Davids Addresses Treatment Options for Patients With IGHV-Unmutated CLL

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc, recently discussed the treatment choices for patients with chronic lymphocytic leukemia (CLL), and the factors he considers when choosing a treatment, based on 2 patient cases. Davids, associate director, Center for Chronic Lymphocytic Leukemia, and assistant professor of medicine, Harvard Medical School, presented these cases during aTargeted Oncologylive case-based peer perspectives dinner.

Case 1

A 75-year-old female reported symptoms of weight loss, fatigue, and pain in the upper left portion of her abdomen. Physical examination showed moderate axillary lymphadenopathy and splenomegaly. Otherwise, the patient is overall well appearing and continues to exercise.

Laboratory results showed:

• White blood cell count (WBC), 48,000; 73% lymphocytes
• Hemoglobin (Hb), 10 g/dL
• Platelets, 125,000/mm3
• Absolute neutrophil count (ANC), 1,800/mm3 (within normal limits)
• Lactate dehydrogenase (LDH), 250 U/L
• Beta-2-microglobulin, 4.2 µg/L
• Cytogenetics by fluorescence in situ hybridization (FISH) showed 11q deletion, IGHV unmutated, and bone marrow biopsy showed diffuse infiltration by CLL.

TARGETED ONCOLOGY:Does this patient require treatment?

Davids:For the treatment of this patient, we think about the International Workshop Group on CLL (iwCLL) criteria. Those include things such as cytopenias, bulky lymph node disease, and constitutional symptoms. It sounds like this patient is not having symptoms for the most part, but she does have some significant anemia. The bone marrow biopsy does show quite significant infiltration of CLL. It's not an emergency to treat this patient, but she seems like she is headed toward needing treatment soon. Given the higher-risk prognostic markers, it's unlikely that she would be able to be observed for much longer, and it is a good time to discuss treatment options with the patient.

TARGETED ONCOLOGY:What factors do you consider when deciding on her therapy?

Davids:This patient does not have deletion 17p, so that is the first thing I think about. Next, I think about the age and comorbidities of the patient, as well as the other prognostic factors. This patient is moderately old, but not frail, and is otherwise healthy. She has some higher-risk markers, like deletion 11q and unmutated IGHV. Those are the key factors when considering treatment options.

TARGETED ONCOLOGY:What were the treatment choices for this patient as initial therapy, and what treatment would you choose?

Davids:There were a variety of reasonable treatment options for a patient like this. I would say the top 3 would be bendamustine with rituximab (Rituxan), ibrutinib (Imbruvica), or chlorambucil with obinutuzumab (Gazyva). Of those 3, in this case, I would likely opt for ibrutinib. The reason is that with the higher-risk markers, especially with the unmutated IGHV, I would not expect a durable response to a chemotherapy-based approach, whereas we have good evidence now suggesting that frontline ibrutinib can be highly effective for patients with unmutated IGHV, so I would recommend ibrutinib for this patient, as was done in this case.

The patient was started on ibrutinib 420 mg daily. After 6 months, she achieved complete remission of her disease and resolution of her symptoms.

ECG at 7 months indicates asymptomatic atrial fibrillation. Patient also has a history of hypertension and hypercholesterolemia.

TARGETED ONCOLOGY:Should the patient be started on an anticoagulant? If so, which one?

Davids:Typically, if I do discover atrial fibrillation in a patient on ibrutinib, if they have not been known to have it previously, I will stop the drug temporarily and come up with a plan of how to manage it. Then I would make a decision about whether anticoagulation is indicated. In terms of that decision, I would use the same kind of metrics that would be used for other patients, such as the CHADS2 score, for example.

This patient is a bit older and does have some cardiovascular risk factors, so she probably would meet the criteria for anticoagulation. In terms of which agent to choose, there are not a lot of safety data for warfarin in this population on ibrutinib, because those patients were excluded from the clinical trials. I would be thinking about either a low molecular weight heparin or a novel oral anticoagulant. Typically, for convenience, most of my patients have opted for an oral novel anticoagulant, so a typical one we would use would be apixaban (Eliquis). I think that would be a good choice for this patient.

I think it's important to mention that I would try to re-challenge the patient on ibrutinib. Although not completely evidence-based, my practice has been to start them back on a lower dose, and over the course of a few days to a week, to try to get them back to the full dose of ibrutinib, as long as they are tolerating it well.

Four years later

During a routine follow-up, the patient reports increasing fatigue. Physical examination shows cervical lymphadenopathy ~4 cm; spleen, palpable, ~17 cm.Laboratory findings showed:

• Absolute lymphocyte count; 112,000 cells/mL
• Hb; 10.8 g/dL
• Platelets; 105,000 cells/mm3

TARGETED ONCOLOGY: What are your impressions at time of progression on ibrutinib? What therapy would you use next and why?

Davids:My impression is that this patient is having clinical progression of CLL, and a change in therapy is warranted. In terms of molecular testing, I would resend the FISH test at this point, and also sequence for TP53 mutation. Not so much because I'm using this information to make a therapeutic decision, because this is not a patient I'm going to give chemotherapy to, but it's more to inform the prognosis. While not yet a part of routine practice, some centers are now sending for BTK mutation testing to see if that could be the cause of the resistance to ibrutinib.

Irrespective of these test results, this is a patient where I would be thinking of switching therapy. Outside of a clinical trial,he therapy I would move to next would be venetoclax (Venclexta). That is based on recently published data showing that venetoclax can be efficacious for this population, with about two-thirds of patients having good response even after progressing on ibrutinib.

Case 2

A 73-year-old male patient complains of increasing bouts of extreme fatigue, abdominal bloating, and intermittent moderate to severe abdominal pain. Past medical history includes type 2 diabetes requiring insulin injections, and chronic lymphocytic leukemia diagnosed 4 years ago and managed with observation.Physical examination includes bulky adenopathy in the cervical and axillary lymph nodes, inguinal lymphadenopathy. Fluid wave test positive for ascites. Abdominal CT showed multi-station bulky lymphadenopathy, hepatomegaly, and splenomegaly.The patient underwent large-volume paracenteses, ascites, sampling positive for CLL involvement.

Laboratory findings showed:

• WBC, 84,000; 97% lymphocytes
• Hb, 9.4 g/dL
• Platelets, 110,000/mm3
• ANC, 1,600/mm3 (within normal limits)
• LDH, 262 U/L
• Beta-2-microglobulin, 8.9 µg/L

Prognostic markers:

• Normal FISH cytogenetics
• Unmutated IGHV
• Positive ZAP70
• Wild-type TP53
• Wild-type NOTCH1
• Bone marrow biopsy showed diffuse infiltration by CLL.

TARGETED ONCOLOGY:What is the prognosis for this patient?

Davids:This is a patient with an intermediate prognosis. The effusions are probably being caused by the CLL. Nonetheless, the fact that there is no TP53 dysfunction is somewhat reassuring in terms of the prognosis. We know that some of the newer agents can help to potentially overcome the negative prognostic impact of factors like the unmutated IGHV.

TARGETED ONCOLOGY:How do you assess the comorbidity burden in patients with CLL?

Davids:Typically, I assess it from how the patient looks, what their functional status is, how independently they are living, and how easy it is for them to move around. I assess this as a fairly rough estimate when I am in front of the patient. There are more formal metrics to do this, such as the CIRS score, which has been used predominantly in the clinical trial setting to more accurately assess comorbidities. This type of scale can be a bit cumbersome to use in clinical practice. So really the same way we assess the functional status for patients with other cancers is the way I would assess a patient with CLL.

TARGETED ONCOLOGY: What are the treatment choices for this patient?

Davids:They are similar to the prior patient. Chemotherapy would be a reasonable option, bendamustine and rituximab would be my preferred chemotherapy-based appraoch. However, my preference again would be to start with ibrutinib, based on its durable efficacy for patients with unmutated IGHV. Also based on the fact that it tends to not cause significant myelosuppression and this particular patient is at a high risk for intraabdominal infection.

The patient was started on ibrutinib 420 mg. The patient developed grade 3 neutropenia after 4 weeks on therapy which was managed and later resolved. Symptoms resolved after 6 months on therapy. Splenomegaly, hepatomegaly, and ascites resolved. Lymph node size was reduced by 80%.

Six months later

Laboratory results after starting ibrutinib therapy showed:

• WBC, 32,000; 28% lymphocytes
• Hb, 11.4 g/dL
• Platelets, 143,000/mm3
• ANC, 1,950/mm3
• LDH, 224 U/L
• Beta-2-microglobulin, 4.7 µg/L

TARGETED ONCOLOGY:How do you manage ibrutinib-associated toxicities in a patient such as this one (cytopenias, hypertension, athralgias/myalgias, diarrhea, and infection)?

Davids:For cytopenias, it's important to point out that we do not think that ibrutinib, in most cases, would be directly causing cytopenias. Typically, cytopenias in these patients on ibrutinib are more related to CLL itself infiltrating the bone marrow, autoimmune cytopenias, or in the relapsed population lingering effects from prior therapies such as chemoimmunotherapy. The way we manage cytopenias is to continue the ibrutinib at full dose anduse growth factor support for neutropenia. We can also use transfusion support for anemia or thrombocytopenia if they are more severe. These cytopenias typically improve over time as better CLL disease control is established with continuous ibrutinib therapy.

Hypertension is a pretty common side effect on ibrutinib. That probably is related to the drug. The effect tends to persist over time in patients on the drug, so it's something that needs to be monitored for this. If there are patients where the hypertension is more significant, then it can be necessary to start an antihypertensive agent. That is usually fine to give alongside ibrutinib.

Infection is common in CLL patients, regardless of what type of therapy they're on; even if they're not on therapy. Things you can do to try to reduce the chances of infection include monitoring immunoglobulin levels, and if a patient has hypogammaglobulinemia and is having recurrent infections to give them IVIG to help boost up their immunity. There have been some recent reports of certain specific types of infections on ibrutinib, things like pneumocystis jiroveci pneumonia (PJP) or aspergillosis. In patients who might be at higher risk for PJP, consideration can be given to prophylaxis with a drug like Bactrim (trimethoprim and sulfamethoxazole). Then there have also been some recent reports of fungal infections in patients on ibrutinib. We don't routinely recommend antifungal prophylaxis, but there should be a high level of suspicion if there is an infection that is not resolving with antibacterial therapy.

Four years later

The patient, now 77 years old, complains of sudden weight loss, fatigue, and drenching night sweats. He has been referred to cardiology for grade 3 hypertension and abnormal ECG results.

Laboratory findings showed:

• WBC, 126,000; 97% lymphocytes
• Hb, 9.9 g/dL
• Platelets, 86,000/mm3
• ANC, 1,126/mm3
• LDH, 422 U/L
• Beta-2-microglobulin; 4.7 µg/L

TARGETED ONCOLOGY:At this point, what are your recommendations for this patient?

Davids:Given the rapid progression on ibrutinib, I do have some concern for transformation to a more aggressive lymphoma, in particularRichter's Syndrome. I would want to get a PET/CT scan to look for any highly FDG-avid nodes. If I saw that, I would want to biopsy the nodes and make sure there is no Richter's Syndrome, because that would have a significant effect on the therapy that I would recommend. If we did in fact find Richter's Syndrome, the patient would probably need to go through a chemotherapy-based approach. If a biopsy did not show Richter's, or if the PET scan was not concerning, then this is a patient that could also benefit from switching to venetoclax.