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Tacrolimus

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Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen.

Participants will receive a double umbilical cord blood transplant using a reduced intensity conditioning regimen.

The conditioning regimen consists of:

Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1

The GVHD prophylaxis regimen consists of:

Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35

Haploidentical Bone Marrow Transplant

The preparative regimen consists of:

Fludarabine 40 mg/m2 IV Days -6, -5, -4,-3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI) 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the 3 months of enrollment or an autologous transplant within 24 months of enrollment or 300 cGy Day -1 for patients who have not received cytotoxic chemotherapy within the 3 months of enrollment and who have not received an autologous transplant within 24 months of enrollment.

The GVHD prophylaxis regimen consists of:

Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL.

Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day -3 until Day 35

Double Umbilical Cord Blood Transplant

Mary Horowitz, MD, MS

Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.

Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate that a median of four months is required to complete searches that result in transplantation; thus, some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor.

Single or dual center studies have shown that partially HLA-mismatched related bone marrow (haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor cells for RIC HCT, thus extending this treatment modality to patients who lack other donors. In order to study the reproducibility, and thus, the wider applicability of these two alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, HCT. These data demonstrate not only the efficacy of both of these approaches, but also that both can be safely exported from the single center setting. Both haplo-BM and dUCB grafts can be obtained rapidly for greater than 90% of patients lacking an HLA-matched donor. This study will test the hypothesis that progression free survival at two years after RIC haplo-BM transplantation is similar to the progression free survival after RIC dUCB transplantation.

Double Cord Versus Haploidentical (BMT CTN 1101)

A Multi-Center, Phase III, Randomized Trial of RIC and Transplantation of (dUCB) Versus HLA-Haplo Related Bone Marrow for Patients With Hematologic Malignancies.(BMT CTN #1101)

Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).

The primary endpoint is PFS at 2 years post-randomization. Death or disease relapse/progression will be considered as events. The time to event is defined as the time interval from randomization to relapse/progression, to death or to last follow-up, whichever comes first. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.

Participants' primary diagnosis was categorized into two large groups: leukemia versus lymphoma. Age was dichotomized into two large groups: age \<= 59 versus age \> 59. The Kaplan-Meier estimate for PFS at 2 years post-randomization are provided for each subgroup.

Neutrophil recovery is defined as achieving an absolute neutrophil count greater than or equal to 500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery.

Platelet recovery is defined by two different metrics as the first day of a sustained platelet count greater than 20,000/mm\^3 or greater than 50,000/mm\^3 with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be designated the day of platelet engraftment.

Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56.

Secondary graft failure is defined as initial donor chimerism ≥ 5% declining to \< 5% on subsequent measurements with time to secondary graft failure beginning at the first day of primary engraftment.

The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined.

The cumulative incidence of cGVHD from the time of transplant will be determined. Data were collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference.

Overall survival is defined as the time interval between date of randomization and death from any cause or for surviving patients, to last follow-up. The time interval between date of transplant and death from any cause or for surviving patients, to last follow-up are also analyzed.

The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence.

Incidence of relapse/progression will be estimated using cumulative incidence function, treating death in remission as a competing risk. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.

They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.

All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported.

Total Time Alive and Not Hospitalized within 6 Months Post Randomization

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Blood and Marrow Transplant Clinical Trials Network

National Marrow Donor Program

Medical College of Wisconsin

Adverse event (AE) reporting was conducted according to the BMT CTN's manual of operating procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.

Participants will receive double unrelated cord blood transplant using a reduced intensity conditioning regimen.

Double unrelated cord blood Transplant: The conditioning regimen consists of:

* Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2
* Cyclophosphamide 50 mg/kg IV Day -6
* Total Body Irradiation (TBI): - 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the last 3 months or an autologous transplant within 24 months of enrollment; - 300 cGY Day -1 for patients who have not received cytotoxic chemotherapy within 3 months of enrollment or an autologous transplant within 24 months of enrollment
* Day 0 will be the day of the double UCB transplant

The GVHD prophylaxis regimen consists of:

* Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is intolerant of cyclosporine or per institutional practice.
* Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum dose 1 g po TID beginning Day-3 until Day 35

Supportive care includes:

- Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until ANC \>1500/mm3 for 3 consecutive measurements on at least two different days

dUCB

Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen.

Haploidentical Bone Marrow Transplant: The conditioning regimen consists of:

* Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2
* Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5
* Total body irradiation (TBI) 200cGy Day -1
* Day 0 will be the day of infusion of non-T-cell depleted bone marrow

The GVHD prophylaxis regimen consists of:

* Cy 50 mg/kg IV Days 3, 4
* Tacrolimus (IV or PO) beginning Day 5 with dose adjusted to maintain a trough level of 5-15 ng/mL. Cyclosporine (trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice.
* Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35

Supportive care includes:

- Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until ANC \>1500/mm3 for 3 consecutive measurements on at least two different days

Haplo-BM

Total

Median (Range)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

KPS describes patient-perceived global quality of life and functioning on a scale of 0-100.

100: No evidence of disease; 90: Normal activity. Minor signs or symptoms of disease; 80: Normal activity with effort. Some signs or symptoms of disease; 70: Cares for self. Unable to continue normal activity; 60: Needs occasional assistance, but cares for most personal needs; 50: Needs considerable assistance and medical care; 40: Disabled. Needs special care and assistance; 30: Severely disabled. Hospital admission indicated; 20: Very sick. Active supportive therapy needed; 10: Moribund; 0: Dead

Karnofsky Performance Score

Acute Myelogeneous Leukemia

Biphenotypic/Undifferentiated/Prolymphocytic Leukemia

Hodgkin's Lymphoma

Large Cell Lymphoma

Follicular Non-Hodgkin's Lymphoma

T-cell Leukemia/Lymphoma

Other Lymphoma

Primary Diagnosis

Remission is defined as \< 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with \> 20% cellularity, peripheral blood counts showing ANC \>1000/µl, including patients in CRp.

Disease risk is assessed in enrolled Leukemia patients.

Disease Risk for Leukemia Patients (N=272)

Complete Response is defined as disappearance of all evidence of disease. Partial Response is defined as regression of measurable disease and no new sites.

Disease risk is assessed in enrolled Lymphoma patients.

Disease Risk for Lymphoma Patients (N=96)

For Adult acute myeloid leukemia (AML), Favorable: t(15:17), inv(16), del(16q), t(16:16), \[t(8:21) without del(9q) or complex\]; Intermediate: normal karyotype, +6, +8, -Y, del(12p), 11q23, t(9:11); Poor: complex karyotype, -5/del(5q), -7/del(7q), abn(3q, 9q, 11q, 21q, 17p), t(6:9), t(9:22).

For Acute lymphocytic leukemia (ALL), Poor: Ph+/t(9:22), t(4:11), 11q23, MLL, hypodiploid, t(8:14), complex.

For Chronic lymphocytic leukemia (CLL), Intermediate: other; Poor: 17p-, 11q-, complex (\>= 5).

Cytogenetics data on leukemia participants were retrieved from CIBMTR. Data is only measured in enrolled Leukemia patients.

Cytogenetics for Leukemia

HLA Match Score includes genetic matching information at HLA-A, -B, and -DRB1 loci or HLA-A, -B, -C, and -DRB1 loci. Matching at all HLA-A, -B, and -DRB1 loci is designated as 6/6 HLA matching. A 4/6 HLA match includes mismatches at any two loci. Matching at all HLA-A, -B, -C, and -DRB1 loci is designated as 8/8 HLA matching. A 6/8 HLA match includes mismatches at any two loci.

Note: \*Not required if potential haplo-donor is a biological parent or child

HLA Matching Score for Haploidentical Donor at Randomization

Matching at all HLA-A, -B, and -DRB1 loci is designated as 6/6 HLA matching. A 4/6 HLA match includes mismatches at any two loci.

HLA Matching Score for Cord Blood Unit 1 at Enrollment

HLA Matching Score for Cord Blood Unit 2 at Enrollment

Statistics is summarized on available data.

Pre-cryopreservation total nucleated cell count

Post-thaw total nucleated cell count

Total nucleated cell count at infusion

Pre-cryopreservation CD34+ cell count

Post-thaw CD34+ cell count

CD34+ cell count at infusion

Pre-cryopreservation CD3+ cell count

Post-thaw CD3+ cell count

CD3+ cell count at infusion

The HCT-CI was developed to identify comorbidities relevant to transplant and act as a tool for risk assessment and before allogeneic hematopoietic stem cell transplantation. Patients with no comorbidities are assigned a score of zero. Arrhythmia, cardiac, bowel, diabetes, cerebrovascular, psychological, mild chronic hepatitis, obesity, infection are assigned a score of 1. Rheumatoid arthritis, peptic ulcer, renal moderate/severe, pulmonary moderate, are assigned a score of 2. Solid tumor, heart valve disease, pulmonary sever, hepatic moderate/severe are assigned a score of 3.

HCT-CI was only measured in the transplanted participants. The total number of participants is different from the overall number of enrolled participants as 11 participants from dUCB arm and 15 participants from Haplo-BM arm were not transplanted.

HCT-comorbidity index (CI)

CMV status was only measured in the transplanted participants. The total number of participants is different from the overall number of enrolled participants as 11 participants from dUCB arm and 15 participants from Haplo-BM arm were not transplanted.

CMV Status at Transplant

Time to transplant was only calculated in the transplanted participants. The total number of participants is different from the overall number of enrolled participants as 11 participants from dUCB arm and 15 participants from Haplo-BM arm were not transplanted.

Time from Diagnosis to Transplant

Prior Autologous Transplant

Number of regimens prior to transplant was only counted in the transplanted participants. The total number of participants is different from the overall number of enrolled participants as 11 participants from dUCB arm and 15 participants from Haplo-BM arm were not transplanted.

Number of Regimens Prior to Transplant

The disease risk index was computed based on participant's primary diagnosis, disease risk and cytogenetic data.

Disease Risk Index

Baseline characteristics for all enrolled participants by treatment arm.

Adam Mendizabal, PhD

The primary null hypothesis of the study is that there is no difference between the 2 year PFS probabilities for dUCB vs. haplo-BM.

The null hypothesis of the study is that there is no difference between the 2 year PFS probabilities for dUCB vs. haplo-BM after adjustment for age, performance score, and disease type.

The primary endpoint analysis is performed using the intent-to-treat principle so that all randomized patients are included in the analysis.

Percentage of Participants With Progression Free Survival (PFS)

By Primary Disease of Leukemia

By Primary Disease of Lymphoma

By Age Group <= 59 years

By Age Group > 59 years

The randomized participants are included in the analysis.

Percentage of Participants With PFS by Treatment Arms in Subgroups

The null hypothesis is that there is no difference between the neutrophil engraftment post-transplantation for dUCB vs. haplo-BM.

The transplanted participants are included in the analysis. A total of 26 patients (11 on the dUCB arm and 15 on the Haplo-BM arm) who did not proceed to the study transplant are excluded.

Percentage of Participants With Neutrophil Recovery

The null hypothesis is that there is no difference between the platelet engraftment to 20k post-transplantation for dUCB vs. haplo-BM.

The null hypothesis is that there is no difference between the platelet engraftment to 50k post-transplantation for dUCB vs. haplo-BM.

Platelet recovery to 20K

Platelet recovery to 50K

Percentage of Participants With Platelet Recovery

Participants With Primary Graft Failure

The null hypothesis is that there is no difference between the secondary graft failure probabilities post-transplantation for dUCB vs. haplo-BM.

Percentage of Participants With Secondary Graft Failure

The null hypothesis is that there is no difference between the aGVHD grade II - IV probabilities post-transplantation for dUCB vs. haplo-BM.

The null hypothesis is that there is no difference between the aGVHD grade III - IV probabilities post-transplantation for dUCB vs. haplo-BM.

grade II - IV

grade III - IV

Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD)

The null hypothesis is that there is no difference between the cGVHD probabilities post-transplantation for dUCB vs. haplo-BM.

Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD)

The null hypothesis is that there is no difference between the OS probabilities at year 2 post-randomization for dUCB vs. haplo-BM.

The null hypothesis is that there is no difference between the OS probabilities at year 2 post-transplant for dUCB vs. haplo-BM.

OS post-randomization

OS post-transplant

The randomized or transplanted participants are included in the analyses.

Percentage of Participants With Overall Survival

The null hypothesis is that there is no difference between the TRM probabilities post-randomization for dUCB vs. haplo-BM.

The null hypothesis is that there is no difference between the TRM probabilities post-transplantation for dUCB vs. haplo-BM

Day 100 Post Randomization

Day 100 Post Transplant

Day 180 Post Randomization

Day 180 Post Transplant

1 Year Post Randomization

1 Year Post Transplant

2 Year Post Randomization

2 Year Post Transplant

Percentage of Participants With Treatment-related Mortality (TRM)

The null hypothesis is that there is no difference between the relapse/progression probabilities post-randomization for dUCB vs. haplo-BM.

The null hypothesis is that there is no difference between the relapse/progression probabilities post- transplantation for dUCB vs. haplo-BM.

Spots Global Cancer Trial Database for haploidentical bone marrow transplant