Hematologic Malignancies
Conditions
Keywords
Acute Leukemias, Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL)/lymphoma, Biphenotypic/Undifferentiated/Prolymphocytic Leukemias, Myelodysplastic syndrome, Chronic myelogenous leukemia, Minimal Residual Disease (MRD) positive leukemia, Leukemia or Myelodysplastic Syndromes (MDS) in aplasia, Myeloproliferative neoplasms/myelofibrosis, Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma, Burkitt's lymphoma, Relapsed T-cell lymphoma, Natural Killer cell malignancies, Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, Lymphoplasmacytic lymphoma, Relapsed multiple myeloma, Bone marrow failure syndromes
Brief summary
This is a single institution phase II study of a reduced intensity conditioning (RIC) followed by a haploidentical hematopoietic cell transplant (haplo-HCT) in persons with diagnosis of hematologic malignancy. Conditioning will consists of fludarabine, cyclophosphamide, melphalan and total body irradiation (TBI) preparative regimen with a melphalan dose reduction for patients ≥55 years old and those with HCT Comorbidity Index (CI) \>3. This study uses a two-stage phase II design with accrual goal of 84 patients, using 28 patients separately for arms A, C and D
Interventions
BIOLOGICALHaplo HCT <55 years old
* Fludarabine (Flu) * Cyclophosphamide (Cy) * Melphalan (Mel) * Total body irradiation (TBI) * Non-T-cell depleted donor bone marrow stem cell infusion Day 0
BIOLOGICALHaplo HCT ≥55 years old
* Fludarabine (Flu) * Cyclophosphamide (Cy) * Melphalan (Mel): Dose reduction by 30% * Total body irradiation (TBI) * Non-T-cell depleted donor bone marrow stem cell infusion
DRUGGVHD Prophylaxis
* Cyclophosphamide (Cy) * Tacrolimus (Tac) * Mycophenolate mofetil (MMF)
BIOLOGICALHaplo HCT ≥55 and < 65 years old
* Fludarabine (Flu) * Cyclophosphamide (Cy) * Melphalan (Mel) * Total body irradiation (TBI) * non-T-cell depleted donor bone marrow stem cells
BIOLOGICALHaplo HCT ≥65 and ≤75 years old
* Fludarabine (Flu) * Cyclophosphamide (Cy) * Total body irradiation (TBI)
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
* Karnofsky performance status of ≥70% or Lansky play score ≥ 70% * A related haploidentical bone marrow donor with up to 2 or 3 HLA locus-mismatches * The donor and recipient must be HLA identical for at least one haplotype (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. * Adequate liver and renal function * Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 40% * Diffusion capacity corrected (DLCOcorr) \> 40% predicted, and absence of O2 requirements * \> 6 months after prior autologous transplant (if applicable) * Agrees to use contraception during study treatment * Voluntary written consent (adult or parent/guardian with presentation of the minor information sheet, if appropriate) * Patients who are HIV+ must have undetectable viral load. All HIV+ patients must be evaluated by Infectious Disease (ID) and a HIV management plan establish prior to transplantation
Exclusion criteria
* \< 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor * Pregnancy or breastfeeding * Current active and uncontrolled serious infection * Acute leukemia in morphologic relapse/persistent disease defined as \> 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods). * CML in blast crisis * Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on salvage therapy. * stable non-bulky disease is acceptable. * Active central nervous system malignancy Criteria For Donor Selection: * Donors must be HLA-haploidentical relatives of the patient, defined as having a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1. * Eligible donors (14-70 years old) include biological children, siblings or half siblings, or parents, able and willing to undergo bone marrow harvesting. * For donors \<18 years, the maximum recipient weight (actual body weight) should not exceed 1.25 times the donor weight (actual body weight)1 In addition, bone marrow product volume should be limited to 20 ml/kg donor weight for donors \<18 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) | 1 year | Percentage of participants that were disease-free survival (DFS) at 1 year post-transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | day 100 | Percentage of participants with incidence of grade II-IV and grade III-IV acute graft versus-host-disease (GVHD). |
| Treatment Related Mortality (TRM) | 6 month, 1 and 2 year | Percentage of participants experiencing treatment related mortality (TRM). |
| Relapse Incidence | 1 and 2 year | Percentage of participants experiencing a relapse incidence at 1 and 2 years. |
| Incidence of Serious Fungal and Viral Infection | at day 100 and 1 year | Percentage of participants experiencing incidence of serious fungal and viral infection post-HCT |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Haplo-HCT <55 Years Old Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients \<55 years old with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2
Haplo HCT \<55 years old: - Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel)
* Total body irradiation (TBI)
* Non-T-cell depleted donor bone marrow stem cell infusion Day 0
GVHD Prophylaxis: - Cyclophosphamide (Cy)
* Tacrolimus (Tac)
* Mycophenolate mofetil (MMF) | 14 |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients ≥55 years old or younger with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3.
Haplo HCT ≥55 years old: - Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel): Dose reduction by 30%
* Total body irradiation (TBI)
* Non-T-cell depleted donor bone marrow stem cell infusion
GVHD Prophylaxis: - Cyclophosphamide (Cy)
* Tacrolimus (Tac)
* Mycophenolate mofetil (MMF) | 21 |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2 aged ≥55 and \< 65 years old.
GVHD Prophylaxis: - Cyclophosphamide (Cy)
* Tacrolimus (Tac)
* Mycophenolate mofetil (MMF)
Haplo HCT ≥55 and \< 65 years old: - Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel)
* Total body irradiation (TBI)
* non-T-cell depleted donor bone marrow stem cells | 8 |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients patients ≥65 and ≤75 years old OR any age group with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3.
GVHD Prophylaxis: - Cyclophosphamide (Cy)
* Tacrolimus (Tac)
* Mycophenolate mofetil (MMF)
Haplo HCT ≥65 and ≤75 years old: - Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Total body irradiation (TBI) | 35 |
| Total | 78 |
Baseline characteristics
| Characteristic | Arm A: Haplo-HCT <55 Years Old | CLOSED Arm B: Haplo-HCT ≥55 Years Old | Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 6 Participants | 0 Participants | 24 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 15 Participants | 8 Participants | 11 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 18 Participants | 8 Participants | 32 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 10 Participants | 16 Participants | 5 Participants | 31 Participants | 62 Participants |
| Region of Enrollment United States | 14 participants | 21 participants | 8 participants | 35 participants | 78 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 5 Participants | 12 Participants | 31 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 3 Participants | 23 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 14 | 13 / 21 | 5 / 8 | 18 / 35 |
| other Total, other adverse events | 10 / 14 | 11 / 21 | 6 / 8 | 15 / 35 |
| serious Total, serious adverse events | 6 / 14 | 9 / 21 | 4 / 8 | 11 / 35 |
Outcome results
Primary
Disease-free Survival (DFS)
Percentage of participants that were disease-free survival (DFS) at 1 year post-transplant
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Haplo-HCT <55 Years Old | Disease-free Survival (DFS) | 57 percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Disease-free Survival (DFS) | 29 percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Disease-free Survival (DFS) | 38 percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Disease-free Survival (DFS) | 57 percentage of participants |
Secondary
Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD)
Percentage of participants with incidence of grade II-IV and grade III-IV acute graft versus-host-disease (GVHD).
Time frame: day 100
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Haplo-HCT <55 Years Old | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade II-IV acute graft versus-host-disease (GVHD) | 21 Percentage of participants |
| Arm A: Haplo-HCT <55 Years Old | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade III-IV acute graft versus-host-disease (GVHD) | 0 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade III-IV acute graft versus-host-disease (GVHD) | 19 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade II-IV acute graft versus-host-disease (GVHD) | 33 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade II-IV acute graft versus-host-disease (GVHD) | 13 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade III-IV acute graft versus-host-disease (GVHD) | 0 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade II-IV acute graft versus-host-disease (GVHD) | 31 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Incidence of Grade II-IV and Grade III-IV Acute Graft Versus-host-disease (GVHD) | grade III-IV acute graft versus-host-disease (GVHD) | 11 Percentage of participants |
Secondary
Incidence of Serious Fungal and Viral Infection
Percentage of participants experiencing incidence of serious fungal and viral infection post-HCT
Time frame: at day 100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Haplo-HCT <55 Years Old | Incidence of Serious Fungal and Viral Infection | Day 100 | 7 Percentage of participants |
| Arm A: Haplo-HCT <55 Years Old | Incidence of Serious Fungal and Viral Infection | 1 year | 14 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Incidence of Serious Fungal and Viral Infection | 1 year | 10 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Incidence of Serious Fungal and Viral Infection | Day 100 | 10 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Incidence of Serious Fungal and Viral Infection | 1 year | 38 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Incidence of Serious Fungal and Viral Infection | Day 100 | 38 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Incidence of Serious Fungal and Viral Infection | Day 100 | 6 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Incidence of Serious Fungal and Viral Infection | 1 year | 11 Percentage of participants |
Secondary
Relapse Incidence
Percentage of participants experiencing a relapse incidence at 1 and 2 years.
Time frame: 1 and 2 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Haplo-HCT <55 Years Old | Relapse Incidence | Relapse Incidence 1 year | 29 Percentage of participants |
| Arm A: Haplo-HCT <55 Years Old | Relapse Incidence | Relapse Incidence 2 year | 29 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Relapse Incidence | Relapse Incidence 2 year | 30 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Relapse Incidence | Relapse Incidence 1 year | 29 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Relapse Incidence | Relapse Incidence 1 year | 75 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Relapse Incidence | Relapse Incidence 2 year | 75 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Relapse Incidence | Relapse Incidence 1 year | 26 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Relapse Incidence | Relapse Incidence 2 year | 28 Percentage of participants |
Secondary
Treatment Related Mortality (TRM)
Percentage of participants experiencing treatment related mortality (TRM).
Time frame: 6 month, 1 and 2 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Haplo-HCT <55 Years Old | Treatment Related Mortality (TRM) | TRM 6 months | 21 Percentage of participants |
| Arm A: Haplo-HCT <55 Years Old | Treatment Related Mortality (TRM) | TRM 2 years | 21 Percentage of participants |
| Arm A: Haplo-HCT <55 Years Old | Treatment Related Mortality (TRM) | TRM 1 year | 21 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Treatment Related Mortality (TRM) | TRM 6 months | 57 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Treatment Related Mortality (TRM) | TRM 2 years | 58 Percentage of participants |
| CLOSED Arm B: Haplo-HCT ≥55 Years Old | Treatment Related Mortality (TRM) | TRM 1 year | 57 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Treatment Related Mortality (TRM) | TRM 1 year | 13 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Treatment Related Mortality (TRM) | TRM 6 months | 13 Percentage of participants |
| Arm C: Haplo-HCT HCT-CI ≤2 Aged ≥55 and < 65yo | Treatment Related Mortality (TRM) | TRM 2 years | 13 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Treatment Related Mortality (TRM) | TRM 6 months | 26 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Treatment Related Mortality (TRM) | TRM 2 years | 27 Percentage of participants |
| Arm D: Haplo-HCT Aged ≥65 and ≤75yo OR Any Age HCT-CI ≥3 | Treatment Related Mortality (TRM) | TRM 1 year | 26 Percentage of participants |