Background:
Certain blood cancers can be treated with blood or bone marrow transplants. Sometimes the donor cells attack the recipient's body, called graft-versus-host disease (GVHD). The chemotherapy drug cyclophosphamide helps reduce the risk and severity of GVHD. Researchers want to learn if using a lower dose of cyclophosphamide may reduce the drug's side effects while maintaining its effectiveness. Such an approach is being used in an ongoing clinical study at the NIH with promising results, but this approach has not been tested for transplants using lower doses of chemotherapy/radiation prior to the transplant.
Objective:
To learn if using a lower dose of cyclophosphamide will help people have a successful transplant and have fewer problems and side effects.
Eligibility:
Adults ages 18-85 who have a blood cancer that did not respond well to standard treatments or is at high risk for relapse without transplant, and their donors.
Design:
Participants may be screened with the following:
Medical history
Physical exam
Blood and urine tests
Heart and lung tests
Body imaging scans (they may get a contrast agent)
Spinal tap
Bone marrow biopsy
Participants will be hospitalized for 4-6 weeks. They will have a central venous catheter placed in a chest or neck vein. It will be used to give medicines, transfusions, and the donor cells, and to take blood. In the week before transplant, they will get 2 chemotherapy drugs and radiation. After the transplant, they will get the study drug for 2 days. They will take other drugs for up to 2 months.
Participants must stay near NIH for 3 months after discharge for weekly study visits. Then they will have visits every 3-12 months until 5 years after transplant.
Participants and donors will give blood, bone marrow, saliva, cheek swab, urine, and stool samples for research.
Acute myeloid leukemia in morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
B-cell acute lymphoblastic leukemia in first or subsequent complete remission
T-cell 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)
Subjects 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.
Leukemia not having achieved morphologic remission (i.e. bone marrow blasts >5% or active extramedullary disease)
Lymphoma not having achieved at least a partial response to prior chemotherapy or radiation
Uncontrolled intercurrent illness that in the opinion of the site PI would make it unsafe to proceed with transplantation.
Sequential
Mycophenolate Mofetil
Drug15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.
Allogeneic HSCT
Procedure/SurgeryStem cell transplant
Fludarabine
Drug30 mg/m2 IV infusion over 30-60 minutes once daily for 5 days (Pre-Transplant days -6 through -2).
Sirolimus
DrugLoading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), 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 +60 with no taper. May be continued beyond the protocol specified stop date if there is GVHD or mixed chimerism.
Filgrastim
Drugbegins on day +5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously, until the absolute neutrophil count is \> 1,000/mm3 over the course of three days or \> 5,000/mm3 on one day. Rounding to the nearest vial is allowed. G-CSF may be stopped early or not administered if required by the clinical circumstance. Additional G-CSF may be administered as warranted.
Cyclophosphamide
DrugPre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant (Pre-Transplant days -6 and -5). Post-transplant: 25 mg/kg/day or 35 mg/kg/day (Post-transplant days +3 and +4).
Mesna
Drug25 or 35 mg/kg (equal to the cyclophosphamide dose) as IV infusion concomitant with cyclophosphamide. Mesna may or may not be given with the pre-transplant cyclophosphamide depending on institutional practice.
Total Body Irradiation (TBI)
Procedure/Surgery400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice daily. Pre-Transplant Day -1 (or Day 0 prior to graft administration)
determine if optimal dose of PTCy to prevent grade III-IV acute GVHD (aGVHD) at day +60
The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals. In addition, a cumulative incidence curve for this endpoint will be constructed.
Grade III-IV acute GVHD at day 100 and 200
Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, non-relapse mortality, and chronic GVHD will be competing risks for acute GVHD. Grade III-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.
Grade II-IV acute GVHD at day 100 and 200
Estimates will be determined using competing risk-based cumulative incidence curves. Grade II-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals.
Rate of Fried s Frailty Phenotypes (FP)
Frequency of different phenotypes
Chronic GVHD at one year
Estimates will be determined using competing risk-based cumulative incidence curves. Graft failure, relapse, donor lymphocyte infusion, and non-relapse mortality will be competing risks for chronic GVHD.
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