EHA 2020 Discussion Addresses New Considerations for Common Transplant Complications | OncLive

EHA 2020 Discussion Addresses New Considerations for Common Transplant Complications

June 17, 2020

A panel of hematologic experts came together for a live Q/A session to discuss promising research related to common clinical complications of hematopoietic stem cell transplantation.

Following the 2020 European Hematology Association Annual Congress, a panel of hematologic experts came together for a live Q/A session, moderated by Joerg Halter, MD, of the University Hospital Basel in Basel, Switzerland, and Stephan Mielke, MD, of the Karolinska Institute in Stockholm, Sweden, to discuss promising research related to common clinical complications of hematopoietic stem cell transplantation (HSCT).

Narsoplimab (OMS721) for the Treatment of Adult HSCT-Associated Thrombotic Microangiopathy (TMA)

HSCT-TMA is a fatal complication of allogeneic HSCT. Its etiology is multifactorial, but endothelial cell injury plays a key role in the pathophysiology of the disease, lead study author, Alessandro Rambaldi, MD, of the University of Milan, said during the Q/A session. The conditioning regimen, immunosuppressive drugs, and infections contribute to the endothelial cell injury, leading to the activation of the lectin pathway of complement. Activated mannan-binding lectin-associated serine protease-2 (MASP-2) cleaves complement component 2 (C2) and C4, initiating a [series] of enzymatic steps that result in activation of C3 and C5 and formation of C5, which is the membrane attack complex.

Investigators conducted a pivotal phase 2 trial with narsoplimab, which is an investigational fully human IgG4 monoclonal antibody binding to MASP-2, in 28 patients with HSCT-TMA with response-based efficacy end points.

The results, which were presented during the virtual conference, showed that 54% patients who received narsoplimab achieved a complete response, and showed that the 100-day survival rate was 68%.

Congress attendees posed questions to the study authors, which are addressed below:

Given the apparent association between endothelial injury and TMA, do you see potential opportunities to use MASP-2 inhibition prophylactically?

Rambaldi: This is possible, in theory. For the time being, I think we should stick to the therapeutic setting.

In your presentation you spoke of endothelial injury being caused by the transplant process. [Patients with severe] coronavirus disease 2019 (COVID-19) appear to exhibit similar endothelial injury of TMA-like features. Have you considered using narsoplimab to treat severe COVID-19–positive patients and block the lectin pathway?

Yes, we have considered that. Ongoing studies are tackling complement activation in this setting.

How long will the effects of narsoplimab persist?

The patients who responded had a prolonged effect. This was one of the most striking effects of the drug. The response was long lasting in patients in whom we saw a clinically meaningful effect.

Would you use narsoplimab or eculizumab (Soliris) first?

In Italy, we don’t have the ability to use eculizumab. Therefore, we’re pleased we had the opportunity to test narsoplimab in this setting. However, the level to which narsoplimab interacts with the complement system in the lectin pathway could be preferable in terms of subsequent infections that might be associated with the use of eculizumab. However, this is just speculation.

Is there a rationale to combine the 2 agents?

[That possibility] is premature for the time being. We would need to wait for trial data to become available.

Did you see any bleeding or thrombotic disorders that you didn’t expect?

We didn’t see any adverse effects with regard to bleeding in these patients, which was one of the most remarkable observations we saw in this group of patients, despite [some incidence] of severe thrombocytopenia.

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

Low-Dose Decitabine Improves Refractory Prolonged Isolated Thrombocytopenia After Hematopoietic Cell Transplantation: A Randomized Multicenter Clinical Trial

In the trial, investigators theorized that low-dose decitabine could increase platelet counts of patients with refractory prolonged isolated thrombocytopenia after HSCT, leading to improved survival. Patients were randomized to 1 of 3 arms: decitabine plus recombinant human thrombopoietin (arm A), decitabine alone (arm B), or conventional therapy (arm C), lead study author, Yaqiong Tang, MD, of the Jiangsu Institute of Hematology, of Soochow University in China, explained during the Q/A session.

The results showed a significant increase in platelet counts in arms A and B beginning in the third week of treatment. Additionally, megakaryocytes were improved in patients who responded to decitabine, suggesting that low-dose decitabine is an effective treatment for patients with refractory prolonged isolated thrombocytopenia after HSCT.

How long was decitabine continued when platelet counts were higher than 30 x 109/L?

Tang: Decitabine was given at a dose of 15 mg/m2 intravenously for 3 consecutive days. 

How would you describe the mechanism of action in this setting?

Decitabine is a hypomethylating agent that’s used in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We used a dosage that is commonly used in MDS. The patients [in our study] had low megakaryocyte counts which may correlate with a damaged bone marrow microenvironment. The damage to the bone marrow microenvironment is almost unavoidable in HSCT recipients. In previous studies, decitabine has been shown to promote megakaryocyte differentiation, maturation, and proliferation.

Single Cord Blood Transplantation for AML Patients Aged 60 Years or Older: A Retrospective Study of the Japan Society for HSCT (JSHCT)

Here, investigators conducted a nationwide retrospective study of cord blood transplantation (CBT) in patients with AML who were at least 60 years of age. Older patients are less likely to find a suitable human leukocyte antigen (HLA)-matched donor, and CBT could be an acceptable alternative donor source, thereby expanding access to allogeneic HSCT, lead study author, Masamichi Isobe, MD, PhD, of The University of Tokyo in Tokyo, Japan, explained during the Q/A session.

The results showed that patients who were at least 70 years of age, were male, had a performance status of at least 1, an HSCT-comorbidity index of at least 3, and CBT before 2012 had significantly higher overall mortality and non-relapse mortality rates with CBT. As such, the investigators concluded that CBT could provide a curative option for older patients with AML with careful patient selection.

Why did you use CBT over haploidentical transplant? Is this result transferrable to other countries with regard to HLA diversity?

Isobe: Urgent [transplant is needed in this population of patients], so we used CBT. Though, we use haploidentical transplant too these days. The next step would be to compare CBT with haploidentical transplant.

Sixty-three percent of patients were not in complete remission (CR) at the time of CBT. What is the impact of remission status on outcome in relation to age and comorbidity index?

We performed a subgroup analysis of patients in CR and those who did not achieve CR. [Outcomes] did not differ by age. The patients who did not achieve CR tend to have [higher] overall mortality.

Comparison of Risk Factors and Mortality of Different Cytomegalovirus (CMV) End-Organ Diseases Following Haploidentical HSCT

The onset time, viral dynamics and mortality differs among different CMV diseases, said lead study author, Xing-Ye Meng, of Peking University People’s Hospital, during the Q/A session.

The results indicated that CMV load and refractory CMV infection are important risk factors for CMV diseases. Moreover, that the mortality of CMV diseases remains high, especially for CMV pneumonia, disseminated CMV disease and CMV encephalitis.

Does CMVG and CMVR increase mortality versus other CMV disease, or versus patients without CMV?

Meng: Compared with other CMV diseases, CMV gastroenteritis and retinitis has significantly lower mortality. Compared with patients without CMV disease, CMV retinitis has a higher mortality rate. However, patients with CMV gastroenteritis did not have higher mortality.

What role could letermovir have for the different subgroups?

Letermovir is a very promising antiviral drug for CMV. However, there are a lack of clinical trials in the [therapeutic space] for patients with CMV diseases. We need further investigation. The incidence of CMV diseases is relatively low, so it’s difficult to perform clinical trials.

Adoptive Immunotherapy With Regulatory and Conventional T-Cells Affords High Rate of Chronic GVHD/Relapse-Free Survival in AML After Myeloablative Haploidentical Transplantation

Study results showed that total marrow and lymphoid irradiation (TMLI) allowed for relatively safe myeloablative conditioning in patients with AML up to 65 years of age. For patients who are ineligible for total body irradiation (TBI), TMLI can boost radiation to the marrow and the lymph nodes, thereby sparing radiation to vital organs.

Notably, results showed that subsequent T-cell depleted HLA-haploidentical transplantation with Treg/Tcon immunotherapy resulted in a remarkably low incidence of relapse-free survival (RFS) and chronic graft-versus-host-disease (cGVHD), lead study author, Antonio Pierini, MD, PhD, of the University of Perugia, explained during the Q/A session.

The rate of cGVHD/RFS was 75% in 50 patients with AML, irrespective of age and risk of relapse.

How would you position this approach with the other haploidentical approaches?

Pierini: We understand that post-transplant cyclophosphamide is available to everyone. [Our approach] can be used in other centers because it is not complicated to produce these cells. With this platform, we can reduce relapse. That’s key for patients with minimal residual disease positivity or those who have a poor disease at diagnosis, such as those with AML and complex karyotype. [Our approach] is extremely powerful to eradicate leukemia.

In the future, we should be able to adopt our transplant strategy and evaluate this with other methodologies in clinical trials.

The 2-year cGVHD/RFS rate was 75%. However, acute GVHD (aGVHD) still occurs in one-third of patients. However, most patients can be cured; they are not steroid refractory. GVHD occurs in patients who do not experience any immunosuppressive treatment, so steroids arrive in a situation where there are no other immunosuppressive agents. That’s the main reason why we see good responses. Only 1 patient had severe cGVHD.

How important is the dose of TBI or TMLI in your approach?

We believe this is key. A lot of studies have shown that a higher dose of TBI results in [a lower] risk of relapse but higher toxicity. It’s important to deliver high-dose TBI in such an environment because it allows for a very good engraftment. It’s not only TBI. Immunotherapy adds another important part. Because we did not see any difference in outcomes in TBI-treated patients and TMLI-treated patients, we are thinking of expanding the approach to younger patients [to avoid the toxicity of TBI].

Reference

Live Q&A panel discussion: stem cell transplantation – clinical: other complications. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual.


x