Outcomes with Allogeneic Hematopoietic Stem Cell Transplantation in Therapy Related Myeloid Neoplasms: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-4884862/v1

In this meta-analysis and systematic review, 7785 patients from 33 original studies reporting outcomes of therapy- related myeloid neoplasms (t-MN) including therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) were included. The survival data were retrieved from Kaplan-Meier (KM) curves to calculate the overall survival (OS) and disease-free survival (DFS) probabilities. 67.3% (n = 5241) of the patients had t-AML. 26.5% (n = 2076) had t-MDS, and 6% had a mixed presentation (n = 468). The age of the patients ranged from 2 to 89 years and 61.7% were females. The pooled median OS was 16.9 months (95% CI: 13.7–21.1) and the estimated mean OS was 46.0 months (95% CI: 42.1–49.6). The pooled median DFS was 8.8 months (95% CI: 7.4–11.2) and mean DFS was 37.8 months (95% CI: 33.4–41.9). The pooled proportion of acute graft versus host disease (aGvHD) was 34% (95% CI: 0.35–0.45, I²: 91.71%, p < 0.0001). Relapse of the myeloid neoplasm was the most common cause of mortality, followed by infections, relapse of the underlying disease, and GvHD. Despite complications, allo-HCT is still the curative treatment option with better outcomes compared to conventional chemotherapy in t-MN. Timely transplants in carefully selected patients with post-HCT interventions could improve outcomes.

Allogeneic hematopoietic stem cell transplantation

therapy-related myeloid neoplasm

therapy-related myelodysplastic syndrome

therapy-related acute myeloid leukemia

Therapy-related myeloid neoplasms (t-MN), which includes therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS), and therapy-related myelodysplastic/myeloproliferative neoplasms (t-MDs/MPN) are secondary malignancies from the cytotoxic effect of anti-neoplastic drugs and ionizing radiations (1). Alkylating agents and radiation-related t-MDS usually present with long latency and rapid progression to AML while the t-AML secondary to topoisomerase II inhibitors have a short latency period (2). Due to the increased worldwide prevalence of chemotherapy survivors, the incidence of t-AML and t-MDS is also increasing (3). Apart from cytotoxic exposure, inherent risk factors for the development of t-AML and t-MDS include germline mutations like TP53, BRCA1, BRCA2, and NF1 (3, 4). High-risk abnormalities like del(5q), − 7/del(7q), and complex karyotypes are rampant in this population. Favorable risk abnormalities like t(8;21), inv t(16), and t(15;17) are underrepresented. Myeloablative conditioning (MAC) regimen and autologous hematopoietic stem cell transplantation (HCT) for primary cancer are also associated with the development of t-MDS/t-AML (5, 6).

Overall, t-AML/t-MDS has a grave prognosis with a reported survival of 10% at 5 years (7). Reported median survival with standard chemotherapy in therapy-related leukemia is 7–12 months (8, 9). Worse outcomes in t-AML/t-MDS patients can be explained by persistence of primary malignancy, prolonged cytopenia from prior therapy, prolonged immunosuppression, antibiotic-resistant polymicrobial colonization, refractoriness to transfusion, diminished tolerance to acute toxicity of treatment, and rapid emergence of resistance to chemotherapy owing to cytogenetics (10). Recently, the number of indications for allogeneic hematopoietic stem cell transplant (allo-HCT) has been increasing in hematologic malignancies and some non-malignant disorders even in patients with co-morbidities due to continuous refinements in this modality (11, 12). Allo-HCT is a potentially curative treatment option in t-AML and t-MDS patients as well (13).

Allo-HCT is not devoid of its limitations and many factors affect the transplant efficacy (11). Prior studies have reported the results of allo-HCT in t-AML and t-MDS patients based on underlying malignancy, patient characteristics, conditioning regimen, donor status, and graft versus host disease (GvHD) prophylaxis. This systematic review and meta-analysis aimed at reporting the outcomes of allo-HCT in t-AML and t-MDS patients including overall survival (OS) as the primary outcome, disease-free survival (DFS), and acute and graft versus host disease (GvHD) rates as secondary outcomes.

Data sources and search strategy

The literature search for this systematic review and meta-analysis was performed according to the guidelines outlined in Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)(14). Three electronic databases (PubMed, Cochrane Library, and ClinicalTrials.gov) were searched from the date of inception to June 1, 2024, using the MeSH terms and keywords for ‘hematopoietic stem cell transplantation’ AND ‘outcome assessment' AND ‘myelodysplastic syndrome’ OR ‘therapy related acute myeloid leukemia’ AND ‘therapy related neoplasm’. No filters or publication time limits were applied. Our literature research produced 1271 results. An additional 10 studies were identified through manual search. All 1281 search results were imported into the Endnote 20 reference manager, and duplicates were removed

Selection criteria

The shortlisted articles were screened independently by two authors. In primary screening, non-relevant articles were excluded based on their titles and abstracts. Full texts of the remaining 36 articles were then assessed for eligibility based on predetermined criteria, set after discussion and consensus between all authors, and approved by the principal investigator. Inclusion criteria were: (1) original studies (clinical trials, retrospective, and prospective cohort), (2) studies reporting data of patients with a median age of 18 years or above (3) studies reporting allo-HCT outcomes in patients with t-MDS and t-AML. Three studies were excluded from secondary screening based on the pediatric patient population. (Fig. 1)

Data extraction

Three authors independently extracted data from the 33 selected studies. Following individual data extraction, data sheets were double-checked for any discrepancies. The data were collected for baseline characteristics, including the number of evaluable patients, age, source of stem cells for primary graft, HCT conditioning regimen, efficacy, and safety, including OS, PFS, RR, NRM, and acute and chronic GvHD rates.

Risk of bias assessment and Quality evaluation

All included studies were treated as non-randomized trials. Therefore, the Risk of bias in cohort studies (JBI Critical Appraisal Checklist for cohort studies) tool was used for assessing the quality of studies (15). This tool assesses the methodological quality of cohort studies across 11 key domains. The checklist helps identify potential biases related to the selection of participants, classification of interventions/exposures, measurement of outcomes, and loss to follow-up. Based on this tool, all the included studies were rated as good and fair. (Supplementary Table 1)

Data analysis

To calculate the OS and DFS probabilities after allo-HCT in patients the survival data were retrieved from Kaplan-Meier curves via the online plot digitizer tool (16). The pooled Kaplan-Meier curves were plotted and analyzed using R software's “MetaSurvival” package (version 4.2.1) (17). Median OS and DFS were also calculated besides the survival probabilities. Moreover, we used STATA version 17.0 to calculate the pooled proportion of the acute GVHD prevalence with metaprop command (18, 19). The Q Cochrane test and I² statistic were applied to measure the heterogeneity across studies (20). The I² statistic was used to quantify the degree of heterogeneity between studies. The result of the Q test was considered statistically significant at 0.1. To assess the potential sources of heterogeneity in the results Galbraith plot and sensitivity analysis were carried out (21, 22). A p-value less than 0.05 was treated as statistically significant.

A total of 7785 patients from thirty-three studies(9, 13, 23–53) reporting the outcomes of allo-HCT in t-AML and t-MDS patients were included for analysis. (Table 1) (Table 2) The age of the patients ranged from 2 to 89 years and 61.7% were females (n = 4143/6710). A total of 67.3% (n = 5241) of the patients had t-AML and 26.5% (n = 2076)) had t-MDS while the remaining 6% had a mixed presentation (n = 468). The median time from prior treatment to development of t-MN was 158 (1-498) months and the median follow-up time was 80 (0-251) months. The underlying conditions were solid malignancies 47% (n = 3182/6760), hematologic malignancies 48% (n = 3346/6760), and other neoplasms/autoimmune diseases 3.4% (n = 232/6760). Chemotherapy alone 43% (1432/3338), chemotherapy plus radiotherapy 39% (n = 1316/3338), auto-HCT 11% (n = 370/3338), and radiotherapy alone 6% (n = 203/3338) were the reported treatment modalities for underlying malignancies. The donor type was matched unrelated (MUD) 35% (n = 1864/5334), matched related (MRD) 52% (n = 2375/5334671/4266), mismatched unrelated (MMUD) 16% (n = 745/5334), mismatched related (MMRD) 3% (n = 167/5334), and haploidentical (haplo) 2.8% (n = 153/5334). The source of stem cells was peripheral blood (PBSC) 64% (n = 3867/6034), bone marrow (BM) 26% (n = 1570/6034), and cord blood (CB) 9.7% (n = 588/6034).

When classified according to the cytogenetic risk, 12% of the patients (n = 709/5966) had favorable risk while 44% (n = 2618/5966) and 44% (n = 2639/5966) had intermediate and adverse risk cytogenetics, respectively. Myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) were given to 52% (n = 3203/6124) and 48% (n = 2921/6124) of the patients, respectively. Data were heterogeneous for GvHD prophylaxis. Calcineurin Inhibitor based regimen (CNI, cyclosporine or tacrolimus alone or in combination with other agents) was used in 72% (n = 28811/4028) of the patients, while T-cell depletion (TCD), Sirolimus, and Post-transplant cyclophosphamide (PTCy) was used in 5%(n = 218/4022), 1% (n = 50/4022) and 0.6% (n = 19/4022) patient, respectively. Other miscellaneous regimens constituted 21% (n = 855/4028).

The median pooled median OS for all patients was 16.9 months (95% CI: 13.7–21.1) and the estimated mean OS was 46.0 months (95% CI: 42.1–49.6) (9, 13, 23, 24, 27, 33–44, 46, 47, 49–51). The pooled OS for all patients was 71.5% (95% CI: 68.2–75.0) at 6 months, 56.3% (95% CI: 52.3–60.7) at 12 months, 39.1% (95% CI: 35.9–42.7) at 36 months, and 33.7% (95% CI: 30.1–37.1) at 60 months (Fig. 2A) (Fig. 5) (Table 3). The pooled median DFS for all patients was 8.8 months (95% CI: 7.4–11.2) and the estimated mean DFS was 37.8 months (95% CI: 33.4–41.9) (13, 24, 27, 33, 36–45, 47, 50, 51). The pooled DFS for all patients was 57.9 (95% CI: 54.1–61.9) at 6 months, 44.9% (95% CI: 41.2–48.9) at 12 months, 32.7% (95% CI: 29.4-) at 36 months, and 33.7% (95% CI: 30.7–37.1) at 60 months. (Fig. 2B) (Fig. 5) (Table 3).

A random effect meta-analysis of 16 studies reported the numbers of aGvHD during 90–100 days after HSCT, the pooled prevalence of aGvHD was 37% (95% CI: 0.30–0.45, I²: 91.71%, p < 0.0001, n = 1865/6371) (Fig. 8) (24, 28–30, 32, 35, 37, 38, 40, 41, 44, 46, 48, 50). A Galbraith plot demonstrated that no studies were outside the 95% CI, meaning they were not outliers (results not shown). In subclass analysis, a random effect meta-analysis of 3 studies in the t-AML group showed that the pooled prevalence of aGvHD was 34% (95% CI: 16% − 54%, n = 1365/5110).(44, 46, 48) For 3 studies in the t-MDS group, the pooled prevalence of aGvHD was 35% (95% CI: 27% − 43%, n = 46/132).(5, 24, 28, 35) Furthermore, in 10 studies in t-AML + t-MDS group, the pooled prevalence of aGvHD was 39% (95% CI: 28% − 50%, n = 454/1129) (Fig. 6). In sensitivity analysis, the elimination of any single study at a time from the meta-analysis ranged from 32% (95% CI: 26%-38%) to 39% (95% CI: 30%-48%) indicating the high robustness of the pooled prevalence estimates (29, 30, 32, 37, 38, 40, 41, 45, 50, 53). Nevill et al. reported the highest chronic GvHD incidence of 88% at 5 years, whereas Gatwood et al. reported the lowest, 21.6% at 3 years (45). Overall, Nabergoj et al. reported the lowest incidence of NRM, 22% at a 2-year follow-up (43).

The highest incidence of NRM was reported by Yakoub-Agha et al., 49% at 2-year follow-up (53). The lowest relapse rate was 17.9% at 2 years reported by Gatwood et al. whereas Maher et al. reported a relapse rate of 51% at 5-year follow-up which is the highest for the entire cohort (33, 40). Among the 47.2% (2860/6058) patients who died, relapse of the myeloid neoplasm was the most common cause of death 25.7% (n = 736), followed by infections 18.5% (n = 531), relapse of the underlying disease 18.1% (n = 518), and GvHD 10.7% (n = 307).

Two studies compared outcomes based on a conditioning regimen (33, 39). Lee et al reported that patients receiving RIC regimens had an increase in relapse incidence (HR:1.52; 95% CI: 1.02–2.26; p = 0.04), lower DFS (HR:1.52; 95% CI: 1.12–2.05, p = 0.007), and OS (HR, 1.51; CI 1.09–2.09; p = 0.012). There were no differences in NRM and GRFS for both groups (39). Gatwood et al. reported RIC regimens have a lower risk of NRM (HR: 0.58; 95% CI: 0.40–0.83, p = 0.00), and improved DFS (HR: 3.15; 95% CI: 1.35–7.37; p = 0.01), OS (HR: 0.69; 95% CI: 0.53–0.89, p = 0.004) compared to MAC group (33).

In subgroup analysis for t-AML patients, the pooled median OS was 16.1 (95% CI: 11.7–21.5) months and the pooled mean OS was 43.8 months (95% CI: 38.3–48.9).(13, 33, 36, 39, 40, 42, 44, 46, 47, 51) The pooled OS at 6, 12, 36, and 60-month were 72.1% (95% CI: 66.8–77.8), 55.3% (95% CI: 49.7–61.5), 37.2% (95% CI: 32.5–42.6), and 31.3% (95% CI: 26.7–36.6), respectively. (Fig. 3A) (Fig. 5) (Table 3) The pooled median DFS was 8.9 months (95% CI: 6.3–13.1) and the pooled mean DFS was 34.4 months (95% CI: 27.3–40.8).(13, 33, 39, 40, 42, 44, 47, 51) The pooled DFS at 6, 12, 36, and 60-month were 57.9% (95% CI: 51.3–65.5), 44.6% (95% CI: 38.0 -52.4), 31.6% (95% CI: 25.9–38.7), and 25.7% (95% CI: 20.3–32.6), respectively. (Fig. 3B) (Fig. 5) (Table 3)

In subgroup analysis for t-MDS patients, the pooled median OS was 15.5 months (95% CI: 10.4–25.8) and the mean OS was 44.9 (95% CI: 36.6–52.3) months.(13, 24, 34–36, 40, 42) The pooled OS at 6, 12, 36, and 60-month were 68.4% (95% CI: 63.4–73.9), 54.6% (95% CI: 47.3–63.0), 38.6% (95% CI: 32.4–45.9), and 33.3% (95% CI: 27.4–40.5) respectively (Fig. 3A) (Fig. 4) (Table 3). The pooled median DFS was 7.9 months (95% CI: 5.3–14.4) and the mean DFS was 35.5 months (95% CI: 24.5–47.6). (13, 24, 40, 42) The pooled DFS at 6, 12, 36, and 60-month were 55.2% (95% CI: 47.8–63.7), 43.3% (95% CI: 35.7–52.6), 30.6% (95% CI: 22.6–41.5), and 25.2% (95% CI: 16.6–38.4), respectively (Fig. 3B) (Fig. 4) (Table 3).

The common determinants adversely influencing OS in t-AML/t-MDS elucidated in literature are advanced age at allo-HCT, poor risk cytogenetics, disease not in clinical remission prior to transplant, and advanced stage of t-MDS. (13, 23, 34, 36, 38, 40, 41, 43, 50) Poor performance status and delay in HCT from t-AML/t-MDS diagnosis also affect negatively (36, 38, 43, 44, 50). In addition, Baranwal et al. described complex karyotype to be associated with inferior OS where other donor and transplant-related factors could not overcome its adverse impact (29). They demonstrated that pathogenic variants in TP53, BCOR, BCORl1, IDH1, or GATA2 genes predicted worse outcomes irrespective of cytogenetic status (29). The 5-year OS was reported to be 22% in a study by Litzow et al, by far the lowest in included studies (13). Compared to that, a study by Tang et al. comprising a younger patient population which was conducted in relatively recent years had a 3-year OS of 66% (51). The observed differences could be due to more high-risk patients in the Center for International Blood and Marrow Transplant Research (CIBMTR) study, older patient population, and non-consistent HCT practices across participating centers. Our pooled OS results are closer to studies done in recent years which could represent the advances in transplant and post-procedure supportive care and GvHD prophylaxis (41, 43). The use of chemotherapy and radiation before allo-HCT was associated with increased relapse and inferior OS in t-AML patients in a Japanese registry study (26).

Similar variables comprising old age, poor performance status, adverse cytogenetics, mismatched HLA status, two or more treatment modalities for primary malignancy, and transplant more than 6 months post-diagnosis affect NRM (27, 33, 40, 50). Higher treatment-related toxicity from repeated chemotherapy cycles could explain poor outcomes with delayed HCT (35). Consolidation therapy resulting in organ damage and repeated infections before transplant also escalates treatment-related mortality (TRM) (50). The European Bone Marrow Transplantation (EBMT) registry study from 1981 to 2006 illustrated improvement in survival per calendar year due to a reduction in NRM (38). Chang et al. also demonstrated decreasing NRM every year after allo-HCT in t-MDS/t-AML patients (30). Infections and GvHD remain a frequent cause of NRM in this analysis as narrated by previous investigators (23, 34, 35).

Most factors affecting OS also contribute to increased RR. Relapse incidence increases with age (13, 23, 38, 45). For patients undergoing allo-HCT, the RR was lower in patients with complete remission (13, 23, 33, 34, 38, 40, 43). Poor performance status and abnormal cytogenetics is associated with earlier relapse (13, 33, 38, 43). Kroger et al. proposed a risk score based on age, disease stage, and cytogenetics to predict overall outcomes including RR (38). Interestingly, Nevill et al. reported a higher RR in those without chronic GvHD which could be from the graft versus leukemia effect (45, 54).

Although the incidence of GVHD is declining with enhanced prophylaxis regimens, it still rests as an important predictor of survival (55). In a study by Nampoothiri et al., the use of cyclosporine-methotrexate (CsA–MTX) GVHD prophylaxis was the post-transplant factor predictive of poor outcome (44). CIMTBR study did not show any difference in outcome based on the type of GVHD prophylaxis (13). In a report by Salas et al., a combination of Anti-thymocyte globulin (ATG), post-transplant cyclophosphamide (PTCy), and CsA effectively reduced acute and chronic GVHD in all donor types (55). In a meta-analysis by Yang et al., ATG reduced the incidence and severity of GVHD in allo-HCT and reduced the use of immunosuppressants (56). In our pooled analysis, no definitive conclusions could be drawn about whether any particular prophylaxis regimen affects GVHD outcomes in allo-HCT for t-AML/t-MDS due to heterogeneity of baseline parameters. More literature reviews and studies are needed on this subject matter.

When tolerated based on age and performance status, MAC has superior OS and disease-free survival (DFS) outcomes in patients in complete remission before transplant (39, 57). Whereas RIC conditioning is suggested due to reduced TRM compared to MAC but has a higher relapse risk (42, 48). Lee et al. mentioned that the RIC cohort had increased RR, NRM, and RFS, whereas the MAC group had improved OS due to a reduced relapse rate (39). On the other hand, Gatwood et al reported better outcomes with RIC conditioning in t-AML owing to the reduced risk of TRM in this heavily pre-treated population (33). One EBMT registry study reported decreased relapse but higher with MAC, but no difference in OS, DFS, and GRFS were observed compared to RIC (48). In another study where the underlying primary was breast cancer, both MAC and RIC had significantly inferior DFS in the advanced stages of the disease (27). Therefore, the optimal conditioning regimen for t-MN patients remains unclear.

To our knowledge, this is the first systematic review and meta-analysis reporting the outcomes of allo-HCT in the largest reported pool of t-AML/t-MDS patients. Our analysis is limited by its pooled nature due to the heterogeneity of included studies and baseline characteristics of patients, retrospective data, lack of randomized trials, paucity of information on disease index, and missing complete molecular and genetic profiles for the cohort Since registry studies were included, there is a chance of overlap in the patient population in the included studies. Furthermore, comparative analysis was not done based on donor type and stem cell source. However, the study's robustness lies in sample size and inclusiveness.

Despite the grim prognosis of t-AML and t-MDS, allo-HCT is a potentially curative option. Timely transplants should be offered to carefully selected patients with good performance status to limit treatment toxicities. Further optimization of allo-HCT and pursuit of a potent and safe GvHD regimen would limit the complications, leading to overall better outcomes.

Competing Interests: The authors declare no competing financial interests.

Disclaimer: None

Acknowledgment

None

Author Contribution

MS was involved in conceptualization, supervision, writing of the original draft, and manuscript review. MKA was responsible for data curation, interpretation of results, manuscript writing, editing, and revision. MFK was responsible for the literature search, and data curation. AK and IMO curated data, performed statistical analysis, and generated Kaplan Meier curves. AB, AB, MZ, and IA curated data, and generated tables. MUM was responsible for reviewing and editing the final draft.

Data Availability Statement

All data extracted and analyzed is presented in the manuscript. For additional information, please reach out to the corresponding author.

Singh ZN, Huo D, Anastasi J, Smith SM, Karrison T, Le Beau MM, et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007;127(2):197-205.
McNerney ME, Godley LA, Le Beau MM. Therapy-related myeloid neoplasms: when genetics and environment collide. Nat Rev Cancer. 2017;17(9):513-27.
Choi G, Huang B, Pinarbasi E, Braunstein SE, Horvai AE, Kogan S, et al. Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms. Cancer Res. 2012;72(24):6425-34.
Schulz E, Valentin A, Ulz P, Beham-Schmid C, Lind K, Rupp V, et al. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. J Med Genet. 2012;49(7):422-8.
Pedersen-Bjergaard J, Andersen MK, Christiansen DH. Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood. 2000;95(11):3273-9.
Vaxman I, Ram R, Gafter-Gvili A, Vidal L, Yeshurun M, Lahav M, Shpilberg O. Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis. Bone Marrow Transplant. 2015;50(5):706-14.
Fianchi L, Pagano L, Piciocchi A, Candoni A, Gaidano G, Breccia M, et al. Characteristics and outcome of therapy-related myeloid neoplasms: Report from the Italian network on secondary leukemias. Am J Hematol. 2015;90(5):E80-5.
Claerhout H, Lierman E, Michaux L, Verhoef G, Boeckx N. A monocentric retrospective study of 138 therapy-related myeloid neoplasms. Ann Hematol. 2018;97(12):2319-24.
Eichenauer DA, Thielen I, Haverkamp H, Franklin J, Behringer K, Halbsguth T, et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2014;123(11):1658-64.
Larson RA. Therapy-related myeloid neoplasms. Haematologica. 2009;94(4):454-9.
Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50(8):1037-56.
McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, et al. Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003-2007 Versus 2013-2017 Cohorts. Ann Intern Med. 2020;172(4):229-39.
Litzow MR, Tarima S, Pérez WS, Bolwell BJ, Cairo MS, Camitta BM, et al. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood. 2010;115(9):1850-7.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Bmj. 2009;339:b2700.
Moola SZCEKRE, Munn, Z., Tufanaru, C., Aromataris, E., Sears, K., Sfetcu, R., Currie, M., Qureshi, R., Mattis, P., Lisy, K. and Mu, P.F.,. Systematic reviews of etiology and risk. In Joanna Briggs Institute reviewer’s manual (Vol. 5, pp. 217-69) Adelaide, Australia: The Joanna Briggs Institute; 2017 [Available from: https://reviewersmanual.joannabriggs.org/.
Web Plot Digitizer [Available from: https://apps.automeris.io/wpd/.
P. S. MetaSurvival: Meta-analysis of a single survival curve using the multivariate methodology of DerSimonian and Laird. R package version 0.1.0 (2022). [Available from: https://github.com/shubhrampandey/metaSurvival.
StataCorp. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC (2021) [
Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health. 2014;72(1):39.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.
Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med. 1988;7(8):889-94.
Tobías A. Assessing the influence of a single study in the meta-anyalysis estimate. Stata Technical Bulletin. 1999;8.
Alam N, Atenafu EG, Kuruvilla J, Uhm J, Lipton JH, Messner HA, et al. Outcomes of patients with therapy-related AML/myelodysplastic syndrome (t-AML/MDS) following hematopoietic cell transplantation. Bone Marrow Transplant. 2015;50(9):1180-6.
Aldoss I, Pham A, Li SM, Gendzekhadze K, Afkhami M, Telatar M, et al. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status. Haematologica. 2017;102(12):2030-8.
Anderson JE, Gooley TA, Schoch G, Anasetti C, Bensinger WI, Clift RA, et al. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 1997;89(7):2578-85.
Araie H, Arai Y, Kida M, Aoki J, Uchida N, Doki N, et al. Poor outcome of allogeneic transplantation for therapy-related acute myeloid leukemia induced by prior chemoradiotherapy. Ann Hematol. 2023;102(10):2879-93.
Armand P, Kim HT, Mayer E, Cutler CS, Ho VT, Koreth J, et al. Outcome of allo-SCT for women with MDS or AML occurring after breast cancer therapy. Bone Marrow Transplant. 2010;45(11):1611-7.
Ballen KK, Gilliland DG, Guinan EC, Hsieh CC, Parsons SK, Rimm IJ, et al. Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasia. Bone Marrow Transplant. 1997;20(9):737-43.
Baranwal A, Chhetri R, Yeung D, Clark M, Shah S, Litzow MR, et al. Factors predicting survival following alloSCT in patients with therapy-related AML and MDS: a multicenter study. Bone Marrow Transplant. 2023;58(7):769-76.
Chang C, Storer BE, Scott BL, Bryant EM, Shulman HM, Flowers ME, et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood. 2007;110(4):1379-87.
De Witte T, Hermans J, Vossen J, Bacigalupo A, Meloni G, Jacobsen N, et al. Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). British Journal of Haematology. 2000;110(3):620-30.
Finke J, Schmoor C, Bertz H, Marks R, Wäsch R, Zeiser R, Hackanson B. Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2016;51(6):771-7.
Gatwood KS, Labopin M, Savani BN, Finke J, Socie G, Beelen D, et al. Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study. Bone Marrow Transplant. 2020;55(1):224-32.
Itonaga H, Kida M, Hamamura A, Uchida N, Ozawa Y, Fukuda T, et al. Outcome of therapy-related myelodysplastic syndrome and oligoblastic acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A propensity score matched analysis. Hematol Oncol. 2022;40(4):752-62.
Jaimes-Albornoz D, Mannone L, Nguyen-Quoc S, Chalandon Y, Chevallier P, Mohty M, et al. Allogeneic Stem Cell Transplantation in Therapy-Related Myelodysplasia after Autologous Transplantation for Lymphoma: A Retrospective Study of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25(12):2366-74.
Kida M, Usuki K, Uchida N, Fukuda T, Katayama Y, Kondo T, et al. Outcome and Risk Factors for Therapy-Related Myeloid Neoplasms Treated with Allogeneic Stem Cell Transplantation in Japan. Biol Blood Marrow Transplant. 2020;26(8):1543-51.
Kobos R, Steinherz PG, Kernan NA, Prockop SE, Scaradavou A, Small TN, et al. Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant. 2012;18(3):473-80.
Kröger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D, et al. Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation. Haematologica. 2009;94(4):542-9.
Lee CJ, Labopin M, Beelen D, Finke J, Blaise D, Ganser A, et al. Comparative outcomes of myeloablative and reduced-intensity conditioning allogeneic hematopoietic cell transplantation for therapy-related acute myeloid leukemia with prior solid tumor: A report from the acute leukemia working party of the European society for blood and bone marrow transplantation. Am J Hematol. 2019;94(4):431-8.
Maher OM, Silva JG, Wu J, Liu D, Cooper LJ, Tarek N, et al. Outcomes of children, adolescents, and young adults following allogeneic stem cell transplantation for secondary acute myeloid leukemia and myelodysplastic syndromes-The MD Anderson Cancer Center experience. Pediatr Transplant. 2017;21(3).
Metafuni E, Chiusolo P, Laurenti L, Sorà F, Giammarco S, Bacigalupo A, et al. Allogeneic Hematopoietic Stem Cell Transplantation In Therapy-Related Myeloid Neoplasms (t-MN) of the Adult: Monocentric Observational Study and Review of the Literature. Mediterr J Hematol Infect Dis. 2018;10(1):e2018005.
Metheny L, Callander NS, Hall AC, Zhang MJ, Bo-Subait K, Wang HL, et al. Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults. Transplant Cell Ther. 2021;27(11):923.e1-.e12.
Nabergoj M, Mauff K, Beelen D, Ganser A, Kröger N, Stölzel F, et al. Allogeneic hematopoietic cell transplantation in patients with therapy-related myeloid neoplasm after breast cancer: a study of the Chronic Malignancies Working Party of the EBMT. Bone Marrow Transplant. 2022;57(7):1072-8.
Nampoothiri RV, Law AD, Lam W, Chen C, Al-Shaibani Z, Loach D, et al. Predictors of Outcomes of Therapy-Related Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation. Hematol Oncol Stem Cell Ther. 2022;15(1):27-35.
Nevill TJ, Hogge DE, Toze CL, Nantel SH, Power MM, Abou Mourad YR, et al. Predictors of outcome following myeloablative allo-SCT for therapy-related myelodysplastic syndrome and AML. Bone Marrow Transplant. 2008;42(10):659-66.
Nilsson C, Hulegårdh E, Garelius H, Möllgård L, Brune M, Wahlin A, et al. Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting. Biol Blood Marrow Transplant. 2019;25(9):1770-8.
Qi HZ, Xu N, Xu J, Dai M, Liu H, Yu GP, et al. Allogeneic hematopoietic stem cell transplantation overcomes the poor prognosis in MLL-rearranged solid tumor therapy related-acute myeloid leukemia. Am J Cancer Res. 2021;11(4):1683-96.
Sengsayadeth S, Labopin M, Boumendil A, Finke J, Ganser A, Stelljes M, et al. Transplant Outcomes for Secondary Acute Myeloid Leukemia: Acute Leukemia Working Party of the European Society for Blood and Bone Marrow Transplantation Study. Biol Blood Marrow Transplant. 2018;24(7):1406-14.
Sevcikova K, Zhuang Z, Garcia-Manero G, Alvarez RH, Kantarjian HM, Mego M, et al. Comprehensive analysis of factors impacting risks and outcomes of therapy-related myeloid neoplasms following breast cancer treatment. Leukemia. 2016;30(1):242-7.
Spina F, Alessandrino PE, Milani R, Bonifazi F, Bernardi M, Luksch R, et al. Allogeneic stem cell transplantation in therapy-related acute myeloid leukemia and myelodysplastic syndromes: impact of patient characteristics and timing of transplant. Leuk Lymphoma. 2012;53(1):96-102.
Tang FF, Huang XJ, Zhang XH, Chen H, Chen YH, Han W, et al. Allogeneic hematopoietic cell transplantation for adult patients with treatment-related acute myeloid leukemia during first remission: Comparable to de novo acute myeloid leukemia. Leuk Res. 2016;47:8-15.
Witherspoon RP, Deeg HJ, Storer B, Anasetti C, Storb R, Appelbaum FR. Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol. 2001;19(8):2134-41.
Yakoub-Agha I, de La Salmonière P, Ribaud P, Sutton L, Wattel E, Kuentz M, et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol. 2000;18(5):963-71.
Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, et al. Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012;47(11):1474-8.
Salas MQ, Prem S, Atenafu EG, Datt Law A, Lam W, Al-Shaibani Z, et al. Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD. Bone Marrow Transplantation. 2020;55(9):1773-83.
Yang X, Li D, Xie Y. Anti-Thymocyte Globulin Prophylaxis in Patients With Hematological Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: An Updated Meta-Analysis. Frontiers in Oncology. 2021;11.
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.

Table 1 is available in the Supplementary Files section.

Table 2: Outcomes of patients with t-MN receiving allogeneic hematopoietic stem cell transplant (n=7785)

Author (year)

type of t-MN (t-AML/t-MDS)

Median follow-up, months (range)

Time to transplant (months)

Overall-survival, (%)

Relapse Incidence,

(%)

TRM/NRM Incidence,

at year

PFS,

at year

RFS,

at year

Acute GvHD Incidence, (%)

Acute GvHD number (total sample size),

Chronic GvHD Incidence at time, (%)

Itonaga et al., 2022

t-MDS

41 (1.1-196)

NA

40

at 3

32.8

at 3

30.9

at 3

NA

Nabergoj et al., 2022

t-AML+

t-MDS

20 (IQR: 5-60)

55 (IQR:34-96)

50

at 2

33

at 2

22

at 2

NA

45

at 2

28

NA

41

at 2y

Nampoothiri et al., 2022

t-AML

21 (range NA)

6 (2-22)

49.3

at 2

17.9

at 2

34.5

at 2

NA

47.6

at 2

NA

39 (68)

NA

Metheny et al., 2021

t-MDS

53 (3-170)

NA

27

at 5

46

at 5

34

at 5

NA

19

at 5

NA

t-AML

74 (3-193)

NA

25

at 5

43

at 5

34

at 5

NA

23

at 5

II-IV: 37

III-IV: 17

NA

41

at 5y

Sevcokova et al., 2015

t-AML + t-MDS

t-AML 15 (0.4-148);
t-MDS 16 (1 -75)

NA

Qi et al., 2021

MLL

18 (5-60)

NA

64.3

at 3

25.0

at 3

NA

60.0

at 3

NA

Non MLL

18M (5-60)

NA

52.7

at 3

47.4

at 3

NA

48.8

at 3

NA

Kida et al., 2020

t-MN

NA

31

at 3

40

at 3

33

at 3

NA

27

at 3

NA

Gatwood et al., 2019

t-AML

MAC: 23.8 (IQR: 5.8-71.6)

RIC: 29.2 (IQR: 11.9-63.6)

MAC: 4.7 (IQR: 3.4-6.4)

RIC: 4.7 (IQR: 3.5-6.5)

37.4

at 2

39.1

at 2

28.9

at 2

NA

31.7

at 2

II-IV: 30.6

III-IV: 13.7

NA

Any: 27

at 2y

Extensive: 12.8

at 2y

Jaimes-Albornoz et al., 2019

t-MDS

22 (0.7-107)

8 (3 - 17)

30

at 3

41

at 3

44

at 3

NA

13 (47)

NA

Nilsson et al., 2019

t-AML

95 (IQR: 48-147)

NA

25

at 5

NA

9 (45)

NA

Metafuni et al., 2018

t-AML + t-MDS

48 (3-195)

10 (2-36)

40.5

at 2

29.6

at 2

44.4

at 2

NA

72.2

at 2

NA

12 (30)

NA

Lee et al., 2018

t-AML

44 (2-182)

5 (0.3-65)

40.4

at 5

37.7

at 5

25.6

at 5

NA

36.5

at 5

NA

38.7

at 5

Maher et al., 2017

t-AML + t-MDS

62 (0.4-251)

41. (1.2-27.2)

36

at 5

51

at 5

NA

30

at 5

NA

19 (32)

33

at 2y

Aldos et al., 2017

t-MDS

57.6 (6-189.6)

NA

49.9

at 5

22.6

at 5

30.2

at 5

NA

47.2

at 5

II-IV: 38.8

26 (67)

NA

Tang et al., 2016

t-AML

40 (6-125)

5.5 (3-23)

66

at 3

20

at 3

3

at 3

64

at 3

NA

II-IV: 41

NA

60

at 2y

Alam et al., 2015

t-AML/t-MDS

72 (16-204)

NA

34

at 2

<60y: 30 at 2

⩾60y: 36 at 2

31

at 2

NA

Eichenauer et al., 2014

t-AML/MDS

72

NA

Kobos et al., 2012

t-MDS/t-AML

71 (26-188)

NA

61.1

at 5

19

NA

61.1

at 5

NA

4 (21)

NA

Spina et al., 2012

t-AML + t-MDS

44 (2-97)

5 (1-25)

37

at 2

33

at 2

32

at 2

NA

34

at 2

NA

9 (29)

NA

Armand et al., 2010

t-AML + t-MDS

36 (13-94)

NA

41

at 3

38

at 3

17

at 3

45

at 3

NA

II-IV: 30

III-IV: 9

NA

54

at 2y

Kroger et al., 2009

t-AML + t-MDS

21 (1-177)

6 (1-278)

35

at 3

31

at 3

37

at 3

NA

33

at 3

NA

138 (461)

NA

Litzow et al., 2009

t-AML + t-MDS

61 (3-187)

NA

22

at 5

31

at 5

48

at 5

21

at 5

NA

39

NA

30

at 5y

Nevill et al., 2008

t-AML + t-MDS

54 (12-161)

3 (1–31)

NA

39

at 5

30

at 5

30

at 5

NA

43

10 (24)

88

at 5y

Anderson et al.,1997

t-AML

60

9 (1-57)

NA

31.3

at 5

44.3

at 5

NA

24.4

at 5

NA

Araie et al., 2023

t-AML

40.8 (1–120)

NA

37.5

at 3

35.2

at 3

28.6

at 3

NA

II-IV: 30.6

III-IV: 9.1

NA

21.6

at 3

Ballen et al.,1997

t-MDS

36 (12-168)

NA

24

at 3

NA

7 (18)

NA

Baranwal et al.,2023

t-AML + t-MDS

5.55 (0.5-27)

NA

33.9 at 5 (t-MDS)

32.3 at 5 (t-AML)

45.1 at 5 (t-MDS)

34.9 at 5 (t-AML)

22.7 at 5 (t-MDS)

35.7 at 5 (t-AML)

NA

51 (134)

NA

Witte et al.,2000

t-AML + t-MDS

NA

35 at 3

36 at 3

46 at 3

NA

35 at 3

NA

Chang et al.,2007

MDS/tAML

NA

33 at 5

NA

29 at 5

NA

165 (249)

NA

Finke et al.,2016

t-AML + t-MDS

90 (0.84-228)

NA

24 at 10

44 at 10

32 at 10

NA

24 at 10

NA

20 (79)

NA

Sengsayadeth et al.,2018

t-AML

27 (IQR: 7.35 - 60.63)

4.62 (IQR: 3.18-6.89)

44.5 at 2

33.7 at 2

27.5 at 2

NA

38.8 at 2

NA

1317 (4997)

33.5 at 2

Witherspoon et al.,2001

t-AML

NA

32 at 5

53 at 5

NA

16 at 5

NA

Yakoub-Agha et al.,2000

t-AML + t-MDS

94.8 (13.2 – 225.6)

5.7 (1.3 – 75.1)

30 at 2

42 at 2

49 at 2

NA

28 at 2

NA

26 (70)

NA

Abbreviations: TRM: Treatment-related mortality, NRM: Non-relapse mortality, y: Year, n: number of patients, PFS: progression-free survival, RFS: relapse-free survival, GVHD: Graft vs host disease, NA: Not Available, MAC: Myeloablative conditioning, RIC: Reduced-intensity conditioning, MLL: Mixed-lineage leukemia

Table 3: Pooled results of OS and DFS in t-MN patients receiving allogeneic hematopoietic stem cell transplant

	t-AML patients		t-MDS patients		All patients
	OS	DFS	OS	DFS	OS	DFS
Pooled 1 month (95% CI), %	95.8 (94.0 – 97.7)	93.3 (90.7 – 96.1)	94.2 (91.7 – 96.6)	90.9 (87.7 – 94.1)	95.6 (94.5 - 96.6)	93.3 (91.4 – 95.2)
Pooled 3 months (95% CI), %	85.4 (81.5 – 89.5)	76.0 (70.1 – 82.5)	82.0 (77.8 – 86.4)	73.2 (66.6 – 80.6)	84.3 (81.8 - 86.8)	76.4 (73.2 – 79.8)
Pooled 6 months (95% CI), %	72.1 (66.8 – 77.8)	57.9 (51.3 – 65.5)	68.4 (63.4 – 73.9)	55.2 (47.8 – 63.7)	71.5 (68.2 – 75.0)	57.9 (54.1 – 61.9)
Pooled 12 months (95% CI), %	55.3 (49.7 – 61.5)	44.6 (38.0 – 52.4)	54.6 (47.3 – 63.0)	43.3 (35.7 – 52.6)	56.3 (52.3 – 60.7)	44.9 (41.2 – 48.9)
Pooled 18 months (95% CI), %	47.6 (42.4 – 53.5)	38.6 (32.2 – 46.3)	47.4 (40.3 – 55.7)	38.8 (30.9 – 48.8)	48.8 (45.1 – 52.9)	40.4 (36.6 – 44.4)
Pooled 24 months (95% CI), %	42.7 (37.8 – 48.3)	35.2 (29.2 – 42.5)	44.2 (37.6 – 51.9)	36.4 (28.8 – 46.0)	44.6 (41.1 – 48.4)	37.0 (33.3 – 41.1)
Pooled 36 months (95% CI), %	37.2 (32.5 – 42.6)	31.6 (25.9 – 38.7)	38.6 (32.4 – 45.9)	30.6 (22.6 – 41.5)	39.1 (35.9 – 42.7)	32.7 (29.4 – 36.6)
Pooled 48 months (95% CI), %	33.4 (28.7 – 40.0)	27.4 (21.9 – 34.4)	35.6 (29.7 – 42.7)	27.6 (19.4 – 39.3)	35.9 (32.7 – 39.4)	29.6 (26.3 – 33.3)
Pooled 60 months (95% CI), %	31.3 (26.7 – 36.6)	25.7 (20.3 – 32.6)	33.3 (27.4 – 40.5)	25.2 (16.6 – 38.4)	33.7 (30.7 – 37.1)	27.9 (24.5 – 31.7)
CI: confidence intervals, OS: overall survival, DFS: Disease-free survival

The authors have declared there is NO conflict of interest to disclose.

Outcomes with Allogeneic Hematopoietic Stem Cell Transplantation in Therapy Related Myeloid Neoplasms: A Systematic Review and Meta-Analysis

Status:

Version 1

Abstract

Figures

Introduction

Methods

Data sources and search strategy

Selection criteria

Data extraction

Risk of bias assessment and Quality evaluation

Data analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1