Chemotherapy-Free Regimens Continue to Change the Game

A better understanding of disease biology has allowed for more tailored, sophisticated treatment options

The combination of vemurafenib and obinutuzumab induced a 100% complete response rate in a small study of 27 patients with relapsed or refractory hairy cell leukemia, according to results reported at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition.¹ With a median follow-up of about 17 months, all patients treated with this chemotherapy-free regimen remained in remission without relapse.

This study is just one of many presented at the conference detailing results of a chemotherapy-free regimen used against a hematologic malignancy. In this case, vemurafenib is an oral BRAF^V600E inhibitor, and obinutuzumab is a CD20-directed monoclonal antibody.

The number of drugs and regimens that fall under the umbrella term of “chemotherapy-free” regimens continues to grow as more is learned about the biology behind hematologic malignancies and other cancers.

Blood Cancers Today recently spoke with several hematologist/oncologists about some of the advances in chemotherapy-free treatment and what it means for the future of cancer care.

What is Chemo-Free?

“The initial description for chemotherapy was to distinguish it from other cancer therapies like radiotherapy or surgical therapy; it included anything that was a chemical substance,” explained Charalambos (Babis) Andreadis, MD, MSCE, Associate Professor of Clinical Medicine at the University of California, San Francisco (UCSF) and Director of the Clinical Research Support Office at the UCSF Helen Diller Family Comprehensive Cancer Center.

“We now use it to imply any DNA-damaging agents that we utilize to treat cancer,” Dr. Andreadis said. “Agents that kill tumor cell DNA but also unfortunately damage other cells.”

Chemotherapy-free regimens, in contrast, include several types of treatment such as targeted therapies, antibody therapy, and immunotherapy.

“Attempting to rely on inherently more accurate or unique forms of inhibition of cancer growth compared to the use of traditional cytotoxic chemotherapy has always been attractive, as it promised to possibly curtail the overall toxicity of inhibition of more global cell-cycle pathways that were innately shared by many cells of various organs in the body,” said Muhamed Baljevic, MD, Associate Professor of Medicine and Director of Plasma Cell Disorders Research and Vanderbilt Amyloidosis Multidisciplinary Programs at Vanderbilt-Ingram Cancer Center. “It also potentially facilitated more effective targeting of tumor cells, as these forms of agents and regimens are normally developed by targeting—as unique as possible—cancer-related proteins, in or outside the cancer cells, that may not be as expressed in other healthy tissues.”

In the late 1980s, scientists identified the CD20 protein on B cells. Although CD20 is also on healthy B cells, it is not on immature or developing cells and is, therefore, a good cancer treatment target. Rituximab, which binds to CD20, was one of the first monoclonal antibodies developed. In early studies, many patients with non-Hodgkin lymphoma who did not respond to chemotherapy responded to rituximab.²

“Another key milestone was the development of a tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia (CML) during the same period, which ultimately became the poster-child success story for development of targeted, small-molecule inhibitors,” Dr. Baljevic said.

Since then, the field of chemotherapy-free regimens has expanded to include many different cancers and not only monoclonal antibodies but also immune checkpoint inhibitors, antibody drug conjugates, bispecific T-cell engagers, and—depending on how it is defined—cellular therapy.

Lymphoid Leukemias

There has been a lot of progress in the development and clinical application of chemotherapy-free regimens in the past decade or two, and one of the most successful areas is in chronic lymphocytic leukemia (CLL), according to Julie M. Vose, MD, MBA, the Neumann M. and Mildred E. Harris Professor and Chief in the Division of Oncology/Hematology at the University of Nebraska College of Medicine.

“In CLL, I would say that between 90% to 95% of patients receive pathway-directed agents or anti-CD20 monoclonal antibodies,” Dr. Vose said. “Less and less chemotherapy is being given, and these agents are being used in the frontline and in relapsed/refractory patients.”

The treatment of CLL was significantly altered with the advent of drugs targeting BCL2 (venetoclax) and Bruton’s tyrosine kinase (BTK; ibrutinib and acalabrutinib). These and other therapies are providing patients with not only a reduction in associated toxicities but also improved outcomes compared with prior standards of care.

A phase III study testing frontline use of rituximab plus ibrutinib in patients with CLL aged 70 or younger established superior progression-free survival (PFS) and overall survival (OS) with this drug combination compared with standard chemoimmunotherapy.³

More recently, the CAPTIVATE trial tested an all-oral, chemotherapy-free regimen of ibrutinib plus veneto­clax in patients with previously untreated CLL. All patients were treated with the combination, and those with confirmed undetectable minimal residual disease were randomly assigned to placebo or ibrutinib. In this group, the two-year PFS was 95% among all patients and 96% among patients without the 17p deletion mutation, showing that the treatment was effective when given for a fixed duration.⁴ These findings were confirmed in the HOVON 141/VISION study.⁵

“In CLL, these regimens are allowing patients to stay in remission for extended periods of time,” Dr. Vose said. “This has meant fewer patients are requiring transplant.”

There has also been a lot of progress in the use of chemotherapy-free regimens in the treatment of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Historically, patients were treated with induction chemotherapy and hematopoietic stem cell transplantation (HSCT) at first remission. However, ALL treatment was transformed with the discovery of the BCR-ABL1 gene sequence and the addition of imatinib to intensive chemotherapy regimens.

More recently, the CD3-CD19 bispecific antibody blinatumomab and the anti-CD22 antibody drug conjugate inotuzumab have further improved outcomes in relapsed or refractory B-cell ALL, including Ph-positive disease. These agents, combined with newer-generation TKIs such as dasatinib or ponatinib, are slowly bringing treatment closer to the chemotherapy-free goal.

“By going through these targets, we are able to deliver more effective therapy and spare patients the need for more intensive approaches, including intensive chemotherapy and HSCT,” said Elias Jabbour, MD, Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.

At the 63rd ASH Annual Meeting & Exposition, Dr. Jabbour and colleagues presented updated results of a phase II study of ponatinib and blinatumomab in Ph-positive ALL. The complete remission (CR)/CR with incomplete count recovery rate was 95%. With a median follow-up of 10 months, the estimated two-year event-free survival and OS rates were both 93%.⁶

In a recently published review of chemotherapy-​free regimens in Ph-positive ALL, Dr. Jabbour and colleagues reviewed all the current evidence for the use of chemotherapy-free frontline regimens and concluded that these promising results with blinatumomab and TKIs “question the role of allogeneic HSCT in first remission.”⁷

Commenting on just how far the field has come, Aaron Gerds, MD, Associate Professor in Medicine, Hematology, and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute, said, “The upfront chemotherapy-free treatment of adult ALL was something that was inconceivable even 10 years ago.”

Lymphomas

There are also a variety of lymphomas, particularly the more indolent lymphomas, where drugs such as ibrutinib and rituximab are being used with very good success, Dr. Gerds said.

In follicular lymphoma (FL), immunomodulatory treatment with lenalidomide and anti-CD20-based combinations have been validated in the frontline and relapsed/refractory settings. Rituximab plus lenalidomide in advanced FL had similar efficacy to rituximab plus chemotherapy but with a differing toxicity profile.⁸

Results of the phase II GALEN study testing obinutuzumab and lenalidomide in patients with previously untreated FL showed that the chemotherapy-free combination produced an overall response rate (ORR) of 92% with a CR rate of 47% at the end of induction, as well as an ORR of 79% with a CR rate of 63% at the end of therapy. At about four years of follow-up, the median PFS was 82%.⁹

Progress is also being made in mantle cell lymphoma (MCL), where standard treatment of young patients was intensive chemotherapy regimens with or without transplant.

“MCL was historically treated with chemotherapy plus HSCT, but in the last eight to nine years, we have been relying on BTK inhibitors as second-line regimens for many patients, with some using them in the frontline [setting],” Dr. Andreadis said.

Recently, the single-arm, phase II WINDOW-1 study tested chemotherapy-free induction with ibrutinib plus rituximab until CR or up to 12 cycles, followed by a consolidative shortened course of intensive chemoimmunotherapy with R-HCVAD (rituximab, cyclophosphamide, vincristine, dexamethasone, and doxorubicin). The regimen yielded a best ORR of 98% with a CR rate of 87% after the chemotherapy-free induction regimen, as well as a global ORR of 90% with a CR rate of 89%. Although not yet chemotherapy-free, the approach is attempting to minimize the number of chemotherapy cycles.¹⁰

Myeloid Neoplasia

In myeloid neoplasia, targeted therapies and drugs not considered to be traditional chemotherapies have been “coming along,” Dr. Gerds said.

“The challenge is identifying targets,” Dr. Gerds said. “The nice thing about lymphoid malignancies is you can target cell surface receptors, and if we throw away the good with the bad, it is okay. You can support a patient even with low lymphocytes. If we knock out myeloid cells, we would take a minimally functioning bone marrow and make even less.”

Instead, researchers are attempting to target unique mutations. About 30% of patients with newly diagnosed acute myeloid leukemia (AML) will harbor mutations in FLT3, and about 20% will have mutations in IDH1 or IDH2.

A phase III study comparing the FLT3 inhibitor gilteritinib with salvage chemotherapy showed a significant improvement in OS and a better response rate with gilteritinib among patients with relapsed or refractory FLT3-mutated AML.¹¹

Three driver genes have been identified in myelo­proliferative neoplasms: JAK2, MPL, and CALR. Although treatment with JAK inhibitors improves constitutional symptoms and splenomegaly, they have not produced remissions or improvements in survival compared with best supportive care.

“These are complex entities that often don’t rely on a single pathway,” Dr. Gerds said. “In myeloid leukemias and myeloid neoplasia, you can block a pathway, but the cells have multiple pathways that they are depending on. It is much more of a game of whack-a-mole, and we still have a long way to go.”

Drawbacks

Many of these targeted agents and immunotherapies have significantly improved outcomes for patients with hematologic malignancies, but no treatment is entirely without a downside.

“While the goals of absolute efficacy and no toxicity remain aspirational for any form of cancer treatment, the reality is that it is very challenging to always identify targets that are purely exclusive to cancer tissue,” Dr. Baljevic said. “Other cellular pathway targets of small-molecule inhibitors can still be associated with important functions in otherwise healthy cells.”

Additionally, as some of the chemotherapy-free drugs or regimens are based on releasing or enhancing immune mechanisms of anti-cancer activity, side effects related to overactivation of the immune system can be common and serious.

Treatment with immune checkpoint inhibitors can lead to a variety of immune-related side effects, including rash, itching, diarrhea, fatigue, painful or swollen joints, loss of vision, or more. BTK inhibitors are linked to increases in cardiac arrhythmias, bleeding, bruising, or infection.

“Many of these treatments have a group of very specific side effects,” Dr. Vose said; however, she noted that most physicians who are familiar with the drugs will be able to effectively manage adverse events.

Another downside is that little is known about the long-term side effects of these newer medications, Dr. Gerds said. In contrast to some chemotherapy regimens that have been around for decades, more follow-up time is needed to get a better picture of long-term effects of targeted agents.

“When we have a chemotherapy-free regimen that cures people, we still have to follow them for 10, 15, or 20 years to see what, if any, effects there are,” Dr. Gerds said. “We want to see improvement not only from the disease but a survival that approaches that of the general population.”

The other important potential drawbacks to these newer therapies are related to access and cost, according to Dr. Andreadis.

“For patients, the biggest downside is access,” Dr. Andreadis said. “Traditional chemotherapy drugs have a well-established reimbursement pattern from the insurance and providers’ perspective. Any patients with any of these cancers can have access to those.”

“Some of the newer, more targeted therapies are a bit more ‘boutiquey,’” he said. “For example, something like chimeric antigen receptor T-cell therapy requires a high level of expertise that the average hematologist/oncologist doesn’t have yet. Referral is needed, and that tends to select out patients who can’t travel or don’t have the resources.”

In addition, the patient financial burden from oral therapies is also significant, and some are not as routinely covered as infusion services might be, Dr. Andreadis said.

Novel therapy combinations in the treatment of multiple myeloma (MM) can cost approximately $145,000 per year compared with about one-third of that for traditional chemotherapy.¹² In MM, it is commonplace for patients to be treated with doublet or triplet therapy, and the duration of therapy on newer agents is also longer.

An analysis of costs in the treatment of CLL estimated that as oral targeted therapies continue to move into the frontline, the per-patient lifetime cost of CLL treatment will increase from $147,000 in 2011 to $604,000 in 2025—a 310% increase. For patients with Medicare coverage, the increase was estimated to increase from $9,200 to $57,000—a 520% increase.¹³

“Oral agents still have rules about copays and deductibles,” Dr. Andreadis said. “That means for some of these drugs that cost $10,000 to $15,000 a month, patients might have a $2,000 a month copay, which is obviously not financially feasible for most people.”

More to Learn

“The shift to chemotherapy-free treatments has been in the making for decades, and it’s still very much ongoing; however, the COVID-19 pandemic has indeed facilitated the shift,” Dr. Baljevic said. “Wherever feasible from the standpoint of similar treatment efficacy and toxicity—there was a shift toward all-oral regimens or at least treatments that lessen the intensity of follow-up visits and laboratory checks within the health care system.”

Even with the ongoing shift, there is much more work to be done to continue to refine these therapies and manage the associated toxicities.

Indeed, there are still certain disease types where the goal of being “chemotherapy-free” is still much further away.

“Aggressive lymphomas have had less of these targeted agents that have been found useful for first-line treatment,” Dr. Vose said.

In subtypes like Hodgkin lymphoma, Burkitt’s lymphoma, or diffuse large B-cell lymphoma, chemotherapy is still used upfront because it is well-established as a long-term cure for patients, Dr. Andreadis explained.

“We are slowly inching away from that, but it has yet to be replaced,” he said.

There is also more being learned about resistance mutations. In CML, mutations in the kinase domain of BCR-ABL are a prevalent mechanism of acquired imatinib resistance. In CLL, mutations in BTK and PLCG2 are found in the majority of patients with acquired resistance to ibrutinib.

“There is more emerging information on these resistance mutations,” Dr. Andreadis said. “We have to keep on top of it by developing second- or third-generation drugs. It is like a game of chess.”

Indeed, with each passing year, the field continues to rapidly change.

“The individual treatment of all of these diseases is getting more complex,” Dr. Gerds said. “For any cancer, we look at mutations and pathways and try to find a targeted agent that would be best for that patient.”

When diseases are broken down into entities like FLT3-mutated AML, for example, clinicians are faced with smaller and smaller “slices of the pie,” Dr. Gerds said, using an analogy.

“While providing progress for our patients, it has made studies difficult and treatment complex,” Dr. Gerds said. “That is why it has become key to partner with folks who are working in the field and staying up to date in order to maximize the use of available therapies.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

1. Park JH, Winer ES, Huntington SF, et al. First line chemo-free therapy with the BRAF inhibitor vemurafenib combined with obinutuzumab is effective in patients with HCL. Presented at the 63rd American Society of Hematology Annual Meeting & Exposition. Abstract 43.
2. National Cancer Institute. Using the immune system in the fight against cancer: discovery of rituximab. March 7, 2014. Accessed July 15, 2022. https://www.cancer.gov/research/progress/discovery/blood-cancer
3. Shanafelt TD, Wang XV, Key NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
4. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865.
5. Kater AP, Levin M-D, Dubois J, et al. Minimal residual disease guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (Hovon141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(6):818-828.
6. Short NJ, Kantarjian H, Konopleva M, et al. Updated results of a phase II study of ponatinib and blinatumomab for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Presented at the 63rd American Society of Hematology Annual Meeting & Exposition. Abstract 2298.
7. Jabbour E, Haddad FG, Short NJ, Kantarjian H. Treatment of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia—from intensive chemotherapy combinations to chemotherapy-free regimens. A review. JAMA Oncol. doi:10.1001/jamaoncol.2022.2398
8. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma.
   N Engl J Med. 2018;379(10):934-947.
9. Bachy E, Houot R, Feugier P, et al. Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study. 2022;139(15):2338-2346.
10. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 2022;23(3):406-415.
11. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740.
12. Allen PB, Flowers CR. Balancing patient value and payer cost in hematologic malignancies: can it be done? Expert Rev Pharmacoecon Outcomes Res. 2018;18(2):123-126.
13. Chen Q, Jain N, Ayer T, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35(2):166-174.