Jaime Rosenberg

A study assessing the cost effectiveness of nusinersen (Spinraza)—approved in December 2016—compared with best supportive care (BSC) in patients with infantile-onset 

 (SMA), found that the disease-modifying therapy exceeded traditional cost-effectiveness thresholds.

 offers the first de novo cost-effectiveness model of these patients in the United States, according to the researchers, who found that at its current price, nusinersen did not fall below the $990,000 quality-adjusted life year (QALY) gained in any analyses performed in the study.

Based on the analyses, which took into account survival, costs, utilities, and whether motor function milestones were sustained over lifetime, the base-case incremental cost-effectiveness results were more than $1.1 million per QALY and nearly $600,000 per life year (LY) compared with BSC.

“The results were most sensitive to the length of survival, the costs associated with treating people with SMA, and the utilities in both the ‘sitting’ and ‘not sitting’ health states,” explained the researchers. “Results from the probabilistic sensitivity analyses found that nusinersen had a zero likelihood of achieving a cost-effective ratio of less than $500,000 per QALY gained.”

Cost effectiveness was calculated after determining that nusinersen led to greater QALYs and LYs (3.24 and 7.64, respectively) than BSC (0.46 and 2.40, respectively), and over a lifetime, the total costs associated with nusinersen were approximately $3.9 million compared with $790,000 for BSC.

“Given the relatively short-term effectiveness and utility data available, a registry to collect long-term data relating to efficacy and utility within infantile-onset SMA patients on treatment is recommended to allow a more accurate estimate of cost-effectiveness,” noted the researchers, who relied on short-term data from the ENDEAR and SHINE clinical trials. They highlight that most of the limitations of their study relate to the lack of available robust data and assumptions required to overcome it.

Their model, which took a health care sector perspective, used 5 health states: permanent ventilation, not sitting, sitting, walking, and death.

The researchers also performed scenario analyses to see if alternative inputs altered the cost-effectiveness results. For example, they used a scenario that took a modified societal perspective and found that the incremental cost per QALY and incremental cost per LY gained for nusinersen compared with BSC were slightly less favorable.

According to the researchers, this was because nonmedical costs, such as modifying the home, accrue for all the health states for a lifetime while patient productivity gains are only used for patients sitting or walking between the ages of 25 and 67 years. In the model, the productivity gains did not offset nonmedical costs since less than 20% of patients receiving nusinersen were in the “sitting” health state and none were in the “walking” health state.

Thokala P, Stevenson M, Kumar V, Ren S, Ellis A, Chapman R. Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US. 

. Published online October 6, 2020. doi:10.1186/s12962-020-00234-8.

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The study offers the first de novo cost-effectiveness model of these patients in the United States, according to the researchers.


Nusinersen Passes Cost-Effectiveness Thresholds for Infantile-Onset SMA

New study findings indicate massive splenomegaly could have a profound impact on outcomes in patients with 

 (MF) who receive an allogenic hematopoietic cell transplantation (allo-HCT).

 offers new insight into the use of splenectomy for these patients. It’s long been debated what role spleen size and splenectomy have on allo-HCT outcomes, as conflicting research on the impact on survival and relapse rates has been published.

“The presence of huge splenomegaly in MF candidates prior to allo-HCT is a frequent cause of concern for transplant physicians,” researchers explained. “Fear of delayed hematological recovery with potential increase in non-relapse mortality (NRM) leads a number of transplant physicians to consider splenectomy as a fundamental step prior to allo-HCT.”

The findings from the new analysis support the use of splenectomy for patients with progressive disease and large splenomegaly, with results indicating bulky splenomegaly is associated with a delay in hematologic recovery, higher rates of NRM, and lower survival.

The analysis included nearly 1200 patients with MF who received an allo-HCT between 2000 and 2017. Over the course of the study period a total of 202 splenectomies were performed.

Having an increasing spleen size at the time of allo-HCT was significantly associated with worse overall survival (

 = .034). Splenectomy was associated with a 36% drop in NRM, which, according to the researchers, occurred even with a greater proportion of these patients having a higher HCT-comorbidity index and lower Karnofsky Performance Status (KPS) scores—2 indicators of poor prognosis for allo-HCT outcomes.

Patients who underwent transplant with less bulky splenomegaly experienced faster engraftment, with a 28-day cumulative incidence of neutrophil recovery of 87% in patients with spleen <5 cm, compared with 81% and 82% for patients with larger splenomegaly. The 100-day cumulative incidence of platelet recovery also decreased with increasing spleen size, dropping from 85% to 79% to 66%.

However, the researchers found that splenectomy did increase the risk of relapse by 43% and appeared to have no benefit on overall survival (hazard ratio = 0.86).

Of note, the researchers observed a decrease in the use of splenectomy over time, with the rate of splenectomy dropping by half in 2017 (28.3% from 2000 to 2009 vs 14.1% from 2010 to 2017). According to the researchers, this could potentially be due to the emergence of novel therapies. For example, the rate dropped further after 2012 when ruxolitinib (RUX) was widely available.

Throughout the study, the researchers also determined the impact of RUX treatment prior to transplant.

“As documented in the non-transplant setting for RUX responding patients, patients achieving spleen length < 5 cm had an improved transplant outcome, with a borderline, although not-statistically significant, survival benefit in RUX-treated patients,” the researchers wrote.

-inhibition on splenomegaly and disease-related symptoms may well have led to improvement of performance status and linked with this observation.”

Polverelli N, Mauff K, Kröger N, et al. Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT). 

. Published online October 16, 2020. doi:10.1002/ajh.26020

Findings from a retrospective analysis support the use of splenectomy for patients with progressive disease and large splenomegaly.

Bulky Splenomegaly Associated With Worse Outcomes in Patients With MF Undergoing Allo-HCT

As the race to approval of a safe and effective vaccine for coronavirus disease 2019 (COVID-19) continues, a group of researchers is warning some of these vaccines could make patients more susceptible to contracting 

, the researchers are urging caution when it comes to the use of adenovirus type-5 (Ad5) vectored vaccines for COVID-19, recalling their research from a decade ago on an Ad5 vectored vaccine in 2 HIV vaccine trials.

“On the basis of these findings, we are concerned that use of an Ad5 vector for immunisation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could similarly increase the risk of HIV-1 acquisition among men who receive the vaccine,” wrote the researchers. “Both the HIV and COVID-19 pandemics disproportionately affect vulnerable populations globally. Roll-out of an effective SARS-CoV-2 vaccine globally could be given to populations at risk of HIV infection, which could potentially increase their risk of HIV-1 acquisition.”

There are several clinical trials assessing Ad5 vectored vaccine candidates underway, including by China’s 

The group’s ”cautionary tale” stems from the Step and Phambili phase 2b trials that studied the efficacy of an Ad5 vectored HIV-1 vaccine in preventing HIV infection. Across both international studies, they found that the vaccine actually increased the risk of HIV among the vaccinated men.

The findings from the Phambili study, in particular, have important implications for the use of the vaccines in COVID-19, according to the researchers, as findings from this study showed that heterosexual men receiving the Ad5 vectored vaccine faced a consistently increased risk of HIV infection. Notably, this increased risk appeared to be limited to men, with women not having an observed increase of infection in the study.

In the Step trial, the risk of acquiring HIV was particularly high among men who were uncircumcised and Ad5 seropositive men who reported having unprotected anal sex with a partner who was HIV seropositive or who had unknown serostatus as baseline.

Of note, the vaccine in both studies did not have the HIV envelope. Meanwhile, in another study that used a DNA prime and an Ad5 vector, both of which had the HIV envelope, there was no observed increase in HIV infection.

The reason for the observed increase in HIV risk remains uncertain, although several follow-up studies have suggested a potential explanation, according to the researchers.

“The vaccine was highly immunogenic in the induction of HIV-specific CD4 and CD8 T cells; however, there was no difference in the frequency of T-cell responses after vaccination in men who did and did not later become infected with HIV in the Step Study,” they wrote. “These findings suggest that immune responses induced by the HIV-specific vaccine were not the mechanism of increased acquisition. Participants with high frequencies of preimmunisation Ad5-specific T cells were associated with a decreased magnitude of HIV-specific CD4 responses and recipients of the vaccine had a decreased breadth of HIV-specific CD8 responses, suggesting that pre-existing Ad5 immunity might dampen desired vaccine-induced responses.”

Other exploratory studies have indicated that the vaccine enhances HIV replication in CD4 T cells or that Ad5-specific CD4 T cells could be more susceptible to HIV infection.

Buchbinder SP, McElrath MJ, Dieffenback C, Corey L. Use of adenovirus type-5 vectored vaccines: a cautionary tale. 

. Published online October 19, 2020.doi:10.1016/S0140-6736(20)32156-5

Researchers are urging caution when it comes to the use of adenovirus type-5 (Ad5) vectored vaccines for COVID-19.


Researchers Warn of Heightened Risk of HIV With Certain COVID-19 Vaccines

 outlines several treatments being investigated for the treatment of patients with 

 (MF) and other myeloproliferative neoplasms (MPNs), generally after they have become resistant or intolerant to Janus kinase (JAK) inhibition, a fundamental of MF treatment.

Although it’s undeniable that the treatment of MPNs has been revolutionized with the use of JAK inhibitors like ruxolitinib, these treatments have been shown to have limited disease-modifying effects and have not demonstrated an ability to prevent the progression of polycythemia vera and essential thrombocythemia to MF or leukemic transformation of MPNs.

Addressing these treatment gaps, several treatments are being studied in patients with MF and related neoplasms, typically in those who have being resistant or intolerant to JAK inhibitor treatment.

For example, telomerase inhibitor imetelstat has shown promise, demonstrating a median overall survival (OS) of 19.9 months for patients receiving 4.7 mg/kg and 28.1 months for patients receiving 9.4 mg/kg of the treatment. For the latter group of patients, 25% achieved a 12-week transfusion independence, 43.2% had a bone marrow fibrosis reduction, and 42.1% had a 

 25% reduction in driver mutation allele burden.

Targeting bone marrow fibrosis in MF has also shown promise, with anti-SLAMF7 monoclonal antibody elotuzumab inhibiting fibrocyte differentiation in vitro and ameliorating bone marrow fibrosis and splenomegaly induced by romiplostim in humanized mice. The treatment is expected to be studied in patients with

-mutated MF who are not eligible for JAK inhibitor therapy.

Those activating p53 through murine double minute 2 (MDM2) inhibition. Idasanutlin monotherapy or in combination with pegylated interferon alfa has shown promise in preclinical studies and led to the initiation of a phase 1 trial, and MDM2 inhibitor KRT-232 is currently being studied in patients with TP53 wild-type MF that has relapsed after or is refractory to JAK inhibitor therapy.

Novel epigenetic therapies. The combination of JAK inhibition and bromodomain and extra-terminal (BET) inhibition has shown promise in preclinical models, and results from the MANIFEST trial assessing ruxolitinib in combination and CPI-0610 has also shown promise.

Those targeting the anti-apoptotic machinery in MF. The combination of ruxolitinib and BH3-mimetic ABT-737 has demonstrated synergy in preclinical MPN models, which also translated into a clinical trial assessing navitoclax, which is the clinical counterpart of ABT-737. This combination will be compared against ruxolitinib and placebo in 2 phase 3 trials.

Widespread use of JAK inhibitors has also put a spotlight on the need for effective treatments for anemia, a frequent adverse event of the therapy, especially in the first 12 to 24 weeks of treatment. There are several treatments in clinical development to address this.

For example, trials assessing the potential of hepcidin mimetics to achieve superior hematocrit control and therefore reduce or eliminate phlebotomy requirements and correct iron deficiency have been initiated. A phase 2 trial of phlebotomy-requiring patients being treated weekly with novel hepcidin mimetic PTG-300 is currently underway.

The clinical development of activin receptor ligand traps has also been closely followed, with luspatercept being studied in a phase 2 trial assessing the anemia response and hemoglobin improvement or red blood cell-transfusion independence.

“One can already foresee a future scenario in which MF patients with more proliferative disease and robust blood counts are treated with ruxolitinib and fedratinib in combination with a BET inhibitor (eg, CPI-0610) or BH3 mimetic (eg, navitoclax) and those with anemia receive either momelotinib or one of the currently approved JAK inhibitors in combination with luspatercept, while those with severe thrombocytopenia at baseline are offered pacritinib,” wrote the researchers.

Bose P, Masarova L, Verstovsek S. Novel concepts of treatment for patients with myelofibrosis and related neoplasms. 

. Published online October 9, 2020. doi:10.3390/cancers12102891

Their study outlines several treatments being investigated for the treatment of patients with myelofibrosis and other myeloproliferative neoplasms, generally after they have become resistant or intolerant to Janus kinase inhibition.

Author | Jaime Rosenberg

Articles

Nusinersen Passes Cost-Effectiveness Thresholds for Infantile-Onset SMA

Bulky Splenomegaly Associated With Worse Outcomes in Patients With MF Undergoing Allo-HCT

Researchers Warn of Heightened Risk of HIV With Certain COVID-19 Vaccines

Researchers Outline Novel Treatment Approaches Being Studied in Myelofibrosis