Managing High-Risk CLL

John F. Gerecitano, MD, PhD:So, this is a case of a relatively young man with a relatively high risk of CLL. Highest risk factor in this case is, of course, the deletion 17p aspect. We do know that these patients are likely to progress more rapidly and be more resistant to standard therapies that are available now for patients with CLL.

This patient was treated frontline with FCR (fludarabine/cyclophosphamide/rituximab), which is one of the more popular chemotherapy regimens and one that tends to lead to the longest durations of remission. There are 2 things about this case that are a little bit different than what would likely be recommended in this day and age. So, now, unfortunately, we know that patients with deletion 17p are less likely to respond to chemotherapy or chemoimmunotherapy. The most current NCCN guidelines actually don’t recommend chemotherapy or chemoimmunotherapy for these patients. So, that’s the one big difference between the way this patient was treated and the way we would likely treat the patient now and going forward. And the other is that even though this patient is at high risk for relative need of therapy in the near future, we try not to treat patients unless there are reasons to treat. If the counts are particularly low, if the patient is symptomatic, or if the disease represents some sort of risk within the next 6 months. And this patient’s hemoglobin is slightly low. Platelets are in the normal range, so I’m not sure if this patient would meet the criteria for need for treatment. And we don’t know even in these high-risk patients that there’s an advantage to treating earlier rather than later.

The major risk factor for CLL that we know of these days is deletion 17p, or mutation in thep53gene. Those are what cause the patient to be most at risk for early progression of disease and most likely to be refractory to common agents that we use, most importantly chemotherapy. This patient’s risk status is primarily that he has deletion 17p.

There are many options for managing high-risk CLL these days. The most current NCCN guidelines recommend that we don’t use upfront chemotherapy or chemoimmunotherapy. But at least 2 or 3 of the new targeted therapies—being PI3-kinase inhibitors; venetoclax or aBCL-2inhibitor; and ibrutinib, a B-cell receptor inhibitor—are all active against disease in patients who do have deletion 17p.

The likely rationale for using FCR in this case was that the treating oncologist wanted a regimen that would lead to the longest duration of remission, and certainly FCR can do that in a large proportion of patients. However, we know now that FCR and chemotherapy, or chemoimmunotherapy in general, don’t work very well in patients with deletion 17p or with unmutated immunoglobulin genes. So, in this patient, I would not have advocated for upfront use of FCR.

Recent research from a German group has shown that maintenance lenalidomide therapy in patients who are at high risk for early relapse after chemoimmunotherapy prolongs progression-free survival. There was a significant benefit in progression-free survival for patients who were treated with maintenance lenalidomide up to the time of progression, versus patients who were treated with placebo. And this was a statistically, as well as clinically, significant progression-free survival benefit. This patient does meet the criteria that were posed in that paper, being high risk for early progression. That paper defined high risk of early progression as minimal residual disease measured on flow cytometry. And although we don’t know that data for this patient, we do know that this patient only achieved a best response of partial remission. So, it’s quite likely that he will have minimal residual disease and be eligible for the treatment criteria that were used for this study.

The lenalidomide dose that was used in this study started at 5 mg for a month, went up to 10 mg for the next 5 months, and then went up 15 mg and continued that dose until the time of progression in patients who were able to tolerate that dose escalation.

Transcript edited for clarity.

Case: A Young Male Patient with High-Risk CLL and Nodal Involvement

January 2017

• A 53-year-old male presents with fatigue, night sweats, and swollen glands
• PMH: hypertension managed with losartan
• PE: left axillary and bilateral cervical adenopathy, 4 cm X 3 cm
• Laboratory findings:
  • WBC; 117.3 X 10⁹/L
  • Lymphocytes; 109.2 X 10⁹/L
  • Hb; 9.6 g/dL
  • Platelets; 174 X 10⁹/L
  • ANC; 1,950/mm³
  • LDH 160 U/L
• Flow cytometry; CD19++, CD5+, CD20+, CD23++, CD38+
• BM; CLL in 86% of cells
• IgVH mutated
• Cytogenetics by FISH; del17p
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with FCR and achieved a partial response to therapy after 6 cycles
  • Left axillary lymph node, 2 cm X 2 cm
  • Lymphocytes; 10 X 10⁹/L
  • Symptoms resolved
• The patient was started on maintenance therapy with lenalidomide

December 2017

• The patient complained of increasing bouts of extreme fatigue, abdominal bloating and intermittent moderate to severe abdominal pain
• PE:
  • 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
• Patient underwent large-volume paracenteses, ascites sampling positive for CLL involvement
• Laboratory findings:
  • WBC; 84,000, 97% lymphocytes
  • Hb; 9.4 g/dL
  • Platelets; 110,000/mm³
  • ANC; 1,600/mm³(WNL)
  • LDH; 262 U/L
  • Beta-2-microglobulin; 8.9 µg/L
• The patient was started on venetoclax
• The patient developed grade 3 neutropenia after 4 weeks on therapy which was managed and later resolved