Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Chronic Myeloproliferative Disorders, Essential Thrombocythemia, Multiple Myeloma, Myelodysplastic Syndrome, Myelofibrosis, Plasma Cell Dyscrasia, Plasma Cell Leukemia, Plasma Cell Neoplasm, Polycythemia Vera, Prolymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
immunosuppression, nonmyeloablative, non-myeloablative, allogeneic, tacrolimus, peripheral blood, cyclophosphamide, mycophenolate mofetil
Brief summary
To see if it is possible to use short-duration tacrolimus after a peripheral blood stem cell transplant in certain malignancies that are considered difficult to engraft.
Detailed description
The main goal is to learn whether a drug called tacrolimus, which is an immune-lowering drug (an immunosuppressant) given after transplant to help prevent certain complications, can be given safely for a shorter period of time than it has been in the past. The experiences with immunosuppression duration with other allogeneic HSCT platforms cannot be directly extrapolated to the high-dose posttransplantation cyclophosphamide platform (another type of immunosuppressant given after transplant to help prevent GVHD). There are presently no published data on the minimum required duration of tacrolimus after nonmyeloablative HSCT that includes high-dose Cy as part of postgrafting immunosuppression. The effectiveness of high-dose posttransplantation Cy in GVHD prevention, however, permits the investigation of this question. At the present time there are few or no cures for diseases studied on this trial outside of a bone marrow or peripheral blood transplant. The peripheral blood for this transplant comes from a relative who is a half-match or haplo match to the participant. Possible donors include parents, siblings, and children. In order to help the bone marrow grow, or take, inside the body, participants will receive chemotherapy and radiation before the transplant. After the transplant participants will receive high doses of cyclophosphamide (Cytoxan®) along with other medications to lower the immune system, such as tacrolimus. These medications may lower the risk of graft versus host disease (GVHD) and of rejection of the peripheral blood graft.
Interventions
DRUGFludarabine
Days -6 through -2: 30 mg/m\^2 IV daily
DRUGCyclophosphamide
Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
RADIATIONTotal body irradiation
Day -1: 200 cGy in a single fraction
DRUGTacrolimus
Start on Day 5 through either Day 60 or Day 90 depending on cohort assignment. May be continued through Day 180 depending on GVHD status.
DRUGMycophenolate mofetil
Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Presence of a suitable related HLA-haploidentical or -matched stem cell donor, or a 10/10 matched unrelated donor * Eligible diagnoses: myelodysplastic syndrome (MDS) with at least 1 poor-risk feature; small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) with 17p deletion or with progression \< 6 months after a second or greater treatment regimen; T-cell prolymphocytic leukemia (PLL) in partial response or better; interferon- or tyrosine-kinase-refractory chronic myeloid leukemia (CML), or CML in second or subsequent chronic phase; Philadelphia chromosome negative (Ph-) myeloproliferative disease, including myelofibrosis; Multiple myeloma or plasma cell leukemia in partial response or better; Hematologic malignancy in complete remission with minimal residual disease (MRD) detectable by conventional cytogenetics, FISH, flow cytometry, or molecular testing * Any previous autologous transplant must have occurred \> 3 months ago * Left ventricular ejection fraction (LVEF) \>= 35%, or shortening fraction \> 25% * Bilirubin \<= 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis) * AST and ALT \<= 5 x institutional upper limit of normal * FEV1 and FVC \>= 40% of predicted; if unable to perform pulmonary function testing, oxygen saturation \> 92% on room air * ECOG performance status \<= 2, or Karnofsky/Lansky status \>= 60
Exclusion criteria
* Pregnancy or active breastfeeding * Uncontrolled active infection * Previous allogeneic transplant * Active extramedullary leukemia or active central nervous system (CNS) malignant disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D90 Cohort) | Day 90 | This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 90. |
| Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D60 Cohort) | Day 60 | This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 60. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Chronic GVHD, Days 90-180 (D90) | Between Day 90 and Day 180 | Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. |
| Number of Participants With Chronic GVHD, Days 60-180 (D60) | Between Day 60 and Day 180 | Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. |
| Number of Participants Who Experience Graft Failure, Days 90-180 (D90) | Between Day 90 and Day 180 | Number of participants who experience graft failure between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. |
| Number of Participants Who Experience Graft Failure, Days 60-180 (D60) | Between Day 60 and Day 180 | Number of participants who experience graft failure between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. |
| Number of Participants Who Experience Disease Relapse, Days 90-180 (D90) | Between Day 90 and Day 180 | Number of participants who experience disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. |
| Number of Participants Who Experience Disease Relapse, Days 60-180 (D60) | Between Day 60 and Day 180 | Number of participants who experience disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. |
| Number of Participants Who Experience Non-relapse Mortality, Days 90-180 (D90) | Between Day 90 and Day 180 | Number of participants who die for any reason other than disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. |
| Number of Participants Who Experience Non-relapse Mortality, Days 60-180 (D60) | Between Day 60 and Day 180 | Number of participants who die for any reason other than disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. |
| Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D90) | Day 360 | Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable. |
| Number of Participants With Grades III-IV Acute GVHD, Days 90-180 (D90) | Between Day 90 and Day 180 | Number of participants who experience grade III or IV acute GVHD between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. |
| Number of Number of Participants With Severe Chronic GVHD, Day 360 (D90) | Day 360 | Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable. |
| Number of Number of Participants With Severe Chronic GVHD, Day 360 (D60) | Day 360 | Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable. |
| Number of Number of Participants Who Experience Graft Failure, Day 360 (D90) | Day 360 | Number of participants who experience graft failure by Day 360. All participants are evaluable. |
| Number of Number of Participants Who Experience Graft Failure, Day 360 (D60) | Day 360 | Number of participants who experience graft failure by Day 360. All participants are evaluable. |
| Number of Participants Who Experience Relapse, Day 360 (D90) | Day 360 | Number of participants who experience disease relapse by Day 360. All participants are evaluable. |
| Number of Participants Who Experience Relapse, Day 360 (D60) | Day 360 | Number of participants who experience disease relapse by Day 360. All participants are evaluable. |
| Number of Participants Who Experience Non-relapse Mortality, Day 360 (D90) | Day 360 | Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable. |
| Number of Participants Who Experience Non-relapse Mortality, Day 360 (D60) | Day 360 | Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable. |
| Number of Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D60) | Day 360 | Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable. |
| Number of Participants With Grades III-IV Acute GVHD, Days 60-180 (D60) | Between Day 60 and Day 180 | Number of participants who experience grade III or IV acute GVHD between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PBSCT D90 Non-myeloablative peripheral blood stem cell transplant (PBSCT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis. Tacrolimus will be stopped at either Day 90 or Day 180 depending on GVHD status.
Fludarabine: Days -6 through -2: 30 mg/m\^2 IV daily
Cyclophosphamide: Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
Total body irradiation: Day -1: 200 cGy in a single fraction
Tacrolimus: Start on Day 5 through either Day 60 or Day 90 depending on cohort assignment. May be continued through Day 180 depending on GVHD status.
Mycophenolate mofetil: Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day) | 57 |
| PBSCT D60 Non-myeloablative peripheral blood stem cell transplant (PBSCT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis. Tacrolimus will be stopped at either Day 60 or Day 180 depending on GVHD status.
Fludarabine: Days -6 through -2: 30 mg/m\^2 IV daily
Cyclophosphamide: Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily
Total body irradiation: Day -1: 200 cGy in a single fraction
Tacrolimus: Start on Day 5 through either Day 60 or Day 90 depending on cohort assignment. May be continued through Day 180 depending on GVHD status.
Mycophenolate mofetil: Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day) | 60 |
| Total | 117 |
Baseline characteristics
| Characteristic | PBSCT D60 | Total | PBSCT D90 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 47 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 70 Participants | 34 Participants |
| Age, Continuous | 63 years | 62.5 years | 62 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 60 Participants | 117 Participants | 57 Participants |
| Sex: Female, Male Female | 19 Participants | 36 Participants | 17 Participants |
| Sex: Female, Male Male | 41 Participants | 81 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 57 | 10 / 60 |
| other Total, other adverse events | 35 / 57 | 16 / 60 |
| serious Total, serious adverse events | 9 / 57 | 5 / 60 |
Outcome results
Primary
Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D60 Cohort)
This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 60.
Time frame: Day 60
Population: Of the 42 patients in the D60 cohort who stopped IS early as prespecified, 10 subsequently relapsed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D60 Cohort) | 42 Participants |
Primary
Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D90 Cohort)
This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 90.
Time frame: Day 90
Population: Safety stopping criteria were not met after discontinuation of tacrolimus at day 90.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D90 Cohort) | 33 Participants |
Secondary
Number of Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D60)
Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D60) | 18 Participants |
Secondary
Number of Number of Participants Who Experience Graft Failure, Day 360 (D60)
Number of participants who experience graft failure by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Number of Participants Who Experience Graft Failure, Day 360 (D60) | 2 Participants |
Secondary
Number of Number of Participants Who Experience Graft Failure, Day 360 (D90)
Number of participants who experience graft failure by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Number of Participants Who Experience Graft Failure, Day 360 (D90) | 0 Participants |
Secondary
Number of Number of Participants With Severe Chronic GVHD, Day 360 (D60)
Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Number of Participants With Severe Chronic GVHD, Day 360 (D60) | 5 Participants |
Secondary
Number of Number of Participants With Severe Chronic GVHD, Day 360 (D90)
Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Number of Participants With Severe Chronic GVHD, Day 360 (D90) | 7 Participants |
Secondary
Number of Participants Who Experience Disease Relapse, Days 60-180 (D60)
Number of participants who experience disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable.
Time frame: Between Day 60 and Day 180
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Disease Relapse, Days 60-180 (D60) | 10 Participants |
Secondary
Number of Participants Who Experience Disease Relapse, Days 90-180 (D90)
Number of participants who experience disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable.
Time frame: Between Day 90 and Day 180
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Disease Relapse, Days 90-180 (D90) | 14 Participants |
Secondary
Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D90)
Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D90) | 16 Participants |
Secondary
Number of Participants Who Experience Graft Failure, Days 60-180 (D60)
Number of participants who experience graft failure between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable.
Time frame: Between Day 60 and Day 180
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Graft Failure, Days 60-180 (D60) | 1 Participants |
Secondary
Number of Participants Who Experience Graft Failure, Days 90-180 (D90)
Number of participants who experience graft failure between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable.
Time frame: Between Day 90 and Day 180
Population: Of the 57 patients in the D90 cohort, 33 stopped IS early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Graft Failure, Days 90-180 (D90) | 0 Participants |
Secondary
Number of Participants Who Experience Non-relapse Mortality, Day 360 (D60)
Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Non-relapse Mortality, Day 360 (D60) | 4 Participants |
Secondary
Number of Participants Who Experience Non-relapse Mortality, Day 360 (D90)
Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Non-relapse Mortality, Day 360 (D90) | 4 Participants |
Secondary
Number of Participants Who Experience Non-relapse Mortality, Days 60-180 (D60)
Number of participants who die for any reason other than disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable.
Time frame: Between Day 60 and Day 180
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Non-relapse Mortality, Days 60-180 (D60) | 2 Participants |
Secondary
Number of Participants Who Experience Non-relapse Mortality, Days 90-180 (D90)
Number of participants who die for any reason other than disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable.
Time frame: Between Day 90 and Day 180
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Non-relapse Mortality, Days 90-180 (D90) | 1 Participants |
Secondary
Number of Participants Who Experience Relapse, Day 360 (D60)
Number of participants who experience disease relapse by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Relapse, Day 360 (D60) | 10 Participants |
Secondary
Number of Participants Who Experience Relapse, Day 360 (D90)
Number of participants who experience disease relapse by Day 360. All participants are evaluable.
Time frame: Day 360
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants Who Experience Relapse, Day 360 (D90) | 14 Participants |
Secondary
Number of Participants With Chronic GVHD, Days 60-180 (D60)
Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable.
Time frame: Between Day 60 and Day 180
Population: Of the 60 patients in the D60 cohort, 42 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants With Chronic GVHD, Days 60-180 (D60) | 1 Participants |
Secondary
Number of Participants With Chronic GVHD, Days 90-180 (D90)
Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable.
Time frame: Between Day 90 and Day 180
Population: Of the 57 patients in the D90 cohort, 33 stopped tacrolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants With Chronic GVHD, Days 90-180 (D90) | 2 Participants |
Secondary
Number of Participants With Grades III-IV Acute GVHD, Days 60-180 (D60)
Number of participants who experience grade III or IV acute GVHD between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable.
Time frame: Between Day 60 and Day 180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants With Grades III-IV Acute GVHD, Days 60-180 (D60) | 3 Participants |
Secondary
Number of Participants With Grades III-IV Acute GVHD, Days 90-180 (D90)
Number of participants who experience grade III or IV acute GVHD between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable.
Time frame: Between Day 90 and Day 180
Population: Of the 57 patients in the D90 cohort, 33 stopped tactolimus early as planned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PBSCT D90 | Number of Participants With Grades III-IV Acute GVHD, Days 90-180 (D90) | 1 Participants |