Low‐dose azacitidine for relapse prevention after allogeneic hematopoietic cell transplantation in children with myeloid malignancies

Oshrine, Benjamin; Shyr, David C.; Hale, Gregory A.; Petrović, Aleksandra

doi:10.1111/petr.13423

Cited by 9 publications

(5 citation statements)

References 27 publications

(58 reference statements)

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“…Small retrospective analyses suggest improved outcomes in patients who receive post-HCT hypomethylating agents with or without additional interventions such as donor lymphocyte infusion (DLI). (29)(30)(31) Our center has adopted a strategy of reducing blast burden to < 5% pre-HCT in patients with lower intensity approaches including HMAs, as well as pursuing post-HCT HMA therapy for relapse prevention.…”

Section: Discussionmentioning

confidence: 99%

Disease burden at time of transplant is a primary predictor of outcomes in pediatric MDS: A single center experience

Bleakley

Dahlberg

Stevenson

et al. 2023

Preprint

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Hematopoietic cell transplantation (HCT) remains the only curative therapy for pediatric myelodysplastic syndrome (MDS) in all but rare cases. While HCT outcomes for pediatric MDS are similar across the largest registry and single center trials, factors identified as contributing to inferior outcomes vary from study to study. We performed an analysis to provide more clarity on the prognostic implications of disease characteristics including blast burden and cytogenetic abnormalities in the current era. We conducted a retrospective analysis of 36 consecutive children (<18 years of age at HCT) who underwent allogeneic HCT for MDS between June 2000 and October 2019 at the Fred Hutchinson Cancer Center. Overall survival (OS) was 77% (95% CI 64-92%) and Relapse-free survival (RFS) was 71% (95% CI 57-88%) at 2-years post-HCT. Patients with < 5% blasts by morphology in the bone marrow at time of HCT showed superior 2-year OS at 87% (95% CI 74-100%) as compared to 54% (95% CI 32-93%) in patients with ≥5% blasts, consistent with an HR of 4.6 (CI 1.14-18.7, p=0.03). The inferior outcomes in patients with ≥ 5% blasts were due to increased relapse incidence (HR 7.6, CI 1.5-39.3) with no difference in NRM or acute GVHD. OS and RFS were comparable to what has been observed in other large, single center studies (OS 77%, RFS 71% at 2 years) and compared favorably to outcomes from the largest multi-center retrospective analyses. The primary disease factors that correlated with inferior OS and/or RFS and relapse were higher disease burden at time of HCT and administration of chemotherapy pre-HCT.

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Section: Discussionmentioning

confidence: 99%

Disease burden at time of transplant is a primary predictor of outcomes in pediatric MDS: A single center experience

Bleakley

Dahlberg

Stevenson

et al. 2023

Preprint

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“…Moreover, there was some heterogeneity in our population, in terms of donor/stem cell sources, GVHD prophylaxis, and age/gender. In addition, the duration of the study period (10 years) was prolonged, with a shift in institutional preferences for donor (eg, umbilical cord blood vs haplo/PTCy), as well as adoption of the practice of employing post‐transplant azacitidine maintenance for relapse prevention toward the end of the study period . While the latter was controlled for in the multivariate analysis, confounding may still be present.…”

Section: Discussionmentioning

confidence: 99%

“…Supportive care with antimicrobial prophylaxis and viral reactivation surveillance was based on institutional standards of care. A subset of patients transplanted after February 2015 received post‐transplant azacitidine maintenance for relapse prevention starting as early as d + 42 for up to nine cycles …”

Section: Methodsmentioning

confidence: 99%

Comparison of melphalan‐ And busulfan‐based myeloablative conditioning in children undergoing allogeneic transplantation for acute myeloid leukemia or myelodysplasia

Oshrine

Adams

Nguyen

et al. 2020

Pediatric Transplantation

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Background:The optimal conditioning regimen for alloHCT in children with myeloid malignancies remains undefined. Procedure:We performed a retrospective review of children undergoing alloHCT for AML and MDS over a 10-year period (2008-2018) at our institution, comparing the outcomes of recipients of either a myeloablative busulfan-or reduced toxicity mel/ thio-based conditioning regimen.Results: A total of 49 patients underwent alloHCT for AML/MDS (mel/thio, N = 21; busulfan, N = 28). Mel/thio recipients were selected due to pretransplant comorbidities. Recipients of mel/thio were more likely to have t-AML, and less likely to have MRD <0.1% at the time of alloHCT (57.1% vs 82.1%). Graft failure was more common in busulfan recipients; engraftment kinetics were similar between groups. Sinusoidal obstructive syndrome was diagnosed in 21% of busulfan and no mel/thio recipients (P = .03). One patient in each group died from TRM. Relapse incidence was comparable (mel/thio-29% vs busulfan-32%); however, relapse occurred significantly later in recipients of mel/thio conditioning (median d + 396 vs d + 137; P = .01). As a result, there was a trend toward improved OS at 1 and 3 years in mel/thio recipients (95% vs 74%, P = .06; and 75% vs 50%, P = .11; respectively). Conclusion:In our single institution, when compared to myeloablative busulfanbased conditioning, use of a mel/thio-based reduced toxicity regimen resulted in comparable outcomes, despite higher risk patient and disease characteristics. Mel/ thio recipients had both more comorbidities and higher risk disease profile, which did not translate into higher rates of either TRM or relapse. K E Y W O R D Sacute myeloid leukemia, hematopoietic cell transplantation, myelodysplastic syndrome, pediatric, reduced toxicity conditioning

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“…26 Unfortunately, this study extension to a phase III randomized controlled trial (RCT), failed to show significant differences for OS and DFS between Aza and control groups (p = .85 and p= .14), respectively. 27 However, pediatric case series [28][29] reported low incidence of relapse with prophylactic low-dose Aza (32 to 36 mg/m 2 ) as maintenance post-HCT. Despite the limitations of small numbers, a potential benefit in disease control of this approach warrants further investigation.…”

Section: Dna Hypomethylating Agents (Hmas) Post-hctmentioning

confidence: 99%

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

Tavares

Pelegrina²

2021

jbmtct

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The best way to manage acute leukemia relapse after HCT is to prevent it, buying time for GVL with immunomodulation and, if no GVHD between days +60 and + 90, prophylactic DLI can be indicate for very high or high risk patients. Short-term low dose of cyclosporine or methotrexate can add safety to pro-DLI, particularly after mismatched or unrelated transplantation. Maintenance with imatinib or dastinib, recommended for Ph-positive ALL, with sorafenib, for FLT3-ITD AML, or azacitidine, for myelodysplastic syndrome patients, can be effective in reducing relapse rates. However, target agent maintenance can add toxicity, depends on patient adherence and demands physician experience to know when is safe to start, how adjust the dose according individual tolerance after transplant and to detect undesirable drug interactions. The second step to avoid hematological relapse is preemptive approach guided by measurable residual disease or mixed chimerism. In patients off immunosuppression, chemotherapy followed by DLI is a useful strategy, and if no response, interferon alpha can be associated to enhance GVL. Target-specific agents can be start at this point either. After relapse, antigen-directed therapy with blinatumumab for CD19 ALL, inotuzumab for CD22 ALL are excellent options to induce MRD negativity and facilitate HCT. Disadvantages of new immunotherapies are: high incidence of VOD with inotuzumab and gemtuzumab; lower response in patients with high leukemia burden or concurrent extramedullary relapse; necessity of consolidation with HCT after a bridging therapy with BiTE and probably with CAR-T cell therapy also. It is important to realize that if remission after chemotherapy is associated with the development of GVHD, then there may be limited benefit (and possibly harm) in consolidating with any kind of cellular therapy. However, for patients who achieved remission without GVHD, either DLI or second transplant can be recommend. Further studies are necessary to determine at which point each strategy might yield the best results.

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Low‐dose azacitidine for relapse prevention after allogeneic hematopoietic cell transplantation in children with myeloid malignancies

Cited by 9 publications

References 27 publications

Disease burden at time of transplant is a primary predictor of outcomes in pediatric MDS: A single center experience

Disease burden at time of transplant is a primary predictor of outcomes in pediatric MDS: A single center experience

Comparison of melphalan‐ And busulfan‐based myeloablative conditioning in children undergoing allogeneic transplantation for acute myeloid leukemia or myelodysplasia

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

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