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All patients treated on this trial will have hematological malignancies that are in remission at the time of the transplant. Their diseases would be expected to relapse with standard therapy alone.

Total body irradiation is given in 8 fractions over 4 days (total dose of 12 Gy).

Total Body Irradiation (TBI)

After TBI, the patients will receive a dose of 2 x 10e8 of their donor's T cells. After this infusion, the patients will have 2 rest days.

Donor Lymphocyte Infusion (DLI)

Cyclophosphamide is administered 2 days after the DLI to help tolerize the donor T cells. It is given at a dose of 60 mg/kg/d for 2 days

Started the day before the transplant to prevent graft versus host disease (GVHD)

Mycophenolate Mofetil (MMF)

Started the day before the transplant to prevent graft-versus-host disease (GVHD)

One day after the cyclophosphamide is finished, the patients will receive a CD34 selected-donor stem cell product. This is the day of transplant.

The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT)

Dolores Grosso, DNP, CRNP

Neal Flomenberg, MD

The primary hypothesis of this research study is that patients in remission undergoing myeloablative haploidentical hematopoietic stem cell transplantation (HSCT) on the Thomas Jefferson University (TJU) 2 Step treatment regimen will have a disease-free survival (DFS) rate at 1 year that is the same or better than the historical DFS of patients with similar diagnoses and ages undergoing matched sibling HSCT. Based on a review of the literature a DFS rate of 50% or better at 1 year would meet the criterion for an effective alternative therapy. A DFS rate of 75% or better would imply superior efficacy of the TJU 2 Step approach over T-replete matched sibling HSCT.

The primary rationale for the development of this research study is to find out if the Thomas Jefferson University (TJU) 2 Step approach to stem cell transplant is an effective treatment for patients with blood cancers who require transplant for long-term survival but are without an available matched-sibling donor. Historically, survival rates for patients undergoing half-matched stem cell transplant have been much lower than those observed after matched sibling stem cell transplant. This may be due to the poor-risk disease features of the patients by the time they are referred for hematopoietic stem cell transplantation (HSCT). Survival post half-matched stem cell transplant has also been affected by the requirement to remove or soothe donor T cells resulting in higher rates of infection and relapse. Newer approaches to haploidentical HSCT, such as the TJU 2 Step approach, utilize cyclophosphamide (CY) to tolerize donor lymphocytes instead of removing them completely from the donor product. This has resulted in less infection without concomitant increase in severe graft-versus-host disease (GVHD) and has increased overall survival as compared to older haploidentical treatment approaches due to decreases in regimen-related morbidity.

Because of the historically low overall survival (OS) after haploidentical HSCT, it has become a procedure of last resort with most centers unwilling to consider it unless all other options are exhausted. With the recent development of regimens such as the TJU 2 Step approach which provide safe, alternative platforms for HSCT, it is now feasible, and ethically more acceptable, for patients without matched sibling donors to undergo HSCT prior to being heavily pretreated or developing resistant disease. In this setting, i.e. equivalent regimen safety profiles and more homogenous patient comparison groups, it is possible to more accurately compare antitumor effects between matched sibling donors and haploidentical donors. There is ample evidence in the literature that HLA mismatching causes GVHD. There is not a large body of evidence supporting the notion that HLA mismatching provides superior tumor control translating into greater relapse free survival. As compared to more common types of transplants where donor T cells are given to the recipient, the investigators would surmise that the T cell tolerization associated with the TJU 2 Step approach may decrease the anti-tumor effects of the donor immune system. Conversely, the greater degree of human leukocyte antigen (HLA) mismatch with exploitation of NK effects may mitigate some of the attenuated T cell alloreactivity.

Thus, in the context of comparable regimen-related toxicity, our major aim in this research study is to compare graft versus tumor effects as measured by disease-free survival (DFS) between matched sibling HSCT and the TJU 2 Step haploidentical HSCT. If DFS is similar despite T cell tolerization, than the TJU 2 Step haploidentical approach should be considered an effective alternative therapy for those patients in remission without a matched sibling donor. The widespread benefit of this outcome would be the enfranchisement of segments of the population who are without available matched donors resulting in a delay or a failure to receive this potentially life-saving therapy. If DFS survival after treatment on the TJU 2 Step haploidentical approach is superior to what would be expected after matched sibling HSCT, then one could conclude that haploidentical HSCT confers greater tumor control forming the basis for future studies regarding the potential benefits of utilizing haploidentical donors over matched sibling donors when both types of donors are available.

Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies in Remission From HLA Partially-Matched Related Donors

1-year post-transplant disease free survival (DFS), defined as success if a patient is alive and disease free at 1-year post-transplant.

Probability of overall survival at 15 months post-treatment, defined as success if a patient is alive 1-year post-transplant.

Sidney Kimmel Cancer Center at Thomas Jefferson University

All patients treated on this trial will have hematological malignancies that are in remission at the time of the transplant. Their diseases would be expected to relapse with standard therapy alone.

Total Body Irradiation (TBI): Total body irradiation given in 8 fractions over 4 days (total dose of 12 Gy).

Donor Lymphocyte Infusion (DLI): After TBI, the patients will receive a dose of 2 x 10e8 of their donor's T cells. After this infusion, the patients will have 2 rest days.

Cyclophosphamide: Cyclophosphamide is administered 2 days after the DLI to help tolerize the donor T cells. It is given at a dose of 60 mg/kg/d for 2 days

Mycophenolate Mofetil (MMF): Started the day before the transplant to prevent graft versus host disease (GVHD)

Tacrolimus: Started the day before the transplant to prevent graft-versus-host disease (GVHD)

Hematopoietic stem cell transplantation (HSCT): One day after the cyclophosphamide is finished, the patients will receive a CD34 selected-do

TJU 2 Step Regimen

Age, Continuous

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Dolores Grosso, CRNP, DNP

Disease-Free Survival (DFS)

Probability of Overall Survival at 15 Months Post-treatment

Overall Study

Micronutrients

Vitamins

Ascorbic Acid

Trace Elements

Antioxidants

Protective Agents

Vitamin C

All study participants will receive the same treatment. Each participant will be given intravenous, which means by vein (IV), vitamin C three times a day for 14 days. Then participants will take vitamin C orally (by mouth in pill form) twice a day each day until 6 months after transplant. The treatment is IV vitamin C 50 mg/kg/day. After completion of the IV vitamin C doses, oral vitamin C 500 mg twice each day.

Intravenous (IV) vitamin C 50 mg/kg/day divided in 3 doses beginning on posttransplant Day +1 and continuing through Day +14; each dose (16.7 mg/kg) given in 50 mL of 5% dextrose and water over 30 minutes every 8 hours

• After completion of the IV vitamin C doses, oral vitamin C 500 mg twice each day beginning on Day +15 and continuing until Day +180

Intravenous (IV) and oral Vitamin C

William B Clark, MD

This phase 2 trial studies the effect of intravenous (IV) vitamin C repletion after myeloablative allogeneic stem cell transplant.

Vitamin C is a nutritional supplement that can help fight inflammation. Most patients who have a stem cell transplant have lower than normal levels of vitamin C in their blood. Patients will receive intravenous Vitamin C the day after transplant for two weeks, followed by oral vitamin C until six months after transplant. The effect of the Vitamin C on non-relapse mortality (NRM), time to engraftment, rate of acute graft-versus-host disease and to characterize the safety and tolerability of the vitamin C regimen.

Therapeutic Use of Intravenous Vitamin C in Allogeneic Stem Cell Transplant Recipients

To determine the effect of parenteral vitamin C on non-relapse mortality (NRM) at one year following myeloablative allogeneic HCT. Non-relapse mortality is defined as defined as mortality from complications of HCT but not tumor relapse, is usually from graft versus host disease (GVHD), infection, or organ failure.

To determine the effect of the vitamin C regimen on the time to hematopoietic engraftment.

Percentage of patients with a diagnosis of acute GVHD

The number of participants who have adverse events related to Vitamin C therapy

Virginia Commonwealth University

Adverse Events (AEs) \>/= grade 3 regardless of expectedness or attribution were recorded

All study participants will receive the same treatment. Each participant will be given intravenous, which means by vein (IV), vitamin C three times a day for 14 days. Then participants will take vitamin C orally (by mouth in pill form) twice a day each day until 6 months after transplant. The treatment is IV vitamin C 50 mg/kg/day. After completion of the IV vitamin C doses, oral vitamin C 500 mg twice each day.

Intravenous (IV) and oral Vitamin C: Intravenous (IV) vitamin C 50 mg/kg/day divided in 3 doses beginning on posttransplant Day +1 and continuing through Day +14; each dose (16.7 mg/kg) given in 50 mL of 5% dextrose and water over 30 minutes every 8 hours

• After completion of the IV vitamin C doses, oral vitamin C 500 mg twice each day beginning on Day +15 and continuing until Day +180

IV Vitamin C Followed by Oral Vitamin C

18 - 21 years

22 - 29 years

30 - 39 years

40 - 49 years

50 - 59 years

60 - 69 years

70 - 79 years

Age, Customized

BMT- CIT Team

The Proportion of Patients That Experience Non-relapse Mortality (NRM)

Time From Transplant to Engraftment

To Determine the Effectiveness of Reducing Acute Graft Versus Host Disease (aGVHD)

No participants had adverse events related to Vitamin C therapy.

Determine Related to Vitamin C Therapy Adverse Events (AEs) Reported Using Criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor	NCT01350245	Acute Myeloid L... Myelodysplastic... Biphenotypic Le... Acute Lymphocyt... Chronic Myeloid... Chronic Lymphoc... Plasma Cell Neo... Lymphoma Hodgkin's Disea... Aplastic Anemia	Total Body Irra... Donor Lymphocyt... Cyclophosphamid... Mycophenolate M... Tacrolimus Hematopoietic s...	18 Years -	Thomas Jefferson University
Therapeutic Use of Intravenous Vitamin C in Allogeneic Stem Cell Transplant Recipients	NCT03613727	Lymphoid Leukem... Myeloid Leukemi... Monocytic Leuke... Myelodysplasia	Intravenous (IV...	18 Years - 77 Years	Virginia Commonwealth University

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