Hematologic Malignancies
Conditions
Keywords
Reduced intensity, partially HLA mismatched allogeneic BMT, Acute leukemias, Chronic leukemias, Myelodysplasia, Lymphomas, Unrelated or non-first-degree related donors, Peripheral blood stem cell transplant
Brief summary
If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, the current study extends our platform of nonmyeloablative, partially HLA-mismatched bone marrow transplant (BMT) and Peripheral Blood Stem Cell Transplant (PBSCT) to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose Cy. Of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. The primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade III- IV GVHD or graft failure.
Interventions
DRUGFludarabine
Fludarabine 30 mg/m2/day
DRUGCytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
RADIATIONTotal Body Irradiation
400 cGy TBI administered in a single fraction
PROCEDUREAllogeneic Blood or Marrow Transplant
DRUGMycophenolate Mofetil
15mg/kg by mouth three times daily
DRUGSirolimus
Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily
DRUGTacrolimus
Tacrolimus 1mg intravenously, daily
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Patient Inclusion Criteria: 1. Patient age 0.5-75 years 2. Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1. 3. Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference. 4. Eligible diagnoses: 1. Relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically 2. Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically: * AML with at least one of the following: * AML arising from MDS or a myeloproliferative disorder, or secondary AML * Presence of Flt3 internal tandem duplications * Poor-risk cytogenetics: Complex karyotype \[\> 3 abnormalities\], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7 * Primary refractory disease * ALL (leukemia and/or lymphoma) with at least one of the following: * Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement * Clear evidence of hypodiploidy * Primary refractory disease * Biphenotypic leukemia 3. MDS with at least one of the following poor-risk features: * Poor-risk cytogenetics (7/7q minus or complex cytogenetics) * IPSS score of INT-2 or greater * Treatment-related MDS * MDS diagnosed before age 21 years * Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy * Life-threatening cytopenias, including those generally requiring greater than weekly transfusions 4. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase. 5. Philadelphia chromosome negative myeloproliferative disease. 6. Chronic myelomonocytic leukemia. 7. Juvenile myelomonocytic leukemia. 8. Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm that has: * progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or * in the case of lymphoma undergone histologic conversion; * patients with transformed lymphomas must have stable disease or better. 9. Poor-risk CLL or SLL as follows: * 11q deletion disease that has progressed after a combination chemotherapy regimen, * 17p deletion disease, * or histologic conversion; * patients with transformed lymphomas must have stable disease or better. 10. Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy: * NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell lymphoma * Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended. * Eligible subtypes of aggressive non-Hodgkin lymphoma include: * mantle cell lymphoma * follicular grade 3 lymphoma * diffuse large B-cell lymphoma or its subtypes, excluding primary CNS lymphoma * primary mediastinal large B-cell lymphoma * large B-cell lymphoma, unspecified * anaplastic large cell lymphoma, excluding skin-only disease * Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt's), in complete remission 5. Patients with CLL, SLL, or prolymphocytic leukemia must have \< 20% bone marrow involvement by malignancy (to lower risk of graft rejection). 6. One of the following, in order to lower risk of graft rejection: * Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or * Previous BMT within 6 months prior to start of conditioning. NOTE: Patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the PI or co-PI. 7. Any previous BMT must have occurred at least 3 months prior to start of conditioning. 8. Adequate end-organ function as measured by: 1. Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction \> 25%, unless cleared by a cardiologist 2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \< 5 x ULN 3. FEV1 and FVC \> 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation \>92% on room air 9. ECOG performance status \< 2 or Karnofsky or Lansky score \> 60 Patient
Exclusion criteria
* Not pregnant or breast-feeding. * No uncontrolled bacterial, viral, or fungal infection. * Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected patients will be determined on a case-by-case basis. * No previous allogeneic BMT (syngeneic BMT permissible). * Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted. Donor Inclusion Criteria: 1. Potential donors consist of: * Unrelated donors * Second-degree relatives * First cousins 2. The donor and recipient must be identical at at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1). 3. Meets institutional selection criteria and medically fit to donate. 4 . Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result. Donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Have Severe Acute Graft-versus-host-disease (GVHD) | Study Day 100 | Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors. Transplant regimen will be determined by acceptable rates of severe acute GVHD (\< 25%). |
| Number of Participants Who Have Transplant-related Nonrelapse Mortality (NRM) | Study Day 100 | Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors. Transplant regimen will be determined by acceptable number of participants with transplant-related NRM. |
| 6-month Probability of Survival as Assessed by Absence of Grade III-IV GVHD or Evidence of Graft Failure. | 6 months | Number of participants who do not have grade II-IV GVHD or evidence of graft failure will be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 2 years | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. |
| Event-free Survival | 7 years | All patients will be tracked from Day 0 to date of first observed disease progression, or death from any cause, or last patient evaluation. Patients will be followed on study to identify instances of death, progression or disease recurrence. |
| Overall Survival | 7 years | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. |
| Cumulative Incidence of Progression or Relapse | 7 years | All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression. |
| Cumulative Incidence of Non-relapse Mortality (NRM). | 7 years | All patients will be tracked from Day 0 to date of first observed disease relapse or progression, or death from disease, or last patient evaluation. Patients who have not progressed or died by their last patient contact visit will be censored at the last date they were assessed and deemed free of relapse or progression. |
| Cumulative Incidence of Acute Grade II-IV GVHD. | 1 year | All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded. |
| Cumulative Incidence of Acute Grade III-IV GVHD | 1 year | All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded. |
| Cumulative Incidence of Chronic GVHD | 1 year | All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded. |
| Cumulative Incidence of Graft Failure | 1 year | Number of cases with less than 5% donor chimerism in blood and/or bone marrow on \~Day 30 or after and on all subsequent measurements, in the absence of documented bone marrow involvement by malignancy. |
| Cumulative Incidence of Neutrophil Recovery | 1 year | Number of cases who achieve a post nadir ANC greater or equal to 500/mm3 for three consecutive measurements on different days. |
| Cumulative Incidence of Platelet Recovery | 1 year | Number of cases who achieve a platelet count greater than 20,000/mm3 or greater than 50,000/mm3 with no platelet transfusions in the preceding seven days, as measured as maintained on at least three consecutive measurements on different days. |
| Cumulative Incidence of Donor Engraftment | 1 year | Number of cases who achieve either mixed donor chimerism is defined as greater than 5%, but less than 95%, donor or full donor chimerism is defined as \> 95% donor. |
| Cumulative Incidence of Failure Free Survival | 7 years | Number of cases who reach the end of the trial without severe acute (grade III-IV) GVHD, graft failure, or non-relapse mortality |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRichard Ambinder, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants |
| Age, Continuous | 53 years STANDARD_DEVIATION 13.37 |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment United States | 87 Participants |
| Sex: Female, Male Female | 38 Participants |
| Sex: Female, Male Male | 32 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 | 2 / 54 | 0 / 1 | 1 / 30 | 0 / 2 |
| other Total, other adverse events | 1 / 54 | 0 / 1 | 0 / 30 | 0 / 2 |
| serious Total, serious adverse events | 1 / 54 | 0 / 1 | 0 / 30 | 0 / 2 |
Outcome results
None listed