Inclusion Criteria:  Patient must be enrolled on APAL2020SC (NCT04726241) Patients must be < 18 years of age at the time of study enrollment  Patients, with or without Down syndrome (DS), and with de novo acute myeloid leukemia, therapy-related acute myeloid leukemia, myelodysplastic syndrome or mixed phenotype acute leukemia that expresses E-selectin ligand on the cell membrane according to APAL2020SC screening results and meet one of the following:  Second or greater relapse or refractory AML as defined below, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular disease Second or greater relapse or refractory myelodysplastic syndrome (MDS) Second or greater relapse or refractory mixed phenotype acute leukemia (MPAL)  Bone marrow relapse: (patients must meet one of the following criteria to be defined as having relapse disease)  A single bone marrow sample showing >= 5% leukemic blasts by flow cytometry performed at the central laboratory, fluorescence in situ hybridization (FISH) testing or other molecular method  A single bone marrow with at least two tests showing >= 1% leukemic blasts; examples of tests include:  Flow cytometry showing leukemia >= 1% by multidimensional flow cytometry (MDF) performed at the central laboratory (performed at hematologics through the screening study APAL2020SC) Karyotypic abnormality with at least one metaphase similar or identical to diagnosis FISH abnormality identical to one present at diagnosis Polymerase chain reaction (PCR) or next generation sequencing (NGS)-based demonstration of leukemogenic lesion identical to diagnosis and >= 1% In cases where a bone marrow aspirate cannot be obtained because of extensive fibrosis, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy. A complete blood count documenting the presence of at least 1,000/ uL (i.e., a white blood count [WBC] count >= 10,000/uL with >= 10% blasts or a WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells (blasts) can also be used if a bone marrow aspirate or biopsy cannot be performed Extramedullary relapse: Biopsy proven extramedullary disease after documented complete remission Refractory disease: Following a re-induction cycle after a second relapse, presence of ≥1% leukemic blasts by flow cytometry performed at the central laboratory (performed only at Hematologics through the screening study APAL2020SC), OR there is persistent extramedullary disease Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age  Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, eg, blood count criteria, the patient is considered to have recovered adequately  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:  >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1 Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (eg. pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)  Stem cell Infusions (with or without total-body irradiation [TBI]):  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD) Autologous stem cell infusion including boost infusion: >= 30 days Cellular Therapy: >= 30 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer [NK] cells, dendritic cells, etc.) External beam radiation therapy (XRT)/External Beam Irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation Patients must not have received prior exposure to uproleselan (GMI-1271). NOTE: Prior therapy with fludarabine and/or cytarabine is permitted  For patients with leukemia:  * Platelet count >= 25,000/uL (may receive platelet transfusions)  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a creatinine based on age/gender as follows:  Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male); 0.4 (female) Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male); 0.5 (female) Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female) Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female) Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female) Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L Albumin >= 2 g/dL Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study  Exclusion Criteria:  Patients with any of the following diagnoses  Patients with isolated central nervous system (CNS) or isolated testicular relapsed or refractory disease Patients with acute promyelocytic leukemia (APL) Patients with juvenile myelomonocytic leukemia (JMML) Patients with a known congenital bone failure syndrome Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study and for 3 months after the last dose of uproleselan (GMI-1271). Abstinence is an acceptable method of birth control Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial Patients who have an uncontrolled infection are not eligible Patients who have received a prior solid organ transplantation are not eligible Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible