Allogeneic hematopoietic stem cell transplant (HSCT) is still the sole curative therapeutic modality despite significant and recent therapeutic developments for patients with myelofibrosis. However, because of the number of patients deemed ineligible for HSCT, investigators must continue to assess the treatment’s safety and efficacy in high-risk patients, said an expert from Yale University School of Medicine.

As such, 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.

 sister publication, 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

This article was originally published on OncLive as 

“Allogeneic HSCT Linked With Favorable Survival Outcomes in Myelofibrosis”

Articles

Allogeneic hematopoietic stem cell transplant (HSCT) is still the sole curative therapeutic modality for patients with myelofibrosis.

Allogeneic HSCT Elicits Favorable Outcomes in Myelofibrosis

Frontline lenvatinib (Lenvima) plus pembrolizumab (Keytruda) has been labeled a “standout option” by Robert J. Motzer, MD, for the treatment of patients with advanced renal cell carcinoma (RCC). Data from a recent clinical trial demonstrated that the combination induced superior progression-free survival, as well as improved quality of life, compared to sunitinib (Sutent) alone.

Results from the phase 3 CLEAR trial (NCT02811861) presented during the 

 showed that the median progression-free survival (PFS) with lenvatinib/pembrolizumab was 23.9 months (95% CI, 20.8-27.7) vs 14.7 months (95% CI, 11.1-16.7) with lenvatinib and everolimus (Afinitor) and 9.2 months (95% CI, 6.0-11.0) with sunitinib.

The stratified hazard ratio with lenvatinib/pembrolizumab vs sunitinib was 0.66 (95% CI, 0.49-0.88; 

Lenvatinib plus pembrolizumab was also found to showcase similar or improved HRQoL and disease-related symptom scores compared with sunitinib, and lenvatinib plus everolimus was found to have similar or worse HRQoL and symptom scores vs those observed with sunitinib.

“The quality-of-life assessments are the perception of a patient. The HRQoL assessments are filled out by the patient on how they perceive their tolerability to the regimen, and how they feel about being on the regimen,” Motzer said. “They are an extraordinarily important metric that needs to be considered seriously when interpreting results of trials, and choosing a regimen.”

Earlier data from the trial supported the submission of a biologics license application for pembrolizumab and a supplemental new drug application for lenvatinib for the frontline treatment of patients with advanced RCC. In May 2021, the FDA granted priority review to the applications in May 2021.

In an interview with Oncology Nursing News®’ sister publication, OncLive®, Motzer, medical oncologist, Kidney Cancer Section head in the Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, discussed the efficacy and HRQoL benefits of lenvatinib/pembrolizumab in patients with advanced RCC, and projected where the regimen might fit into the treatment paradigm.

®: Could you speak to the rationale of conducting the HRQoL analysis of the CLEAR trial?

: CLEAR was a 3-arm trial that compared pembrolizumab plus lenvatinib with everolimus plus lenvatinib, and [then compared] both of those arms with sunitinib in patients with clear cell RCC as a first-line therapy.

Results showed that both lenvatinib-containing arms met their primary end point, showing improvement in progression-free survival [PFS] compared with sunitinib. [However,] only the lenvatinib/pembrolizumab [arm] showed an increase in overall survival [OS]; the results for lenvatinib plus everolimus compared with sunitinib were similar.

The efficacy observed in this trial was quite striking—particularly for the lenvatinib plus pembrolizumab arm, with a very high response rate of over 70%, a 16% complete response rate, and a median PFS of approximately 24 months. The safety profile was as anticipated for both arms compared with sunitinib. The results presented during the 2021 ASCO Annual Meeting [focused on] HRQoL [outcomes].

What is your expectation for where the combination of pembrolizumab plus lenvatinib will fit into the RCC treatment landscape? How will this regimen impact subsequent treatment use?

We have been successful in the past few years, in terms of developing better regimens [for the] first-line treatment [of patients with] RCC. [This success is] largely based on the [emergence of] newer TKIs, [such as] axitinib [Inlyta], lenvatinib, cabozantinib [Cabometyx], and the use of immunotherapy. [This includes] both immunotherapy combinations, such as ipilimumab [Yervoy] and nivolumab [Opdivo], and more recently, TKI/immunotherapy combinations. Results [with these combinations] have been very striking. [These regimens] have come about in a very short time, but clearly, all these options are better than a single-agent TKI.

However, we are still sorting out whether there is a role for one vs the other, or which regimen might be best or particularly useful for a community oncologist to administer. We studied lenvatinib plus pembrolizumab at our center in a large, single-arm trial of over 140 patients and I had personal experience with that regimen. It really appeared to be an excellent regimen in terms of efficacy and manageable safety.

What I was most impressed with in the phase 3 trial is the magnitude of efficacy that we saw, coupled with manageable toxicity. It is a standout [option] for use in first-line therapy, and certainly, along with the others, it should be a choice [in this setting].

Do any subgroups appear to derive more benefit with this treatment regimen than others?

With the lenvatinib/pembrolizumab regimen, one of its best features are that it seems to be effective across the board. [We see efficacy] in patients, regardless of risk group. The favorable-risk patients did very well with [this approach], as well as the intermediate- and the poor-risk patients. Those who had sarcomatoid elements also did very well [with the doublet]. It is a very reliable regimen, [for which we know that] we are going to see a positive effect.

What were the key findings from the HRQoL analysis of the trial?

We performed several analyses. In a mixed-model analysis, we looked at longitudinal changes from baseline to [time] on study. In the other [analysis], we looked at time to deterioration, which was one end point [of the trial], as well as time until definitive deterioration, which served as another end point. [Results from the] QoL studies suggested that [these end points] were either similar or better with some scales with [regard to] lenvatinib plus pembrolizumab compared with sunitinib.

The time until definitive deterioration was the standout [finding because it was] in favor of lenvatinib plus pembrolizumab. The hallmark of that analysis is that it looks at QoL, by these scales, over time. As such, patients who continue on the trial, even those who were treated beyond progression or those with a [long] PFS, appear to, over time, have a better QoL.

In general, I would say that the scores were the same, or better, with lenvatinib plus pembrolizumab. On the other side of the coin, when we looked at lenvatinib plus everolimus, for the most part, the scores were either the same or worse [than what we saw with sunitinib]. This makes sense because the combination is comprised of 2 targeted therapies, and there is a fair amount of toxicity that has been associated with it. The results were quite fitting with what we have seen in terms of efficacy and safety for both of these regimens [in the past].

What is the take-home message from this research?

The standout from the overall trial was the efficacy gain [observed with] lenvatinib plus pembrolizumab. Those results were extremely impressive, and [demonstrate that this regimen] is a good choice for the first-line treatment [of patients with] RCC. The toxicity was certainly manageable with lenvatinib plus pembrolizumab. In my own experience, is that over time, the toxicities are quite manageable with dose reduction, as needed. Patients can stay on treatment for long periods of time. I have patients who were treated on this program for years. Those metrics are assessed by clinicians and research staff.

[However, we always need to ask ourselves,] how does the patient feel about [the regimen]? I was quite impressed that this [efficacious] combination had either similar or better scores than what we have seen with sunitinib, which has been our standard of care for more than a decade.

Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). 

. 2021;39(suppl 15):4502. doi:10.1200/JCO.2021.39.15_suppl.4502

Merck and Eisai receive priority review from FDA for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck. May 6, 2021. Accessed July 9, 2021. https://bit.ly/2PYnqtM

“Lenvatinib/Pembrolizumab’s Favorable HRQoL Leads to “Standout” Option for Frontline RCC”

The efficacy and health-related quality of life benefits associated with the combination of lenvatinib and pembrolizumab make it a favorable treatment for advanced renal cell carcinoma, says an expert from Memorial Sloan Kettering Cancer Center. 

Ryan Scott

Articles

Allogeneic HSCT Elicits Favorable Outcomes in Myelofibrosis

Lenvatinib-Pembrolizumab Combo Induces ‘Impressive’ Results in Patients with Advanced Kidney Cancer