Incorporation of Chemotherapy-Free Regimens Improve Outcomes in Hematologic Malignancies

Thomas Kipps, MD, PhD

The advent of novel targeted therapies, such as BTK inhibitors, antibody-drug conjugates (ADC), TKIs, and JAK inhibitors, have transformed the management of several hematologic malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Hodgkin lymphoma, chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS), according to a panel of experts from the University of California, San Diego (USCD) Moores Cancer Center during an OncLive® Institutional Perspectives in Cancer (IPC) webinar on leukemia/lymphoma.

“The pace of the progression of improvements in the treatment strategies for patients with hematologic malignancies is sometimes overwhelming for clinicians who are busy trying to treat their patients and keep them [in remission],” said Thomas Kipps, MD, PhD, chair of the IPC meeting, during an interview with OncLive®.

“We are dedicated to stretching the envelope to improve the therapies that exist today because we are not satisfied. We want to improve efficacy and decrease toxicity. Hopefully, we can also decrease cost as well to [allow] patients to have fruitful and productive lives after therapy,” Kipps added.

During the interview, Kipps, a professor of medicine, the Evelyn and Edwin Tasch Chair in Cancer Research, and deputy director of Research Operations at the UCSD Moores Cancer Center, discussed navigating treatment regimens in CLL and MCL, the success of brentuximab vedotin (Adcetris) in Hodgkin lymphoma, choosing between TKIs in CML, and the importance of transfusion independence in MDS.

OncLive®: During the IPC meeting, Michael Choi, MD, of UCSD Moores Cancer Center, discussed key updates in CLL. What does treatment selection between continuous and fixed-duration therapy look like in this disease?

Kipps: There has been a tremendous improvement in outcomes for patients [will CLL] with the advent of targeted therapies, particularly BTK inhibitors. These drugs are oral and bioavailable by mouth. They have made the application of therapy easy to patients. They are generally very well tolerated and have a high success rate in producing clinical responses in our patients. Right now, we have the first-generation [BTK inhibitor] ibrutinib [Imbruvica] as well as the second- and third-generation BTK inhibitors acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. We have another drug, tirabrutinib, that may be approved. These drugs all work by covalently binding to and inactivating the BTK enzyme.

There is work on yet another generation of BTK inhibitors that do not covalently bind to BTK, so they may be good drugs to use in patients who develop resistance to covalent BTK inhibitors.

Dr Choi highlighted the fact that we have 5-year progression-free survival [(PFS) data for BTK inhibitors]. The RESONATE-2 trial [NCT01722487], which compared frontline ibrutinib with chlorambucil for the treatment of patients with CLL who had comorbidities and were over the age of 65 years, revealed striking improvement in PFS [with ibrutinib]. [The results were so impressive] that [ibrutinib] was approved for patients younger than 65 years of age. The National Comprehensive Cancer Network guidelines now recommend ibrutinib as a go-to drug for the treatment of patients with CLL.

The important point is that many of the adverse prognostic factors that govern poor responses to chemotherapy or chemoimmunotherapy regimens seem to fall by the wayside with BTK inhibitors. Now, 7-year data are showing a tremendously long PFS provided patients stay on the drug. That is one of the drawbacks here. These drugs have the potential to induce clinical responses, but they require maintenance therapy. Therefore, patients are relegated to take these agents ad infinitum. For some patients, that is formidable because they may have adverse effects that are sometimes worse during the early onset of drug therapy, but then become annoying in that the patient wishes to get off therapy altogether.

The big debate, as Dr Choi highlighted, is the decision of whether we can go back to developing fixed-duration treatment or whether we are relegated to using drugs forever in patients in the way we treat hypertension or diabetes. The advent of venetoclax [Venclexta], which targets the BCL-2 protein that protects the cell from undergoing cell death, has proven to be highly effective and able to induce deep clinical remissions to make it possible for patients to stop therapy after 1 year of treatment. The deep clinical remissions are truly significant with patients having no evidence of disease clinically and molecularly by next-generation sequencing. Fixed-duration therapy is being considered for many younger patients; however, there is a catch. We know from our experience of chemoimmunotherapy and venetoclax that some patients, even if they achieve a very deep clinical remission, may show recurrence of the disease that requires therapy again. Some of the signatures of those proteins were highlighted by Dr Choi and primarily involve the expression of unmutated antibody genes, as well as other markers, such as TP53 mutations. It’s apparent that we need to come to a better understanding of which patients are suitable for fixed-duration vs continuous therapy.

One trial Dr Choi highlighted that I’m very excited about is the CAPTIVATE trial [NCT02910583], which looks at patients with CLL treated with fixed-duration therapy. The outcome of that trial is being discussed. There is also another part of the trial which allows patients to be stratified by virtue of minimal residual disease [MRD]. Those patients who have MRD at the end of 1 year of therapy may be randomized to receive ibrutinib or ibrutinib plus venetoclax. Patients with no evidence of MRD will be randomized to receive nothing at all or ibrutinib. The combination of these drugs and the ability to look at these trials will help us delineate which patients are suitable for fixed-duration vs continuous therapy.

Benjamin Heyman, MD, of UCSD Moores Cancer Center, discussed the current state and future directions of treatment in MCL. How have BTK inhibitors transformed treatment for this patient population, and what notable agents are in clinical development?

MCL is arguably a more aggressive disease by and large than CLL, but [the diseases] share some features, such as the expression of CD5 and being a B-cell malignancy. However, there tends to be an intractable nature and a tendency for the disease to progress, owing to the high-level expression of cyclin D1, which according to translocation 11;14 causes this important protein that is involved in the regulation of the cell cycle to be overexpressed.

It’s been a challenge [to treat patients with MCL]. Drugs like ibrutinib tend to be successful [in MCL]. Acalabrutinib has been approved [in MCL also]. This is progress in that it obviates having to use more chemotherapy regimens, which may be less well tolerated, particularly in older patients. However, there is a tendency for [patients] to not achieve complete responses [CRs]. Some of the large studies that have been reported show that only about 20% of patients may achieve a CR with ibrutinib and only slightly more with acalabrutinib, although head-to-head trials have not been done. Arguably, this is not the same batting average that we have in CLL, so there are strategies to combine [BTK inhibitors] with other agents.

Dr Heyman highlighted a trial that I’m excited about. In full disclosure, the antibody zilovertamab vedotin he mentioned is one that I developed in my laboratory, but I’m excited about it because it’s being examined by clinicians like Dr Heyman in multicenter clinical trials. This drug appears to have the ability to block a signaling pathway in MCL that is not blocked by ibrutinib. Trials are using this drug in combination with ibrutinib. It appears that they are showing a higher batting average with respect to obtaining CRs in patients with relapsed/refractory MCL who had prior BTK inhibitor therapy. That is very exciting to me. The safety signal suggests there doesn’t seem to be a larger level of toxicity [with the combination] than with BTK inhibitors alone.

One study that did come out using zilovertamab vedotin that was conjugated to a tubulin synthesis inhibitor called MMAE was also used for the treatment of patients with aggressive relapsed/refractory MCL. The results showed a good CR rate. That [trial] was reported recently in the New England Journal Medicine Evidence. This multi-institutional trial is looking at zilovertamab vedotin as a single agent that targets ROR1, which is found in high levels in MCL and may represent a new target we can go after to achieve meaningful responses through another targeted therapy. I’m certainly biased, but it is something I’m watching with great interest. It is exciting to see these things develop and see patients doing well.

Erin Reid, MD, of UCSD Moores Cancer Center, discussed Hodgkin lymphoma and the success observed with the ECHELON-1 (NCT01712490) regimen. Could you speak to the importance of brentuximab vedotin as a treatment option for this patient population?

Hodgkin disease is one that we’ve had great success in treating patients, who by and large, can achieve high rates of clinically deep remissions and enjoy many years of PFS and overall survival [OS]. Patients [with Hodgkin lymphoma] are typically younger, so the quest is in determining what the long-term toxicities of therapy are. Clearly, more is not always better. We try to use more in the treatment of patients with cancer because it is like a battle. If we skimp off the therapy, the cancer might get the upper hand. In the case of Hodgkin disease where response rates are so high, the challenge is to find regimens that are less toxic without lowering the overall clinical responses that might be considered curative.

One way [to find that balance] is to do head-to-head clinical trials. Dr Reid mentioned the ECHELON-1 trial, which used brentuximab vedotin, an antibody that binds to another cell protein found at high levels in Hodgkin lymphoma. Like zilovertamab vedotin, brentuximab vedotin is another ADC coupled with MMAE. [Brentuximab vedotin] has activity in patients with relapsed Hodgkin disease.

The ECHELON-1 study compared the use of brentuximab vedotin in combination with AVD [(doxorubicin, vinblastine, and dacarbazine) vs ABVD (AVD plus bleomycin)]. Essentially, brentuximab vedotin was substituted for bleomycin. The multicenter study involved thousands of patients. We are now able to witness the 5-year survival data, as well as [the data] for patients who tested negative for PET evaluations. Patients who are negative by PET typically have very deep clinical responses. A high percentage of those patients may go on to be cured of their disease.

In that category of patients, we saw a significant improvement in patients treated with brentuximab vedotin vs ABVD. Certainly, patients who had PET-positive disease [benefitted], and maybe the difference was even more apparent there. This represents an advance that may allow us to escape some of the toxicities associated with bleomycin, such as pulmonary toxicities. [ADCs], including brentuximab vedotin and zilovertamab vedotin, can cause peripheral neuropathy, so we have to monitor closely for that.

It is encouraging that in the ECHELON-1 trial, the 5-year follow-up of patients with brentuximab vedotin noted that the neuropathy tends to abate over time and doesn’t become a debilitating toxicity. This is something we have to follow. Obviously, trying to minimize toxicity now is the name of the game because we have high response rates and improvement in outcomes [with brentuximab vedotin].

James K. Mangan, MD, PhD, of UCSD Moores Cancer Center, highlighted advances in CML, noting the 5-year safety data of the phase 3 BFORE trial (NCT02130557). How is the field navigating between available TKIs in this disease?

[CML] is the poster child of leukemias because it was the first to be successfully managed with targeted therapy using the drug imatinib [Gleevec] that has been approved for almost a decade. [Imatinib] inhibits the ABL kinase, which is the kinase that is dysregulated by the translocation that couples BCL with the c-ABL kinase. [This results] in a fusion protein that is dysregulated and constituently activated, which by itself can drive the expansion of a clone of myeloid cells into leukemia. That has been shown in mice. We have put that gene into overdrive in mice to develop CML, so it is a gene that can cause the disease.

So, it was sensible to try to develop a drug that can target the enzyme. Imatinib is one such drug. It certainly is a go-to frontline drug for patients with CML that is relatively well tolerated and can result in deep CRs in which disease cannot be detected by molecular means. [Imatinib] has been a game changer for patients who used to be facing a 3-year death sentence. After 3 years on average, patients would have blast crisis where they would develop a type of very aggressive leukemia that was refractory to multi-agent chemotherapy and generally [died from their disease].

[Imatinib] has improved the survival of patients, but like anything, other companies saw this and developed other drugs. These are the second-generation ABL kinase inhibitors, including nilotinib [Tasigna] and dasatinib [Sprycel]. These agents also have activity and many bind to the same area of the ABL kinase. It’s understandable that the tumor may find an escape mechanism like with BTK inhibitors. The enzyme can become mutated in subclones of the disease that might be selected. Now, there are also third-generation drugs that can inhibit even the enzyme that has this mutation at position [T315I] in the ABL kinase. Bosutinib [Bosulif] is one that we talked about [during the meeting].

It is important that we don’t ignore a patient who initially responded to these drugs and is showing signs of progression. We want to test for the presence of that mutation using molecular sequencing. If we find the mutation is present in the ABL kinases, going to some of these other new drugs can work in these cases.

There is also interest in developing improvements [to these approaches]. Bosutinib is a drug that is being compared with imatinib in the BFORE trial in patients with CML who require frontline therapy. [Bosutinib] stacked up very well [against imatinib]. In December of 2017, [bosutinib] was approved by the FDA on accelerated approval for the treatment of patients with CML. Typically, this drug is used in the second-line setting. However, the BFORE trial raises the issue of whether it can be considered a frontline agent. Bosutinib is generally very well tolerated. With bosutinib vs imatinib, a fifth to a quarter of patients may discontinue treatment for reasons of intolerance or toxicities. Most commonly, toxicities with bosutinib included diarrhea and increased hepatic transaminases. We have to monitor patients because these toxicities are something to contend with, particularly when we are considering chronic therapy.

It’s always good to have choices because if we have a patient who is intolerant to one drug, we can choose something else. Perhaps, by chance, the patient may not be intolerant to or have toxicities with the other drug. It is always good, as a physician treating patients, to have a choice and develop algorithms for [selecting] what drug to go with when [a patient] develops resistance or intolerance.

We also have to consider cost. Imatinib has become practically generic, so therefore, the cost of the drug may be much less compared with bosutinib. Cost-benefit analyses have been conducted between bosutinib, nilotinib, and dasatinib. They seem to argue that [bosutinib] is better than the latter drugs in terms of quality of life, although it is difficult to assess. We have to look at toxicities, including cost toxicities, to try to [optimize] managing our patients with well-tolerated and effective regimens.

Finally, Tiffany N. Tanaka, MD, of UCSD Moores Cancer Center, spoke to the current state of MDS. What is the importance of a patient with MDS achieving transfusion independence and how are novel agents better suited to get a patient to that status?

There have been advances in MDS, which has been a challenge as most patients present later in life. Therefore, they have associated comorbidities. Also, we have patients with [bone] marrow that is not functioning well by definition, so they typically have poor tolerance to chemotherapy.

A lesson that has been learned through history is that we don’t treat these patients with high-dose chemotherapy because they don’t generally recover from such treatment. Newer agents have been developed, including drugs like fedratinib [Inrebic] that inhibit the JAK2 kinase. These drugs are important adjuncts to the treatment of patients with MDS. However, the rule is to still use supportive care and judgement when [selecting] therapy.

Fortunately, in many cases, the disease is very indolent, and patients can be supported through blood products and antimicrobial therapy. In the case of blood products, transfusion sometimes gets difficult because patients may develop high levels of serum ferritin and iron overload, which can create toxicity. Therefore, any strategy that may not be curative but can reduce the number of transfusions required over time may be beneficial so patients can avoid iron overload, which may not be easily treated by iron-chelation therapy.