Clinical Insights: August 2018

Tuesday, August 07, 2018

Release Date: August 22, 2018
Expiration Date: August 22, 2019


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN18August
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Innovation in CAR T

Off-the-Shelf Solution Offers Renewable, Reproducible Process of CAR T-Cell Therapy

Kristie L. Kahl

An off-the-shelf, dual-targeted chimeric antigen receptor (CAR) T-cell approach yielded positive results in preclinical specificity, functionality, and efficacy studies, according to findings presented at the 2018 American Association for Cancer Research (AACR) Annual Meeting.

FT819, manufactured by Fate Therapeutics Inc, is an off-the-shelf, T-cell receptor (TCR)–less CD19-targeted CAR T-cell product. “This product is responsive, cytotoxic, and specific,” noted Bob Valamehr, PhD, vice president of cancer immunotherapy at Fate Therapeutics Inc. The hope is that this product will be more accessible to patients than are conventional CAR T-cell therapies, which tend to be highly personalized and time-consuming to produce and consist of enough cells for only a singledose treatment with variable quality.

MASTER BANK OF CAR T CELLS

In this new approach, investigators begin with cells from a healthy donor rather than the patient. To generate FT819, they combine reprogramming of peripheral blood-derived T cells with targeted insertion of a CD19 CAR into the T-cell receptor α constant (TRAC) locus under the transcriptional control of its endogenous regulatory elements to generate a single cell-derived clonal TRAC-targeted CAR-expressing master pluripotent stem cell (iPSC) line.

“Our off-the-shelf vision starts with an iPSC—a pluripotent cell that has the unique ability of unlimited self-renewal and the capacity to differentiate into 200 cell types. Using this cell, we can effectively place multiple attributes into a cell at the single cell level and create a master cell bank,” Valamehr explained.

In creating the master line cell, the iPSC line for the production of CAR T cells provides distinct advantages over autologous and allogeneic approaches. Investigators are able to produce large quantities of what Valamehr called “universal CAR19 T cells” that are not patient restricted and capable of multidose application.

Donor T cells can attack the patient’s tissues and organs, potentially resulting in graft-versus- host disease (GVHD); therefore, it is critical to deactivate or remove TCR.

“[FT819] is pure for CAR expression and has complete elimination of TCR. As we have been told through several clinical trials, even few cells expressing TCR can elicit GVHD. So this pure product is now safe and highly efficacious,” Valamehr said.

Results of in vitro functional studies showed that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19- positive tumor cells by producing cytokines (IFN-γ, TNF-α, and IL-2) and mediators of cell death (CD107a/CD107b, perforin, and granzyme B). FT819 was also found to be target specific by attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells. FT819 also has a second targeting receptor designed to broaden the therapy’s efficacy: a CD16 Fc receptor that can bind to tumor cells coated with antibodies, which enables the agent to be administered in combination with other proven cancer treatments, like monoclonal antibodies targeting CD20-positive tumor cells, to potentially overcome tumor antigen escape.

Also in the results of the in vitro studies, FT819 was shown to elicit antibody-dependent cell-mediated cytotoxicity when combined with a therapeutic antibody targeting CD20, all through the expression of the CD16 Fc receptor.

POTENTIAL ROBUST MANUFACTURING

Valamehr noted that the cells can be can be packaged, stored, and made readily available for treatment of a large number of patients. Although the product is still in the preclinical stages, Valamehr hopes it will be evaluated in investigational new drug studies in the coming year. “FT819 is an off-the-shelf CAR T-cell therapy with the potential to improve safety and efficacy, address antigen escape, broaden patient accessibility, and reduce cost of manufacture delivery and really begin to make this available to the masses.”

REFERENCE
Peralta E, Hardy I, Ortiz E, et al. Generation of off-the-shelf TCR-less CAR-targeted cytotoxic T cells from renewable pluripotent cells for cancer immunotherapy. In: Proceedings from the 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract LB-108.
 
Professional Responsibility

The Role of the Oncology Nurse in CAR T-Cell Therapy

Katie Kosko

Oncology nurses play a crucial role in monitoring and managing adverse events (AEs) associated with chimeric antigen receptor (CAR) T-cell therapy, as well as in educating staff, patients, and caregivers on what they may experience before, during, and after treatment.

Nurses from Dana-Farber Cancer Institute in Boston, Massachusetts; Moffitt Cancer Center in Tampa, Florida; and Sylvester Comprehensive Cancer Center in Miami, Florida—centers that participated in the pivotal ZUMA-1 trial—assembled practical clinical implications and best practices for implementing CAR T-cell therapy. The findings were presented during a poster session at the Oncology Nursing Society 43rd Annual Congress held in Washington, DC, from May 17 to 20.1

One of the most severe AEs associated with CAR T-cell therapy is cytokine release syndrome (CRS), also known as a cytokine storm, which is caused by a large, rapid release of cytokines from immune cells affected by the immunotherapy. Common signs include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing.

CAR T-cell therapy is also associated with neurologic events (NEs) such as seizure and aphasia, as well as other common AEs like cytopenia. In the ZUMA-1 trial, adult patients with refractory, aggressive non-Hodgkin lymphoma were given axicabtagene ciloleucel (Yescarta). Investigators determined an 82% objective response rate and a 58% complete response rate. The most common AEs of grade 3 or higher during treatment were neutropenia (78%), anemia (43%), and thrombocytopenia (38%).2 Grade 3 or higher CRS and NEs occurred in 12% and 31% of patients, respectively.

“The thing that is unique regarding these CAR T therapies is the incidence of cytokine release syndrome and neurologic events that can happen,” Kathleen McDermott, BSN, RN, OCN, BMTCN, Dana-Farber Cancer Institute, said in an interview with Oncology Nursing News®. “It’s the vigilance and close monitoring of the patients that matters so we can intervene early and pick up subtle symptoms, then treat them appropriately.”

To help the multidisciplinary care team learn about CAR T treatment, the nurses discussed preparations that cancer centers can make. Care teams should undergo educational/training sessions that include details on the nurse’s role in identifying CRS and NEs.

In addition, facilities need to identify key individuals responsible for patients undergoing CAR T, develop continuing education programs, develop order sets specific to CAR T-cell therapy to ensure quick and safe administration, and place training materials in online repositories and on the nursing unit for easy reference.

Patient wallet cards list key information, such as the AEs associated with axicabtagene ciloleucel and when a patient should contact their oncologist. The card is meant to be given to a physician or an emergency department staff if a patient experiences any of the AEs listed. Investigators said staff should decide who should receive a card, such as a family member or a caregiver.

“These patients and their families are familiar with chemotherapy, so they know the [adverse] effects because they have been through it,” she said. “When CAR T came about, they were like, ‘What do you mean I may have a fever of 105 that’s not really related to an infection?’ They also didn’t understand that neurological toxicities may cause confusion or they may be out of it for days. That’s very scary for patients and their families.”

Staff used a number of tools to educate patients and caregivers at their cancer centers, including fact sheets and handouts on CAR T cells, CRS, and NE and AE treatment flow sheets. They conducted one-on-one educational meetings and group classes and developed a personalized treatment calendar for each patient. They also referred patients to social services to help with logistical planning.

Staff can take certain safety measures after infusion to help ensure patient safety. Investigators recommended proactively addressing the logistics of keeping patients safe after infusion and establishing a transition plan for patients without adequate care. Nurses working with these patients should educate family and caregivers about early recognition and reporting of CRS and NEs, as well as about the risk of late NEs and how to intervene.

The investigators also suggested that nurses could start with the medical center’s current posttransplant patient safety requirements and then modify those requirements for post–CAR T care as the center gains experience.

In addition, patients should stay close to the treatment center for at least 4 weeks after treatment and avoid driving or operating heavy machinery until at least 8 weeks after resolution. The investigators also found that education on CAR T-cell therapy reduced patient and caregiver anxiety and increased compliance.

REFERENCES
1. McDermott K, Kahle N, Beaupierre A, et al. Chimeric antigen receptor T cell treatment for aggressive, refractory non-Hodgkin lymphomas: nursing implications of the ZUMA-1 trial of axicabtagene ciloleucel. Presented at: Oncology Nursing Society 43rd Annual Congress; May 17-20, 2018; Washington, DC. Poster IS-18. 2. Neelapu SS, Locke FL, Barlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi: 10.1056/NEJMoa1707447.

Nurse Perspective

  Sherry Adkins, MSN, RN, ANP-C 
Sherry Adkins, MSN, RN, ANP-C
Advanced Practice Nurse, Department of Lymphoma/Myeloma
The University of Texas MD Anderson Cancer Center
Houston, Texas


The recent FDA approval of 2 commercial chimeric antigen receptor (CAR) T-cell products for the treatment of certain B-cell malignancies marks just the beginning of the expected explosion of cellular products that are forthcoming. Oncology nurses/nurse practitioners play an important role in the early identification and treatment of toxicities associated with this therapy. Acute toxicities—cytokine release syndrome CRS and neurotoxicities—are not expected beyond 60 days posttreatment. Being familiar with the expected timing and severity of these toxicities for individual products can help determine when closer monitoring is required.

Patient characteristics such as high tumor burden, co-morbidities, and the development of early CRS have been identified as risk factors which increase the likelihood of developing more severe toxicities. Other patient characteristics and potential bio-markers continue to be studied to help identify high risk patients.

Current treatment for toxicities includes anti-IL 6 therapy (tociluzumab; siltuximab) and corticosteroids, both of which thus far, have not been shown to affect efficacy; however, the long-term effects are yet to be determined. CARs which incorporate a “suicide switch” to control toxicity are being administered via clinical trials in the hopes of further improving the safety profile of cellular therapies.

Potential long-term and late side effects of this treatment often surpass the 60-day window of expected toxicities, including low blood counts (possibly requiring transfusions, growth factors, and antibiotic prophylaxis) and B-cell aplasia/hypogammaglobulinemia. Patients who develop frequent infections may require support with monthly immunoglobulin G until their B-cells recover. 

 
Multiple Myeloma

CAR T-Cell Therapy Extends PFS by 1 Year in Heavily Pretreated Myeloma

Silas Inman

The use of the anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy bb2121 showed promise in the treatment of patients with relapsed/refractory heavily pretreated multiple myeloma, according to results of a study presented at the 2018 American Society of Clinical Oncologt (ASCO) Annual Meeting. Participants in the multicenter, phase I CRB-401 study experienced a median progression-free survival (PFS) of 11.8 months and a median duration of response of 10.8 months.

At the March 29, 2018, data cutoff for the trial, the median follow-up for patients treated with a dose of >150 x 106 CAR+ was 194 days. At this point, the complete response (CR) or stringent CR (sCR) rate was 50%, with an additional 36.4% of patients’ having a very good partial response (VGPR). The objective response rate (ORR) was 95.5%. In contrast, those treated with an inactive dose (50 x 106) had an ORR of 33.3% and a 1.9-month median duration of response.

Responses to bb2121 were seen regardless of BCMA expression levels for patients treated with a dose of 450 x 106. In those with low BCMA expression, the ORR was 100% at a median of 168 days of follow-up. The sCR/CR rate in this group was 37.5%, and the VGPR rate was 50%. In those with high BCMA expression, the ORR was 91% after 311 days of follow-up. The sCR/CR rate was 54.5%, and the VGPR rate was 27.3%.

“[At active doses], bb2121 induces deep and durable responses in heavily pretreated multiple myeloma patients,” said lead author Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center in Boston. “It didn’t matter if you had low or high BCMA expression; patients still responded, and the majority of plasma cells do express BCMA.”

In the first portion of the study, patients received bb2121 in doses ranging from 50 x 106 to 800 x 106 (N = 21). In a subsequent dose expansion stage, an additional 22 patients received bb2121 at 150 to 450 × 106 CAR+ T cells. Prior to infusion of the CAR T-cell therapy, patients received conditioning with fludarabine; (30 mg/m2) and cyclophosphamide; (300 mg/m2).

In the dose-escalation stage, all patients tested positive for BCMA expression. In the dose expansion phase, patients with low expression (<50%; n = 10) and high expression (≥50%; n = 12) were included. The median follow-up for the escalation stage was 345 days, compared with 87 days in the expansion arm.

The median age of patients in the escalation stage was 58 years (range, 37-74), and 38% had high-risk cytogenetics. In the expansion group, the median age was 65 years, and high-risk cytogenetics were present for 41% of patients. Patients had received 7 and 8 prior therapies in the escalation and expansion groups, respectively. Twenty-nine percent and 32% of those in the escalation and expansion groups, respectively, were pentarefractory.

All 16 evaluable responding patients were negative for minimal residual disease (MRD). In this group, the median PFS was 17.7 months. “MRD negativity in the bone marrow was seen very early on, as early on as a month,” noted Raje. In 2 patients without a response, both tested MRD-positive. In the nonresponding group, the median PFS was 2.7 months. When looking at persistence of the bb2121 CAR+ T cells, the vector was detectable at 6 months for 44% of patients (n = 7). By month 12, the vector was detectable for 20% of patients (n = 2). Peak expansion numbers were higher in responding patients compared with nonresponders (P = .005).

“A dose response relationship was observed across all active doses, and we did see higher CAR T-cell expansion in patients who were responders versus nonresponders,” Raje said.

TEAES RESOLVED RAPIDLY

The most common grade ≥3 treatment-emergent adverse events (TEAEs) of interest for bb2121 were neutropenia (79%), thrombocytopenia (51%), anemia (44%), cytokine release syndrome (CRS; 5%), and neurotoxicity (2%). Low-grade CRS occurred in 63% of patients, and low-grade neurotoxicity was apparent in 33% of bb2121- treated patients.

Most TEAEs were treatable and resolved rapidly. By day 32, absolute neutrophil counts increased to ≥1000/μL for 78% of patients. Platelet counts recovered to ≥50,000/μL for 55% of patients by day 32. There were no grade 4 CRS events and no fatal CRS or neurotoxicity events. Tocilizumab was required for 21% of patients and corticosteroids were administered for 9% of patients.

“Interestingly enough, we found that this product is extremely well tolerated,” said Raje. “We did see CRS in almost 60% of patients, but most of it was managed and it was grade 1 and 2 with very little grade 3 CRS, and we had [just] 1 patient with grade 4 neurotoxicity, who is now completely recovered.”

Based on an earlier assessment of the dose escalation trial, bb2121 was granted a breakthrough therapy designation by the FDA in November 2017. A global phase II trial, known as KarMMa, is currently open for enrollment and will serve as the basis for a regulatory submission for bb2121. The trial plans to enroll 94 patients with relapsed/refractory multiple myeloma (NCT03361748).

REFERENCE
Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).    
 
Lymphoma

Liso-Cel Shows Promise in High-Risk Diffuse Large B-Cell Lymphoma

Silas Inman

A promising CD19-directed chimeric antigen receptor (CAR) T-cell therapy, lisocabtagene maraleucel (JCAR017; liso-cel), may result in durable remissions among patients with high-risk diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma.

According to updated findings from the phase I, multicenter TRANSCEND trial presented at the 2018 ASCO Annual Meeting, liso-cel demonstrated a durable complete remission (CR) rate of 46% at 6 months for patients with high-risk DLBCL.

At the 6-month assessment for the dose being used in an ongoing pivotal cohort, the ongoing objective response rate (ORR) was 49% (95% CI, 32%-66%), with a CR rate of 46% (95% CI, 30%-63%). Durable responses were seen across poor-risk DLBCL subgroups, particularly those with double- or triple-hit lymphoma (n = 16), in whom the ORR with liso-cel was 62.5%. Moreover, chemorefractory patients who relapsed in less than 12 months on stem cell transplant had an ORR of 53.3% with liso-cel.

Patients achieving a CR with the pivotal dose had a 12-month overall survival (OS) rate of 89% (95% CI, 72%-96%), with a median OS that was not yet reached. In those with a partial response (PR), the median OS was 10.3 months (95% CI, 6.8–not evaluable) and the 1-year OS rate was 33% (95% CI, 9%-60%).

“[Liso-cel] induced durable responses in highrisk patients with relapsed/refractory aggressive non-Hodgkin lymphoma,” said lead investigator Jeremy S. Abramson, MD, MMSc, clinical director, Center for Lymphoma, Massachusetts General Hospital Cancer Center in Boston. “The overall survival findings are far superior to what we might anticipate with traditional therapies in this relapsed/refractory DLBCL population.”

In a dose-findings portion of the TRANSCEND study, 2 dose levels (DLs) were used: 5 x 107 cells (DL1) as a single- or double-dose and liso-cel at 1 x 108 cells (DL2) as a single dose. After the dose-findings portion of the study, DL1 and DL2 as single infusions were further studied in a core assessment, with DL2 moving into the pivotal cohort focused on DLBCL. Additionally, prior to CAR T-cell infusion, patients received lymphodepleting fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days.

Liso-cel was successfully manufactured for 99% of patients. There were 102 evaluable patients enrolled in the full study, with 73 assessable in the core group. Of the core population, there were 51 patients treated with the dose selected for the pivotal cohort. Eight patients were successfully treated in the outpatient setting.

The median age of patients in the core group was 60 years (range, 20-82), with 33% ≥65 years of age. Seventy-three percent had DLBCL, and 27% had DLBCL transformed from follicular lymphoma. Twenty-two percent had double- or triple-hit lymphoma. Two-thirds of patients (67%) were chemorefractory, and patients had received a median of 3 prior therapies (range, 2-8), with 49% having never achieved a CR to prior therapy.

Thirty-eight percent of patients had received a prior autologous stem cell transplant. “Ninety percent of treated patients have at least 1 poorrisk disease feature predictive of short-median OS,” Abramson noted.

In the core population, 88% of those in a CR at 3 months continued to have a CR at 6 months. After a median of 8 months of follow-up, 93% of patients with a CR at 6 months continued to have an ongoing response. The median duration of response in those achieving a CR was not yet reached (95% CI, 10.2–not evaluable). Those with a partial remission had a median duration of response of 2.1 months (95% CI, 1.0-5.0).

“The duration of response curves flatten out after the 3-month point, in both the full and the core data sets,” said Abramson.

ADVERSE EVENTS RELATED TO LISO-CEL

Across the full study population, the most frequently occurring treatment-emergent adverse events were neutropenia (63%), anemia (53%), fatigue (46%), thrombocytopenia (34%), decreased appetite (29%), nausea (28%), hypotension (26%), cough (26%), headache (25%), dizziness (25%), constipation (25%), and diarrhea (25%).

“The most common adverse events, which occurred in the majority of subjects, were cytopenias. This is expected after fludarabine and cyclophosphamide for lymphodepleting therapy. This was followed by fatigue,” said Abramson. “All other toxicities occurred only in a minority of subjects and are low grade, including cytokine release syndrome.”

In the full trial across all dose levels, 37% of patients had grade 1/2 cytokine release syndrome (CRS). There was 1 grade 3/4 event (1%). Neurotoxicity of any grade occurred in 23% of patients. Serious neurotoxicity was experienced by 13% of patients, and the remainder had a grade 1/2 event. Overall, 43% of patients had either neurotoxicity or CRS.

“We saw a low overall use of rescue medications, including 17% use of tocilizumab and 21% use of corticosteroids,” said Abramson. “We see no difference in neurotoxicity or CRS between DL1 and DL2, supporting our decision to explore DL2 in the pivotal cohort.”

FUTURE DEVELOPMENT

The pivotal cohort of the TRANSCEND trial exploring DL2 of liso-cel has fully enrolled participants, Abramson noted. “We will continue to evaluate this product in the outpatient setting, including in the pivotal cohort,” he added. “We look forward to presenting this data at a future meeting.”

If the data are positive, Juno Therapeutics, the company developing liso-cel, plans to submit a biologics license application to the FDA. Based on earlier findings for the CAR T-cell therapy, liso-cel received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

Session discussant Caron Jacobson, MD, MMSc, noted that findings for liso-cel from the TRANSCEND trial were competitive with data for the already-approved CAR T-cell therapies axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah).

“Liso-cel is competitive with axi-cel and tisagenlecleucel in terms of efficacy, durability of response, and safety,” said Jacobson, from the Dana-Farber Cancer Institute in Boston. “However, comparing across studies should be done cautiously, as there may be an impact of bridging therapy on disease burden and toxicity risk, and there are patient eligibility differences. Comparative data may come from single-institution experiences with all 3 products.”

REFERENCE
Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36(suppl; abstr 7505).

 
Leukemia

Exploring CAR T-Cell Therapy as a Bridge to HCT in ALL

Jason Harris

Investigators at the National Institutes of Health (NIH) are exploring whether chimeric antigen receptor (CAR) T-cell therapy can enhance the effectiveness of treatment with hematopoietic cell transplant (HCT) among patients with relapsed/ refractory acute lymphoblastic leukemia (ALL).

CAR T-cell therapy can induce next-generation sequencing (NGS) negativity, suggesting a “synergistic” relationship with HCT that could enhance patient outcomes. Results were presented at the 2018 American Society of Pediatric Hematology/ Oncology Conference from an interim analysis of patients treated on a phase I trial that led investigators to conclude that CAR T-cell therapy may help patients “bridge” to HCT, especially patients who are NGS-negative. However, that conclusion is based on results from just 4 patients.

“We have seen that CAR-induced remissions may serve as an effective bridge to transplant,” said Haneen Shalabi, DO, cellular therapy fellow, Pediatric Oncology Branch, NIH. “Consolidative HCT following CAR may synergistically improve [event-free survival] and [overall survival] for this high-risk population.”

She added that there were no instances of acute or chronic graft-versus-host disease (GVHD) or transplant-related mortality (TRM) recorded. Results from previous studies performed at the NIH have shown that anti-CD19 CAR T-cell therapy induced minimal residual disease (MRD)–negative remission with high disease-specific survival following HCT. The investigators conducted this follow-up study to explore CAR T-cell persistence, depth of remission, and GVHD after transplantation.

Twenty-four children and young adults with relapsed/refractory CD22-positive ALL who had a complete remission (CR) following treatment in the phase I study of CD22/CD41BB were included in the results. Of these patients, 20 patients did not undergo HCT following CAR T-cell treatment, and 15 of these patients then relapsed.

The median time to relapse was 3 months (range, 2-12). Nineteen (95%) of 20 patients had undergone prior HCT, and 11 (55%) had received prior anti-CD19 CAR therapy.

Four patients proceeded to HCT at a median of 70 days (range, 54-117) after CAR T-cell treatment. All 4 had undergone prior CD19 immunotherapy, and 3 had CD19-negative disease. The median patient age was 13 years (range, 12-30), 3 of the 4 patients were male, and 3 underwent total body irradiation (TBI)–based conditioning. Two patients were receiving their first HCT, and those patients remained in an MRD-negative CR for 1 year following CAR T-cell treatment. Three patients had detectable CAR T cells on their pretransplantation bone marrow, leading investigators to suggest “the possibility of ongoing antileukemia surveillance prior to initiation of the conditioning regimen.”

One patient remains in ongoing remission at 15 months after transplantation. Shalabi said that when they considered using CAR T cells as a bridge to stem cell transplant, the investigators wanted to examine the depth of CAR-induced remissions. NGS-based MRD analysis was available for 8 patients on the CD22 protocol. All were MRD-negative by flow cytometry, while 2 had NGS-positive disease. NGS testing demonstrated disease burden reduction over time.

“The impact of CAR persistence peritransplant still requires further analysis,” she said. Investigators also wanted to determine whether CAR persistence was necessary in the peritransplant setting for better outcomes. Seventy-five percent of patients who received the CD22/ CD41BB CAR regimen had detectable CAR when they began the preparative regimen. Shalabi said there was no evidence that CAR persistence had any effect on post-HCT outcomes, though she noted that the small sample size may have played a role in that result.

She said that eventually investigators determined that not all CARs were created equal. “Shorter-acting CARs may be preferred when persistence is not desired and a transplant option is readily available,” noted Shalabi.

One of the most important questions generated by these results, and one that will be addressed in a future trial, explained Shalabi, is whether patients with ALL who are NGS-based MRD-negative prior to transplant can receive a conditioning regimen without TBI. Such a regimen might reduce the risk for TRM and longterm comorbidities by allowing for a reduction in intensity of HCT conditioning.

REFERENCE

Shalabi H, Delbrook C, Stetler-Stevenson M, et al. Chimeric antigen receptor T-cell (CAR-T) therapy can render patients with ALL into PCR-negative remission and can be an effective bridge to transplant (HCT). Presented at: 2018 American Society of Pediatric Hematology/Oncology Conference; May 2-5, 2018; Pittsburgh, PA. Poster 1017.

Nurse Perspective

Jan Garza-Dennis, RN, ANP-C, AOCNPJan Garza-Dennis, RN, ANP-C, AOCNP
Leukemia Department
The University of Texas MD Anderson Cancer Center
Houston, Texas



Acute lymphocytic leukemia (ALL) has become a disease that, in children, responds well to treatment. In adults, however, it can be very difficult to treat, and it can relapse. The current use of tumor specific engineered chimeric antigen receptor (CAR) T-cell infusion is proving to be a very valuable therapy for adult patients with ALL.

According to study results published by Sorror and colleagues in the journal Biology of Blood and Marrow Transplantation (2015), more than 50% of patients with refractory B cell malignancies are demonstrating durable complete responses to CD19 CAR T-cell therapy.

All of these patients are at high risk for certain toxicities, such as cardiac and neurological adverse events, and cytokine release syndrome (CRS) can affect multiple organs after infusion of CAR T cells. Therefore, bedside nurses have been educated at our facility to acutely monitor these patients.

Registered nurses are trained to observe any CRS neurotoxicity and to document it in the electronic health record. They perform mini mental exams and handwriting tests on the patients daily. RNs and advanced practice providers/physicians also use a 10-point neurological assessment designed to detect any toxicity associated with CAR T-cell therapy, and then assign a score based on that scale. Nurses also closely monitor patients’ blood pressure and respiratory status; watch carefully for arrhythmias; and adhere to strict fluid intake and output goals. Numerous labs, such as C-reactive protein and ferritin, are ordered daily.

We find that specific algorithms like these, for toxicity assessment and control, can ensure quality care and management for this special population.


External Resources

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