Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PT-Cy) in acute myeloid leukemia in complete remission: incidence and risk of graft failure

The study presented by Annalisa Ruggeri, MD, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, analyzed graft failure and contributing risk factors after the use of unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PT-Cy) in patients with acute myeloid leukemia (AML) in complete remission.

HLA-haploidentical HSCT, represents a form of allogeneic HSCT (allo-HSCT), whereby donors and recipients share a single inherited identical copy of the HLA loci-containing chromosome. A biological parent or child of the recipient is HLA-haploidentical and each sibling has a 50% chance of being a match.1,2

The primary limitation of haplo-HSCT is the host immune system recognizing donor cells as foreign, initiating graft-versus-host disease (GvHD) and ultimately, graft failure (GF) – one of the most critical complications that can occur post-haplo-HSCT. To address this, PT-Cy has become widely used to reduce the incidence of GvHD and is recognized as a highly effective prophylactic measure. However, the incidence and risk factors of graft failure after haplo-HSCT using PT-Cy are not clearly known.3

Utilizing the EBMT and Acute Leukemia Working Party (ALWP) registry, this study was able to analyze 1270 patients with AML. The patients underwent haplo-HSCT using PT-Cy, receiving their first transplant in either their first or second complete remission. In 40% of cases, bone marrow was the stem cell source.

The cumulative incidence of GF at day 45, excluding non-engraftment due to early relapse of the original disease, was 6.6 %, with 43 patients experiencing a primary GF. This is an important point to highlight, as it is lower than what has been previously reported following T-cell depleted haplo-HSCT (10–20 %), an alternative conventional therapy for GvHD prophylaxis. Nine patients suffered from delayed engraftment (> 45 days), a complication that is a risk factor for worse overall survival.4

Among the patients with primary GF, 29 were able to undergo a second allo-HSCT – a salvage therapy that should be performed quickly to avoid severe infectious complications. Two-year overall survival for those receiving a second haplo-HSCT transplant was 32%.

Analysis of the main risk factors that could be modified in order to prevent GvHD was performed. The three main risk factors associated with graft failure were:

  • Diagnosis of secondary leukemia,
  • The use of bone marrow as stem cell source
  • The use of a reduced intensity conditioning regimen

In summary, this study highlights lower incidence of GF when using PT-Cy as GvHD prophylaxis when compared to conventional approaches. An important take home message is that the clinician must consider performing further patient analysis to investigate risk factors contributing to GvHD and should plan for the potential need for a rescue strategy with secondary transplant.

TA-TMA and the potential benefit of narsoplimab

Thrombotic microangiopathy (TMA) is an endothelial damage syndrome that results in thrombosis in capillaries and arterioles, it’s increasingly found as a complication of autologous and allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). TMA is a severe and life-threatening syndrome that can occur in patients with no other underlying comorbidities.5

TMA often presents as a triad of microangiopathic hemolytic anemia, thrombocytopenia and organ dysfunction, often in the kidneys or central nervous system.The classic pathophysiologies of TMA are hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP).7 However, in patients that have received an allo-HSCT, another syndrome is also observed – transplant-associated TMA (TA-TMA), of which a similar triad is seen. It is associated with graft-versus-host disease (GvHD), presents in both pediatric and adult patients and is typically an early complication of transplants of up to 100 days, although it has also been observed as late presentation.8

Currently, there is no gold-standard treatment for patients with TA-TMA, and so researchers have been focusing on understanding the treatment and identifying the trigger. Eleni Gavriilaki, MD, PhD, George Papanicolaou Hospital, Thessaloniki, Greece, discussed the use of narsoplimab, a monoclonal antibody targeting mannan-binding lectin serine protease 2 (MASP-2), for the treatment of TA-TMA. The lectin pathway is part of the complement cascade and has very important interactions with other pathways, as well as immune cells. It is crucial that the role of the lectin pathway in TA-TMA is understood in order to exploit it as a therapeutic target. The lectin pathway also has the potential to help clinicians understand the diagnostic dilemmas they are presented with TA-TMA.

Data obtained so far with respect to narsoplimab and inhibition of the lectin pathway is very encouraging for TA-TMA. A Phase II study using narsoplimab in TA-TMA patients was able to achieve a high overall survival (OS) in these patients – an endpoint that is usually difficult to achieve, with previous control group studies obtaining an OS of near to 0. Dr Gavriilaki further discussed narsoplimab in the context of COVID-19, a very hot topic for scientists all over the world. Recent data has shown that the lectin pathway is actively involved in elements of COVID-19, with future data being published on the effectiveness of narsolimab, and other complement inhibitors, in COVID-19 patients.

Managing adenovirus infection in hematopoietic stem cell transplant recipients

Adenoviruses (ADVs) are a group of common viruses that can cause a wide range of illnesses and symptoms, that can infect the lining of the eyes, airways and lungs, intestines, urinary tract and nervous system. ADV is a very severe complication in patients post-hematopoietic stem cell transplant (HSCT) and can cause significant morbidity and mortality in the immunocompromised.9,10

ADV has a particularly high incidence in the pediatric population post-HSCT, with a prevalence of up to 27%. Usually infecting humans in their early life, ADV remains persistent in lymphoreticular tissue such as tonsils and intestines. As a healthy child matures, viral shedding can occur for months or years. However, immunocompromised HSCT pediatric patients are particularly susceptible and ADV can trigger severe, systemic illnesses such as hepatitis and encephalitis.11

Per Ljungman, MD, PhD, Karolinska Institute, Stockholm, Sweden, presented the issue of there currently being no licensed antiviral agent against ADV due to the discontinued development of the existing drug, brincidofovir (BCV), by the then current license holder. BCV was used under compassionate use and is an antiviral drug with broad-spectrum activity.

Many transplant centers have used BCV as a very important drug against ADV, however, they are now having to return to the use of cidofovir – the traditional drug used for ADV in HSCT patients. Patients taking cidofovir report numerous side effects and in vitro studies have shown lower intracellular levels of the active drug compared to BCV.12,13

Looking forward, Prof. Ljungman suggests that there is potential light on the horizon in the form of intravenous BCV. SymBio, a Japanese pharmaceuticals company, recently announced the approved global clinical development plan for a BCV intravenous formulation, specifically prioritizing the development targeting ADV infection occurring post-HSCT. Although this drug will not be available for the foreseeable future, there is hope for this area of high unmet medical need.14

Allogeneic hematopoietic stem cell transplants in acute myeloid leukemia: matched siblings versus haploidentical donors

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has the potential to provide a cure for relapsed-refractory (R/R) acute myeloid leukemia (AML), a hematological malignancy with poor prognosis. The likelihood of finding a human-leukocyte-antigen identical (HLA-id) sibling donor is ~25-30%, and therefore, for those 70-75% of patients lacking an HLA identical donor, an HLA-haploidentical (HLA-haplo) donor provides a promising alternative. HLA-haplo donors can be mismatched family members and recently, the outcomes with haplo recipients have improved.

Studies comparing data from HLA-id versus HLA-haplo are limited, and so Arnon Nagler, MD, MSc, Chaim Sheba Medical Center, Tel-Hashomer, Israel, presents data from a retrospective study comparing the outcomes of allo-HSCT from HLA-haplo (n = 389) and HLA-id (n = 1654) sibling donors in R/R AML, using the European Society of Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP) registry.15

All HSCTs were performed during the period 2007–2015 and the median age at transplant was 52-years old. Those in the haplo group received either post-transplant cyclophosphamide (PT-Cy), in vivo T-cell depletion, or both. The primary endpoint of the study was overall survival (OS) according to the type of donor, defined as the probability of being alive at any time point and secondary endpoints included leukemia-free survival (LFS), severity of graft-versus-host disease (GvHD) and GvHD relapse-free survival (GRFS).

Results demonstrated a higher engraftment rate in the HLA-id sibling patients, with no difference in cumulative incidence (CI) of acute GvHD between the two groups, however, a significantly higher CI of chronic and severe GVHD was observed in the HLA-id sibling recipients. Furthermore, HLA-haplo recipients also saw an increase in non-relapse mortality, lower OS, LFS and GRFS.

Looking to the future, haplo donors may provide an appropriate alternative in the absence of HLA-id sibling donor for R/R AML patients in critical need of an allo-HSCT. HLA-haplo is improving as a therapeutic option but is still second best to the superiority of the sibling. Dr. Nagler highlights the next goals of haplo-HLA in HSCT are aiming to reduce the transplant-related mortality and infection rate.

References

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Written by Frankie Lewns

Edited by Tom Southgate

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