Ryan Scott

This content originally appeared on our sister site, OncLive.

Patients with previously treated relapsed/refractory multiple myeloma treated with CART-ddBCMA had an overall response rate (ORR) of 100%, according to data from a phase 1 trial (NCT04155749).

These data, from 31 patients, were presented at the 2022 ASCO Annual Meeting. Notably, patients achieved responses that deepened over time.

Among those who responded to treatment, 94% experienced a very good partial response or better rate of 94%, and 71% experienced a complete response (CR)/stringent CR (CR/sCR). Of the 24 patients who had a minimum follow-up of 6 months and a median follow-up of 13.3 months, 92% still responded to treatment at 6 months. Of the 16 patients who had a minimum follow-up of 12 months and a median follow-up of 17.7 months, 94% had an ongoing response at 6 months and 69% were still responding at 12 months.

“CART-ddBCMA appears to be a highly effective, durable chimeric antigen receptor (CAR) T-cell therapy for highly refractory patients with high-risk features,” Frigault,  administrative director, Cellular Therapy Service, Massachusetts General Hospital and assistant professor, Medicine, Harvard Medical School. “It was [well] tolerated, and the pivotal phase 2 study [NCT05396885] should hopefully recapitulate the findings [we observed] from [the] phase 1.”

 spoke to Frigault about the findings from a phase 1 trial investigating the safety and efficacy of CART-ddBCMA in patients with multiple myeloma in whom all previous lines of treatment had failed. He  shared additional research opportunities for the CAR T-cell therapy.

®: What was the design of the phase 1 trial evaluating CART-ddBCMA in patients with relapsed/refractory multiple myeloma?

: [At the 2022 ASCO Annual Meeting,] we presented data from the phase 1 trial of CART-ddBCMA; [this was] a first-in-human, dose-escalation study, where we we examined how CART-ddBCMA would work in relapsed/refractory multiple myeloma.

This was [done in] a patient population that had to have been exposed to all 3 major classes of multiple myeloma therapy: [a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody]. They had to have [received] at least 3 prior lines of therapy or be triple refractory, and they needed [to have] measurable disease at the time of treatment.

We [examined the therapy at] 2 dose levels: 100 x 106 CAR-positive cells and 300 x 106 CAR-positive cells. The most impressive component of all this was that we saw an 100% ORR [with the therapy] across both dose levels. These were exciting data, and we look forward to expanding this into a pivotal [phase 2] study.

What else should be known about the population examined in the trial?

This was a heavily pretreated group of patients. They had [received] a median of 5 prior lines of therapy, and they had multiple high-risk features, including high disease burden. In particular, something that we know [correlates with] a poor prognosis for durability of responses, is extramedullary disease; 39% of patients had extramedullary disease at the time of treatment. [Furthermore], 68% of patients were penta-refractory, meaning that they were refractory to all 3 major drug classes, including 2 drugs from 2 of those classes.

Could you expand on the efficacy data reported during the meeting?

We saw impressive findings. [I mentioned that the therapy elicited] an ORR of 100%, [which included] a 71% CR/sCR rate. The interesting thing [to note] is that these responses continued to deepen over time.

Although we had a median follow-up of 12.1 months for the total patient population, if you looked at patients who [had] beyond 12 months [of follow-up], the 16 patients with a median follow-up of 17.7 months, half of those patients had extramedullary disease, which is a higher-risk prognostic factor. Despite that, [69% of those] patients were still in an ongoing response.

We are still waiting for the data to mature, but [this] is promising for these patients.

What were the safety data reported with CART-ddBCMA?

Something that was encouraging was the fact that [CART-ddBCMA] was very well tolerated. Only 1 grade 3 event of immune effector cell–associated neurotoxicity syndrome [(ICANS) occurred in someone who received the therapy at 100 x 106 CAR-positive cells], which is our recommended phase 2 dose. All [cases of] cytokine release syndrome [CRS] was grade 1 or 2 [at 100 x 106 CAR+ cells]. CRS [cases] were all managed with tocilizumab [Actemra] and steroids.

Importantly, we did not see any atypical neurotoxicity, [like] the Parkinson-like syndrome that we are seeing with some other BCMA-directed therapies. It is reassuring that this treatment was very tolerated and appeared to be safe.

I am hoping that the pivotal [phase 2] study can begin enrollment by the end of 2022. We have a lot of patients who need highly effective BCMA-directed therapies. Currently, there are not sufficient slots for manufacturing, and there are many patients who would substantially benefit from CART-ddBCMA and other BCMA-directed CAR T-cell therapies.

This product can significantly impact access and could improve outcomes for patients, many of which are passing away prior to getting their slot allocation. I am optimistic to be able to enroll [patients to this] pivotal study and potentially see a new product on the block that can benefit patients.

Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. 

. 2022;40(suppl 16):8003. doi:10.1200/JCO.2022.40.16_suppl.8003

Articles

Matthew J. Frigault, MD, discussed safety and efficacy findings on CART-ddBCMA.

Achieving Deep Responses With CART-ddBCMA in Relapsed/Refractory Multiple Myeloma

This article previously appeared on our sister site, 

Relmacabtagene autoleucel (relma-cel; Carteyva) elicited durable responses and a high overall survival (OS) rate in Chinese patients with relapsed/refractory large B-cell lymphoma (LBCL), according to 2-year follow-up data from the phase 2 RELIANCE trial (NCT04089215) presented during the 2022 ASCO Annual Meeting.

At a median follow-up of 24 months (95% CI, 23.9-24.1) , the best overall response rate (ORR) achieved with the autologous CD19-targeted CAR T-cell therapy was 77.6% among 58 evaluable patients, which included a complete response (CR) rate of 53.5%. The median duration of response (DOR) was 20.3 months (95% CI, 4.86–not estimable [NE]), and the 2-year DOR rate was 40.3%.

Moreover, the median progression-free survival (PFS) with the therapy was 7 months (95% CI, 4.76-24.15), and the median OS was not yet reached. The 2-year PFS and OS rates were 38.8% and 69.3%, respectively.

“Relma-cel demonstrated durable responses with a high 2-year overall survival [OS] rate,” lead study author Zhitao Yang, MD, of the Department of Lymphoma and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) of Peking University Cancer Hospital & Institute in Beijing, China, and colleagues, wrote in a poster presentation of the data. “The median OS has not yet been reached for responding patients, and [there was] a manageable safety profile.”

RELIANCE was the first study of a CD19-directed CAR T-cell therapy to receive investigational new drug approval by the China National Medical Products Administration. Prior results from the study showed high response rates and low toxicity with relma-cel.

The study enrolled patients who were 18 years or older with histologically LBCL who received at least 2 prior lines of therapy. Patients were required to have an ECOG performance status of 0 or 1, an accessible PET-positive lesion, a measurable CT-positive lesion, adequate organ function, and acceptable vascular access for leukapheresis.

 Those who received prior CD19-targeted therapy needed to confirm that their lesions still expressed CD19.

Key exclusion criteria included central nervous system (CNS)–only involvement, a history of another primary malignancy that has not been in remission for at least 2 years, or any history of a serious cardiovascular disease, among others.

Fifty-nine adult patients were randomized to receive relma-cel at 100 x 10

 CAR-positive T cells. Prior to CAR T-cell infusion, all patients received lymphodepleting chemotherapy, and some received bridging chemotherapy.

The primary end point of the study was 3-month ORR. Secondary end points included 3-month CR rate, DOR, PFS, OS, and safety.

Additional data showed that among evaluable patients who received relma-cel at 100 x 10

 CAR-positive T cells (n = 21), the median DOR was 23.3 months (95% CI, 5.16-NE). Those who were administered the therapy at 150 x 10

 CAR-positive T cells (n = 24), experienced a median DOR of 6.0 months (95% CI, 2.99-NE).

In patients who received relma-cel at 100 x 10

 CAR-positive T cells (n = 27), the median PFS was 8.8 months (95% CI, 5.55-NE). For those who received the therapy at 150 x 10

 CAR-positive T cells (n = 31), the median PFS was 5.5 months (95% CI, 2.96-21.19).

Regarding safety, 91.5% of patients experienced at least 1 treatment-related adverse effect (TRAE) with relma-cel, and 55.9% had at least 1 effect that was grade 3 or higher in severity. Any-grade cytokine release syndrome (CRS) and neurotoxicity occurred in 47.5% and 20.3% of patients, respectively; these effects were grade 3 or higher in 5.1% and 3.4% of patients, respectively.

The median duration of any-grade CRS was 7 days (range, 1-118), and the median time to CRS was 4 days (range, 1-10). The median duration of any-grade neurotoxicity was 12.5 days (range, 1-49), and the median duration of neurotoxicity was 8.5 days (range, 2-11).

The other most common grade 3 or higher TRAEs included neutropenia (40.7%), leukopenia (22%), lymphopenia (11.9%), thrombocytopenia (11.9%).

Although relma-cel has shown to have manageable safety and to produce substantial durable responses in this population, further follow up is needed, according to the study authors.

Ying Z, Song Y, Yang H, et al. Two-year follow-up result of RELIANCE study, a multicenter phase 2 trial of relmacabtagene autoleucel in Chinese patients with relapsed/refractory large B-cell lymphoma. 

. 2022;40(suppl 16):7529. doi:10.1200/JCO.2022.40.16_suppl.7529

CD19-targeted CAR T cells for relapsed and refractory (R/R) non-Hodgkins lymphoma. ClinicalTrials.gov. Updated January 22, 2021. Accessed August 17, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04089215

At a median follow-up of 24 months, the best ORR achieved was 77.6% among 58 evaluable patients with large B-cell lymphoma treated with relma-cel. 

Long-Term RELIANCE Trial Data Shows Durability With Relma-Cel in LBCL

This article originally appeared on our sister site, 

Investigators at Moffitt Cancer Center are exploring a new follicle-stimulating hormone receptor (FSHR)–mediated CAR T-cell technology (CER-T) in patients with recurrent ovarian cancer as part of a phase 1 clinical trial (NCT05316129).

“All the evidence that we have indicates that [this CER-T approach] behaves exactly as CAR T-cell [therapy], with the only difference that the targeted motif is different. We are selecting 4-1BB as the stimulatory domain,” Jose Conejo-Garcia, MD, PhD, chair of the Department of Immunology at Moffitt Cancer Center, said in an interview with 

®. “Other CAR T-cell [therapies] use CD28 [as a stimulatory domain, which] can be more sensitive. However, what we have [learned] from patients who have received CAR T cells is that 4-1BB–based CAR [T-cell therapies] appear to be more persistent. We decided to go for persistence to prevent further recurrence, as opposed to enhancing cytotoxic activity in the short term, which is what CD28-based [therapies] appear to provide.”

Several CAR T-cell therapies have proved to be efficacious in hematological cancers; however, developing a safe, effective CAR T-cell approach for solid tumors has remained a challenge. The autologous cell therapy is composed of engineered T cells that target the FSHR, which is detected at immunological levels exclusively on the granulosa cells of the ovaries.

Conejo-Garcia noted that FSH is overexpressed in approximately 60% of patients with ovarian cancer, and that preclinical research has demonstrated that FSHR becomes upregulated upon resistance to chemotherapy.

The phase 1 trial is recruiting patients with a pathologically confirmed diagnosis of high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma that expresses the FSHR antigen.

 To be eligible for enrollment, patients need to have an ECOG performance status of 2 or better, a life expectancy of at least 3 months, and acceptable bone marrow, renal, and hepatic function. Patients also must have received 1 prior platinum-based chemotherapy regimen and be considered refractory to treatment. Patients also need to have measurable disease.

 pathogenic mutation should have previously received a PARP inhibitor and subsequently experienced disease progression. Patients can, but are not required to, receive 6 additional previous chemotherapy treatment regimens. Conejo-Garcia added that the trial is aiming to include a patient population that is devoid of available treatment options.

The estimated enrollment for the trial is 48 participants, who will intraperitoneally or intravenously receive 1 infusion of FSHR T cells at the following dose levels (DL): 1 x 10

The primary end point of the trial is to identify the maximum tolerated dose of the FSH-CER T cells. Secondary end points will include duration of response, duration of stable disease, and overall survival with this approach. Additionally, investigators plan to track the persistence of T cells to better understand its effectiveness, according to Conejo-Garcia. Additionally, the effect of CER-T on pre-existing antitumor immunity will also be explored.

“By reducing tumor burden, and inducing antigen spreading, we hoped that pre-existing polyclonal responses [already] operating in the [patient] would get boosted,” Conejo-Garcia explained. “That would provide stronger antitumor immunity that would control tumor growth more effectively.”

It has also been hypothesized that CER-T could have a positive impact in other solid tumors that overexpress FSH, since CAR T-cell therapies have not yet made any headway in those patients.

“This could have a major impact on the field of gynecologic malignancies. We have preliminary evidence that the FSHR could be expressed in other tumor [types], namely kidney cancer,” Conejo-Garcia said. “[This is] for reasons we do not understand. We are investigating. We hope that this could be extended to other patients, if successful and safe."

The trial will be piloted by lead investigator Robert Wenham, MD, MS, FACOG, FACS, who is the chair of the Department of Gynecologic Oncology at Moffitt Cancer Center.

In March of 2021, Anixa filed an investigational new drug application with the FDA for the CER-T approach. However, the application was placed on clinical hold in April 2021 after the regulatory agency requested additional information regarding the agent.

 The company provided that data to the FDA in May 2021,

 and so, in August 2021, the clinical trial investigating CER-T in ovarian cancer was cleared for initiation.

Anixa Biosciences announces the initiation of its ovarian cancer CAR-T phase 1 trial at Moffitt Cancer Center. News Release. Anixa Biosciences, Inc. May 30, 2022. Accessed April 28, 2022. 

Infusion of autologous T cells engineered to target FSH receptor in recurrent ovarian cancer. ClinicalTrials.gov. Updated April 7, 2022. Accessed April 28, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05316129

Anixa Biosciences and Moffitt Cancer Center report US FDA request of additional information for CAR-T Therapy. News release. Anixa Biosciences, Inc. April 19, 2021. Accessed April 28, 2022. 

Anixa Biosciences and Moffitt Cancer Center receive additional information request from US FDA for CAR-T IND application. News release. Anixa Biosciences, Inc. May 20, 2021. Accessed April 28, 2022. 

Anixa Biosciences and Moffitt Cancer Center announce FDA clearance to initiate clinical trial of ovarian cancer CAR-T immunotherapy. News release. Anixa Biosciences, Inc. August 30, 2021. Accessed April 28, 2022. 

Several CAR T-cell therapies have proved to be efficacious in hematological malignancies; however, developing a safe and effective CAR T-cell approach for solid tumors has remained a challenge.

New CAR-T Technology Being Explored in Phase 1 for Solid Tumors

This content originally appeared on our sister site, 

Researchers examined patients with relapsed or refractory multiple myeloma who developed disease progression after BCMA-directed CAR T-cell therapy and found an overall response rate (ORR) of 45% with subsequent first-line salvage therapy in this population.

These findings, from a retrospective study, were presented at the 2021 ASH Annual Meeting and Exposition. Oliver Van Oekelen, MD, MSc, resident, internal medicine and PhD student, Icahn School of Medicine, Mount Sinai, discussed these findings.

He discussed how novel agents, including bispecific antibodies, demonstrated encouraging responses in patients with multiple myeloma who relapsed on BCMA-directed CAR T-cell therapy, and how this provides insight into a setting in which little is known about treatment sequencing.

“There are good options for patients with myeloma who are highly refractory and who relapse after BCMA-directed CAR T-cell therapy,” Van Oekelen said. “Depending on the profile of the patient, we should try to offer them options, such as T-cell engagers, combination chemotherapy, as well as combination regimens with novel agents.” - Oliver Van Oekelen, MD, MSc

®: What served as the rationale for this analysis?

Van Oekelen: In multiple myeloma, we recently received the approval of idecabtagene vicleucel [ide-cel; Abecma], a BCMA-directed CAR T-cell therapy, and other CAR T-cell therapies are under development and will be approved soon.* Sadly, most patients, even though the CAR T-cell therapies are highly effective, relapse at some point.

An important outstanding question now is: How are we going to approach patients who relapse after BCMA-directed agents whether that’s CAR T-cell therapy, bispecific antibodies, or antibody-drug conjugates [ADCs]? We had the opportunity to look at patients who were treated on a BCMA-directed CAR T-cell therapy trial at Mount Sinai. Specifically, how these patients were treated and how they did after their relapse on the trial.

Could you describe the patient population that was included in the analysis?

In total, [77] patients were treated with BCMA-directed CAR T-cell therapy. These patients came from several studies and were treated with different CAR T-cell therapies but mostly [ide-cel] and ciltacabtagene autoleucel [cilta-cel; Carvykti].

As the starting date for our analysis, we took the date when the patient relapsed on the therapy. Although it was relatively rare, a handful of patients received a second infusion of CAR T-cell therapy. In that case, we considered the date of relapse after the reinfusion as the start date for our analysis. A total of 34 patients had relapsed.

[Those 34 patients] were part of the data set that we’re studying and expanding over time as more patients relapse. We looked at clinical characteristics and the treatments that they received, and in many cases, patients received multiple lines of therapy. Then we looked at the efficacy of those treatment regimens to see which were associated with the best responses.

The bottom line in terms of results is the fact that there is life after CAR T-cell therapy and that there are options for patients who relapse. A big concern was: What does the clinical outcome look like in terms of progression-free survival or overall survival [OS]? In the study, we found that the first line of therapy after CAR T-cell therapy was associated with an ORR of 45%. That means that half of the patients [who relapsed] had a response to the first subsequent treatment that was tried. The treatment options that were explored most were bispecifics in clinical trials and combination chemotherapy regimens, such as DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin] or similar regimens, with or without stem cell boosts to account for cytopenias.

It turns out [that bispecifics] showed efficacy in a [respectable] number of patients, suggesting that, for example, the option of bispecific therapy after CAR T-cell relapse is something to explore for patients who are eligible for this therapy.

We also wanted to look at OS, because we have data from historical cohorts, suggesting that patients who are triple-class refractory or penta-refractory have poor survival outcomes. It was hopeful to see that patients who relapsed after CAR T-cell therapy had an OS that was relatively long. It was reassuring to see that patients after their relapse on CAR T-cell therapy in our data set had an OS of about 15 months.

That means that there are options that we can offer them, and that some patients have durable responses. The most durable responses were seen in patients treated with T-cell engagers, such as bispecifics, and we’re excited to explore that further.

An important limitation of our study is that all the patients that we evaluated were those enrolled on a clinical trial. As the therapy becomes available to patients commercially, it’s important to keep studying whether these results also translate to the general myeloma population.

Van Oekelen O, Mouhieddine TH, Pan D, et al. Clinical outcomes and treatment strategies for relapsed/refractory myeloma patients after relapse on BCMA-targeted CAR T. 

. 2021;138(suppl 1):2704. doi:10.1182/blood-2021-152243

: This interview took place prior to the February 28, 2022, FDA approval of cilta-cel for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Oliver Van Oekelen, MD, MSc, resident and PhD student, Icahn School of Medicine, Mount Sinai, discussed findings from a retrospective study.

Bispecific Antibodies Effective After CAR T-Cell Relapse in Myeloma?

Allogeneic hematopoietic stem cell transplant (HSCT) remains the sole curative therapeutic modality for patients with myelofibrosis, despite recent significant therapeutic developments. Since high numbers of patients are often deemed ineligible for HSCT, it is crucial to examine the safety and efficacy of allogeneic HSCT to help guide treatment decisions for high-risk patients.

Jan Philipp Bewersdorf, MD, and other investigators led a systemic review and meta-analysis that examined safety and efficacy data for allogeneic HSCT from 43 prior studies. Results from the analysis, which were presented at the 2021 ASCO Annual Meeting, showed that the 1-, 2-, and 5-year overall survival (OS) rates for patients who underwent transplant were 66.7%, 64.4%, and 55.0%, respectively.

Because of this, investigators concluded that transplant should be considered for patients with high-risk myelofibrosis.

“We tried to synthesize the available evidence on the safety and efficacy of transplant in myelofibrosis, to identify patients, as well as disease and transplant characteristics, to see we could help physicians to better counsel patients and select them for this therapeutic modality,” Bewersdorf said.

, Bewersdorf, a hospital resident at Yale University School of Medicine, discussed the outcomes and risks of allogeneic HSCT in patients with myelofibrosis, as well as remaining questions for the modality.

: Could you discuss the rationale for this analysis in myelofibrosis?

: [For patients with] myelofibrosis, the only potentially curative therapeutic modality is allogeneic HSCT. However, this is a procedure that is associated with significant risks, especially related to graft-vs-host disease [GVHD], as well as the ensuing immunosuppression and graft failure. It is very important to identify patients that are candidates for this curative therapy, but also not expose them to unnecessary risk.

Unfortunately, most patients with myelofibrosis are older and not transplant eligible. There has never been a randomized clinical trial that compares transplant vs no transplant, and that is where the lack of high-quality evidence to guide treatment selection comes in. As such, we tried to synthesize the available evidence on the safety and efficacy of transplant in myelofibrosis to identify patients, as well as disease and transplant characteristics, to see we could help physicians to better counsel patients and select them for this therapeutic modality.

What methods were implemented to evaluate this? What methods and design were utilized on the trial?

We conducted a systematic review, as well as a meta-analysis, and this was done in conjunction with a medical librarian who had extensive experience in the field. A search strategy was devised, and it was then peer reviewed by a separate librarian. The study protocol was then prospectively registered on a platform called PROSPERO, which is the standard for systematic reviews and meta-analyses. We searched multiple databases looking for all studies, from inception to our study cutoff date, which was October 2020, which reported outcomes on allogeneic transplant in myelofibrosis. The co-primary end points were 1-year, 2-year, and 5-year OS.

This provided information across the entire spectrum, from early mortality to 5-year OS, which could be considered a surrogate for long-term survival. At the same time, we were looking into safety and key outcomes, including the incidence and severity of GVHD, graft failure, and nontransplant-related mortality. We then conducted several subgroup analyses based on underlying disease risk, stratified by the Dynamic International Prognostic Scoring System, as well as patient age and the intensity of their conditioning regimen.

What were the key efficacy findings observed from the analysis?

The search retrieved 43 studies that were eligible for inclusion [on our analysis], and those studies reported outcomes on 8700 patients. The studies were conducted from the 1990s through 2020. This is a huge spectrum of patients, with various treatment characteristics, and depicts the development in the field over the last few decades. [In terms of OS rates, we found that they were] 66.7% at 1 year and 55.0% at 5 years.

The big caveat is that this is not a randomized clinical trial. There is certainly some selection bias, in terms of which patient proceeds to transplant vs most patients with myelofibrosis that never make it to transplant because they are older or have significant comorbidities. However, for patients with higher-risk myelofibrosis, compared with those who do not undergo transplant, those results compare favorably.

In terms of safety, what was observed from the analysis?

We looked at 2 safety outcomes: non-relapse mortality and GVHD. This is one of our main findings, in my opinion, especially when we counsel patients. Rates of 1-year non-relapse mortality were 25.9%, which is a significant number. It increases slightly over time, but most transplant-related mortality occurs within the first year. At 5 years, we had a non-relapse mortality rate of 30.5%.

Graft failure occurred at a rate of 7%, which is much higher compared with other diseases where we do allogeneic transplant, including acute myeloid leukemia. However, it is not unexpected in myelofibrosis.

This is less devastating than death, but something that will have a significant impact on the quality of life [QoL], time in the hospital, and healthcare expenses, is acute GVHD which has an incidence rate of 44%. This is across all severity grades and includes grade 2 GVHD, which is very manageable, but we also found that 15% [of patients developed] grade 3/4 GVHD. For chronic GVHD, we found an incidence rate of 46.5%.

What are the clinical implications of these findings?

The main conclusion is that myelofibrosis has a poor prognosis, but it occurs along a spectrum. There are patients with low-risk myelofibrosis who do very well over many years. [Some of these patients] have significant comorbidities, but we have novel treatments like ruxolitinib [Jakafi], as well as other JAK inhibitors, that have significantly improved the quality of -life, and overall survival benefit. [However, these treatments are not] disease modifying. They are not curative.

The only curative option is transplant. For young patients with high-risk disease, and potentially some cytogenetic abnormalities or mutations, they should be considered for transplant. The 5- year OS rate of 55% highlights how it has a substantial impact compared with patients who do not go to transplant. However, patient selection is key, and safety needs to be taken into consideration.

Are there any next steps planned with this research?

The main purpose was to summarize and synthesize the current state of the evidence, and to highlight what we already know, what we do not know, and explain what the shortcomings in the current state of the evidence are. We were unable to evaluate the impact of cytogenetic abnormalities, and certain mutational testing was not able to be performed because most of our studies were republished when those tests were not widely available. As such, we do not know if a patient who has a certain mutation is at higher risk and should undergo transplant.

Additionally, ruxolitinib was approved years ago, but many of the studies we examined were conducted before that was the standard of care. In patients who received treatment with ruxolitinib either before or after transplant, we do not know the impact of the agent, or any other JAK inhibitors, on the outcomes. We have seen developments in transplant overall, with better donor selection, changes in conditioning regimens, and GVHD prophylaxis.

All of these impacts are very interesting for myelofibrosis, but this is something that should ideally be studied in a clinical trial.

Bewersdorf J, Sheth A, Vetsa S, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis: a systematic review and meta-analysis. 

. 2021;39(15): 7045. doi:10.1200/JCO.2021.39.15_suppl.7045

Jan Philipp Bewersdorf, MD, hospital resident at Yale University School of Medicine discussed the safety and efficacy of allogeneic hematopoietic stem cell transplant in myelofibrosis.

Allogeneic HSCT Yields Favorable Outcomes in Myelofibrosis

Tisagenlecleucel (Kymriah), a CAR T-cell product, has shown durable responses in adult patients with relapsed/refractory follicular lymphoma with a safety profile that compares favorably with other available products.

spoke with Stephen J. Schuster, MD about these data from the 

At a median follow-up of 10.9 months, tisagenlecleucel elicited an objective response rate of 86.2% among 94 patients with relapsed/refractory follicular lymphoma who were evaluable for efficacy; this included a complete response rate of 66.0%. The median duration of response had not yet been reached, and the median time to next anti-lymphoma treatment had not yet been reached.

Moreover, the median progression-free survival (PFS; 95% CI, 12.1–not evaluable [NE]) and the median overall survival (95% CI, NE–NE) had not yet been reached. The 6-month PFS rate with the CAR T-cell therapy was 76% (95% CI, 65%-84%).

“When we are backed into a corner, meaning our existing therapies do not work, guess what? This [agent] works in those patients,” Schuster said. “The response rates are very high, but what is more important, is the durable responses [that we saw] in the pilot study was 60% at 5 years, and this looks like it will be the same.”

®, Schuster, director of Lymphoma program and Lymphoma translational research, at Penn Medicine, and Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research, further discussed the clinical implications of the phase 2 ELARA trial evaluating tisagenlecleucel in patients with relapsed/refractory follicular lymphoma.

®: What was the rationale for the ELARA study?

: My area of expertise is the treatment of lymphomas, or blood cancers that are derived from lymphocytes. A common [challenge faced] in our practice [has to do with our] patients who have follicular lymphoma, which is the second most common form of non-Hodgkin lymphoma. We care for a lot of these patients. Many patients do just fine without any therapy, or with our existing therapies. However, a small subset of these patients have problematic disease, and even though this is supposed to be a slow-moving disease which may or may not need treatment, they run through our existing options quickly. We needed something new for them.

What are the clinical implications of this study?

The study offers a new treatment approach for those patients [who need] more options. Not all patients with follicular lymphoma are going to need this approach, but some will. The study is important because this is a biologically-based treatment regimen, meaning that patients with prior responses to chemotherapy or those with diseases that have resistance mechanisms to chemotherapy, will still respond. Immunotherapies, like this form of cellular immunotherapy, are agnostic. All the things which bode for failure of response to conventional agents are irrelevant when we are using this approach. We had piloted this approach in a study that began in 2014, and we treated 14 patients who needed this kind of advanced therapy. Of those patients, approximately two-thirds are still in remission now, beyond 5 years.

These findings offer hope in the sense that if a patient needs therapy, and existing therapies are inadequate—if they go through a couple of therapies, such as anti-CD20–based therapies like rituximab [Rituxan] with or without chemotherapy, and it is not working—this is an alternative that will work in those situations where [those] therapies have failed. If offers hope even for the patients who do not need it, should they ever get into that situation. We already have 5 years of follow-up, and this study has just under 1 year of median follow-up, as of the last data cutoff, which was September 2020.

Other [approaches are] on the horizon for these patients, as well, but this is a nice option; it is capable, with a single treatment, to result in durable responses with acceptable toxicity. Earlier this year, the FDA had approved another form of CAR T-cell therapy for follicular lymphoma, axicabtagene ciloleucel [Yescarta; axi-cel], and it is very effective. However, I suspect we do not have the same number of years of follow-up with that [product], although it [appears to be] equally active. The treatment itself is a little more intensive [and it comes with] adverse effects [AEs] that require using the hospital. What is nice about tisagenlecleucel is that the toxicity is minimal, and it can be utilized in an outpatient setting.

It will change clinical practice; it has changed mine. This study included 97 patients, and the pilot only had 14. However, the response rates and toxicities that have been observed are similar. I am optimistic that we are going to see excellent long-term results with this approach for some patients. Again, not all patients need it. It is [appropriate for] a subset of patients, but it should be reassuring to all patients that this therapy is available, should they ever need it.

Is there anything else that you would like to add?

Early in the development of the CAR T-cell approach, much of the work was done in patients with acute leukemias, such as acute lymphoblastic leukemia. The toxicities are vastly different in patients with leukemia than they are in those with lymphoma. Even among patients with lymphoma, the toxicities [experienced by] those with follicular lymphoma are different than the [ones reported by patients with] large cell lymphoma.

There is a [misconception] that this is an incredibly toxic therapy, but it is not, [when we] look at the data. If we look at serious episodes of AEs that are unique to CAR-T cell therapy, for example, cytokine release syndrome [CRS], no grade 3 or higher CRS [was reported with the product]. In acute leukemias and large cell lymphomas, a significant percentage of patients, particularly in leukemia, will experience grade 3 or higher CRS. [This is] very exciting in that the safety signal is good.

Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: primary analysis of the phase 2 ELARA trial. 

. 2021;39(suppl 15):7508. doi:10.1200/JCO.2021.39.15_suppl.7508

Stephen J. Schuster, MD, discussed tisagenlecleucel's efficacy and safety over other available treatments for relapsed/refractory FL.