Clinical Trial Finder

Inclusion Criteria for Transplant Recipient:

• - Age less than or equal to 21 years.

• - Any of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic HCT (this includes any stage of disease - such as refractory due to induction failure, refractory in relapse, or in any CR - as long as the hematologic malignancy remained persistent or returned after a previous allogeneic HCT): - ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) - Has a suitable single haplotype matched (≥ 3 of 6) family member donor.

• - Does not have any other active malignancy other than the one for which this transplant is indicated.

• - If prior CNS leukemia, it must be treated and in CNS CR.

• - Does not have current uncontrolled bacterial, fungal, or viral infection.

• - There is no minimum time from the previous transplant, but patients must meet the following criteria: - Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%.

• - Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2.

• - Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing.

• - Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See Appendix A).

• - Bilirubin ≤ 3 times the upper limit of normal for age.

• - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age.

• - Not pregnant.

If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment.

• - Not breast feeding.

Inclusion Criteria for Haploidentical Donor:

• - At least single haplotype matched (≥ 3 of 6) family member.

• - At least 18 years of age.

• - HIV negative.

• - Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).

• - Not breast feeding.

• - Regarding donation eligibility, is identified as either: - Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR.

• - Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.

Blood progenitor cells will be obtained from a partially matched adult family member (donor). After processing and filtration using the CliniMACS device, cells will be infused into participants meeting eligibility criteria. Prior to transplant, participants will receive a conditioning treatment of rabbit ATG, cyclophosphamide, fludarabine, thiotepa, melphalan, and rituximab. Mesna will be given to help prevent side effects of cyclophosphamide. Tacrolimus will be given to help reduce the risk of GVHD. G-CSF will be given after transplant to help the donor progenitor cells make white blood cells faster so that the immune system is better able to fight infection. Blood progenitor cells will be given in two infusions on Day 0 and Day +1. Progenitor cells then move through the blood stream to the bone marrow space where they should begin to grow. Participant blood will be monitored for 100 days to assure that the progenitor cells begin to grow. If the growth is low, additional progenitor cells may be given. Blood tests will be monitored for up to one year to observe how well the donor cells grow and their effect on the infection-fighting system.

Arms

Experimental: Treatment

Participants receive a conditioning regimen of antithymocyte globulin (rabbit), cyclophosphamide, mesna, fludarabine, thiotepa, tacrolimus (first 5 participants enrolled), sirolimus (used beginning with 6th enrolled participant), melphalan, rituximab. This is followed by HPC,A infusion (transplant), then by G-CSF and blinatumomab. Cells for infusion are prepared using the CliniMACS System.

Interventions

Drug: - Anti-thymocyte globulin (rabbit)

Given intravenous (IV) prior to transplant on Days -14, -13, -12.

Drug: - Blinatumomab

Given by continuous IV infusion at least 2 weeks post-engraftment. Blinatumomab will be given only to patients with CD19+ malignancies.

Drug: - Cyclophosphamide

Given by IV infusion prior to transplant on Day -9.

Drug: - Fludarabine

Given IV prior to transplant on Days -8, -7, -6, -5, and -4.

Drug: - G-CSF

Given IV or subcutaneous (SQ) following transplant on Days 6 and 7.

Drug: - Melphalan

Given IV prior to transplant on Days -2 and -1.

Drug: - Mesna

Given IV prior to cyclophosphamide administration and at approximately 3, 6, and 9 hours after cyclophosphamide infusion.

Drug: - Rituximab

Given IV prior to transplant on Day -1.

Drug: - Tacrolimus

Given oral (PO) or IV beginning prior to transplant on Day -2. The dose will begin to taper at approximately day +60 after transplant in the absence of GVHD. Tacrolimus was used for the first 5 participants enrolled on study. Subsequent participants receive sirolimus.

Drug: - Thiotepa

Given IV prior to transplant on Day -3.

Biological: - HPC,A Infusion

Hematopoietic Progenitor Cell, Apheresis (HPC,A) infusion of TCRɑβ+ depleted cells on day of transplant (Day 0) and HPC,A infusion of CD45RA+ depleted cells on Day +1 following transplant.

Device: - CliniMACS

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Drug: - Sirolimus

Given orally (PO) starting Day 0. The dose will be tapered off over two weeks starting on Day +42 in the absence of GVHD.