Evolving Strategies in First-Line Chronic Lymphocytic Leukemia: Is There a Role for Chemoimmunotherapy?

With the enormous progress made in treatment and management, many oncologists have called this the golden age of chronic lymphocytic leukemia (CLL). The past few years alone have seen the approval of multiple agents, including small molecule inhibitors that have led to longer, more durable periods of disease control. However, the introduction of these new drugs into the armamentarium has raised an important question regarding standard of care: is there still a role for chemoimmunotherapy in the first-line setting? At the NCCN 2019 Annual Congress: Hematologic Malignancies, Drs. William G. Wierda and Jennifer R. Brown presented opposing sides of the debate.

The advent of more effective agents for chronic lymphocytic leukemia (CLL) has ushered in a new era of treatment, shifting previous lines of therapy and evolving strategies of disease control. Although chemoimmunotherapy has long been the mainstay of treatment, its role in induction therapy and beyond has been limited by small molecule inhibitors that promise durable remissions. At the NCCN 2019 Annual Congress: Hematologic Malignancies, William G. Wierda, MD, PhD, Professor of Medicine, The University of Texas MD Anderson Cancer Center, and Jennifer R. Brown, MD, PhD, Professor of Medicine, Harvard Medical School, and Director of the CLL Center, Dana-Farber Cancer Institute, debated the merits of using chemoimmunotherapy in the first-line setting. Moderated by Andrew D. Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center, the debate was followed by a panel discussion that included Jeremy S. Abramson, MD, MMSc, Massachusetts General Hospital Cancer Center; Nitin Jain, MD, The University of Texas MD Anderson Cancer Center; and Jae Park, MD, Memorial Sloan Kettering Cancer Center.

No Role for Chemoimmunotherapy

According to Dr. Wierda, there are currently 2 approaches with non–chemoimmunotherapy-based treatment. The first approach using small molecule inhibitors, particularly Bruton tyrosine kinase (BTK) inhibitors, is to have a sustained and durable period of disease control with continuous therapy. The other strategy, said Dr. Wierda, is to have deep remissions with fixed-duration treatment using a selective inhibitor of B-cell lymphoma 2 (Bcl-2). “I would argue that small molecule inhibitors offer a better approach than being exposed to genotoxic chemotherapy,” he said.

However, Dr. Wierda also highlighted essential tests that must be conducted before starting patients on treatment. Routine fluorescence in situ hybridization analysis detects deletion of the region of chromosome 17 (17p13−) that includes the gene coding for p53 (TP53). It is important to know the percentage of cells with the deletion, he said, and noted that del(17p) status and TP53 mutation status can change. IGHV mutation status is also important to test for because it factors into treatment selection, he added.

Recent results of several phase III randomized clinical trials have shown the effectiveness of BTK inhibitor–based therapy in frontline CLL. These trials include RESONATE-2,1 which compared ibrutinib with chlorambucil; iLLUMINATE,2 which analyzed ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab; the 3-arm Alliance trial,3 which randomized patients to ibrutinib monotherapy versus ibrutinib + rituximab versus bendamustine/rituximab; and the ECOG E1912 trial,4 which compared ibrutinib + rituximab versus a fludarabine/cyclophosphamide/rituximab (FCR) regimen.

“All of these trials were positive in showing longer progression-free survival [PFS] for the ibrutinib-based arm compared with chemoimmunotherapy,” said Dr. Wierda. “Although no differences in overall survival [OS] were found, I would argue that is partly due to study design. With longer follow-up, we may see differences in OS emerging, and the ECOG study did, in fact, demonstrate a difference.”

A separate trial called CLL14,5 conducted by the German CLL Study Group, also showed positive outcomes in PFS for patients randomized to venetoclax/obinutuzumab versus chlorambucil/obinutuzumab, although no differences in OS were seen. More importantly, although treatment with ibrutinib is continuous therapy, venetoclax-based therapy is fixed duration. As shown in the CLL14 trial, PFS at 2 years was comparable to the outcomes seen with ibrutinib (80% to 90%).

“The other key point to remember,” Dr. Wierda added, is that in patients for whom chemoimmunotherapy initially fails, they “can still go on to a small molecule inhibitor, which is associated with a very long survival.”

Furthermore, the advantage of using small molecule inhibitor–based therapy is not limited to PFS. As Dr. Wierda explained, chemotherapy is genotoxic and carries risk for long-term complications. Patients treated with the FCR regimen have 3% to 5% incidence of developing myelodysplastic syndromes. Nevertheless, for a subset of patients with IGHV mutation, chemoimmunotherapy may still be the preferred option, he acknowledged. As evidenced by the MD Anderson phase II data6 and the CLL8 trial,7 approximately 50% of patients with mutated IGHV experienced long-term PFS suggestive of a cure, and 60% were negative for minimal residual disease. However, this plateau was not achieved in patients randomized to bendamustine-based treatment in CLL10.8

“If you're thinking about chemoimmunotherapy, FCR is the best treatment to give patients because of this plateau,” said Dr. Wierda. “It’s potentially curative in half of patients with IGHV mutation.”

A Role for Chemoimmunotherapy

Despite the positive outcomes achieved with these new agents, Dr. Brown argued that there remains a role for chemoimmunotherapy in CLL. “We know that ibrutinib, with or without obinutuzumab, substantially improves PFS compared with chlorambucil and also compared with chemoimmunotherapy, although not quite as dramatically as when compared to chlorambucil-based therapy,” she said. “We also know that venetoclax/obinutuzumab improved PFS compared with chlorambucil/obinutuzumab in the CLL14 study, as recently reported.”

Nevertheless, improvements in PFS have not necessarily translated to an OS benefit. “If the patients were actually living longer, short-term PFS would matter, but they're not,” said Dr. Brown. “I contend that ibrutinib did not improve OS compared with chemoimmunotherapy in these studies.”

Although the RESONATE-2 trial reported an OS benefit,1 this was due to a poor comparator of chlorambucil and very limited crossover, she said. When obinutuzumab was added to chlorambucil in the iLLUMINATE study,2 OS curves completely overlapped.

“ECOG E1912 reported an OS benefit based on extremely few events, many of which were not clearly related to the disease or its treatment,”3 said Dr. Brown. “These need to be further evaluated with more follow-up.” Furthermore, said Dr. Brown, not all patients are experiencing improved PFS with small molecule inhibitors versus chemoimmunotherapy. Data from the ECOG and Alliance trials3,4 showed that patients with low-risk mutated IGVH disease did equally well with chemoimmunotherapy as targeted agents, and in the CLL14 study,5 this subgroup experienced similar results with chlorambucil/obinutuzumab as with venetoclax/obinutuzumab.

“The half of patients who have mutated IGHV are not even getting an improved PFS,” said Dr. Brown. “In fact, this mutated subgroup has the potential for prolonged treatment-free remission or even cure with chemoimmunotherapy.” According to data from the MD Anderson phase II study,6 more than half of patients with IGHV-mutated disease treated with FCR with more than 12-year follow-up have shown the potential for cure.

“In what diseases do we give up potentially curative therapy for the requirement of continuous therapy with ongoing residual disease, accumulative side effects, and clearly no cure, which is what we’re talking about with ibrutinib?” said Dr. Brown. “Even if ibrutinib did eventually have similar PFS, it would still have the requirement of continuous therapy, toxicity, and cost.”

Nonhematologic and Financial Toxicity

Although the ECOG E1912 trial3 showed worse hematologic toxicity with the FCR regimen, nonhematologic toxicity with ibrutinib and rituximab is “quite significant,” said Dr. Brown. Grade ≥3 treatment-related adverse events throughout observation included cardiac toxicity (6.5%), ventricular arrhythmia or cardiac arrest (0.9%), atrial fibrillation (3.2%), hemorrhage (1.1%), hypertension (18.8%), and diarrhea (4.3%).9 Moreover, said Dr. Brown, nonhematologic toxicity was even worse on the Alliance trial,4 which had an older patient population.

“In both of the ibrutinib arms, patients had increased infections, increased atrial fibrillation, increased hypertension, and increased rates of unwitnessed death,” she said. “In fact, the chance of dying of an adverse event on the ibrutinib arms with the median follow-up of 2.5 years was 7%.”

As Dr. Brown reported, older patients on ibrutinib have a higher rate of discontinuation, and patients with comorbidities have reduced event-free survival and OS. In the real-world setting, discontinuation rates on ibrutinib are twice what is seen on trial, she added. The toxicity is not limited to ibrutinib, either. Data from CLL14 showed an 8% rate of death related to adverse events in the venetoclax arm, with more infections and cardiac disorders, primarily after therapy was completed.

Financial toxicity must also be considered. One estimate of the impact of oral BTK targeted therapy moving from the relapsed setting to the first-line setting (for ibrutinib) found a 6-fold increase in cost.10 “Novel agents are not saving money, and the financial impact extends beyond the healthcare system,” said Dr. Brown. “Out-of-pocket costs for Medicare patients receiving ibrutinib in the frontline setting have been estimated at $60,000. Most patients cannot afford this.”

According to Dr. Brown, young fit patients with IGHV-mutated CLL should clearly receive 6 months of FCR therapy for possible cure, but young fit patients with CLL with unmutated IGHV or older patients can receive chemoimmunotherapy, as well. “Even though you don’t see the same plateau, bendamustine/rituximab can also be effective in the older patients and have prolonged remissions without a survival disadvantage,” she said. “They have a predictable side-effect profile for 6 months, and certainly in the older patients, bendamustine/rituximab is often less toxic than ibrutinib is with its cardiac side effects.”

Finally, given the success of novel agents in the second line of treatment, patients may be losing a line of therapy if novel agents are used early on.

“We don’t know that chemoimmunotherapy will work after ibrutinib, but we know that ibrutinib works well in the second-line setting,” said Dr. Brown. “That’s something to consider as we manage this chronic disease over a patient’s lifetime. We need to continue to have chemoimmunotherapy in our armamentarium.”

References

  • 1.

    Barr PM, Robak T, Owen C, . Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 2018;103:15021510.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Moreno C, Greil R, Demirkan F, . Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE [abstract]. Blood 2018;132(Suppl 1):Abstract 691.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Shanafelt TD, Wang V, Kay NE, . A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912) [abstract]. Blood 2018;132:Abstract LBA-4.

    • Search Google Scholar
    • Export Citation
  • 4.

    Woyach JA, Ruppert AS, Heerema NA, . Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018;379:25172528.

  • 5.

    Fischer K, Al-Sawaf O, Bahlo J, . Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:22252236.

  • 6.

    Thompson PA, Tam CS, O'Brien SM, . Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303309.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Fischer K, Bahlo J, Goede V, . Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208215.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Eichhorst B, Fink AM, Bahlo J, . First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928942.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Shanafelt TD, Wang XV, Kay NE, . Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 2019;381:432443.

  • 10.

    Barnes JI, Divi V, Begaye A, . Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p. Blood Adv 2018;2:19461956.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Disclosures: Dr. Wierda has disclosed that he is a consultant for Genzyme Corporation and receives grant/research support from AbbVie, Inc., Acerta Pharma, Genentech, Inc., Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP, Juno Therapeutics, Inc., Karyopharm Therapeutics, Kite Pharma, Cyclacel Pharmaceuticals, Inc., GlaxoSmithKline/Novartis Pharmaceuticals Corporation, Loxo Oncology, Inc., miRagen Therapeutics, Inc., Oncternal Therapeutics, Inc., Xencor, Inc., Pharmacyclics, and Sunesis Pharmaceuticals, Inc. Dr. Brown has disclosed that she is a consultant for Abbvie, Acerta, Astra-Zeneca, Beigene, Catapult, Dynamo Therapeutics, Juno/Celgene, Kite, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem; has received honoraria from Janssen; received grant/research support from Gilead, Loxo, Sun and Verastem; and is a scientific consultant for Morphosys and Invectys. Dr. Zelenetz has disclosed that he received consulting fees from AbbVie, Inc., Amgen Inc., AstraZeneca Pharmaceuticals LP, Celgene Corporation, Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP, Novartis Pharmaceuticals Corporation, Adaptive Biotechnologies Corporation, Genentech, Inc./Roche Laboratories, Inc., and Pharmacyclics; is a scientific advisor for AbbVie, Inc., AstraZeneca Pharmaceuticals LP, and MorphoSys AG; and receives grant/research support from BeiGene, Gilead Sciences, Inc., MEI Pharma Inc., and Roche Laboratories, Inc. Dr. Abramson has disclosed that he receives consulting fees from AbbVie, Inc., Bayer HealthCare, Celgene Corporation, EMD Serono, Genentech, Inc., Janssen Pharmaceutica Products, LP, Karyopharm Therapeutics, Kite Pharma, and Roche Laboratories, Inc. Dr. Jain has disclosed that he is a consultant for AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Genentech, Inc., Janssen Pharmaceutica Products, LP, Adaptive Biotechnologies, Precision Biosciences, Verastem, and Pharmacyclics; receives grant/research support from AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech, Inc., Incyte Corporation, Adaptive Biotechnologies, ADC Therapeutics, Cellectis, Precision Biosciences, Servier, Verastem, Pfizer, Inc., and Pharmacyclics; is a scientific advisor for AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Genentech, Inc., Janssen Pharmaceutica Products, LP, Adaptive Biotechnologies, Precision Biosciences, Verastem, and Pharmacyclics; and has received honoraria from AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Genentech, Inc., Janssen Pharmaceutica Products, LP, Adaptive Biotechnologies, Precision Biosciences, Verastem, and Pharmacyclics. Dr. Park has disclosed that he receives grant/research support from Amgen Inc., Genentech, Inc., Incyte Corporation, Juno Therapeutics, Inc., Kite Pharma, Novartis Pharmaceuticals Corporation, and Servier; and is a scientific advisor for from Amgen Inc., AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, Incyte Corporation, Kite Pharma, Novartis Pharmaceuticals Corporation, Allogene Therapeutics, Autolus Therapeutics plc, and Takeda Pharmaceuticals North America, Inc.

Correspondence: William G. Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030. Email: wwierda@mdanderson.org; and Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. Email: jennifer_brown@dfci.harvard.edu
  • 1.

    Barr PM, Robak T, Owen C, . Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 2018;103:15021510.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Moreno C, Greil R, Demirkan F, . Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE [abstract]. Blood 2018;132(Suppl 1):Abstract 691.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Shanafelt TD, Wang V, Kay NE, . A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912) [abstract]. Blood 2018;132:Abstract LBA-4.

    • Search Google Scholar
    • Export Citation
  • 4.

    Woyach JA, Ruppert AS, Heerema NA, . Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018;379:25172528.

  • 5.

    Fischer K, Al-Sawaf O, Bahlo J, . Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:22252236.

  • 6.

    Thompson PA, Tam CS, O'Brien SM, . Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303309.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Fischer K, Bahlo J, Goede V, . Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208215.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Eichhorst B, Fink AM, Bahlo J, . First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928942.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Shanafelt TD, Wang XV, Kay NE, . Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 2019;381:432443.

  • 10.

    Barnes JI, Divi V, Begaye A, . Cost-effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia in older adults without deletion 17p. Blood Adv 2018;2:19461956.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 927 927 25
PDF Downloads 374 374 16
EPUB Downloads 0 0 0