections and neutropenia do get better in terms of incidence with [time]. But obviously, if they have to stop [treatment] in the first year, it’s still detrimental to them. One thing [to keep in mind when] monitoring patients is that time on therapy does increase risks for hypertension. Atrial fibrillation and bleeding remain a risk throughout treatment. Often, they first appear early on treatment.

What other Bruton tyrosine kinase (BTK) inhibitors would you consider for treatment of this patient?

The phase 3 ASCEND study [NCT02970318] was recently updated, presented, and published. In the relapsed/refractory [setting], it looked at acalabrutinib vs either choice of BR [bendamustine and rituximab] or idelalisib/rituximab. This was mostly done internationally, especially with approvals and availability at the time. The primary end point was PFS.³

The difference in PFS of acalabrutinib was not reached vs 16 months with either idelalisib/rituximab or BR [HR, 0.41; 95% CI, 0.20-0.49; P < .0001]. PFS by subgroup is as we’ve seen with [ibrutinib, with benefit in most patients].

There are less hematological toxicities vs chemoimmunotherapy. You will see more of other AEs like diarrhea [with chemoimmunotherapy and PI3K inhibitors], and these can be seen [at lower rates] with BTK inhibitors.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2022. Accessed November 16, 2021. https://bit.ly/3jemRoI}

_{2. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031‐2042.doi:10.1182/blood-2018-08-870238}

_{3. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Abstract presented at: 24th European Hematology Association Congress; June 13-15, 2020; Amsterdam, Netherlands. Accessed November 16, 2021. https://bit.ly/3DpVphZ}