Treating CLL With Bruton's Tyrosine Kinase Inhibitors

Part 1: Sandoval Sus Discusses Recommended Treatments for a Patient With CLL

During a live virtual event, Jose Sandoval Sus, MD, discussed with participating physicians frontline recommended treatment options for patients with chronic lymphocytic leukemia based on a case scenario, with questions by Targeted Oncology.


  • A 71-year-old woman reported symptoms of weight loss and increasing fatigue.
  • Medical history: hypertension, medically controlled
  • Physical examination: axillary lymphadenopathy, spleen palpable about 4 cm below costal margin, ill appearing, and continued only limited daily activity
  • Laboratory results:
    • White blood cell count: 47,000/mm3, 76% lymphocytes
    • Hemoglobin: 8.7 g/dL
  • Platelets count: 115,000/mm3
  • Absolute neutrophil count: 3600/mm3
  • Lactate dehydrogenase: 250 U/L
  • β2-Macroglobulin: 4.3 μg/L
  • Flow cytometry: CD5+, CD20+, CD23+
  • Fluorescence in situ hybridization (FISH): deletion 11q (del[11q])
  • Molecular analysis: IGHV unmutated
  • Bone marrow biopsy: diffuse infiltration by chronic lymphocytic leukemia (CLL), 90%-95%

Targeted OncoloogyTM: What would be the guideline-recommended approach to treating this patient?

SANDOVAL SUS: A quick review of the updated NCCN [National Comprehensive Cancer Network] guidelines gives us a good basic-level understanding of what we have to assess and why it would be useful...for prognostication and to discuss the natural history of CLL with our patients, but also for choosing the best therapy for our patient.1

Important baseline characteristics that we need to assess, especially when we’re going to start treatment on our patients, are the TP53 status and the IGHV region. Then again, when we have mutated TP53; that will be an unfavorable prognosis for patients with CLL, especially if you were planning on giving chemoimmunotherapy. Also, IGHV mutational status, if it’s unmutated, which is a bit counterintuitive, carries an unfavorable prognosis for CLL.

There are some other markers that are surrogates for the mutational status of IGHV, including the percentage of CD38 and Zap70 expression on the CLL cells and CD49d. CD38 was considered unfavorable when it is 30% [or greater], Zap70 when it is 20% or greater, and CD49d equal to or more than 30%. However, nowadays, it’s not straightforward or directly correlated with the mutational status of IGHV. For the most part, we have access to a laboratory where we can send the assessment of the IGHV; that will be the most appropriate way to go.

The fluorescence in situ hybridization, the FISH, on these patients is important to establish a baseline prognosis, especially when we’re going to treat them. More than 80% of our patients with CLL will have some type of alteration on FISH, some type of mutation. The most common, in 55% of our patients, will be the del(11q) as a sole abnormality, which is good because it [indicates] a good prognosis. A neutral prognosis, not good or bad, is trisomy 12. Unfavorable, especially in the era of chemoimmunotherapy, [were] del(11q) and deletion 17p [del(17p)].

A complex karyotype, which is a bit more challenging to obtain in patients with CLL because of the slow growth of those cells, is unfavorable [when there are] 3 or more unrelated chromosome abnormalities in more than 1 cell on karyotype. But these cells need to be stimulated. We usually cannot get the karyotype from peripheral blood. Sometimes we can, but most of the time we cannot, and we usually try to assess that on the bone marrow biopsy. It’s important for some specific instances of treatment of patients with CLL, but it’s not necessary.

At a live virtual meeting, Sandoval Sus asked oncologists what they would offer this patient.

What do the NCCN guidelines recommend as therapy for this patient? How would you determine which one is most suitable?

The NCCN guidelines divide the treatment of CLL between patients [who] are frail or have significant comorbidities [versus patients who are considered to be fit based on age]. Usually they put the magic age at 65 years, but we all know, especially in South Florida, that 65 is sometimes just a number.

CLL is a disease of elderly patients, with a median age at diagnosis of 72 years. In those patients, the preferred regimens will be ibrutinib [Imbruvica], acalabrutinib [Calquence], and venetoclax [Venclexta] plus [rituximab (Rituxan), all with a category 1 recommendation].

There are some other recommendations, [such as] single-agent chlorambucil or rituximab; we usually don’t use those treatment strategies. Rituximab can be considered as a single agent if you’re thinking of CLL-related autoimmune hemolytic anemia, especially if you want to pair it with a steroid. The same goes for obinutuzumab [Gazyva] as a single agent, unless the patient is [elderly] and is not interested in any other types of therapies.

In the guidelines, they put the same treatment options for patients in the frail or older group. As other recommendations, the good old FCR—fludarabine, cyclophosphamide, and rituximab, [which] have been proven to be effective chemoimmunotherapy in at least 3 randomized, phase 3 clinical trials—is included. Also, bendamustine plus an anti-CD20 monoclonal antibody and some other options that we don’t use [are listed under other recommendations].

CASE (continued)

The patient was started on ibrutinib 420 mg daily.


1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2022. Accessed December 9, 2021.