Wierda Compares Treatment Options for Patients With CLL

William G. Wierda, MD, PhD

William G. Wierda, MD, PhD

During a recentTargeted Oncologycase-based peer perspective presentation, William G. Wierda, MD, PhD, revealed the treatment options and decisions he makes when treating patients with chronic lymphocytic leukemia (CLL). Wierda, a D.B. Lane Cancer Research Distinguished Professor; section head of chronic lymphocytic leukemia with the Department of Leukemia; medical director of Leukemia Center; and executive medical director for hematologic malignancies, The University of Texas MD Anderson Cancer Center, explained his treatment decisions based on a patient’s case scenario.

Case

A 75-year-old woman reported symptoms of weight loss and fullness in her left upper quadrant. Her past medical history revealed hypertension and hypercholesterolemia, which were both controlled medically. On physical exam, she had a moderate axillary lymphadenopathy and her spleen was palpable approximately 4 cm below the costal margin. Otherwise, she was well appearing and continued her daily activity.

The patient’s laboratory results were notable for the following: white blood count, 48,000 u/L; 73% lymphocytes; hemoglobin (Hb), 9.1 g/dL; platelets, 125,000/mm³; absolute neutrophil count, 1800/mm³(within normal limits); lactate dehydrogenase, 250 U/L;β₂-macroglobulin, 4.2 µg/L.

Her flow cytometry was positive for CD5, CD19, and CD23. Additionally, fluorescence in situ hybridization (FISH) revealed an 11q deletion. A molecular analysis also revealed her disease wasIGHVmutated andTP53wild-type. She underwent a bone marrow biopsy, which showed diffuse infiltration by CLL.

Targeted Oncology: What are your general impressions of this patient?

WIERDA:This is a 75-year-old patient with some symptoms, including weight loss and fullness in the right upper quadrant because she has splenomegaly. Otherwise, she is active. She has some medical issues, including hypertension and hypercholesterolemia. Probably the most notable feature of her blood counts is that her Hb is 9.1 g/dL, which makes her [CLL] a Rai stage III. A Hb of 11 g/dL or lower is Rai stage III, and a platelet count of 100,000 mm³is stage IV. Virtually all patients with CLL have bone marrow infiltration, so the bone marrow is not used in the criteria for staging. It is based on blood counts and physical exam.

She has a typical phenotype. FISH showed 11q deletion. For a 75-year-old, the most important information regarding treatment decision is FISH and whether the patient has 17p deletion. In terms of evaluating a patient who you think needs treatment, you definitely need to have FISH. You should also have mutation testing forTP53; however, it is less common compared with FISH. A bone marrow biopsy is not needed for diagnosis. Patients don’t like them, and you don’t need them. Diffuse pattern is prognostic, but we don’t use it to categorize or direct treatment. We should do it in some instances; for example, if you want to evaluate a cytopenia that you think might be related to something else. Ninety-five percent of patients who have an 11q deletion will have an unmutatedIGHV. We doIGHVsequencing, but I would expect a patient with an 11q deletion to have unmutatedIGHV, which was the case for this patient.

The Hb is a little bit lower than I would expect from a patient who has untreated and progressive CLL. I would also be interested to know what the reticulocyte count is to make sure the patient is not having hemolysis.

Targeted Oncology: What is the prognosis for this patient?

WIERDA:This patient is medium risk. The prominent prognostic factor for this patient [is] the 11q deletion. With chemoimmunotherapy, 11q is a high-risk feature because, although these patients will get a remission with the chemoimmunotherapy-based treatment, the remissions don’t last long, and [these patients] relapse sooner than patients who have a 13q deletion, for example. They will need repeated treatment.

If you look at our data for frontline fludarabine, cyclophosphamide, and rituximab (Rituxan), the overall survival (OS) with long-term follow-up is the same for patients with 11q deletion as it is for patients with trisomy 12 or 13q.¹The problem for them is that they relapse, and they need repeated treatment. For chemoimmunotherapy, unmutatedIGHVis also associated with a shorter remission duration and need for retreatment. Wild-type TP53is actually not a bad feature; it’s a good feature.

In terms of today’s treatment, if we are talking about nonchemoimmunotherapy treatment, such as a small molecule inhibitor—based therapy like ibrutinib (Imbruvica)or venetoclax (Venclexta), patients with 17p deletion and unmutatedIGHVare in the middle of the road, at medium risk. In this case, it would not be a high-risk patient. 

Targeted Oncology: Does this patient require treatment?

WIERDA:I use a Hb of 10 g/dL as my threshold—progressive anemia with a Hb that is dropping. When patients drop below 10 g/dL, as in this patient, I will usually start treatment. A platelet count of 100,000 mm³is another criterion for treatment. When a patient is having progressive thrombocytopenia and their platelet count drops below this number, that would be a trigger for treatment, [as would] symptoms such as night sweats, fatigue, [and] unintentional weight loss, which doesn’t sound like she has much of. I would probably watch this patient for a month or 2, but I would be making plans for treatment when they come in for their first visit.

When we look at our database and evaluate patients from diagnosis to time to treatment, virtually all the unmutated cases, which [comprise] most of our patients with an 11q deletion, will eventually need treatment. On average, it is about 3 to 5 years from diagnosis. The unmutated status is highly predictive for needing treatment. We also do sequencing forATMmutations.ATMis the gene that is lost in 11q deletion, and about 40% of patients who have an 11q deletion will also have a mutation inATM. In our data analysis, that has also been associated with a shorter time to first treatment.

Targeted Oncology: What factors do you consider when deciding on her therapy? What are the treatment choices?

WIERDA:The age is important because it tells you whether patients can receive more intensive chemoimmunotherapy. FISH is important because you want to know whether they have a 17p deletion. If they don’t have a 17p deletion, your options are chemoimmunotherapy or small molecule inhibitors. If they do have a 17p deletion or a mutatedTP53, you should not give chemotherapy. Rather, you should give small molecular inhibitor—based therapy. We don’t use chemotherapy with those patients.

For this patient, we can talk about 2 different treatment approaches. One is chemoimmunotherapy; the other is small molecular inhibitor—based therapy, particularly Bruton tyrosine kinase (BTK)–based therapy. Ibrutinib is approved now in the frontline setting. We have gone through a progression of development in chemoimmunotherapy. In a 75-year-old, some would consider chlorambucil plus a CD20 antibody or bendamustine (Treanda) plus a CD20 antibody as a chemoimmunotherapy option. The other option would be a small molecule inhibitor.

Targeted Oncology: How do these treatment options compare with each other?

WIERDA:Chemoimmunotherapy-based therapy and small molecular inhibitor—based therapy are totally different in terms of approaches and goals of treatment. For chemoimmunotherapy-based treatment, we are talking about a defined treatment course. There will likely be remission and a treatment-free period of observation. [Patients] will eventually relapse and need retreatment. For chlorambucil and a CD20 antibody, the median progression-free survival (PFS) is about 2.5 years. It is about 4 years with bendamustine plus rituximab (BR), but BR is more of a myelosuppressive regimen and is a bit more difficult to give, especially for a patient at this age.

The other option is ibrutinib-based therapy. The standard dose for ibrutinib is 420 mg daily. Ibrutinib would be my treatment for a patient such as this because the patient has an unmutatedIGHV, and virtually all patients with an unmutatedIGHVwill have relapse after chemotherapy. They don’t have a long remission duration. This patient would likely have a shorter PFS than the median if we were talking about chemoimmunotherapy. The outcomes are poorer and the need for retreatment is higher with a chemoimmunotherapy-based treatment.

There are some data that show that the PFS for ibrutinib is similar in the frontline setting to what it is in first relapse. So you could give this patient chemoimmunotherapy, have a period of remission, and then move on to ibrutinib-based therapy. It would be reasonable, but I would rather spare the patient the myelosuppression and the risk for second myelodysplastic syndrome/acute myeloid leukemia. I think chemoimmunotherapy is a risk for Richter transformation, so I don’t like to expose [patients] to unnecessary chemoimmunotherapy. The drawback of a small molecular inhibitor is that, although it is a very effective treatment, it will require continuous treatment because most of those patients will get a partial remission and not a complete remission.

Targeted Oncology: Is there a preference of treatment in the National Comprehensive Cancer Network (NCCN) guidelines?

WIERDA:We changed the NCCN guidelines within the past year because there was a lot of debate, for many years, regarding the order of treatment options.¹There was a discussion at the last meeting we had, and the decision was made to list them in alphabetical order. It used to be in order of preference. They are categorized as preferred regimens or other recommended regimens. Within the preferred are the categories. So you can kind of get an idea of how things are prioritized, but it is a bit more difficult when it is in alphabetical order and you have to sort through it.

Targeted Oncology: What is the rationale for chemoimmunotherapy in patients with CLL?

WIERDA:The CLL11 trial was a frontline trial for patients over 65 years of age.²There were 3 arms: chlorambucil monotherapy, chlorambucil plus rituximab, and chlorambucil plus obinutuzumab (Gazyva) or type 2 CD20 antibody. The best performance was with chlorambucil plus obinutuzumab in terms of PFS as well as OS. There were no greater incidences or toxicities associated with the CD20 antibody.

With chlorambucil and obinutuzumab, the median PFS is about 2.5 years. So you can expect a 2.5-year remission with this regimen. Per the last update that was given, there was an improved OS favoring patients who received chlorambucil plus obinutuzumab compared with rituximab and chlorambucil. I believe a lot of these patients, upon relapse, got a small molecule inhibitor. That does affect the survival analysis and outcome, but the curves are statistically significantly different. Everyone wants to eventually get rid of chlorambucil, and I think that will happen. There are some data that were revealed at the American Society of Hematology Annual Meeting that will be important and probably lead to getting rid of a lot of the chemotherapy that we use.

Targeted Oncology: What is the rationale for small molecule inhibitors in patients with CLL?

WIERDA:The other option is a small molecule inhibitor, particularly a BTK inhibitor. Ibrutinib was approved in the frontline setting based on the RESONATE-2 trial.³This was a randomized trial of chlorambucil or ibrutinib as frontline therapy for all-comer patients over the age of 65, with the exclusion of 17p deletion. The chlorambucil therapy was given for a year, and ibrutinib was continuous until progression.

It is a positive trial for patients who received ibrutinib, with a much longer PFS compared with chlorambucil. In the analysis, it appeared that patients with an 11q deletion did better in terms of PFS on ibrutinib than those without. However,IGHVstatus did not really have an impact on outcome. The patients who had a mutated versus unmutated IGHVdid similarly with ibrutinib-based therapy. Patients with an unmutated IGHVhad a shorter PFS with chlorambucil. 

In terms of the marketing data, it is about fifty-fifty in terms of the number of patients who get chemoimmunotherapy versus ibrutinib in the frontline setting. I don’t really know what is driving that other than people are more comfortable using chemotherapy. It is a different endpoint and a different goal of therapy compared with small molecule inhibitor—based therapy.

The patient was started on ibrutinib 420 mg daily.

Targeted Oncology: What are some of the adverse events (AEs) associated with ibrutinib?

WIERDA:There are a few AEs that we see with ibrutinib. There is a risk for bleeding. It inhibits collagen-induced platelet aggregation, so there is bleeding and bruising. The incidences of severe bleeding are about 3% to 5%. Atrial fibrillation occurs with this agent, with incidences of about 10%. It depends on what trial you look at. There are features that you can identify in patients who have an increased risk for atrial fibrillation, such as a coronary artery disease history. Hypertension is also an AE, and that is something that starts to become more prominent the longer a patient is on the drug. You can have diarrhea with the agent, and that is usually mild. Rash and oral ulcerations are also possible AEs. Uncommonly, you can see fatigue.

Targeted Oncology: What would your approach be to management of atrial fibrillation?

WIERDA:I will not have patients on 3 agents that are anticoagulants. I would not have a patient on aspirin, for example, with Plavix and ibrutinib. I would drop one of them, preferably the aspirin. We have had problems with bleeding complications for patients who are on all 3. Warfarin is a contraindication for ibrutinib therapy, so you can’t have a patient on warfarin and ibrutinib.

I see more AEs in patients who are older. For patients who do happen to be older, I will usually start at a lower dose. You can always increase the dose. If you have a problem, you can always decrease the dose as well. But I would rather be in a position in which I’m going up on the dose if I’m not seeing the therapeutic effect that I want, rather than having problems with toxicities and having to decrease the dose.

If I have a patient who has gone into atrial fibrillation, my management strategy is to manage it and try to keep them on treatment. I will send the patient to the cardiologist, they will then go on an anticoagulant and a β-blocker, and they are medically managed. I try to keep them on target with treatment rather switching them to another treatment.

Targeted Oncology:Are there instances in which you discontinue ibrutinib therapy?

WIERDA:If you have a patient who has a bleed, such as a central nervous system bleed, I would probably take that patient off the drug. I would then move on to the next category of therapy.

References:

1. Wierda WG, Zelenetz AD, Gordon LI, et al. NCCN Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia. nccn.org/professionals/physician_gls/pdf/cml_blocks.pdf. Published January 24, 2018. Accessed December 5, 2018.
2. Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented at: 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
3. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia.N Engl J Med. 2015;373(25):2425-2437. doi: 10.1056/NEJMoa1509388.