The Changing Landscape of Treatment in Acute Myeloid Leukemia

Koenig, Kristin; Mims, Alice S.; Levis, Mark J.; Horowitz, Mary M.

doi:10.1200/edbk_279129

Cited by 13 publications

(15 citation statements)

References 54 publications

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“… 9 As relapse is not the primary cause of death in patients with MDS undergoing alloHCT, the choice of conditioning intensity is currently dependent on the estimated ability of a patient to tolerate transplant-related toxicity. 26 AlloHCT remains the only curative therapy for MDS; however, given the median age at diagnosis, many patients will not be eligible for myeloablative approaches. 27 , 28 As it is now possible to determine the genomic basis of disease before and after transplantation, personalized approaches for alloHCT of patients with MDS are now conceivable with targeted strategies for those with detectable TP53 , RAS pathway (including FLT3 ), IDH and JAK2 mutations, immune augmentation, or other therapies potentially able to supplement the impact of chosen conditioning intensity to minimize relapse risk.…”

Section: Discussionmentioning

confidence: 99%

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Dillon

Gui

Logan

et al. 2021

JCO Precision Oncology

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PURPOSE Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.

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Section: Discussionmentioning

confidence: 99%

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Dillon

Gui

Logan

et al. 2021

JCO Precision Oncology

View full text Add to dashboard Cite

show abstract

“…9 As relapse is not the primary cause of death in MDS patients undergoing alloHCT the choice of conditioning intensity is currently dependent on the estimated ability of a patient to tolerate transplant-related toxicity. 25 AlloHCT remains the only curative therapy for MDS, however given the median age at diagnosis many patients will not be eligible for myeloablative approaches. 26,27 As it is now possible to determine the genomic basis of disease before and after transplantation, personalized approaches for alloHCT of MDS patients are now conceivable with targeted strategies for those with detectable TP53 , RAS-pathway (including FLT3), IDH and JAK2 mutations, immune augmentation or other therapies potentially able to supplement the impact of chosen conditioning intensity to minimize relapse risk.…”

Section: Discussionmentioning

confidence: 99%

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Dillon

Gui

Logan

et al. 2020

Preprint

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Myelodysplastic Syndrome (MDS) patients are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). The utility of ultra-deep genomic testing to predict, and the impact of conditioning intensity to prevent, MDS relapse are unknown. Targeted error-corrected DNA sequencing was performed on pre-conditioning blood samples from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901 phase III randomized clinical trial which compared outcomes by alloHCT conditioning intensity in adult patients with less than 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pre-transplant assessment. Using a previously described set of 10 gene regions, 42% of patients had mutations detectable prior to randomization to reduced intensity or myeloablative conditioning. Testing positive was associated with increased rates of relapse and decreased overall survival. In those testing positive, relapse rates were higher and relapse-free survival was lower in reduced intensity versus myeloablative conditioning arms. Testing additional genes, including those associated with MDS, did not improve prognostication. This study provides evidence that post-transplant relapse rates in MDS patients are highest in those with pre-transplant genomic evidence of high-risk disease. In those testing positive, randomization to myeloablative conditioning lowered but did not eliminate relapse risk.

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“…Probability result from differences in the biology of the leukemic blasts in older versus younger patients, or a combination of these factors [29,31], also has shown that elderly patients that show karyotype anomalies, especially those in the high-risk category, do not benefit from intensive chemotherapy [32,33]. us, the SC : daunorubicin combination seems to overcome the difficulties of two classic antineoplastics against AML, one of the most common types of leukemia in adults according to the American Society of Clinical Oncology [34]. e mechanism of protection and action of SC : daunorubicin is not known but it is known that an alternative treatment for AML, known as CAG, consists of a lowdose regimen of cytarabine, aclarubicin, and G-CSF [21].…”

Section: Journal Of Oncologymentioning

confidence: 99%

Improved Survival of Leukemic Mice Treated with Sodium Caseinate in Combination with Daunorubicin without Toxicity

Aguíñiga-Sánchez

Meléndez-Ibarra

Ledesma‐Martínez

et al. 2021

Journal of Oncology

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In recent years, low doses of chemotherapy have been resumed and explored for the treatment of acute myeloid leukemia. Thus, CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was approved by the US Food and Drug Administration, to deliver a synergistic 5 : 1 molar drug ratio into leukemia cells to a greater extent than normal bone marrow cells and significantly enhance survival compared with conventional treatment in older and newly diagnosed AML patients, but overall survival rate remains low; therefore, the need for new therapeutic options continues. Sodium caseinate (SC), a salt of casein, the main milk protein, has cytotoxic effect in leukemia cell lines, but promotes proliferation of hematopoietic normal cells, while its administration in leukemic mice promotes survival for more than 40 days, but bone marrow surviving mice still harbour leukemic cells, but it is not known whether the combination with cytarabine or daunorubicin can improve survival without damaging normal hematopoietic cells. Here, it is shown that, in vitro, the combination of the IC25 of SC-cytarabine or SC-daunorubicin synergizes in the elimination of leukemic cells, with evident induction of apoptosis, while the proliferation of mononuclear cells of bone marrow is not affected. In leukemic mice, the combined administration of SC-daunorubicin or SC-cytarabine promotes the highest survival rate at 40 days; in addition, no autoproliferating cells were detected in the bone marrow of survivors of more than 60 days, evidence of eradication of leukemic cells, but only the bone marrow of mice treated with the SC-daunorubicin combination proliferated in the presence of interleukin-3, which shows that this combination is not toxic to normal bone marrow cells, thus emerging as a possible antileukemic agent.

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The Changing Landscape of Treatment in Acute Myeloid Leukemia

Cited by 13 publications

References 54 publications

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Improved Survival of Leukemic Mice Treated with Sodium Caseinate in Combination with Daunorubicin without Toxicity

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