Myeloablative Allo HSCT With Related or Unrelated Donor for Heme Disorders

-Inclusion Criteria:

• Age: ≤ 60 years of age

• Performance Status: Karnofsky ≥ 70%, Lansky play score ≥ 70

• Consent: Voluntary written consent (adult or legally authorized representative; orparental/guardian)

• Adequate Organ Function:

• Renal: Creatinine <2x upper limit of normal. Patients above this limit musthave creatinine clearance ≥ 40 ml/min/1.73m2 as determined by anage-appropriate method, such as cystatin C GFR.

• Hepatic: Bilirubin, AST, alkaline phosphatase <4 times the upper limit ofinstitutional normal

• Pulmonary: Diffusion capacity of oxygen, corrected for hemoglobin, > 50% ofpredicted. For pediatric patients not able to undergo PFTs or diffusiontesting: O2 sat of >95% on room air

• Cardiac: Absence of decompensated congestive heart failure, or uncontrolledarrhythmia and left ventricular ejection fraction > 45%. For children not ableto cooperate with MUGA or echocardiography, such should be clearly stated inthe physician's documentation

• HIV Status: HIV infection with undetectable viral load. All HIV+ patients mustbe evaluated by Infectious Disease (ID) and a HIV management plan establishprior to transplantation

Other Inclusion Criteria:

• Women of child bearing potential and sexually active males with partners of childbearing potential must agree to use adequate birth control for the duration oftreatment.

• Donor Availability: Patients considered for transplantation must have a sufficientgraft as based on current criteria of the University of Minnesota Blood and MarrowTransplantation Program

• Eligible Diseases and Status: Patients are eligible unless their treatment is to beguided by a higher priority protocol.

• Acute Leukemias: Must be in remission by morphology (≤5% blasts). Also a smallpercentage of blasts that is equivocal between marrow regeneration vs. early relapseare acceptable provided there are no associated cytogenetic markers consistent withrelapse.

• Acute Myeloid Leukemia (AML) and related precursor neoplasms: 2nd or greatercomplete remission (CR); first complete remission (CR1) in patients > 60 years old;CR1 in ≤ 60 years old that is NOT considered as favorable-risk.

• Favorable risk AML is defined as having one of the following:

• 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

• Acute prolymphocytic leukemia (APL) in first molecular remission at the end ofconsolidation

• Very high risk pediatric patients with AML: Patients <21 years, however, areeligible with (M2 marrow) with < 25% blasts in marrow after having failed one ormore cycles of chemotherapy.

• Acute lymphoblastic leukemia (ALL)/lymphoma: second or greater CR; CR1 unable totolerate consolidation chemotherapy due to chemotherapy-related toxicities; CR1high-risk ALL.

• High risk ALL is defined as having one of the following:

• Evidence of high risk cytogenetics, e.g. t(9;22), t(1;19), t(4;11), other MLLrearrangements, IKZF1

• 30 years of age or older at diagnosis

• White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis

• CNS leukemia involvement during the course of disease

• Slow cytologic response (>10% lymphoblasts in bone marrow on Day 14 ofinduction therapy)

• Evidence of persistent immonophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy

• Very high risk pediatric patients with ALL: patients <21 years are also consideredhigh risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of inductionor M3 marrow at the end of induction. They are eligible once they achieve a completeremission.

• Chronic Myelogenous Leukemia excluding refractory blast crisis: To be eligible infirst chronic phase (CP1) patient must have failed or be intolerant to one or moretyrosine kinase inhibitors.

• Plasma Cell Leukemia after initial therapy, in patients who have achieved at least apartial remission

• Myeloproliferative Neoplasms/Myelofibrosis, either primary as a result ofpolycythemia vera or essential thrombocythemia, with disease risk of intermediate orhigh-risk according to DIPSS criteria. Blasts must be <10% by bone marrow aspiratemorphology.

• Myelodysplasia (MDS) IPSS INT-2 or High Risk (i.e. RAEB, RAEBt) or Refractory Anemiawith severe pancytopenia, transfusion dependence, or high risk cytogenetics ormolecular features. Blasts must be < 10% by a representative bone marrow aspiratemorphology.

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal ZoneB-Cell Lymphoma or Follicular Lymphoma are eligible if there was diseaseprogression/relapse within 12 of achieving a partial or complete remission. Patientswho had remissions lasting > 12 months, are eligible after at least two priortherapies. Patients with bulky disease (nodal mass greater than 5 cm) should beconsidered for debulking chemotherapy before transplant.

• Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia areeligible after initial therapy in CR1+ or PR1+.

• Diffuse large Cell NHL > CR/> PR: Patients in CR/PR with initial short remission (<6months) are eligible, or those who have failed/or are not eligible for autologoustransplant.

• Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other high-grade NHL after initialtherapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year.

• Multiple Myeloma beyond PR2: Patients with chromosome 13 abnormalities, firstresponse lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may beconsidered for this protocol after initial therapy.

• Juvenile myelomonocytic leukemia

• Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR.

• MRD positive leukemia (AML, ALL or accelerated/blast phase CML). Selected patientsin morphologic CR, but with positive immunophenotypic (flow cytometry) or molecularevidence of MRD may be eligible if recent chemotherapy has not resulted in MRDnegative status.

• Natural Killer Cell Malignancies

• Acquired Bone Marrow Failure Syndromes except for Fanconi Anemia or DyskeratosisCongenita

• Other Leukemia Subtypes: A major effort in the field of hematology is to identifypatients who are of high risk for treatment failure so that patients can beappropriately stratified to either more (or less) intensive therapy. This effort iscontinually ongoing and retrospective studies identify new disease features orcharacteristics that are associated with treatment outcomes. Therefore, if newfeatures are identified after the writing of this protocol, patients can be enrolledwith the approval of two members of the study committee.

Exclusion Criteria:

• Chemotherapy refractory large cell and high grade NHL (i.e., progressive diseaseafter > 2 salvage regimens)

• CML in blast crisis

• Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing onsalvage therapy.

• Evidence of progressive disease by imaging modalities or biopsy - persistent PETactivity, though possibly related to lymphoma, is not an exclusion criterion in theabsence of CT changes indicating progression.

• Active central nervous system malignancy

• if ≤ 18 years old, prior myeloablative transplant within the last 6 months. If >18years old prior myeloablative allotransplant or autologous transplant

• Active HIV infection or known HIV positive serology

• active uncontrolled infection

• Pregnant or breastfeeding. The agents used in this study include Pregnancy CategoryD: known to cause harm to a fetus. Females of childbearing potential must have anegative pregnancy test prior to starting therapy.