Sergio A. Giralt, MD, deputy division head, Division of Hematologic Malignancies, Melvin Berlin Family Chair in Multiple Myeloma, Memorial Sloan Kettering Cancer Center, discusses the potential utility of omidubicel in hematologic malignancies. 

The results of a randomized phase 3 clinical trial (NCT01597778) demonstrated similar 2-year progression-free survival rates with double unrelated umbilical cord blood transplant vs human leukocyte antigen (HLA)–haploidentical bone marrow transplant in patients with chemotherapy-sensitive lymphoma or acute leukemia in remission. 

In recent years, the number of cord blood transplants has decreased likely because the procedure is associated with slow engraftment and high resource utilization, says Giralt. However, during the 47th Annual Meeting of the EBMT, findings from a phase 3 trial of omidubicel, a cryopreserved cellular product derived from a single umbilical cord blood unit and expanded 

, vs standard umbilical cord blood transplant (UBCT) in patients with high-risk hematologic malignancies following myeloablation were presented virtually. The results demonstrated improved CD34-positive cell expansion and quicker time to neutrophil engraftment with omidubicel vs UBCT. 

As such, clinical trials could explore cord blood transplant with omidubicel to benefit patients who do not have a related or unrelated donor available, concludes Giralt. 

Videos

Sergio A. Giralt, MD, discusses the potential utility of omidubicel in hematologic malignancies.  



Dr. Giralt on the Potential Utility of Omidubicel in Hematologic Malignancies 

The MASP-2 inhibitor narsoplimab (OMS721) demonstrated high response rates and a significant improvement in laboratory markers and organ function irrespective of subgroup in adult patients with high-risk hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA), according to findings from a pivotal phase 2 trial (NCT02222545) presented during the 

The response rate was 61% (n = 17) among all patients treated with narsoplimab (n = 28; 95% CI, 40.6%-785%; 

 < .0001). In patients treated per protocol with at least 4 doses of narsoplimab (n = 23), the response rate was 74% (n = 17; 95% CI, 51.6%-89.8%; 

“Based on external advisory feedback, the estimated response rate for this patient population was 15% and this was indeed the FDA-agreed efficacy threshold for the primary end point in this clinical trial,” said lead study author, Alessandro Rambaldi, MD, a professor in the Department of Oncology and Hematology-Oncology at the University of Milan, and head of the Hematology and Bone Marrow Transplant Unit at ASST Papa Giovanni XXIII in Bergamo, Italy, in a virtual presentation of the data.

Moreover, responses were observed with narsoplimab in the overall population irrespective of subgroup, including age (<65, 58%; ≥65, 75%), sex (male, 65%; female, 50%), acute graft-versus-host disease (GVHD, 63%; no GVHD, 56%), significant infection (yes, 63%; no, 50%), multiple organ TMA involvement (yes, 64%; no, 57%), mismatched donor (yes, 60%; no, 61%), and transfusion within 2 weeks prior to first narsoplimab dose (yes, 56%, no, 100%).

Additionally, patients responded regardless of baseline platelet count (≤20 x 10

/L, 61%), kidney dysfunction (yes, 57%; no, 71%), pulmonary dysfunction (yes, 40%; no, 65%), neurological dysfunction (yes, 63%; no, 58%), or gastrointestinal dysfunction (yes, 100%; no, 59%).

Endothelial injury syndromes, such as HSCT-TMA, GVHD, veno-occlusive disease/sinusoidal obstruction syndrome, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage, are common pathways for many early transplant complications caused by conditioning regimens, immunosuppressive agents, infections, and alloreactivity.

“TMA is a serious and life-threatening syndrome that is underrecognized and can occur in up to 40% of patients undergoing stem cell transplantation. TMA may co-exist with other endothelial injury syndromes, such as GVHD, thus leading to an increase in morbidity and mortality after transplantation,” said Rambaldi.

Narsoplimab is an investigational, fully human IgG4 monoclonal antibody that inhibits MASP-2, an effector enzyme of the lectin pathway of complement. In HSCT-TMA, narsoplimab blocks the lectin pathway activation that results from endothelial injury. The agent also blocks MASP-2–mediated coagulation and activation of kallikrein. In turn, narsoplimab leaves the effector function of the adaptative immune response intact to fight infection.

On January 19, 2021, the FDA granted a priority review designation to a biologics license application for narsoplimab for the treatment of patients with HSCT-TMA.

 The FDA is expected to make a decision regarding the approval of narsoplimab by July 17, 2021 and does not plan to hold an advisory committee meeting to discuss the application.

The single-arm, open-label study was initiated as a phase 2 trial; however, after the FDA granted a breakthrough therapy designation to narsoplimab for patients with HSCT-TMA, the study was converted into a pivotal trial, explained Rambaldi.

The study protocol specified that patients receive 4 mg/kg or 370 mg of intravenous narsoplimab once weekly for at least 4 weeks.

Eligible patients had to be 18 years or older and have persistant HSCT-TMA defined as a platelet count less than 150,000/µL, evidence of microangiopathic hemolysis, such as the presence of schistocytes, serum lactate dehydrogenase (LDH) above the upper limit of normal, or haptoglobin below the lower limit of normal, and renal dysfunction for at least 2 weeks following modification or discontinuation of calcineurin inhibitors.

Patients with coexisting conditions, including GVHD, recent controlled infection, refractory underlying disease or relapse, and multiple organ dysfunction, were eligible for enrollment. 

Patients who received eculizumab (Soliris) within 3 months prior to screening or had a positive direct Coombs test or serious uncontrolled infections at entry were excluded.

The co-primary end points of the study were response-based efficacy and safety and tolerability. Efficacy was defined as an improvement in TMA laboratory markers of platelet count and LDH and improvement in clinical status, which comprised any predefined criteria in blood, renal, pulmonary, gastrointestinal, or neurological markers. Secondary end points included 100-day survival, overall survival (OS), and change from baseline in laboratory markers.

The median age of patients was 48, and most patients were male (n = 20; 71.4%). The majority of patients had malignant underlying disease (n = 27; 96.4%).

Risk factors for poor outcomes included the presence of GVHD (n = 19; 67.9%), significant infection (n = 24; 85.7%), pulmonary dysfunction (n = 5; 17.9%), neurological dysfunction (n = 16; 57.1%), multiple organ involvement (n = 14; 50.0%), and renal dysfunction (n = 21; 75.0%). Moreover, 93% of patients had multiple risk factors for poor outcomes.

Additional data showed a 68% (n = 19) 100-day survival rate following HSCT-TMA diagnosis among all patients treated with narsoplimab. In patients treated per protocol, the 100-day survival rate was 83% (n = 19). Finally, among responders (n = 17), the 100-day survival rate was 94% (n = 16).

The median OS for the overall patient population was 274 days (95% CI, 103-not estimable [NE]). In the per-protocol population, the median OS was 361 days (95% CI, 176-NE). In the responder population, the median OS was NE (95% CI, 273- NE).

Regarding safety, 96.4% (n = 27) of patients in the overall population reported any adverse effect (AE). The most common AEs observed in at least 15% of patients treated with narsoplimab included pyrexia (n= 10; 35.7%), diarrhea (n = 9; 32.1%), vomiting (n = 9; 32.1%), nausea (n = 7; 25.0%), neutropenia (n = 7; 25.0%), fatigue (n = 6; 21.4%), hypokalemia (n = 6; 21.4%), and back pain (n = 5; 17.9%).

“The patient population had a high expectant death rate,” said Rambaldi. “In such a sick population with so many comorbidities, narsoplimab was well tolerated.”

Of note, 6 patients died during the core study period because of events commonly reported with HSCT, such as neutropenic sepsis, septic shock, progressive acute myeloid leukemia, TMA, and GVHD.

Narsoplimab is also under investigation in several phase 3 trials that are evaluating the agent’s use in other lectin pathway–associated diseases and other endothelial injury syndromes, including IgA nephropathy (NCT03608033) and atypical hemolytic uremic syndrome (NCT03205995).

Rambaldi A, Claes K, Goh YT, et al. Narsoplimab (OMS721), a MASP-2 inhibitor, for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA): subgroup analyses. Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; Virtual. Abstract OS4-2.

Biologics license application for narsoplimab in HSCT-TMA accepted for priority review by U.S. FDA. News release. Omeros Corporation. January 19, 2021. Accessed March 16, 2021. 

Study of the safety and efficacy of OMS721 in patients with immunoglobulin A (IgA) nephropathy. ClinicalTrials.gov. Posted July 31, 2018. Updated May 30, 2019. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03608033.

Safety and efficacy study of OMS721 in patients with atypical hemolytic uremic syndrome (aHUS). ClinicalTrials.gov. Posted July 2, 2017. Updated October 18, 2018. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03205995.

Articles

The MASP-2 inhibitor narsoplimab demonstrated high response rates and a significant improvement in laboratory markers and organ function irrespective of subgroup in adult patients with high-risk hematopoietic stem cell transplant–associated thrombotic microangiopathy.

Narsoplimab Elicits Responses Across High-Risk HSCT-TMA Subtypes

The engineered cord endothelial cell (E-CEL) product AB-205 showed an encouraging safety profile along with robust effects in eliminating oral/gastrointestinal (GI) severe regimen-related toxicities (SRRT) in patients with systemic lymphoma undergoing high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-AHCT), according to interim results of the phase 1b/2 AB-205-001 trial that were presented during the 

Overall, the agent was found to be well tolerated with no clinically significant infusion-related reactions. The adverse events (AEs) reported on study were consistent with that in an AHCT population, and the maximum-tolerated dose was not reached, explained lead study author Carolyn Mulroney, MD, in a presentation during the meeting.

“AB-205 has significant potential to address a serious unmet need in patients undergoing HDT-AHCT,” said Mulroney,a hematologist/medical oncologist, and associate professor of medicine at University of California San Diego Health. “This drug has been granted Orphan Drug Designation by the FDA. The highest dose of 20 x 10

 E-CEL/kg demonstrated robust effect in eliminating oral/GI severe regimen-related toxicities.”

HDT-AHCT is potentially curative for patients who have high-risk, chemotherapy-sensitive lymphomas. Additionally, while HDT eradicates malignant cells, it also can cause severe injury to healthy tissues via vascular endothelial damage. Some of these are SRRT, which lead to high symptom burden and life-threatening organ toxicities. The risk of these SRRTs could make select patients ineligible for AHCT, especially in those who are older.

Moreover, while hematopoiesis is largely rescued by AHCT, there are no effective treatments that are able to repair endothelial damage, Mulroney explained.

AB-205 is an off-the-self E-CEL product comprised of allogeneic human E4*CD31*umbilical endothelial cells. These engineered cells can respond to cytokines produced by damaged cells and release angiocrine factors that act via juxtacrine and paracrine mechanisms and support microvasculature repair through interactions with intact endothelial cells.

Data from preclinical models demonstrated that AB-205 restores the natural healing process of the marrow, spleen, and GI tract, and that it also accelerates hematopoietic recovery and increases survival following LD50 irradiation.

In the phase I dose-escalation study (NCT03925935), investigators enrolled patients with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma undergoing their first hematopoietic stem cell transplant, and were eligible for HDT-AHCT; an ECOG performance status of 0 to 1 was required. Localized radiation and posttransplant maintenance were permitted.

Cohorts were enrolled sequentially following safety assessment of the previous cohort. Doses were as follows: 5 x 10

 E-CEL/kg on day 0 (cohort 3), and 20 x 10

 E-CEL/kg in a split dose of 50% on day 0 and the other remaining 50% on day 2 (cohort 4).

AB-205 was administered intravenously, and high-dose therapy regimens consisted of carmustine, etoposide, cytarabine, and melphalan (BEAM); bendamustine, etoposide, cytarabine, and melphalan (BeEAM); cyclophosphamide, carmustine, and etoposide (CBV); and thiotepa, busulfan, and cyclophosphamide (TBC).

Patients received standard of care prophylaxis and supportive care.

The primary end point was safety; secondary end points included severe and duration of grade 3 or higher oral/GI toxicities, and time to neutrophil and platelet engraftment. Exploratory outcome measures were progression-free survival (PFS), non-relapse mortality, overall survival (OS), and lymphoid recovery.

In order to establish a modern historical control concurrent with study enrollment, a chart review was concurrently conducted of 45 consecutive patients undergoing AHCT for systemic lymphoma. Patients received conditioning with HDT with BEAM, BeEAM, or CBV from 2019 to 2020.

Baseline characteristics were stratified between 2 dose ranges of AB-205 (<20 x 10

 E-CEL/kg) and the chart review cohort. In total, the median age was 56.6 years, and 37.6% of patients were younger than 60 years. Sixty-two percent of patients were male, and 71% were diagnosed with NHL. The median number of prior therapies was 2; HDT regimens were BEAM (87.6%), BeEAM (9.3%), and CBV (3%). The median CD34+ count was 4.56 x 106/kg.

The median duration of follow-up was 8.1 months (range, 3.7-16.6) and no deaths occurred in the 29 patients. One patient, who was a 61-year-old male with stage IV diffuse large B-cell lymphoma and had a partial response to 2 lines of chemoradiation, relapsed at day +101.

No evidence suggested that AB-205 has a detrimental effect on either PFS or OS, Mulroney said.

Safety data were evaluable for 29 patients with systemic lymphomas. Patients experienced treatment-emergent AEs and serious AEs occurred in 31% of patients. Additionally, 1 dose-limiting toxicity, which was prolonged thrombocytopenia (>28 days) was observed during dose escalation at the 10 x 10

 E-CEL/kg-dose. This was considered to be unrelated to study treatment.

 E-CEL/kg cohort (n = 11), AEs were hypokalemia, oral mucositis, supraventricular tachycardia, upper respiratory infection, and epistaxis (9% each; n = 1 each). In the 20 x 106 E-CEL/kg (n = 18), hypokalemia occurred in 11% of patients; angina pectoris, sepsis, enterocolitis infectious, depression, hyperkalemia, hypocalcemia, dehydration, hypertension occurred at 6% each (n = 1 each).

The clinically meaningful end point of oral/GI SRRT, which was defined as grade 3 or higher oral mucositis, nausea/vomiting, or diarrhea, was also evaluated. Low-rates of this SRRT were reported with the <20 x 10

 E-CEL/kg dose (0%) when compared with the control cohort (60%).

Oral/GI regimen-related toxicities, which were defined as all-grade events, were at lower rates with AB-205 at both the <20 x 10

 E-CEL/kg doses in regard to oral mucositis (64% and 50%, respectively), nausea/vomiting (64% and 28%), diarrhea (82% and 50%). The control cohorts were 69%, 89%, and 82%, respectively.

Investigators also evaluated time to neutrophil and platelet engraftment. The median time to neutrophil engraftment was 10 days, the median time to platelet engraftment was 11 days, and the rate of platelet engraftment within 1 day of neutrophil engraftment was 69%. The median time to discharge from AHCT was 12 days.

In the chart review, the median neutrophil engraftment, platelet engraftment, and rate of platelet engraftment within 1 day of neutrophil engraftment was 12, 18, and 16%, respectively. The median time to charge from AHCT was 16 days.

Mulroney added that these data were the basis for the FDA’s Regenerative Medicine Advanced Therapy designation, and the findings were the subject of an end-of-phase 2 meeting with the regulatory agency.

A pivotal, double-blind, placebo-controlled, randomized study for potential registration with AB-205 is planned for US and EU sites.

Mulroney C, Scordo M, Abedi M, et al. Open label dose escalation trial of AB-205 (E-CEL® cells) in adults with systemic lymphoma undergoing high-dose therapy and autologous hematopoietic cell transplantation (HDT-AHCT). Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; virtual.

The engineered cord endothelial cell product AB-205 showed an encouraging safety profile along with robust effects in eliminating oral/gastrointestinal severe regimen-related toxicities in patients with systemic lymphoma undergoing high-dose therapy and autologous hematopoietic stem cell transplantation.

AB-205 Shows Tolerability, Robust Effects in Patients With Lymphoma Undergoing HDT-ASCT

Omidubicel was associated with a significantly improved median time to neutrophil engraftment compared with standard umbilical cord blood (UCB) transplantation in patients with high-risk hematologic malignancies, according to results of a phase 3 trial that were presented during the 

Findings showed that, in the intent-to-treat (ITT) population (n = 125), the median time to neutrophil engraftment was 12.0 days (95% CI, 10.0-15.0) compared with 22.0 days (95% CI, 19.0-25.0) in the control UCB arm (

 <.001). In the as-treated group (n = 108), these median times were 10.0 days (95% CI, 8-13) and 20.5 days (95% CI, 18-24), respectively (

Additionally, omidubicel was associated with a 41% reduction in the risk of death compared with standard UCB (HR, 0.59; 95% CI, 0.29-1.12; 

 = .16); however, the study was not powered to look at overall survival, explained lead study author Guillermo F. Sanz, MD, PhD.

“This global phase 3 randomized study demonstrates that transplantation with omidubicel results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said Sanz, of the Department of Hematology at Hospital Universitari i Politècnic la Fe, in Valencia, Spain, in a virtual presentation during the meeting. “These data suggest that omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation.”

Omidubicel is a cellular product that consists of 2 cryopreserved fractions derived from a single entire cord blood unit and is thawed at transplant centers immediately prior to infusion. The cells are obtained after CD133+ selection ex vivo expanded for 21 days in the presence of nicotinamide. The agent also comprises non-cultured CD133-negative cells that include T cells, Sanz added.

Nicotinamide has been found to increase stem and progenitor cells, to inhibit differentiation and increase migration, bone marrow homing, and engraftment efficiency, while preserving cellular functionality and phenotype.

A prior phase 1/2 trial explored omidubicel in 36 patients with high-risk hematologic malignancies who were undergoing myeloablative conditioning; 78% of patients had an intermediate/high disease-risk index. Treatment was given to patients at a median dose of 6.3 x 10

Results showed that omidubicel led to very fast hematopoietic engraftment in this patient population. The median time to neutrophil engraftment was 11.5 days, the median time to platelet engraftment was 34 days, and the median days that patients were alive and out of the hospital prior to day +100 was 73 days (

 <.001 for all as compared with 146 similar patients reported to the Center for International Blood and Marrow Transplant Research).

 Moreover, the treatment led to durable long-term hematopoietic engraftment that lasted for more than 10 years.

In the phase 3 study, patients with high-risk acute myeloid leukemia (n = 60), acute lymphoblastic leukemia (n = 41), myelodysplastic syndromes (n = 9), chronic myeloid leukemia (n = 6), and lymphoma (n = 5), and rare leukemia (n = 4) were randomized 1:1 to receive omidubicel or standard UCB. To be eligible for enrollment, patients had to be between the ages of 12 years and 65 years, be candidates for allogeneic stem cell transplantation, and not have a matched donor. Patients were from 33 centers in the United States, Europe, South America, and Asia.

Cord blood units were selected prior to randomization, which was stratified by treatment center, disease risk index, age, and intent to perform single vs double cord transplant in the control arm.

The primary end point of the trial was time to neutrophil engraftment; secondary end points were time to platelet engraftment, infections by 100 days posttransplant, and hospitalizations, which was defined as the days alive and out of the hospital in the first 100 days posttransplant.

The intent-to-treat population (n = 125) included 62 patients on omidubicel and 63 on standard transplant. In the as-treated population, patients received transplant with omidubicel (n = 52) or control (n = 56) per protocol.

Patient characteristics were well balanced between the 2 arms. More than half (57.5%) of patients were male and the median age was 41.5 years. Most patients were White (58%), and 13% of patients were Latino. Twenty-four percent of patients had low-risk disease, while 42% had moderate-risk disease, and 34.5% had high/very high-risk disease. The myeloablative conditioning regimens were 2 total body irradiation-based regimens with thiotepa, fludarabine, and cyclophosphamide (48.5%) or 1 with thiotepa, busulfan, and fludarabine (44%).

In the first cord blood unit, the HLA match was 4/6 in 73.5% of patients, 5/6 in 24.5%, and 6/6 in 2% of patients. In patients who received a second cord blood unit, which applied to the control arm only, the 4/6, 5/6, and 6/6 HLA matches occurred in 74%, 24%, and 2%, respectively. Additionally, 32.5% and 67.5% of patients had single and double intended UCB transplant, respectively.

Data also showed that the median CD34-positive cell expansion was 130-fold (range, 32-233). In the ITT population, the cumulative day 42 incidence of platelet engraftment was 55% with omidubicel vs 35% with the control arm (95% CI, 0.03-0.35; 

 = .028). In the as-treated population, the median time to platelet engraftment was 37 days (95% CI, 33-42) with omidubicel and 50 days (95% CI, 42-58) for the control arm (

Grade 2/3 bacterial or invasive fungal infection by 100 days in the ITT population was lower with omidubicel at 37% compared with 57% in the control arm (

 = .027). This was similar with viral infection rates at 10% vs 26% with omidubicel and control, respectively (

Omidubicel recipients had a median 60.5 days alive and out of the hospital in the first 100 days posttransplant compared with a median 48.0 days for patients on the control arm (

Sanz noted no differences in grade 2/3 acute graft-vs-host disease (GVHD) with the omidubicel and control arms (

 = .33); this trend cascaded into chronic GVHD at 1 year (

There was a trend toward lower non-relapse mortality (

 = .09) with omidubicel compared with the control arm; the risk for relapse was similar in both arms (

Moreover, the disease-free survival rate was higher with omidubicel vs that of the control arm (

 = .68), but Sanz noted that, similar to the OS report, the trial was not powered to assess this end point.

Sanz GF, Stiff PJ, Cutler CS, et al. Results of a phase III randomized, multicenter study comparing omidubicel with standard umbilical cord blood transplantation (UCBT) in patients with high-risk hematologic malignancies following myeloablation. Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; Virtual. Abstract GS2-7.

Horwitz ME, Wease S, Blackwell B, et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. 

. 2019;37(5):367-374. doi:10.1200/JCO.18.00053

Omidubicel was associated with a significantly improved median time to neutrophil engraftment compared with standard umbilical cord blood transplantation in patients with high-risk hematologic malignancies. 

Omidubicel Showcases Promising Outcomes in High-Risk Hematologic Cancers Following Myeloablation

Coverage of the 2021 EBMT Annual Meeting, held virtually March 14-17, 2021. 

2021 EBMT Annual Meeting | Supplements and Featured Publications

Dr. Giralt on the Potential Utility of Omidubicel in Hematologic Malignancies

Narsoplimab Elicits Responses Across High-Risk HSCT-TMA Subtypes

AB-205 Shows Tolerability, Robust Effects in Patients With Lymphoma Undergoing HDT-ASCT

Omidubicel Showcases Promising Outcomes in High-Risk Hematologic Cancers Following Myeloablation