Is Fludarabine Dead in CLL?

Professor of medicine in hematology at the Stanford University Medical Center in Stanford, California
Director of the lymphoid malignancy program at the Cleveland Clinic in Cleveland, Ohio

A few short years ago, fludarabine was considered the gold standard of front-line treatment for chronic lymphocytic leukemia (CLL), providing better response rates than old standby, chlorambucil. Now, in an era of monoclonal antibodies and targeted therapies, fludarabine is losing its place as leader of the pack. ASH Clinical News has invited Steven Coutre, MD, and Mitchell Smith, MD, PhD, to debate the question: “Is fludarabine dead in chronic lymphocytic leukemia?” Dr. Smith will be arguing “no,” while Dr. Coutre will be arguing “yes.”


Steven Coutre, MD: We have had fludarabine for decades, and today, the standard front-line treatment for chronic lymphocytic leukemia (CLL) remains chemoimmunotherapy with a fludarabine-based regimen – fludarabine, cyclophosphamide, and rituximab (FCR), or fludarabine, bendamustine, and rituximab (BR).

At present, with the newer therapies (such as the Bruton tyrosine kinase inhibitor ibrutinib and the PI3 kinase delta inhibitor idelalisib), we don’t have the randomized trials comparing them with fludarabine-based regimens to give us definitive answers about outcomes such as durable remissions. Having said that, however, there is enough experience with the newer agents to have at least some qualitative impressions.

I do think the antibody therapeutics and the kinase inhibitors have an advantage from a side effect profile. The oral drug ibrutinib has been extremely well-tolerated with very favorable quality-of-life results.1 Clearly, for the average older patient with CLL, taking a well-tolerated oral drug is preferred to receiving an intravenous chemotherapy drug. For better or worse, patients do not view these types of newer agents as “real chemotherapy,” which is part of their allure.

It is also not hard to imagine that, based solely on the data that we have now, these newer drugs will likely lead to more durable remissions, particularly with the kinase inhibitors. But we can’t draw those conclusions yet until we have the necessary randomized trial data.

Mitchell Smith, MD, PhD: Fludarabine is not for everyone. Older CLL patients’ risk for adverse events and toxicities increases as they age, and fludarabine-associated toxicity might also be an issue in patients with renal dysfunction. In younger, fitter patients, however, we do have long-term follow-up data showing impressive results with fludarabine-based regimens.2 We don’t want to completely throw out fludarabine-based regimens, because in the right patient population they can be beneficial.

As far as the impact on patient quality-of-life, yes, fludarabine is “real chemotherapy” delivered intravenously; however, this takes place for a defined six-month period. With that limited, six-month regimen, fludarabine leads to years-long survival in some patients with CLL.

With these newer oral agents, however, patients will have to take the drug for basically the rest of their lives, and we just do not have long-term data. Late or unexpected toxicities are still a worry. It is a bit premature to ask patients to commit to one of the new oral agents.

Dr. Coutre: I would agree that the concept of time-limited therapy with a fludarabine-based regimen can be very attractive compared with the uncertainty of long-term use of cancer drugs, particularly for younger patients. We do have good follow-up for at least three years with ibrutinib and have not seen any new concerns.3 If you are looking at a 20-year horizon of treatment for younger patients, we are never going to be able to answer questions about late side effects in real time. Even with the randomized trials, those issues will take an incredibly long time to address.

I believe new agents like ibrutinib and idelalisib will start to dominate the second-line treatment landscape. In the past, patients would relapse after the FCR regimen and would just get FCR again. When bendamustine entered the treatment landscape, patients who relapsed were treated with that because at least it was different. In my mind, there really isn’t a good reason to give patients a fludarabine-based regimen for a second time. There certainly are concerns with myelosuppression in that setting, and even when switching to another fludarabine-based regimen like BR, there are concerns about the cumulative effects of the drug.

Dr. Smith: Right, in terms of second-line treatment, I would agree that following FCR with another chemoimmunotherapy regimen leads to issues with prolonged myelosuppression. So, yes, in that case, there is no question that newer oral agents will play a role.

In the front-line setting, however, we really need to question whether there is still a role for fludarabine. Are we ready to let go of a tried-and-true regimen that has durable remissions in a high percentage of CLL patients, then wait to use these novel agents as second-line treatments when necessary? Or, is it time to throw out FCR completely? My answer would be no, we are not ready to throw it out yet. However, I definitely agree that further down the line, these novel agents should be the drug of choice, rather than continuing to beat up the patients’ bone marrow with additional cytotoxic agents.

Dr. Coutre: We might not be ready to completely let go of fludarabine, but there is absolutely a need for newer treatment options. When it comes right down to it, the average CLL patient is 70 years old at the time of diagnosis and does not need immediate treatment, so the average CLL patient is receiving first-time treatment in his or her 70s. In clinical trials, however, the average participant age is far less than that. This gives us a skewed data set not representative of the patients seen in daily practice.

Many times, those clinical trial patients were receiving BR or single-agent rituximab instead of FCR; BR was believed to be a kinder, gentler approach, but single-agent rituximab is not even particularly effective as a single agent in CLL. Those are the patients for whom we need better treatment options. The newer agents – well-tolerated oral drugs that control the disease – fit the bill.

We will continue to learn more as we gain more experience using the drugs in front-line and relapsed settings, but we know one thing for sure: Chemoimmunotherapy followed by further chemoimmunotherapy in CLL just leads to more immunosuppression and infection, and that is how most patients die from this disease.

Dr. Smith: Absolutely, but when we think about the optimal use of fludarabine, we have to remember that we are talking about treating a selective subpopulation. All the trials suggest, again, that the risks of short- and long-term toxicities increase as patients age. In the appropriately selected patient population, however, fludarabine has a role. In the German CLL10 trial, patients older than 65 years did not have as good outcomes, and patients 65 years and younger with active disease do need treatment; that is where fludarabine-based regimens are needed.4 I absolutely agree that we do need new treatments, particularly for older, frailer patients, who make up a large segment of the CLL patient population.

From my standpoint, we should reserve fludarabine for young, fit patients, as they will tolerate the treatment and do well. Older, frailer patients are not great candidates for these regimens, and we know that deletion 17p patients do not do well with any type of chemoimmunotherapy, including FCR.5

When examining the data from the studies on FCR, yes, you do have to keep in mind that this is a carefully selected population, and their experience should not be generalized to that of the older, more common patient that you see in daily practice.

Dr. Coutre: That is interesting, and I agree that results from these studies may seem impressive and encouraging, but when you apply them to practice, you often find longer duration of myelosuppression than was expected, leading to increased infections. In the recent FCR-versus-BR trial, patients receiving FCR had a higher rate of myelosuppression, which translated to more significant infections.4 Those infections were not increased during therapy, but immediately after therapy. So, the prolonged effects of these regimens are very real. If we can avoid those in CLL treatment, that would be beneficial.

Dr. Smith: These newer drugs are promising, but fludarabine certainly isn’t dead yet. Sure, everyone would like to replace fludarabine with an oral drug that leads to durable results with minimal toxicities. That would be wonderful. But we haven’t found that yet. There are concerns with these newer agents, just as there are concerns about fludarabine.

However, we’ve been using fludarabine for 20 years and are able to address those concerns: We know how to address myelosuppression; we can give prophylactic antivirals, antifungals, antibiotics, and growth factors to help patients through treatment; and patients can remain off treatment for a prolonged period. In the German CLL10 trial, the median progression-free survival was well over four years,4 which did not mean that patients required treatment then, just that they had disease progression; they might go another couple years before they need treatment. Patients benefit from a very long treatment-free interval with fludarabine-based regimens, as long as physicians are careful about selecting and monitoring them.

With the oral agents, we simply do not have that experience, and we have concerns about unusual toxicities: bleeding issues and atrial fibrillation with ibrutinib, and immunologic responses such as colitis with idelalisib. We also have to consider the cost of these new agents; they tend to be very expensive, and because patients will take these drugs for many years, that is a significant cost. We have to decide if that is feasible for everyone, especially in the case of patients with indolent CLL who may not need constant therapy.

Dr. Coutre: That is a relevant point, certainly in the United States where national systems often make decisions about drug approvals and reimbursement based on cost-benefit analyses. Having a large group of patients suddenly on very expensive drugs is a bit frightening, so I don’t think this is a switch that will happen immediately. There is a lot of research interest in seeing whether or not these drugs need to be used continuously. This will be a major issue as their use becomes more widespread.

Dr. Smith: The other issue with front-line treatment with novel oral agents (ibrutinib in particular) is evidence of shorter survival after patients experience disease progression.6 It is unknown whether that is related to the patient population (i.e., a heavily pre-treated patient population that was destined have rapid regrowth) or if we are somehow altering the biology or selecting rapidly growing clones (i.e., perhaps we have disturbed the biology of the disease and made it more progressive). We would hate to have that happen in a patient with more indolent disease. That’s a definite concern in the background: If you treat patients earlier, will it do more harm than good?

Dr. Coutre: That’s true. The data we have so far are from a somewhat skewed population. In the limited clinical trials experience with ibrutinib and idelalisib in the upfront setting, the findings are much different. To date, very few of those patients have progressed. For example, in a small study of 31 patients who received front-line ibrutinib, only one patient has progressed.7
This patient also progressed very early during treatment, so the nature of his or her disease was likely a bit different than others’. Other patients continue to do well and have been treated for close to five years now.

It is obviously an exciting time, with the prospect of innovative and potentially transformative new therapies. The challenge moving forward is to find the best way to use them, to determine which patient populations benefit most from which drugs, and to know whether there is still a role for our standard approaches in those patient populations.

Dr. Smith: It is very encouraging that we have trials underway comparing chemoimmunotherapy versus novel agents. Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin.


References

  1. Barrientos JC, O’Brien S, Brown JR, et al. “Hematologic and Immunologic Function and Patient Well-Being for the Phase III RESONATE™ Study of Ibrutinib vs. Ofatumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphoma.” Abstract #4696. Presented at the 56th ASH Annual Meeting, December 8, 2014.
  2. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-80.
  3. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.
  4. Eichhorst B, Fink AM, Busche R, et al. “Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to  Bendamustine (B) and Rituximab (BR) in Previously Untreated and Physically Fit Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Final Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study).” Abstract #19. Presented at the 56th ASH Annual Meeting, December 6, 2014.
  5. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99:1350-5.
  6. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-7.
  7. O’Brien SM, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Lancet Oncol. 2014;15:48-58.

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