Lindsay Fischer is the Associate Editor at ONN. She joined MJH life sciences in 2021 after graduating from Rutgers University with majors in both English and Spanish and a minor in creative writing. When she is not writing, or researching the latest oncology nursing news, Lindsay is an amateur backpacker and rollerblader. Email Lindsay at lfischer@mjhlifesciences.com

Because immunotherapy activates the immune system instead of suppressing it, immune-related adverse events (irAEs) are completely different than AEs typically associated with chemotherapy, explained Lisa A. Kottschade, MSN, APRN, CNP.

Kottschade, nurse practitioner-associate professor of oncology, Mayo Clinic-Rochester, recently presented at the ONS Bridge about irAE management. Her presentation, “The Long and the Short of it: Monitoring Immune Related Toxicity Across the Cancer Continuum” highlighted the 4 most common categories of irAEs, as well as some of the life-threatening irAEs oncology nurses should be aware of.

“I tell people to think of it as kind of like putting the pedal to the metal in the car,” described Kottschade in reference to irAEs. “They can attack any tissue organ or body system. They can be severe and there have been fatalities reported.”

“It's really important to remember that these are not the same mechanisms of action for side effect management, thereby treatments being very different. So how do we deal with this? Education, education, education. You know, we need to know and educate our patients. We need to educate other care providers outside of oncology. We need to recognize these immune-related adverse events very early because we know that if we delay that, we're going to have worsening adverse events.”

Dermatologic irAEs are most commonly associated with anti-CTLA4 and anti-PD1 blockades, shared Kottschade, noting that these events are seen about 40% of the time with single agent therapies and around 60% with combination therapies. Most patients will experience diffuse maculopapular rash and/or pruritus, as well as vitiligo. It is possible for patients to develop Stevens-Johnson syndrome or toxic epidermal necrolysis and between 10% to 30% of patients experience pruritus despite the absence of rash.

She advised that nurses take into consideration the percentage of body surface area covered by rash. Patients should be taught to report any skin peeling, fever, or lesions in their oral, anal, or genital area.

Immunotherapy will generally continue if the dermatologic irAE (rash, bullous pemphigoid, lichenoid reaction, pruritus) is a mild grade 1. Treatment for this grade irAE includes oral antihistamines and high dose topical steroids. Oral steroids are considered necessary if the rash progresses to grade 2, as well as treatment with moderate potency topical steroids and/or prednisone at a dosage of 0.5-1 mg/kg/day. It may be appropriate to consider holding immunotherapy.

When a patient experiences a rash that is grade 3 or higher, it becomes necessary to discuss the risk-benefit ratio with patients. Prednisone should be administered at 0.5-1 mg/kg/day and dosage increased to 2 mg/kg/day if the condition does not improve. At grade 3 or 4, it may become appropriate to admit the patient to inpatient care and to consult urgent dermatology.

Nurse management of rash or pruritus involves contacting the patient 1 to 2 times between treatments, assessing medication compliance with both topical and oral prescriptions, and instructing the patient to avoid hot showers, excessive drying, and anything that might further irritate the skin.

Diarrhea and colitis, the 2 common gastrointestinal irAEs, are more commonly associated with anti-CTLA-4 inhibitors (30%) than with PD1/PD-L1 inhibitors (15%) but are most common with combination therapy (50%). Colitis shares histologic features with Crohn’s disease and fatal bowel perforation is reported in 1% of patients treated with ipilimumab (Yervoy).

To manage GI irAEs, nurses should determine the number of stools over baseline, assess abdominal pain, if there is any blood or mucus present in the stool, fever, and promptly rule out any infectious etiology, taking care to not hold steroids while awaiting results. If any of the previously noted irAEs present themselves, bowel perforation should be ruled out immediately.

The CTCAE grading of diarrhea defines an increase of 4 stools over baseline per day as grade 1 severity. An increase of 4 to 6 stools is considered grade 2. An increase of 7 stools is considered grade 3 and is considered cause for hospitalization. An increase greater than 7 stools is considered life threatening.

Kottschade also presented an algorithm to manage diarrhea/colitis related to immune checkpoint inhibition. For all grade irAEs, other causes should first be ruled out through stool studies including C. difficile and enteric pathogens. Grade 1 irAEs should be managed with the BRAT diet. If the condition progresses but is still grade 1, then entocort 12 mg or uceris 9mg daily should be administered. Grade 2 irAEs should be treated with entocort 12 mg or uceris 9mg daily and, upon progression, prednisone should be added to treatment at 0.5-2.0 mg/kg daily.

Grade 3 gastrointestinal irAEs should be treated with entocort 12 mg or uceris 9mg daily plus, prednisone at 1.0-2.0 mg/kg daily. If the AE progresses, a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily. If the severity becomes grade 4, not only should a gastroenterologist should be consulted and solumedrol should be given at 1 gm IV daily, but infliximab should be given at 5 mg/kg and colectomy should be considered if condition worsens.

Patient education should focus on increasing fluid intake and instructing them to report an increase in stool frequency, bloody stools, or abdominal pain. Patients should be contacted weekly between treatments and bi-weekly if they begin to present with higher grade irAEs.

Kottschade emphasized that with the diarrhea colitis, “many patients can have really good responses to steroids within 1 to 2 days. But they also can have rebound diarrhea. So patients we see in the hospital that we're giving high-dose steroids to intravenously and we switch them over to oral, a lot of times we will hang on to them another 24 to 48 hours because they have a lot of rebound diarrhea where they're back, having as many stools as they were at baseline. We generally don't start taper until the patients at grade 0 or 1. And if they have been started on both budesonide and systemic steroids are going to start tapering the systemic steroids first. We caution against giving antidiarrheals to patients with greater than grade 2 diarrhea because it can get toxic megacolon and are at higher risk for perforation.”

Hepatotoxicity, or asymptomatic transaminitis and/or hyperbilirubinemia is seen in 30% of patients treated with combination therapy (15% of which present with grade 3 or 4 severity) and less than 10% of patients treated with monotherapy, Kottschade explained.

Around 0.2% of patients experience hepatic failure. Nurses should rule out new or progressive hepatic involvement by malignancy. She also advised utilizing the algorithm-based treatment chart from the National Comprehensive Cancer Network (NCCN).

Nursing specific management of hepatitis involves assessing compliance with steroids and other immunosuppressants, instructing patients to avoid acetaminophen and alcohol, and emphasizing the need for patients to get their laboratory blood draws as instructed.

The 2 main classifications of endocrinopathies include thyroid dysfunction, which is most common with PD-L1 endocrinopathies, and pituitary dysfunction, which is most common with anti-CTLA-4 inhibitors.

Thyroid dysfunction accounts for between 0% and 15% of cases but is more associated with combination therapy (40%) than with single agent regimens.

Nurses should assess patients who experience thyroid disorders for fatigue, hair loss, weight fluctuations, palpitations, sweating, nervousness, cold intolerance, and tightness of clothing around neck.

“Again, assessing for kind of the normal side of side effects that we expect from hypo/hyperthyroidism, we're going to see fatigue in both, [as well as] hair loss, and weight gain. For hyperthyroidism, we're also going to see palpitations and sweating, it's going to be important to know if they're tachycardic because we do treat with that they may be cold and tolerant and both may experience feeling that tightness around their neck if they have cold in there.”

Nursing responsibilities in monitoring patients with thyroid disorders include monitoring patient compliance with medication, persistently reassessing symptoms, educating patients in proper method for thyroid replacement medications.

“This is really important,” Kottschade emphasized. “I find a lot of patients don't take this correctly. You know when our first thing upon rising and an hour prior to food or other medications and nothing but water, avoiding iron and acids and calcium supplements when they can.”

Nurses should also monitor for hypophysitis, sometimes known as the “run over by a truck” phenomenon.” “[These] patients are going to come in and say oh, you know, Lisa, I just feel like I got hit by a truck. I'm sleeping 18 hours a day. I can't do anything. I can barely get out of bed. I've got this horrible headache and I feel kind of sick to my stomach. These patients are going to have undetectable ACTH & AM cortisol levels,” advised Kottschade. In addition, 75% of these patients will show an enlarged pituitary gland on an MRI.

“We always want to make sure that we don't have new involvement of central nervous system (CNS), either cancer or worsening of their CNS disease if already present,” she reminded the audience. “Assess for the following things again, fatigue, nausea, vomiting, and the unrelenting headache. Patients may just tell you they feel weak. In patients who have primary adrenal insufficiency we may see abnormal sodium so low sodium and high potassium and low sugars.”

Because primary adrenal insufficiency (AI) is a medical emergency, these patients will need to immediately go to the ICU. Marked by volume depletion electrolyte abnormality and low or undetectable cortisol and high SCTH, these patients will require fluid replacement, electrolyte replenishment, and high dose steroids (1-2 mg/kg) once they are hospitalized. 

In comparison, patients with secondary AI will have low or undetectable am cortisol and low ACTH. This can come from hypophysitis or long-term steroids use.

Education for patients with adrenal insufficiency includes taking their steroids as directed and ensuring that patients understand that they will likely be needing their steroids lifelong. “We do this in conjunction with our endocrine colleagues, but it's great for oncology nurses to be able to reinforce that and know what that teaching is” she said.

Patients will need to understand “sick day” steroids, stress dose steroids, and will need to wear a medical alert bracelet since most pituitary and adrenal abnormalities do not resolve.

Pneumonitis may present asymptomatically, but symptoms include shortness of breath at rest, orthopnea, and dyspnea on exertion, and can also include dry nagging cough, chest pain and fever. Pneumonitis can be seen radiographically.

Although neurotoxicity is not a common irAE, when it occurs, it can be life-threatening.

The incidence rate for this irAE e is 3.8 % with CTLA-4 inhibitors, 6% with PD-1 inhibitors, 12% with combination therapy, Kottschade explained, and presentation can vary due to

nonspecific symptoms and a wide range of differentials.

Typical onset is anywhere between 3 days to 17 months, but the median is 6 weeks. Some of the conditions associated with neurotoxicity include Guillan Barre syndrome, myasthenia gravis, central or peripheral neuropathy, encephalitis, aseptic meningitis, and transverse myelitis.

Conditions associated with cardiac toxicity are myocarditis/pericarditis/cardiomyopathy. While exact incidence rates vary, once patients develop a cardiac toxicity, the fatality rate is about 50%.

“In summary, we know that immune checkpoint inhibitors are really great cancer therapies. And these target our host immune system, we need to carefully assess our patients prior to each ICI therapy,” concluded Kottschade. She reminded nurses that prior to immunotherapy initiation, patients should be assessed for their prior autoimmune conditions, transplant history, as well as vaccination or antibiotic status, because these factors can impact whether immunotherapy is appropriate for the individual.

Moving forward, Kottschade hopes to see better monitoring and early recognition of some of the life threatening irAEs. She also anticipates treatment optimization across tumor types that affect various organs.

The final point that Kottschade discussed was conversations surrounding survivorship issues. “It's hard to have a discussion with a 30-year-old patient who is going to get adjuvant nivolumab for her resected high-risk melanoma and look her in the eye and say, ‘Hey, if I happen to blow your pituitary or something else, you may not be able to get pregnant.’ [But] that's a big discussion that we should be having with our patients.”

“We don't know all the long-term side effects, especially in the adjuvant population, but it's something that I think in the [interest] of full disclosure, we should be talking with our patients with,” she concluded.

Kottschade LA. The long and the short of it: monitoring immune related toxicity across the cancer continuum. Present

Articles

An expert on immune toxicity management discusses dermatologic, gastrointestinal, hepatic, and endocrine irAEs and how nurses can help educate their patients to monitor these symptoms. 

Patient Education Key in Managing Immune-Related Adverse Events

The Hematology/Oncology Nurse Practitioner Fellowship at Sylvester Comprehensive Cancer Center in Miami, Florida, demonstrates how advanced practice fellowship programs prepare new graduates for success in oncology. The program, which is accredited with distinction by the American Nurses Credentialing Center through the Practice Transition Accreditation Program,

 rotates fellows through the different subspecialties of oncology across a 52-week period. These rotations include breast, gastrointestinal, hematology, stem cell, inpatient, and outpatient, as well as support services, such as the social work team and palliative care.

In addition, fellows are required to complete a quality improvement project and present their findings. The program initially began with the objective of improving retention rates of employees. In the 5 years since the fellowship began, Sylvester has successfully retained 100% of their fellows; each graduated fellow continues to work at Sylvester today.

“I can say that it was definitely one of the best career decisions I have made...and that it opened a lot of doors for me,” said Amber Thomassen, APRN-BC, AOCNP, in an interview with 

 Thomassen, advanced practice supervisor of clinical operations, was the first fellow to graduate from the program in 2017. Today, Thomassen oversees the current fellows both as direct supervisor and as a mentor.

She reminisced about how the fellowship transformed her own career goals. “At first, I thought I wanted to work with solid tumors, but because of my experience with the fellowship, I got to experience the hematology side of things and participate in research in hematology clinical trials. I knew it existed, but [before the fellowship], I really had no experience there. Right now, I do phase 1 research with hematology patients, so I kind of found that whole niche through the fellowship,” Thomassen said.

Fellows are given a timeline with specific competencies they are required to meet, and they check in with their supervisor biweekly to both ensure that these competencies are being met in accordance with the timelines and maintain an open line of communication between the program coordinators and the nurses. Additionally, the program always has at least 2 fellows and pairs current and graduated fellows together, so the fellows always have a support system they can turn to with questions.

“That is the difference between the fellowship versus going out into real practice,” said Jessica MacIntyre, APRN, NP-C, AOCNP, executive director of clinical operations at Sylvester Comprehensive Cancer Center. “A lot of people fear saying that they don’t know something [or] saying that they need help, especially if you’re talking to a clinician colleague…so we develop that mentorship over time, and they develop bonds together.”

“You need to be flexible,” Thomassen and MacIntyre said. Because there are frequent rotations and schedules will change, nurses applying to the program must have the capability to perform while they learn a myriad of topics, meet many new personalities, and handle the emotional and mental components that accompany advanced practice oncology care.

In addition, the program prefers nurses that have recently graduated with their nurse practitioner degree. Not only is it difficult to complete the fellowship and attend school simultaneously, but the fellowship also seeks to provide a strong foundation for which the nurse can build their career. The ideal candidate is a nurse who is truly passionate about oncology and seeks to be an advocate for change within the area of medicine.

“It is a great opportunity for any institution to showcase the value of the advanced practice role and the value that nurse practitioners are going to be having in oncology, knowing that we do need to train because oncology is becoming more and more complex,” MacIntyre said. “As we evolve more and as we find all these new technologies and all these new drugs, you will need more experienced people. It is going to be more difficult to transition to a nurse practitioner without that background.” 

Oncology nurse practitioner fellowship. University of Miami Sylvester Comprehensive Cancer Center. Accessed August 8, 2021. 

https://umiamihealth.org/sylvester-comprehensive-cancer-center/healthcare-professionals/the-office-of-education-and-training/oncology-nurse-practitioner-fellowship

The Oncology Nurse Practitioner Fellowship at Sylvester Comprehensive Cancer Center exposes fellows to the gamut of oncology care and teaches the skills they need to succeed.

Advanced Practice Fellowships Prepare Recent Graduates for Success in Oncology 

The FDA approved pembrolizumab (Keytruda) in combination with chemotherapy, with or without bevacizumab (Avastin), to treat patients with persistent, recurrent, or metastatic cervical cancer whose tumors harbor PD-L1, as demonstrated by an FDA-approved test, according to a press release issued by the agency.

Notably, the FDA has also granted regular approval to pembrolizumab as a monotherapy for the same patient population on or after chemotherapy. The agency granted this indication an accelerated approval, with its companion diagnostic, PD-L1 IHC 22C3 pharmDx, in June 2018.

This approval was based on findings from the multicenter, randomized, double-blind, placebo-controlled, phase 3 KEYNOTE-826 trial (NCT03635567). Findings from the trial’s interim analysis were recently presented at the 

The trial assessed 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy, irrespective of PD-L1 expression status. Participants were randomized into 2 treatment cohorts: The experimental cohort received pembrolizumab 200 mg plus chemotherapy with or without bevacizumab, while the control cohort received placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was administered until disease progression, unacceptable toxicity, or 24 months of treatment.

The trial’s primary end points were overall survival (OS) and progression-free survival (PFS) as determined by RECIST v1. With a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Median OS was not reached in the pembrolizumab arm (95% CI, 19.8-not reached [NR]) and was 16.3 months (95% CI, 14.5-19.4) in the placebo arm (HR, 0.64; 95% CI, 0.50-0.81; 

 = 0.0001). Median PFS was 10.4 months in the experimental arm (95% CI, 9.7-12.3) and 8.2 months in the control arm (95% CI, 6.3-8.5), respectively (HR, 0.62; 95% CI, 0.50-0.77; 

Objective response rates were 68% in the experimental group and 50% in the control. In addition, patients taking pembrolizumab experienced a median DOR of 18.0 months, compared with 10.4 months in the pembrolizumab arm.

“Adding pembrolizumab to chemotherapy with or without bevacizumab provides statistically significant, clinically meaningful improvements in PFS and OS in patients with persistent, recurrent, or metastatic cervical cancer. The significant benefit was observed in all primary analysis populations and was generally consistent across protocol-specified subgroups,” lead study author Nicoletta Colombo, MD, PhD, director of the Gynecologic Oncology Division at the European Institute of Oncology and associate professor of Obstetrics and Gynecology at the University of Milan-Bicocca in Milan, Italy, said in a recent presentation of the findings. “Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care for the treatment [of these patients].”

The most common adverse events (AEs) observed in the experimental arm included peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite.

Pembrolizumab should be administered at 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed October 13, 2021. https://bit.ly/3lE3vNS

Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA2_PR

Pembrolizumab is approved both in combination with chemotherapy, with or without bevacizumab, and as a single agent for the treatment of patients with recurrent or metastatic cervical cancer. 

FDA Approves Pembrolizumab Combination to Treat First-Line Cervical Cancer

The FDA has approved abemaciclib (Verzenio) as an adjuvant therapy in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) to treat hormone receptor (HR)-positive, human epidermal growth factor receptor2 (HER2)-negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test, according to a press release issued by Eli Lilly and Company.

"Women and men living with high-risk HR-positive, HER2-negative early breast cancer want to do all they can to reduce the risk of the disease coming back, with the hope of living free of cancer. The approval of [abemaciclib] provides a new treatment option to help them do just that," said Jean Sachs, chief executive officer, Living Beyond Breast Cancer, in the release. "This approval brings new optimism to the breast cancer community."

The regulatory decision is based on findings from the randomized, open-label, 2-cohort, multicenter, phase 3 monarchE trial, designed to evaluate abemaciclib plus standard endocrine therapy versus standard endocrine therapy alone in adult patients with HR-positive, HER2-negative, node-positive, resected EBC with clinical and pathological features consistent with a high risk of disease recurrence. Patients were treated with either 2 years of abemaciclib 150 mg twice daily plus standard endocrine therapy, or with standard endocrine therapy as a monotherapy. Patients in both cohorts were prescribed adjuvant endocrine therapy for 5 to 10 years.

The primary end point was invasive disease-free survival (IDFS), defined as the length of time before the breast cancer returns, new cancer develops, or death, and has already been met a pre-specified interim analysis in the intent-to-treat population. Patients receiving abemaciclib have demonstrated superior IDFS compared with those treated with endocrine therapy as a monotherapy.

Overall survival data is not yet ready for analysis and investigators are continuing to conduct additional follow-ups.

No new safety signals were detected in the monarchE trial. Safety and tolerability were assessed across 5,591 patients, of which the most common adverse events (AEs) were diarrhea, infections, fatigue, nausea, headache, vomiting, stomatitis, dizziness, rash, and alopecia.

Laboratory abnormalities to monitor for include an increase in creatinine, a decreased white blood cell count, decreased neutrophil count, anemia, lymphocyte count, platelet count, increased ALT, increased AST, and hypokalemia.

Patients should receive blood counts and liver function tests prior to initiating treatment with abemaciclib. These tests should continue every 2 weeks for the first 2 months, monthly for the following 2 months, and so on, as clinically indicated. Patients taking this medication will also require monitoring for thrombosis and pulmonary embolism.

Patients should be taught to immediately initiate antidiarrheal therapy, increase oral fluids, and notify their health care providers at the first sign of loose stools. The labelling for the drug includes precautions for diarrhea, neutropenia, interstitial lung disease hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.

In addition, patients should understand that this drug poses serious risk to a fetus. The label urges patients to plan accordingly by using effective contraception.

"The design and results of the monarchE study are practice-changing and represent the first advancement in adjuvant treatment of HR-positive, HER2-negative breast cancer in a very long time," said Sara M. Tolaney, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, and investigator on the monarchE study. "This FDA approval for Verzenio in combination with endocrine therapy in the early breast cancer setting has the potential to become a new standard of care for this population. We are encouraged by the marked reduction in the risk of recurrence even beyond the two-year treatment period in these patients, and I'm grateful to be able to offer this as a treatment option to my patients."

Eli Lilly and Company News Release. FDA approves Verzenio® (abemaciclib) as the first and only CDK4/6 inhibitor for certain people with HR+ HER2- high risk early breast cancer. Lilly. Published October 13, 2021. 

https://investor.lilly.com/news-releases/news-release-details/fda-approves-verzenior-abemaciclib-first-and-only-cdk46.

Abemaciclib is the first and only FDA approved CDK4/6 inhibitor to treat HR-positive, HER2-negative high-risk early breast cancer.

FDA Approves Abemaciclib for HR+, HER2– High-Risk Early Breast Cancer

A post-hoc analysis of a phase 3 trial published in 

demonstrated that autologous hematopoietic stem-cell transplantation (HSCT) induced superior long-term benefit in patients with mantle cell lymphoma (MCL) in comparison with interferon alfa.

The sustained efficacy associated with HSCT supports its role as standard frontline treatment for this population, however, new targeted therapies may potentially challenge that role.

Data from an exploratory intention-to-treat analysis showed that the median progression-free survival (PFS) for those who underwent HSCT was 3.3 years (95% CI, 2.5-4.3) vs 1.5 years (95% CI, 1.2-2.0) for those who received interferon alfa maintenance (adjusted hazard ratio [aHR], 0.50; 95% CI, 0.36-0.69; 

 < .0001). Moreover, the median overall survival (OS) was 7.5 years (95% CI, 5.7-12.0) in the HSCT group compared with 4.8 years (95% CI, 4.0-6.6) in the interferon alfa group (aHR, 0.66; 95% CI, 0.46-0.95; 

Moreover, for patients who received induction therapy without rituximab (Rituxan), the aHR for PFS in the HSCT group vs interferon alfa group was 0.40 (95% CI, 0.26-0.61; 

< .0001), compared with 0.72 (95% CI, 0.42-1.24; 

= .087) in patients who did receive rituximab. The aHR for OS in the HSCT group vs interferon alfa group was 0.52 (95% CI, 0.33-0.82; 

= .016) without rituximab and 1.05 (95% CI, 0.55-1.99; 

= .680) for patients who received rituximab.

“Whether an autologous HSCT should be generally recommended despite the available additional therapeutic options cannot be appropriately addressed with this trial alone,” lead author Anna-Katharina Zoellner, MD, of Ludwig-Maximilians-University Hospital of Munich-Grosshadern, Munich, Germany, and colleagues, wrote. “However, the absence of any significant benefit of autologous HSCT for patients after rituximab-containing induction underlines the need to further explore the value of autologous HSCT in comparison with the most effective regimens available.”

Data from several studies done over the past 2 decades have demonstrated that HSCT results in high response and PFS rates. As such, this approach serves as the current standard of care for younger, fit patients with MCL in advanced stages.

This study, which was initiated in 1996 by the European Mantle Cell Lymphoma Network, was one of the first to establish the role of this modality. This was also the first to have an open-label, multicenter, randomized, phase 3 trial design that was conducted to specifically analyze the safety and efficacy of HSCT vs interferon alfa maintenance therapy following a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like induction therapy, without or with rituximab (R-CHOP), in patients with advanced-stage MCL who were younger than 65 years of age.

Primary results from the trial showed that although autologous HSCT significantly prolonged PFS over vs maintenance interferon alfa, the OS benefit with the former was not found to be statistically significant at a median follow-up of 25 months. In the 15 years since the primary publication of the study, treatment for this patient population has evolved substantially, with use of rituximab in induction therapy, as well as high-dose chemotherapy regimens, and targeted treatments.

For the current report, investigators sought to examine the long-term results from the trial, including OS, in patients with primary advanced-stage MCL treated with high-dose radiochemotherapy and autologous HSCT, or interferon alfa maintenance in remission following chemotherapy without or with rituximab. Additionally, the study authors assessed whether the efficacy of HSCT was modified by the addition of rituximab to frontline induction in this setting.

A total of 292 patients were registered to the European Mantle Cell Lymphoma Network trial. These patients were between the ages of 18 years and 65 years and had previously untreated advanced stage III and IV MCL. Those with a poor performance status, defined as an ECOG performance status of higher than 2, or who had severe cardiac, pulmonary, hepatic, or renal impairment, were excluded from the research.

Patients were randomized 1:1, prior to induction, to receive either myeloablative radiochemotherapy followed by autologous HSCT (n = 134) or interferon alfa maintenance afterinduction therapy was completed (n = 135).

Induction therapy consisted of 4 cycles of CHOP for those who experienced a complete remission (CR) following 4 cycles, or 6 cycles for all others; CHOP-like regimens; or a combination of IV rituximab at a dose of 375 mg/m2 on day 0 or 1 of each cycle plus CHOP. Those who were given CHOP received intravenous (IV) cyclophosphamide at a dose of 750 mg/m2 on day 1, IV doxorubicin at a dose of 50 mg/m2 on day 1, IV vincristine a dose of 1.4 mg/m2 on day 2, and oral prednisone at a dose of 100 mg/m2 on days 1 through 5; this was repeated every 21 days.

Per protocol, further treatment for patients who did not have a partial remission (PR) after 6 cycles of induction therapy was up to the discretion of the treating physician.

Additionally, patients randomized to the HSCT arm received intensified stem-cell mobilization chemotherapy. Myeloablative therapy was given within 2 months of mobilization and consisted of a total body irradiation and a high-dose cyclophosphamide regimen. The previously harvested peripheral blood stem cells were then reinfused on day 0 and granulocyte colony-stimulating factor was started on day 1.

Those randomized to the interferon alfa arm received 2 additional cycles of conventional chemotherapy to balance the mobilization scheme. Subcutaneous interferon alfa was thereafter given at a starting dose of 6 × 106 IU 3 times weekly until disease progression. The dose was adapted based on toxicity.

Patients were the followed until disease progression, through assessment history, physical examinations, ultrasound examinations of the abdomen, and a complete laboratory investigation every 3 months. Chest radiography was performed every 6 months, and survival follow-up until death was planned.

The primary outcome of the post-hoc analysis was PFS from the end of induction until disease progression or death among those who achieved a remission. The secondary outcome was OS from end of induction to death.

Participants included in the analysis had a median age of 55 years (range, 47-60), and the majority were male (78%), had stage IV disease (82%), and an ECOG performance status of 1 (53%). Moreover, 73% of patients had a low-risk disease, 29% had elevated serum lactate dehydrogenase concentration, and 40% had B symptoms present.

Regarding induction treatment, 51% received CHOP, 39% received CHOP with rituximab, and 10% received a CHOP-like chemotherapy regimen. By the end of induction, 29% achieved a CR and 71% experienced a PR.

Of the 114 patients with MCL enrolled to the interferon arm and the 118 patients enrolled to the HSCT arm, 81 and 93 patients, respectively, experienced remissions following induction treatment.

Results from an exploratory analysis of secondary malignancies revealed no clear effect of autologous HSCT vs maintenance interferon alfa on the risk of secondary myelodysplastic syndrome or leukemia (HR, 1.6; 95% CI, 0.31-8.3; 

Moreover, data from an exploratory subgroup analysis, showed that patients who achieved a CR after induction therapy experienced a median PFS of 3.9 years (95% CI, 3.0-7.5) in the HSCT group vs 1.9 years (95% CI, 1.06-3.00) in the interferon alfa group (

= .0003); those who achieved a PR had a median PFS of 2.5 years (95% CI, 2.3-4.3) and 1.4 years (95% CI, 1.1-2.0), respectively (

Patients who achieved a CR following induction therapy reported a median OS of 9.7 years (95% CI, 6.7–not reached [NR]) in the HSCT group vs 6.5 years (95% CI, 4.0-18.5) in the interferon alfa group (

= .15); those who achieved a PR had a median OS of 6.3 years (95% CI, 5.1-12.0) and 4.6 years (95% CI, 3.7-7.4), respectively (

Patients who received an induction regimen without rituximab experienced a significantly increased PFS and OS following HSCT compared with interferon alfa maintenance therapy, according to findings from further exploratory subgroup analyses.

Specifically, the median PFS was 3.1 years (95% CI, 2.5-4.3) in the HSCT group vs 1.2 years (95% CI, 1.0-1.9) in the interferon alfa group (

< .0001). The Cox regression analysis adjusted for MIPI score showed an aHR of 0.40 (95% CI, 0.26-0.61). Moreover, the median OS was 6.7 years (95% CI, 5.4-12.9) and 4.3 years (95% CI, 3.6-6.6), respectively (

= .016). The aHR was 0.52 (95% CI, 0.33-0.82).

For those treated with a rituximab-containing induction regimen, the median PFS survival was 3.4 years (95% CI, 2.4-6.8) in the HSCT group vs 1.7 years (95% CI, 1.4-5.9) n the interferon alfa group (

= .087). The aHR was 0.72 (95% CI, 0.42-1.24). Additionally, the median OS was 9.6 years (95% CI, 5.5-12.2) and 5.5 years (95% CI, 4.6–NR), respectively (

= .68). The Cox regression analysis adjusted to MIPI score gave an adjusted HR of 1.05 (95% CI, 0.55-1.99).

“On the basis of these mature data, the significantly improved PFS after autologous HSCT is independent of remission status after induction therapy, with OS showing the same trend,” study authors concluded. “Therefore, these data from the first randomized phase 3 trial of the European Mantle Cell Lymphoma Network underline the relevance of post-induction autologous HSCT in the context of a CHOP-like induction therapy.”

However, the treatment of the disease has changed since the start of this trial. As such, data from ongoing efforts like the phase 3 TRIANGLE trial (NCT02858258) could serve to challenge the future role of autologous HSCT in young patients with MCL.

Zoellner A-K, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. 

. 2021;8(9):e648-e657. doi:10.1016/S2352-3026(21)00195-2

This article was originally published on OncLive as “Autologous HSCT Shows Sustained Long-Term Benefit in MCL, But Role May Be Rechallenged By Novel Approaches”

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