The overall response rate (ORR) achieved with ruxolitinib (Jakafi) at day 28 proved to be higher than what was achieved with best available therapy (BAT) in patients with steroid-refractory acute graft-vs-host disease (aGVHD), irrespective of organ involvement, according to data from a post-hoc analysis of the phase 3 REACH2 trial (NCT03112603).

The findings, which were presented during the EBMT 48th Annual Meeting, indicated that the ORR elicited with ruxolitinib (n = 96) among those who had lower gastrointestinal (GI) tract involvement at day 28 was 57% vs 33% with BAT (n = 115; odds ratio [OR], 2.70; 95% CI, 1.54-4.74). In those with skin involvement, the ORRs with ruxolitinib (n = 93) and BAT (n = 74) were 72% and 47%, respectively (OR, 2.99; 95% CI, 1.55-5.79).

Moreover, in those with upper GI involvement, ruxolitinib (n = 28) induced an ORR of 68% vs 38% with BAT (n = 37; OR, 3.35; 95% CI, 1.19-9.44). Lastly, in patients who had liver involvement, the ORRs achieved with ruxolitinib (n = 36) and BAT (n = 26) were 44% and 19%, respectively (OR, 4.04; 95% CI, 1.16-14.09).

“From this post-hoc analysis, [we learned that] in patients with steroid-refractory aGVHD, the response rates were higher with ruxolitinib compared with BAT, regardless of organ involvement, and it is also true when considering aGVHD grade—all of this is good news,” lead study author Mohamad Mohty, MD, of the Haematology and Cellular Therapy Department, of Saint-Antoine and Sorbonne University, said in a presentation on the data.

For patients with aGVHD, standard initial treatment is corticosteroids, which are known to have a heavy toxicity burden. Moreover, 35% to 60% of patients become refractory to this approach. Those with steroid-refractory aGVHD often present with or progress to severe disease, and the mortality rate in these patients is 70% or higher.

The multicenter, randomized, open-label REACH2 trial enrolled patients with grade II to IV steroid-refractory aGVHD who were at least 12 years of age and who had evidence of myeloid and platelet engraftment. If patients had active uncontrolled infection, severe organ failure, overlap syndrome, or had failed previous allogeneic hematopoietic stem cell transplant within 6 months, or disease relapse, they were excluded.

Study participants were randomized 1:1 to receive either oral ruxolitinib at a twice-daily dose of 10 mg or investigator’s choice of therapy, which could have included antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, an mTOR inhibitor in the form of everolimus (Afinitor) or sirolimus (Rapamune), etanercept (Enbrel), or infliximab (Remicade).

Study participants received treatment for up to 24 weeks. Randomization was stratified according to grade of aGVHD at baseline (II vs III vs IV). Notably, standard supportive therapy was permitted in both treatment arms, as well as the continued use of calcineurin inhibitors and glucocorticoids.

The primary end point of the trial was ORR at day 28, and a key secondary end point was durable ORR at day 56. Other secondary end points included 6-month overall survival and non-relapse mortality.

At a data cutoff date of July 25, 2019, a total of 309 patients underwent randomization; 154 patients received ruxolitinib and 155 patients were given BAT. The median age in the investigative arm was 52.5 years (range, 12-73) vs 54.0 years (range, 13-71) in the control arm; 59.7% and 58.7% of patients, respectively, were male. The majority of patients were White.

In the ruxolitinib arm, 34.4% of patients had grade II acute GVHD at randomization, 46.1% had grade III disease, and 19.5% had grade IV disease; these rates were 34.2%, 46.5%, and 19.4%, respectively, in the BAT arm. Of those in the investigative arm, 62.3% had lower GI involvement, 60.4% had skin involvement, 18.2% had upper GI involvement, and 23.4% had liver involvement. Of those in the control arm, 74.2% of patients had lower GI involvement, 47.7% had skin involvement, and 23.9% had upper GI involvement, and 16.8% had liver involvement.

Data showed that the ORR with ruxolitinib was significantly higher with ruxolitinib than it was with BAT at day 28 and day 56. Day-28 ORRs in the investigative (n = 154) and control (n = 155) arms were 62% and 39%, respectively (OR, 2.64; 95% CI, 1.65-4.22; 

< .001). Of those who responded to ruxolitinib, 34% achieved a complete response (CR) and 28% experienced a partial response (PR). Among those who responded to BAT, the CR and PR rates were 19% and 20%, respectively.

The ORR achieved with ruxolitinib at day 56 was 40% vs 22% with BAT (

< .001). Of those who responded to treatment in the investigative arm, the CR rate was 27% and the PR rate was 13%. Of the responders in the control arm, the CR and PR rates were 16% and 6%, respectively.

Notably, the ORR was higher with ruxolitinib vs BAT, irrespective of acute GVHD grade. Among those with grade II disease who received ruxolitinib (n = 53), the ORR was 75%, vs 51% with BAT (n = 53; OR, 2.96; 95% CI, 1.30-6.76). Among those with grade III disease, the ORRs achieved with ruxolitinib (n = 71) and BAT (n = 72) were 56% and 38%, respectively (OR, 2.15; 95% CI, 1.10-4.20). In those who had grade IV disease, the ORR with ruxolitinib (n = 30) was 53% vs 23% with BAT (n = 30; OR, 3.76; 95% CI, 1.24-11.38).

For the post-hoc subgroup analysis by organ class, investigators examined day-28 ORR by aGVHD involvement in 4 organ classes: lower GI, skin, upper GI, and liver. They also evaluated the percentage of patients with a 1-stage-or-more improvement from baseline by organ class at day 28 and day 56, excluding those with stage 0 disease at baseline.

Additional data presented during the meeting showed that a greater proportion of patients in the ruxolitinib arm experienced an improvement of 1 stage or more from baseline at day 28 and day 56 than those in the BAT arm, across the 4 organ classes examined.

 for the treatment of adult and pediatric patients aged 12 years and older who had steroid-refractory aGVHD.

 The regulatory decision was supported by findings from the phase 2 REACH1 trial, which showed that when ruxolitinib was combined with corticosteroids, it induced an ORR of 57% at day 28 with a CR rate of 31% in this patient population.

Mohty M, Zeiser R, Galvin J, et al. Ruxolitinib vs best available therapy in patients with steroid-refractory acute graft-vs-host disease: a comparison of response by organ class from the randomized, phase 3 REACH2 study. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Abstract OS10-03.

Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host fisease. 

. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635

FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. News release. FDA; May 24, 2019. Accessed April 15, 2022. 

Articles

The overall response rate achieved with ruxolitinib at day 28 proved to be higher than what was achieved with best available therapy in patients with steroid-refractory acute graft-vs-host disease, irrespective of organ involvement.

Ruxolitinib Elicits High Responses in Steroid-Refractory aGVHD, Regardless of Organ Involvement

Treatment with a treosulfan-based conditioning regimen led to a superior event-free and overall survival (OS) compared with busulfan-based conditioning in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), according to a post-hoc subgroup analysis of the phase 3 MC-FludT.14/L trial (NCT00822393) that were presented during the EBMT 48th Annual Meeting.

The benefit was observed in elderly patients and in those with comorbidities.

Data showed that the 2-year event-free survival (EFS) rate was 64.7% (95% CI, 57.1%-71.3%) with treosulfan and 53.3% (95% CI, 45.2%-60.7%) with busulfan (HR, 0.64; 85% CI, 0.45-0.90; 

Additionally, the treosulfan-based regimen had a 2-year OS rate of 72.8% (95% CI, 65.5%-78.8%) compared with 64.7% with busulfan (95% CI, 56.7%-71.6%). Overall, the treosulfan-based conditioning regimen led to a 35% reduction in the risk of disease progression or death compared with busulfan (HR, 0.65; 95% CI, 0.43-0.96; 

“This post-hoc subgroup analysis confirms the clinically relevant benefit of the treosulfan/fludarabine regimen as a relatively well-tolerated and effective preparative regimen for allogenic HCT in elderly and/or comorbid AML patients,” lead study author FriedrichStölzel, MD, of the University Hospital Carl Gustac Carus Dresden in Germany, said in a virtual presentation during the meeting.

Allogeneic HCT is a curative therapeutic option for patients with AML and myelodysplastic syndromes (MDS), and chemotherapy-based conditioning regimens are recommended for patients with myeloablative conditioning and reduced-intensity conditioning strategies. Currently, there are limited randomized data for this patient population who are older and have comorbidities.

Treosulfan combined with fludarabine has previously demonstrated tolerability in patients with AML and MDS in a dose-range finding trial as well as two phase 2 trials.

In the AML cohort of the prospective, multicenter, phase 3 MC-FludT.14/L trial, investigators randomized 352 elderly and comorbid patients from 31 European transplant units in 5 countries to receive treosulfan intravenously (IV) at 3 x 10 g/m

 (n = 184) or busulfan IV at 6.4 mg/kg plus fludarabine at 5 x 30 mg/m

 (n = 168). All patients were given cyclosporine plus methotrexate on days +1, +3, and +6.

To be eligible for enrollment, patients with AML in first or consecutive hematologic remission or MDS had to have a Haematopoietic Cell Transplantation Comorbidity Index (HCT-CI) greater than 2 and/or be at least 50 years old, a Karnofsky performance index of at least 60%, and a matched related or unrelated donor (≥910 human leukocyte antigens class I or II allele identities).

Stratification factors included cytogenetic/molecular risk group, donor type, and transplant center.

The primary end point was EFS within 2 years following allogeneic HSCT, and secondary outcome measures included engraftment, completion of donor-chimerism, OS, relapse/progression incidence, non-relapse mortality, acute and chronic graft-vs-host disease (GVHD), and safety. At the EBMT 48th Annual Meeting, data from the full analysis set of patients with AML were presented.

Regarding baseline characteristics for the patients with AML, more than half (56%) were male, the median age was 60 years (range, 31-70), and 95% of patients were aged at least 50 years. The median HCT-CI at baseline was 3; 59% of patients had HCT-CI greater than 2. Patients either had low- (11%), intermediate- (41%), or high-risk disease (35%), or not available (14%).

Results also showed that the complete donor chimerism rate at day +28 was 94% (95% CI, 90%-97%) with treosulfan and 87% (95% CI, 81%-92%) with busulfan. At day +100, these rates were 87% (95% CI, 81%-91%) and 83% (95% CI, 76%-88%), respectively. However, these results were not found to be statistically significant, Stölzel said.

Regarding cumulative index relapse and progression, the median was not available in either arm (HR, 0.82; 95% CI, 0.56-1.22; 

 value [b] = .5569). The 2-year cumulative index relapse/progression rates were 29.0% (95% CI, 21.9%-36.0%) with treosulfan and 26.9% (95% CI, 20.3%-33.5%) with busulfan. This was no significant difference between the 2 arms, he noted.

Cumulative index non-relapse mortality rates were also not available in either arm (HR, 0.62; 95% CI, 0.33-1.15; 

 value [b] = .1045) and the 2-year rates were 8.4% (95% CI, 4.3%-12.5%) with treosulfan and 14.7% (95% CI, 4.3%-12.5%).

There was no statistical difference in cumulative index chronic GVHD between the treosulfan and busulfan arms at a median 266 days and 371 days, respectively (HR, 1.16; 95% CI, 0.86-1.56; 

 = .3447). However, Stölzel said that extensive cumulative index GVHD, which was not available in either arm, was statistically significantly better with treosulfan (HR, 0.53; 95% CI, 0.31-0.88; 

Additionally, the 2-year GVHD relapse-free survival rates were 52.9% with treosulfan and 39.6% with busulfan (HR, 0.69; 95% CI, 0.50-0.95; 

StölzelF, Stelljes M, Beelen D, et al. GVHD and GFRS in patients with AML undergoing allogeneic transplantation with treosulfan- versus busulfan-based conditioning: a subgroup analysis of the randomized pHASE III MC-FLUDT.14/L trial. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Abstract OS16-06.

Casper J, Wolff D, Knauf W, et al. Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. 

. 2010;28(20):3344-3451. doi:10.1200/JCO.2009.23.3429.

Ruutu T, Volin L, Beelen DW, et al. Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial. 

. 2011;96(9):1344-1350. doi:10.3324/haematol.2011.043810.

Casper J, Holowiecki J, Trenschel R, et al. Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning.

. 2012;47(9):1171-1177. doi:10.1038/bmt.2011.242.

Treatment with a treosulfan-based conditioning regimen led to a superior event-free and overall survival compared with busulfan-based conditioning in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation, according to a post-hoc subgroup analysis of the phase 3 MC-FludT.14/L trial. 

Treosulfan-Based Conditioning Improves Survival in Elderly, Comorbid Patients With AML

Pegcetacoplan (Empaveli) treatment was associated with hemoglobin stabilization and normalization, as well as a superior change from baseline in hemoglobin levels, which showed a meaningful correction of anemia, in patients with complement inhibitor–naïve paroxysmal nocturnal hemoglobinuria (PNH), according to results of the phase 3 PRINCE trial (NCT04085601). The findings were presented during the EBMT 48th Annual Meeting.

Data showed that the avoidance of greater than 1 g/dL decrease from baseline was 85.7% with pegcetacoplan vs 0% with the control arm (

 <.0001), and hemoglobin levels that were at least gender-specific lower limit of normal (LLN) were 45.7% with pegcetacoplan and 0% with the control group (

 = .0010). There was a 0.4% change from baseline to week 26 in hemoglobin levels in the pegcetacoplan arm vs 0.8% in the control arm (

Additionally, pegcetacoplan was superior to the control arm in change from baseline in lactate dehydrogenase (LDH) levels at week 26 at -1870.5 U/L vs -400.1, respectively (

 <.0001). Pegcetacoplan also led to greater improvements in LDH normalization in the absence of transfusions at 65.7% compared with 0%, respectively (

“Patients with PNH that were naïve to complement inhibitor treatment displayed meaningful hematologic and clinical improvements through 26 weeks of pegcetacoplan treatment, as demonstrated by improved hemoglobin levels, lactate dehydrogenase levels, and transfusion avoidance, and improvements in quality of life,” lead study author Andrija Boganovic, MD, of the Clinic of Hematology, University Clinical Center of Serbia and Faculty of Medicine, University of Belgrade in Belgrade, Serbia, said in a virtual presentation during the meeting. “These results emphasize the potential of pegcetacoplan to provide disease control for adults with PNH that are naïve to complement inhibitor therapy.”

PNH is a rare and severe blood disorder in which destruction of red blood cells causes thrombosis and leads to organ damage and potentially premature death. Pegcetacoplan is a targeted C3 inhibitor that is indicated for adult patients with PNH who remain anemic, despite C5 inhibition.

In the phase 3 PRINCE study, investigators screened 53 complement inhibitor–naïve patients aged 18 years or older with PNH who were then randomized 2:1 to receive pegcetacoplan at 1080 mg subcutaneously twice weekly (n = 35) or a control group of no complement inhibitors (n = 18). If patients’ hemaglobin levels decreased by 2 or more g/dL from baseline, they were permitted to cross over to pegcetacoplan (n = 11).

Patients were stratified by red blood cell transfusion within the 1 year prior to screening (<4 vs ≥4).

To be eligible for enrollment, patients could not have received a complement inhibitor within 3 months prior to screening, must have had hemoglobin levels below LLN (males, ≤13.6 g/dL; females, ≤12.0 g/dL), and LDH levels at least 1.5 times the upper limit of normal ([ULN]; 1.5 times ULN; ≥339 U/L).

Coprimary end points were hemoglobin stabilization and change from baseline in LDH levels at week 26. Secondary outcome measures included change from baseline in hemoglobin levels at week 26, transfusion avoidance, and incidence and severity of adverse events (AEs) through week 26.

The primary reasons for patient withdrawal on study (n = 3) were due to death (n = 1 on each arm but were unrelated to treatment) and lost to follow-up (n = 1 on pegcetacoplan).

Further findings showed that pegcetacoplan also demonstrated statistical superiority in transfusion avoidance at 91.4% compared with 5.6% for the control arm (

 <.0001), indicating significant alleviation in transfusion burden. Also, patients on pegcetacoplan were transfused with 0.6 median units through week 26 compared with the median 3.3 units in the control group (

Investigators also conducted an analysis of composite endpoints of transfusion requirements and hemoglobin drop was performed “to overcome possible bias of patients in the control group escaping prior to receiving transfusion,” Bogdanovic noted. However, 88.6% and 9% of pegcetacoplan- and control-treated patients, respectively, met none of the criteria.

Patients treated with pegcetacoplan achieved clinically meaningful improvements in FACIT-Fatigue scores compared with the control group through weeks 4 to 26 that were found to be consistent with improved hematologic parameters and transfusion avoidance (

 = .0610). This was not found to be statistically significant, which Bogdanovic said could be due to the small sample size and high variability in the control group. Also, the patients in the pegcetacoplan group reached the normal and healthy adult score for the FACIT-Fatigue scale.

Regarding safety, most AEs on the pegcetacoplan arm were found to be mild (34.8%) or moderate (28.3%) in severity, with 8.7% total AEs with pegcetacoplan defined as severe. There were no serious AEs related to treatment, and no treatment-related AEs led to discontinuation of pegcetacoplan or study withdrawal.

No cases of acute hemolysis were seen in either arm through week 26. The most common treatment-emergent AEs in the pegcetacoplan and control arms were injection site rejection (30.4% vs 0%, respectively), hypokalemia (13.0% vs 11.1%), dizziness (10.9% vs 0%), and fever (8.7% vs 0%).

The safety findings suggest a favorable risk-benefit profile with pegcetacoplan in this patient population, Bogdanovic concluded.

Bogdanovic A, Wong RS, Navarro JR, et al. Efficacy and safety of pegcetacoplan treatment in complement-inhibitor naïve patients with paroxysmal nocturnal haemoglobinuria: results from the phase 3 PRINCE study. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Abstract OS15-02.

Pegcetacoplan treatment was associated with hemoglobin stabilization and normalization, as well as a superior change from baseline in hemoglobin levels, which showed a meaningful correction of anemia, in patients with complement inhibitor–naïve paroxysmal nocturnal hemoglobinuria.

Pegcetacoplan Improves Efficacy in Complement Inhibitor–Naïve Paroxysmal Nocturnal Hemoglobinuria

Checkpoint inhibitors prior to allogeneic hematopoietic cell transplant (HCT) improved progression-free survival (PFS) and relapse incidence in patients with Hodgkin lymphoma. However, the treatment did not improve non-relapse mortality (NRM) or overall survival (OS), according to findings of a Center for International Blood and Marrow Transplant Research (CIBMTR)/EBMT (European Society for Blood and Marrow Transplantation) analysis (2020-R-03) that were presented at the EBMT 48th Annual Meeting.

Results showed that those who previously received a checkpoint inhibitor led to a 25% reduction in the risk of disease progression or death compared with those who did not (HR, 0.75; 95% CI, 0.59-0.95; 

 = .0171). The administration of checkpoint inhibitors in this setting also highlighted a lower incidence of relapse (HR, 0.53; 95% CI, 0.38-0.75; 

However, there was no OS improvement with the prior use of checkpoint inhibition (HR, 0.96; 95%, 0.72-1.27; 

 = .76949), nor an improvement in NRM (HR, 1.1; 95%CI, 0.78-1.56; 

“The bottom line is that, as we have predicted, there was a significant improvement in progression-free survival and relapse in favor of prior checkpoint inhibition, but it did not translate into a higher overall survival,” lead study author Miguel-Angel Perales, MD, a medical oncologist and chief of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, said in a virtual presentation during the meeting. “Patients who had prior [checkpoint inhibition] should still be referred to allogeneic transplant. We have a curative treatment. The results in our study and other studies…support very high rates of cure for these patients and that should be the strategy we adopt.”

Pembrolizumab (Keytruda) is approved for adult patients with relapsed/refractory classical Hodgkin lymphoma and pediatric patients with refractory classical Hodgkin lymphoma, or classical Hodgkin lymphoma that has relapsed after 2 or more lines of therapy. Additionally, nivolumab (Opdivo) is indicated for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous HCT and posttransplant brentuximab vedotin (Adcetris).

While checkpoint inhibitors are used in Hodgkin treatment, it is thought that utilizing this class of agents prior to allogeneic transplant could worsen transplant complications, such as graft-vs-host disease (GVHD). These complications, therefore, are believed to lead to worse outcomes.

In the CIBMTR/EBMT study, investigators sought to examine the impact of prior checkpoint blockade on outcomes with allogeneic HCT in 1729 adults (CIBMTR, n = 403; EBMT, n = 1326) with Hodgkin lymphoma who received a first allogeneic HCT via minimal residual disease, minimal undetectable disease, or haploidentical donor from 2008 to 2009. Most patients (74%) received a reduced-intensity conditioning (RIC)/nonmyeloablative (NMA) regimen, and 20% of patients had previously received a checkpoint inhibitor.

A total 46.1% of patients who received a checkpoint inhibitor had a haploidentical donor compared with 31.8% of those who did not have an immunotherapy agent. GVHD prophylaxis comprised posttransplant cyclophosphamide, a calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) in 51.6% and 32.3% of patients, respectively, while the remaining were given CNI-based prophylaxis with MMF or methotrexate. Additionally, 81.6% and 73.7% of patients who did and did not receive a checkpoint inhibitor, respectively, had chemotherapy-sensitive disease at the time of transplantation.

The median follow-up was 24 months for the checkpoint inhibitor–cohort and 38 months in the arm with no checkpoint inhibitor. Additional factors that were found to impact OS included age (HR, 1.02; 95% CI, 1.01-1.02; 

 = .00001), sex (female vs male; HR, 0.76; 95% CI, 0.64-0.92; 

 = .00381), partial response (HR, 1.39; 95% CI, 1.11-1.73; 

 = .00367), and refractory disease (HR, 2.25; 95% CI, 1.81-2.8; 

Myeloablative conditioning vs RIC/NMA (HR, 1.24; 95% CI, 1.02-1.5; 

 = .03276) and a Karnofsky performance score greater than 90 (HR, 1.45; 95% CI, 1.2-1.76; 

Furthermore, in patients who only received checkpoint inhibitors, PFS (HR, 0.61; 95% CI, 0.38-0.97; 

 = .03821) and relapse (HR, 0.43; 95% CI, 0.2-0.92; 

 = .03038) were improved in haploidentical donor recipients; however, this did not have an impact on OS.

Additionally, while grade 2 to 4 acute GVHD was increased with the use of checkpoint inhibitors (HR, 1.33; 95% CI, 1.03-1.71; 

 = .02677), there was no impact on the cumulative incidence of grade 3 to 4 acute (HR, 1.39; 95% CI, 0.94-2.05; 

 = .09886) and chronic GVHD (HR, 0.98; 95% CI, 0.77-1.25; 

“Future studies are needed to identify the best donor and GVHD prophylaxis in these patients,” the authors noted.

Perales M-A, Awan F, Boumendil A, et al. Outcomes of allogeneic HCT in patients with Hodgkin lymphoma in the era of checkpoint inhibitors: a joint CIBMTR and EBMT analysis. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Presidential abstract.

Checkpoint inhibitors prior to allogeneic hematopoietic cell transplant improved progression-free survival and relapse incidence in patients with Hodgkin lymphoma, but the treatment did not improve non-relapse mortality or overall survival.

Checkpoint Blockade Before Allogeneic Transplant Improves PFS, But Not OS, in Hodgkin Lymphoma

A pediatric patient with severe transplant-associated thrombotic microangiopathy (TA-TMA) responded to treatment with narsoplimab after experiencing disease progression on eculizumab (Soliris), according to findings presented in a poster during the 48th Annual Meeting of the EBMT.

“[The infant] developed severe TA-TMA that progressed on adequate blockade of terminal pathway using eculizumab, who had an excellent response to narsoplimab, emphasizing the role of lectin pathway activation in the pathophysiology of TA-TMA,” lead study author Michelle L. Schoettler, MD, an assistant professor in the Department of Pediatrics at Emory University School of Medicine, and coinvestigators wrote in the poster.

TA-TMA–related multi-organ failure is often fatal following treatment with hematopoietic cellular therapy. However, complement and endothelial dysfunction are potentially key disease drivers, even while the lectin pathway’s role in TA-TMA is not well characterized.

MASP-2 is an effector enzyme of the lectin pathway of the complement system, and narsoplimab is a MASP-2 monoclonal antibody. Currently, there is a biologics license application under review with the FDA for use as a potential therapeutic option in adult patients with hematopoietic stem cell transplant–associated TMA.

In May 2021, the FDA extended the review period following a response from the drug developer, Omeros Corporation, to an information request issued by the regulatory agency. The FDA classified the response as a major amendment, which requires additional time to adequately review. The new action date under the Prescription Drug User Fee Act is October 17, 2021.

Findings of a phase 2 trial (NCT02222545) previously showcased the activity with narsoplimab.

 Here, the agent elicited a complete response rate of 54% (95% CI, 34%-72%) in the total patient population (n = 28). Among 23 patients who received treatment in accordance with study protocol, who had received 4 weeks or more of dosing, the objective response rate with the agent was found to be even higher, at 65% (95% CI, 43%-84%).

However, the efficacy and safety of narsoplimab in pediatric patients have been limited to date. In the analysis presented at the 48th Annual Meeting of the EBMT, investigators evaluated narsoplimab in an infant with refractory TA-TMA that was complicated by diffuse alveolar hemorrhage (DAH).

The patient was a 9-month-old female with KMT2A-MLL leukemia who underwent a 10/10 unrelated bone marrow transplant that was conditioned with busulfan and cyclophosphamide. She experienced veno-occlusive disease, which required ventilator support, renal replacement, and a peritoneal drain.

On day +18, the patient experienced anemia, thrombocytopenia, elevated lactate dehydrogenase, schistocytes, proteinuria, hypertension, and elevated sC5b-9, all of which led to a TA-TMA diagnosis.

Treatment with eculizumab was administered on day +18 and organ function was initially improved and was later extubated and had recovered renal function. However, despite adequate CH50 suppression, the patient developed worsening hematologic markers of TMA and acute respiratory failure on day +34, which required re-intubation. She was diagnosed with DAH and was restarted on CRRT. The patient was also found to have evidence of alternative complement activation with elevated C3a and Bb.

Eculizumab had been discontinued to prevent additional risk of infections, and narsoplimab was then administered at a 4-mg/kg dose intravenously beginning on day +57.

Following narsoplimab for 6 weeks, TA-TMA hematologic markers had improved and the patient was then extubated without any recurrent pulmonary bleeds, CRRT was stopped, and proteinuria improved. To date, narsoplimab is still being administered twice weekly.

The patients’ primary disease relapsed at day +100.

Regarding safety, narsoplimab was found to be well tolerated. Additionally, there was Bb, C3a, C5a, and sC5b-9 normalization plus decreased platelet and hemoglobin transfusion needs. This suggests the rapid reversal of organ dysfunction seen in this patient was likely from lectin pathway blockade, the authors noted.

Schoettler M, Bryson E, Deeb L, et al. Compassionate use of narsoplimab to treat transplant associated thrombotic microangiopathy in a pediatric patient with multi-organ failure. Presented at: 48th Annual Meeting of the EBMT; March 19-23, 2022; virtual. Abstract P377.

Omeros announces extension of FDA review period for narsoplimab in HSCT-TMA. News release. Omeros Corporation. May 20, 2021. Accessed March 22, 2022. https://bwnews.pr/3oEFq9j.

Rambaldi A. Smith M, Whitaker S, et al. Narsoplimab (OMS721) for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; virtual. Abstract S262.

A pediatric patient with severe transplant-associated thrombotic microangiopathy responded to treatment with narsoplimab after experiencing disease progression on eculizumab.

Pediatric Patient With Severe TA-TMA Elicits Response to Narsoplimab

Axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated a clinically improvement in quality of life (QOL) compared with standard of care (SOC) chemotherapy in the second-line setting for patients with relapsed/refractory large B-cell lymphoma (LBCL), according to patient-reported outcome (PRO) data of the phase 3 ZUMA-7 trial (NCT03391466).

The findings, which were presented during the 48th Annual Meeting of the EBMT, showed that the QOL benefit with the CD19-directed CAR T-cell therapy was observed at day 100 as measured by multiple validated PRO instruments.

“The superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line [relapsed/refractory] LBCL,” lead study author Mahmoud Elsawy, MD, MSc, of Queen Elizabeth II Health Sciences Centre and Dalhousie University in Canada, and coinvestigators, wrote in a poster presented during the meeting.

Clinical outcomes are poor for patients with LBCL who experience early relapse or are refractory to frontline therapy, and the second-line SOC treatment is often linked with poor health-related QOL. Axi-cel is currently FDA approved for the treatment of adult patients with relapsed/refractory LBCL after at least 2 lines of systemic therapy.

In the multicenter, open-label, phase 3 ZUMA-7 trial, investigators evaluated axi-cel vs SOC in patients with relapsed/refractory LBCL in the second-line setting.

A total 359 patients across 77 sites were randomized 1:1 to receive axi-cel plus conditioning chemotherapy (n = 180) or SOC with investigator-selected platinum-based chemoimmunotherapy (n = 179). At day 50, an initial disease assessment was conducted; those who were on the axi-cel arm continued to day 100, day 150, and long-term follow-up. Patients who had either a complete or partial response to SOC proceeded to high dose chemotherapy (HDT)-autologous stem cell transplant (ASCT). Nonresponders received additional treatment off protocol.

To be eligible for enrollment, patients had to be at least 18 years old, have LBCL that was relapsed/refractory within 12 months of frontline therapy, and intended to proceed to HDT-ASCT. Stratification factors included response to first-line therapy and second-line age-adjusted International Prognostic Index (sAAIPI) score. It was optional to include steroid-only bridging therapy without chemotherapy.

Primary efficacy findings of the trial were presented at the 2021 ASH Annual Meeting.2 At a median follow-up of 24.9 months, findings showed that the median event-free survival (EFS) was 8.3 months (95% CI, 4.5-15.8) for patients on axi-cel compared with 2.0 months (95% CI, 1.6-2.8) for those on SOC chemotherapy (HR, 0.40; 95% CI, 0.31-0.51; 

 < .001). The 2-year EFS rates in the investigative and control arms were 40.5% (95% CI, 33.2%-47.7%) and 16.3% (95% CI, 11.1%-22.2%), respectively. The EFS benefit was observed across key patient subgroups.

The data presented at the 48th Annual Meeting of the EBMT encompassed the first comparative analysis of PRO with axi-cel compared with SOC in this patient population.

The instruments that were utilized included: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire‑Core 30 (QOLC-C30), a 30-item cancer-specific questionnaire that included global health status, functional, and symptom scales; EQ-5D-5L, a general questionnaire with 5 QOL domains along with a global assessment; and Work Productivity and Activity Impairment (WPAI): General Health, which measures work productivity and activity impairment.

The assessments were taken at baseline, day 50, day 100, day, 150, month 9, and every 3 months thereafter from randomization up to 2 years or time of EFS event—whichever occurred first. The analysis population included all patients who had a baseline PRO and at least 1 measure completed on days 50, 100, or 150. Clinically meaningful changes were noted as being 10 points for each EORTC QLQ-C30 score, 7 for EQ-5D-5L Visual Analogue Scale (VAS) score, and 0.06 for EQ-5D-5L score. Additional exploratory analyses were also conducted.

Regarding baseline characteristics of the QOL analysis set (n = 296), 30% of patients were aged at least 65 years old and 42% of patients had an sAAIPI score of 2 to 3. Seventy percent of patients had primary refractory disease, and patients either had high-grade B-cell lymphoma (double-/triple-hit; 19%), had negative double-/triple-hit status (60%), or were not tested (21%).

Results showed that for patients treated with axi‑cel compared SOC, there was a statistically significant and clinically meaningful difference in mean change of scores from baseline at day 100, favoring axi-cel, on all prespecified PRO domains, including EORTC QLQ-C30 Physical Functioning (

 <.0001), EORTC QLQ-C30 Global Health Status/QOL (

 values were .0124 and .0004 for EORTC QLQ-C30 Global Health Status/QOL and EQ-5D-5L VAS, respectively. Sensitivity analyses that controlled for covariates and patterns of missingness also demonstrated similar findings at day 100.

Furthermore, the mean estimated scores for patients on the axi‑cel arm returned to or exceeded scores at baseline by day 100 to day 150 compared with month 9 or later for those on the SOC arm.

Regarding the exploratory analyses, axi-cel also showcased statistically significant differences in change from baseline for nausea and vomiting, diarrhea, insomnia, and appetite loss measures at day 100; role functioning at day 100 and day 150; and social functioning, fatigue, and dyspnea measures at day 100, day 150, and month 9.

Finally, in terms of work productivity and activity impairment, patients on axi‑cel had statistically significant (

 < .05) lower mean absenteeism and lower mean activities impairment at day 100 vs SOC.

The authors noted, however, that score comparisons at later time points warrant cautious interpretation because “attrition due to disease progression, new lymphoma therapy, or death was disproportionately higher on the SOC arm and may select patients with the best outcomes.”

“The data also suggest faster recovery to pretreatment QoL with axi‑cel compared with SOC,” the authors concluded.

Elsawy M, Chavez JC, Avivi I, et al. Patient‑reported outcomes in ZUMA‑7, a phase 3, randomized, open‑label study evaluating the efficacy of axicabtagene ciloleucel (axi‑cel) versus standard‑of‑care therapy in relapsed /refractory large B‑cell lymphoma. Presented at: 2022 EBMT Annual Meeting; March 19-23, 2022; virtual. Abstract P104.

Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. 

. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133.

Axicabtagene ciloleucel demonstrated a clinically improvement in quality of life compared with standard of care chemotherapy in the second-line setting for patients with relapsed/refractory large B-cell lymphoma.

Axi-Cel Shows Clinically Meaningful Improvement in QOL in Second-Line Relapsed/Refractory LBCL