1. Fuerst, Mark L.

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NEW YORK-In this era of novel agents, should chronic lymphocytic leukemia (CLL) patients be treated early, or should therapy be deferred? That was the question debated by two experts at the 2017 Great Debates & Updates in Hematologic Malignancies meeting, held April 7-8.


Matthew Davids, MD: Intervene Early


Matthew Davids, MD, Associate Director, Center for CLL, Dana-Farber Cancer Institute, Boston, outlined goals for treating CLL patients. "Low-risk patients should avoid treatment for those who will never need it. In those for whom treatment is inevitable, minimize toxicity, although you can accept some. Decrease the risk of clonal evolution, prolong time to progression, and prolong overall survival (OS). We don't know whether achieving these goals is optimized with traditional treatment criteria or by early intervention."


Biological factors are powerful predictive markers in CLL. To obtain markers, clinicians can use cytogenetic abnormalities (FISH), immunoglobulin gene mutations (IGHV), and novel mutations (TP53, NOTCH1). "Subclinical mutations lead to poor prognosis in CLL. Acquisition of genomic instability portends poorer survival," he said.

Matthew Davids, MD. ... - Click to enlarge in new windowMatthew Davids, MD. Matthew Davids, MD

FISH remains an important predictive marker in the novel agent era. "FISH cytogenetics shows patients with del 17p have shorter survival than those with 13q deletion," he said, adding that immunoglobulin Vh gene mutation status is also a powerful tool to predict survival, while the predictive value of IGHV for novel agents is less clear.


The German CLL Study Group and Mayo Multivariable Prognostic Index can help identify CLL patients at low, intermediate, or high risk. The model includes age, sex, del 17p, del 11q, IGHV mutation status, beta-2 microglobulin, and thymidine kinase. Patients with somatic mutations, such as TP53 or NOTCH1, require treatment sooner, noted Davids.


There is no survival advantage to early treatment with chlorambucil, he said, noting that the gold standard chemoimmunotherapy in high-risk CLL is fludarabine, cyclophosphamide, and rituximab (FCR).


The CLL7 trial investigated early intervention with FCR in high-risk CLL. The results show a significant event-free survival benefit with FCR, but with a cost of significant toxicity, including severe cytopenias and infections. There was no OS benefit. "A more toxic strategy does not make sense for initial intervention," said Davids.


Two novel targeted agents now in use in CLL include ibrutinib and venetoclax. Ibrutinib is highly active in front-line CLL, including high-risk patients, and is generally safe and well-tolerated. However, ibrutinib resistance is observed in high-risk CLL patients.


Mutations are more commonly found in patients with genomic complexity. "We know that CLL genomic complexity increases over time. We don't know whether early intervention with ibrutinib in high-risk patients will reduce the risk of mutations, and whether that will translate to improved survival," he stated. The ongoing 6-year CLL12 German study looks to answer these questions.


Venetoclax is a small molecule, selective oral Bcl-2 inhibitor and was first tested in CLL, which is known to be highly Bcl-2 dependent. Venetoclax monotherapy is highly active in relapsed/refractory CLL.


Together, ibrutinib plus venetoclax appears to be highly synergistic. "This combination therapy may reduce risks, such as tumor lysis syndrome, and allow for time-limited therapy," he explained. This interesting combination is now in clinical trials, using ibrutinib for debulking, and to determine whether there is an OS benefit in the high-risk setting.


Davids concluded by suggesting that clinicians need to make a leap of faith with early intervention with ibrutinib. "Sometimes we should wait for robust trial data. Sometimes we need to extrapolate from existing data. But there are risks to inaction," he said. "Existing data are sufficient to consider early intervention with ibrutinib in high-risk CLL patients with some evidence of progression for those who do not yet meet IW-CLL treatment criteria."


Richard Furman, MD: No Early Intervention


No Early Intervention

There has been a change in the natural history of CLL, with an increase in OS for patients as a group. By stage, there is no OS benefit for CLL patients with Binet stage A and B, but there is a benefit seen in Binet stage C. "We have seen a shift toward earlier stage disease at diagnosis. Early diagnosis does not lead to a better outcome," stated Richard Furman, MD, Director of the CLL Research Center at Weill Cornell Medicine in New York. "There is no reason to intervene early until we have proven survival benefit to patients."


To support his case, Furman noted results from the FCR 300 study in CLL. About 30 percent of the patients at 10 years were free from progression. About three-quarters of patients show long-term survival even with mutations. "The majority of mutated patients would likely have done well with any therapy," he said. "This is why we need good phase III data."

Richard Furman, MD. ... - Click to enlarge in new windowRichard Furman, MD. Richard Furman, MD

Also, the study found a high cost to patients in term of secondary cancers post-FCR. "Some 40 percent of deaths of CLL patients are associated with second solid tumors, acute leukemia/MDS, or Richter's transformation (RT). FCR toxicity is a potential reason to delay therapy," said Furman.


Recent data from an ibrutinib phase II trial of 5-year outcomes showed excellent survival in treatment-naive patients. "A 5-year progression-free survival is not adequate for most CLL patients." Ibrutinib was well-tolerated, but was associated with adverse events, including diarrhea, bruises, intercranial hemorrhage, hypertension, and issues in impairment of the immune system.


The risk of developing resistance to ibrutinib is most commonly due to base pair mutations. "RT patients likely have other biological risk factors, such as NOTCH1. Different biology increases the risk of transformation," noted Furman.


Resistant clones exist prior to ibrutinib therapy. "Ongoing active mutation allows cancer cells to grow. Even starting treatment earlier wouldn't make a difference. Patients would still become resistant."


In conclusion, Furman said that "no paradigm in CLL for early treatment with chemotherapy has had an impact upon outcome. Early intervention is associated with earlier risk for adverse events. With ibrutinib, treatment when indicated by current IW-CLL standards demonstrates phenomenal disease control and eradication, but even ibrutinib is associated with significant toxicities. Patients with XLA do not do well long-term. For those patients who do develop progression of disease on ibrutinib, evidence suggests resistant clones are present prior to the start of therapy."


Mark L. Fuerst is a contributing writer.