Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the Elderly: Review of Literature and New Perspectives
1 Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma.
2 Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma.
Received: July 27, 2020
Accepted: October 18, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020081 DOI 10.4084/MJHID.2020.081
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myeloid leukemia (AML) in patients over the age of 60 carries a poor
prognosis, mainly due to unsatisfactory control of leukemia with
According to the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER), there are 3000 new cases per year of AML in patients aged 70 to 79 years in the United States (US). This increased incidence in older adults is attributed to environmental exposures and age-related clonal hematopoiesis. Both animal and human models reveal many changes in aging stem cells, such as genome instability, longer frequency in the cycle, and shortening of telomere lengths.[6-8]
Old Patients with AML
The percentage of patients with favorable cytogenetics drops from 17% in patients younger than age 56 to 4% in patients older than 75 years, while unfavorable cytogenetics increase from 35% to 51% in older patients. This is due to a larger proportion of chromosomal abnormalities involving chromosomes 5,7,17 and complex aberrant karyotypes.[13,14] The likelihood of prolonged survival is low for any patient with unfavorable cytogenetics, regardless of age, whereas among patients with intermediate and good risk cytogenetics- t(8;21) and inv(16)-, patients older than 65 seem to do much worse than younger patients.
A recent multicentric review of 373 cases of core-binding factor confirms that the incidence of drug resistance, as a cause of induction failure and relapse following successful remission induction, increases significantly with patient age.
Finally, age profoundly affects older patients with a poor ECOG performance status (PS), whose early death rate may be very high.
Prognosis and Initial Treatment
Allogeneic Hemopoietic Stem Cell Transplantation (HSCT)
Nevertheless, despite increasing patients' age in transplantation, only 6% of AML patients over 60 years undergo an allograft in the USA, and also HLA typing is still performed in reduced numbers. This indicates that many Hematology Units are unwilling to seriously consider an allogeneic HSCT as a treatment option for older patients with AML.
Conditioning Regimens in Older AML
On the other hand, NMA regimens, as well as RIC regimens, preserve GVL with a relatively low TRM. One of these NMA regimens combines low dose TBI (2 Gy) and fludarabine and has been widely used in older patients: in a large multicenter study on 372 patients aged 60–75 years, the 5-year cumulative incidences of TRM and relapse were 27% and 41%, and the 5-year OS 35%.
Reduced dose cyclophosphamide (45 mg/kg instead of the conventional 120 mg/kg) was used in another study, in 56 patients with AML (n = 41) and MDS (n = 15): TRM was 9% and DFS 45%. Indeed significantly reduced TRM may favorably affect the OS of older patients with comorbidities.
A large retrospective study from the Center for International Blood and Marrow Transplantation Research (CIBMTR) included 545 AML patients, aged 40-79 in the first remission, who underwent a RIC HSCT: there was no impact of age on TRM, DFS, and OS. The 2-year OS in the age groups 60–64 and 65 years or over was 34% and 36%. A meta-analysis of 14 studies, including 749 AML patients allografted with RIC regimens, showed a 35% 3-year DFS, with a plateau of the relapse curves beyond one year.
Comparing Myeloablative Regimens with NMA or RIC
A retrospective EBMT study was performed in 714 AML patients, aged 55 years and over, grafted from a matched unrelated donor (MUD) (median age 35 years) or an HLA identical matched sibling donor (MSD) (median age 61 years): there was no significant difference in 3-year TRM (17% versus 23%; p = 0.17), relapse rate (37% versus 30%; p = 0.12), and OS (49% in both). Single Center studies have led to discrepant results, sometimes favoring a young unrelated donor's choice over an older matched sibling. Haploidentical family donors (HAPLO) and unrelated cord blood (CB) units are additional options for patients who lack an HLA related or unrelated donor:[35,36] in a study from Seattle, patients with minimal residual disease (MRD) at transplant did better after a UCB transplant as compared to an unrelated transplant, mainly due to a lower risk of relapse. In a prospective study from Minnesota, 98 patients with AML aged 55 years or over underwent a RIC HSCT using a matched sibling donor or an unrelated CB unit. There were 26 AML patients in the sibling donor group and 44 in the CB group: there was no difference in OS, relapse rate, and TRM. Cord blood HSCT recipients had a lower incidence of chronic GVHD at 2-years post-transplant (61 versus 33%).
HAPLO donors are being widely used worldwide after the demonstration that post-transplant cyclophosphamide (PT-.CY), combined with a calcineurin inhibitor (CNI) and mycophenolate (MMF), can effectively protect patients from acute and chronic GvHD.
A CIBMTR study compared HAPLO donors with MUD in AML patients and found no difference in the main outcomes. One advantage of selecting a HAPLO donor, compared to an unrelated donor, is the immediate availability of a family member. Therefore family HLA typing should be performed upfront: in the absence of a suitable HLA identical sibling, a matched unrelated donor and family haploidentical donors may be considered. Unrelated cord blood units can also be considered as an alternative stem cell source.
Graft versus Host Disease
Transplant Related Mortality
Is Allogeneic HSCT the Best Post-Remission Therapy for Older Patients with AML?
Older AML Patients Beyond the First Remission
Therefore, the disease phase is a significant predictor of AML patients' outcome and calls for careful identification of residual disease before the transplant. The choice of an appropriate conditioning regimen, effective GvHD prophylaxis, and donor selection, in other words, the choice of a given transplant platform, may also encourage results in older AML patients with advanced disease, as shown in a recent study.
Exceeding the Limit of 70 Years of Age
The EBMT has compared the outcome of 713 AML patients aged ≥70 years to 16161 patients aged 50 to 69 years who underwent HSCT between 2004 and 2014. Acute and chronic GvHD were comparable in the two age groups. TRM was higher in the older patients (34% vs. 24%), and overall 2-year survival was lower (38% versus 50%). However, when selecting only active disease patients, the two-year survival was comparable 35% and 33%. This study on a large number of patients suggests that 70 years is not an insurmountable barrier, and again selection of patients and selection of the transplant platform needs to be taken into account.
The Role of Cytogenetics
The more unsatisfactory outcome seen in patients with adverse risk cytogenetics is a problem since the conditioning regimen cannot be intensified, and prophylactic cellular therapies may risk GvHD.
Targeted Therapy and HSCT
or death in the sorafenib-group versus placebo-group was 0.39 (p=0.013), and the 24-months probability of relapse was 47% with placebo versus 15% with sorafenib (HR=0.256,log-rank p=0.002). Patients with undetectable MRD prior to HSCT and those with detectable MRD after HSCT had the strongest benefit from sorafenib treatment.
TRM was comparable in the two groups. Gilteritinib, a highly selective, oral FLT3 inhibitor with activity against both FLT3 mutation subtypes (ITD and TKD), was tested in patients with relapsed/ refractory AML: significantly more patients in the gilteritinib group proceeded to an allogeneic HSCT, as compared to the placebo (25% vs. 15%, p=0.02), and also showed a survival advantage. Trials of gilteritinib as part of first-line induction or consolidation therapy and post-HSCT maintenance therapy are underway to assess the best timing for anti-FLT3 intervention to improve treatment outcomes.
These novel treatment strategies, aiming to induce MRD-negativity before HSCT, might synergize with post HSCT maintenance, hopefully even in the older population.
Geriatric Assessment in older AML
The comorbidity score can be integrated with a geriatric assessment in patients over the age of 60, and more so over the age of 70 to better tailor the intensity of the conditioning regimen and the type of GvHD prophylaxis.
Improvements in the conditioning regimens and the donor's choice and improvement in supportive care have had a positive impact on the outcome.
Understanding the "biological" age rather than the chronological age is an area of active investigation. Assessment of quality of life endpoints, function, and symptoms in older adult survivors of HSCT is also important.
New protocols are being designed to reduce leukemia relapse after HSCT, a major cause of failure, and include genetically engineered donor lymphocyte infusions, early tapering of immunosuppression, and MRD monitoring before and after HSCT, maintenance therapy post-HSCT, and targeted therapy.
On top of these, possibly early transplantation may represent a simple and effective way of bringing to transplant a larger proportion of patients with AML. Figure 1 outlines a theoretical approach for older patients with AML: risk stratification should identify intermediate and high risk AML, and CGA assessment would then select fit patients; HLA typing and induction therapy would follow, with the possible identification of a suitable donor; an allogeneic HSCT could be performed as early as possible. The advantage of an early transplant would be to avoid prolonged and repeated periods of neutropenia and possibly prevent chemo/radioresistance of the leukemic cells.
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