Background:
Blood cancers (such as leukemias or lymphomas) often do not respond to standard treatments. A transplant of blood stem cells from a healthy donor can help people with these cancers. Sometimes these transplants cause serious side effects, including a common immunologic problem called graft-versus-host disease. A drug called cyclophosphamide given early after the transplant (post-transplantation cyclophosphamide, PTCy) can reduce these complications. But sometimes this drug has its own negative effects. Furthermore, studies in mice suggest that an intermediate, rather than very high, dose of this drug may best protect against graft-versus-host disease.
Objective:
To find out if a lower dose of PTCy is more helpful for people who undergo blood stem cell transplants.
Eligibility:
People aged 18 and older who have a blood cancer and are eligible for a transplant of blood stem cells from another person. Healthy donors are also needed but must be related to the individual needing the transplant.
Design:
Participants will undergo screening. Transplant recipients will have imaging scans and tests of their heart and lung function. They will be assessed for the status of their cancer, including bone marrow taken from their pelvis and possibly also scans and/or fluid drawn from the spine depending on the disease type.
Donors will be screened for general health. They will give several tubes of blood. They will give an oral swab and saliva and stool samples for research.
Recipients will be in the hospital at least 4 to 6 weeks.
They will have a temporary catheter inserted into a vein in the chest or neck. Medications will be given and blood will be drawn through the catheter.
The transplanted stem cells will be given through the catheter. Participants will receive medications both before and after the transplant.
Participants will return to the clinic at least once a week for 3 months after leaving the hospital. Follow-up visits will continue periodically for 5 years.
Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
AML of any risk in second or subsequent morphologic complete remission
Acute lymphoblastic leukemia in first or subsequent complete remission
Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
Participants who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 2 weeks prior to the date of beginning conditioning.
Active nursing.
Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is: metastatic, or relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment, or limited disease treated with curative intent treatment within the last 2 years. This excludes non-melanoma skin cancers.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents.
Sequential
Melphalan
DrugMatched HCT: 100 mg/m\^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m\^2 IV on day -6 over approximately 20-30 minutes.
Sirolimus
DrugSirolimus: Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg)\^d, then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions and may be modified based on institutional practice.
Total Body Irradiation (TBI)
RadiationHaplo HCT only: A dose of 200 cGy will be administered on day -1.
Cyclophosphamide
Drugbased on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.
Mycophenolate Mofeti
Drug15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.
Fludarabine
DrugMatched HCT: 25 mg/m\^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 40 mg/m\^2/day infused IV over approximately 30-60 minutes from day -5 to day -2
Allogeneic HSCT
Procedure/SurgeryStem cell transplant
Mesna
Drugequal to the cyclophosphamide dose (50, 35, 25, or 15 mg/kg) as IV infusion concomitant with cyclophosphamide. Mesna is dosed in the same way as cyclophosphamide regarding ideal vs. actual body weight.b Dosing may be modified based on institutional standard practice.
Filgrastim
Drugbegins on day +5 at a dose of 5 mcg/kg/day (actual body weight; dose rounding is permitted e.g., nearest vial or syringe size) and is administered daily subcutaneously or IV until the absolute neutrophil count is \> 1000 cells/mm3 for three days or \> 5000 for one day.
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Treatment groupsSee each treatment group below.
Phase II: Evaluate the efficacy of PTCy, at the lowest dose determined for each HLA-matching arm from phase I, as assessed by 1-year GVHD-free relapse-free survival (GRFS) rate.
1-year GRFS and 95% CI per arm will be estimated using Kaplan-Meier curves.
Phase I: Determine the lowest effective dose of PTCy in combination with sirolimus and mycophenolate mofetil as GVHD prophylaxis after reduced intensity conditioning and PBSCT, as assessed by primary graft failure AND Grade III-IV acute GVHD as ...
Number of evaluable subjects and DLT will be summarized per dose level in each arm.
Estimate rates of symptomatic BK virus cystitis. (Phase I and II)
To evaluate symptomatic BK virus cystitis using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing the outcome.
Estimate rates of hematopoietic recovery/engraftment. (Phase I and II)
Rate and timing of neutrophil and platelet engraftment also will be evaluated descriptively, including fractions who attain each condition at day 28, 42, and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting subjects.
Estimate rates of Grade II-IV and III-IV acute GVHD at 100 days (Phase I and II)
To evaluate for grades II-IV and III-IV acute GVHD at 100 days using Kaplan-Meier curves or competing risk-based cumulative incidence curves. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.
Estimate non-relapse mortality at one year (Phase II only)
To evaluate non-relapse mortality at one year, estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other.
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