Allogeneic Hematopoietic Stem Cell Transplantation Using Treosulfan Conditioning with Post-Transplant Cyclophosphamide for the Treatment of Hematologic Malignancies

Inclusion Criteria

• Age 2 to 75 years
• Karnofsky score ≥ 70% (≥ 16 years) or Lansky score ≥ 50 (< 16 years)
• 5/6 or 6/6 related donor, OR a 5-8/8 HLA-A, B, C, DRB1 allele match unrelated donor, OR a haplotype (at least 5/10) related donor. Donors will be requested to provide peripheral blood stem cells (PBSCs) with donors consented only to bone marrow (BM) harvest included. The prioritization and selection of donors will be determined by the current UMN Blood and Marrow Transplantation (BMT) donor selection guideline
• Acute leukemias: Must be in remission by morphology (≤ 5% blasts)
• Acute myeloid leukemia (AML) and related precursor neoplasms: * 2nd or greater complete remission (CR) * First complete remission (CR1) in patients > 60 years old * CR1 in ≤ 60 years old that is NOT considered as favorable-risk as below * CR1 with persistently minimal residual disease (MRD) positive by polymerase chain reaction (PCR), or other validated high-sensitivity molecular detection method following treatment * Complete remission with incomplete blood count recovery (CRi) with no evidence of leukemia by flow or morphology: These patients may be taken to transplant if after treatment remain with aplastic bone marrow and no morphological or flow-cytometry evidence of disease ≥ 28 days post-therapy Favorable risk AML is defined as having one of the following in a MRD negative remission state: * t(8,21) without cKIT mutation * inv(16) or t(16;16) without cKIT mutation * Normal karyotype with mutated NPM1 and wild type FLT-ITD * Normal karyotype with double mutated CEBPA (bZip-in-frm) * Acute prolymphocytic leukemia (APL) in first molecular remission at the end of consolidation
• Biphenotypic/undifferentiated/prolymphocytic leukemias in first or subsequent CR
• Chronic myelogenous leukemia in chronic or accelerated phase, or chronic myelogenous leukemia (CML) blast crisis in morphological remission (< 5% blasts by flow cytometry or immunohistochemistry [IHC]): * Chronic phase patients must have failed at least two different tyrosine kinase inhibitors (TKIs), been intolerant to all available TKIs or have T315I mutation * Patients with CML blast crisis in CR are only eligible if there is a feasible TKI maintenance plan following BMT
• Myelodysplastic syndrome: Molecular International Prognostic Scoring System (IPSS M) stratified patients * Low-risk (myelodysplastic syndrome [MDS]) transfusion dependent despite hypomethylation (HMA) therapy * Intermediate/moderate to very high risk (International Prognostic Scoring System [IPSS], Revised [R]-IPSS or IPSS-M moderate high to very high) * Therapy-related MDS * If ≥ 10% blasts, the patient requires chemotherapy for cytoreduction to < 10% blasts prior to transplantation * World Health Organization (WHO) classification: Refractory anemia with excess of blasts (RAEB)-1, RAEB-2; severe cytopenias: Absolute neutrophil count (ANC) < 0.8, anemia or thrombocytopenia requiring transfusion; poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS, low-risk transfusion dependent MDS refractory to HMA therapy
• Chronic myelomonocytic leukemia: IPSS-Molecular (Mol) intermediate-1 or higher, or CPSS intermediate or higher; blasts must be < 10% by bone marrow aspirate morphology
• Myeloproliferative neoplasms/myelofibrosis – with transfusion dependence or expected survival under 5 years by Dynamic International Prognostic Scoring System (DIPSS), DIPSS-plus, Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (MY-SEC) or Mutation-Enhanced IPSS for transplant-age patients (MPSS70) version (Vs.) 2.0 calculator
• Other leukemia subtypes: A major effort in the field of hematology is to identify patients who are of high risk for treatment failure so that patients can be appropriately stratified to either more (or less) intensive therapy. This effort is continually ongoing and retrospective studies identify new disease features or characteristics that are associated with treatment outcomes
• Transaminases ≤ 5 x upper limit of normal (ULN) except for patients with Gilbert’s syndrome or hemolysis
• Total bilirubin ≤ 2.5 mg/dL except for patients with Gilbert’s syndrome or hemolysis
• A normal creatinine (adults) or creatinine clearance ≥ 40 mL/min (pediatrics). Adults with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have estimated glomerular filtration rate (GFR) ≥ 40 ml/min/1.73m^2
• Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 40%. For children that are not able to cooperate with MUGA and echocardiography, such should be clearly stated in the physician’s note
• Diffusion capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) ≥ 40% predicted, and absence of oxygen (O2) requirements. For children that are not able to cooperate with pulmonary function tests (PFTs), a pulse oximetry with exercise should be attempted. If neither test can be obtained it should be clearly stated in the physician’s note
• If recent confirmed mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease
• HIV infection with undetectable viral load. All HIV+ patients must be evaluated by Infectious Disease (ID) and a HIV management plan established prior to transplantation
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 12 months post-transplant. Non-childbearing is defined as > 1 year post-menopausal or surgically sterilized. Examples of highly effective birth control methods include but are not limited to the following: * Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm) * Oral contraceptive pills * Depot or injectable birth control * Intrauterine device (IUD) * Transdermal contraceptive patch * Vaginal contraceptive ring * Contraceptive implants Note: Rhythm method or abstinence alone is not considered an adequate method of contraception. Plan must be documented in electronic medical record (EMR) at consent
• Voluntary written consent (adult or parent/guardian with presentation of the minor information sheet, if appropriate)

Exclusion Criteria

• Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a negative pregnancy test prior to starting therapy
• Untreated or uncontrolled active infection
• Active central nervous system malignancy. Patients with prior involvement must show clearance prior to enrollment (by two negative lumbar punctures [LPs] or a negative brain magnetic resonance imaging [MRI] if previously positive)
• CML in a blast crisis not in remission
• Blast count > 10% for MDS or CMML or myelofibrosis
• Previous irradiation to areas of the body such that the radiation oncologist determines 200 cGy of total body irradiation (TBI) cannot safely be given
• Less than 3 months since prior myeloablative transplant