Reduced-intensity, Related-donor Bone Marrow Transplantation Followed by High-dose Cyclophosphamide for Hematologic Cancers

Phase 2

Terminated

Conditions: Leukemia
Myelodysplastic Syndrome
Lymphoma

Interventions: Drug: Fludarabine
Drug: Busulfan
Drug: Cyclophosphamide
Drug: Mycophenolate Mofetil
Drug: Tacrolimus

Registration Number: NCT01135329

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary: This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a "mini" transplant for patients with blood cancers, using bone marrow from a relative.

The main goal of the study is to determine how quickly the donor's bone marrow "takes" in your body. Other goals include describing how many people accept the bone marrow and how quickly the blood counts come up; describing Graft-versus-host disease (GVHD) and other complications; and describing how many people survive without progressive cancer and survive overall

Detailed Description: At the present time there are few or no cures for people with cancer of the blood or lymph glands outside of a bone marrow transplant (BMT). BMT has developed over several decades of research as an effective treatment of various malignant and nonmalignant hematologic diseases.

This research is being done to learn more about reduced-intensity bone marrow transplantation (BMT), also known as a "mini" transplant for patients with blood cancers, using bone marrow from a relative. The bone marrow for this transplant comes from a relative who is a half-match or "haplo" match to you. Possible donors include parents, siblings, and children.

"Mini" transplants have been given to many people with various cancers but are considered experimental. Over 200 people at Johns Hopkins have received mini transplants with high doses of cyclophosphamide after the transplant. However, the chemotherapy combination and other treatment given before those transplants were different from what is in this study. Although all of the chemotherapy and immune-lowering drugs used in this study are approved by the Food and Drug Administration (FDA), the combination of medications used in this study are not FDA approved and are experimental.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

First-degree related donor who is at minimum HLA haploidentical
Eligible diagnoses:
1. Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm that has progressed during multiagent therapy, failed at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histological conversion:
  - Follicular grade 1 or 2 lymphoma
  - Follicular lymphoma not otherwise specified
  - Marginal zone (or MALT) lymphoma
  - Lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia
  - Hairy cell leukemia
  - Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL)
  - Prolymphocytic leukemia
  - Low grade B-cell lymphoma, unspecified
  - Multiple myeloma
  - Plasma cell leukemia
2. Poor-risk SLL or CLL, defined by an 11q or 17p deletion, histological conversion, or disease progression < 6 months after a purine analog-containing regimen
3. Aggressive lymphoma that has failed at least one prior regimen of multiagent chemotherapy, and patient is either ineligible for autologous BMT or autologous BMT is not recommended:
  - Hodgkin lymphoma
  - Follicular grade 3 lymphoma
  - Mantle cell lymphoma or leukemia
  - Diffuse large B-cell lymphoma (excluding primary CNS lymphoma). Eligible subtypes include primary mediastinal large B-cell lymphoma, T-cell rich large B-cell lymphoma, and large B-cell lymphoma not otherwise specified.
  - Burkitt's lymphoma/leukemia
  - Atypical Burkitt's lymphoma/leukemia (high grade B-cell lymphoma, unclassified, including that with features intermediate between Burkitt's and diffuse large B-cell lymphoma)
  - Anaplastic large cell lymphoma
  - Plasmablastic lymphoma
  - Peripheral T-cell lymphoma
4. Relapsed or refractory acute leukemia in second or subsequent remission
5. Poor-risk acute leukemia in first remission
6. 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
  - Primary refractory disease
    - ALL (leukemia and/or lymphoma) with at least one of the following:
  - Adverse cytogenetics
  - Clear evidence of hypodiploidy
  - Primary refractory disease
    - Biphenotypic leukemia
    - MDS with at least one of the following features:
    - Poor-risk 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
7. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase
8. Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)
9. Chronic myelomonocytic leukemia
10. Juvenile myelomonocytic leukemia
  - For patients with SLL, CLL, or prolymphocytic leukemia, < 20% of bone marrow cellularity involved by this process
  - Adequate end-organ function:
Left ventricular ejection fraction greater than or equal to 35%
Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN
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
- ECOG performance status < 2 or Karnofsky or Lansky score > 60

Exclusion Criteria

Pregnant or breast-feeding
Uncontrolled infection Note: Infection is permitted if there is evidence of response to medication. Eligibility of HIV infected patients will be determined on a case-by-case basis.
Any previous BMT within 3 months prior to start of conditioning
Active extra-medullary leukemia or known active Central Nervous System (CNS) involvement by malignancy. Such disease treated into remission is permitted.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Transplant	Fludarabine	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Transplant	Busulfan	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Transplant	Cyclophosphamide	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Transplant	Mycophenolate Mofetil	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Transplant	Tacrolimus	Reduced-intensity transplant with a fludarabine- and busulfan-based preparative regimen. GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil.

Primary Outcome Measures

Name	Time	Method
Chimerism in Unsorted Peripheral Blood	Day 60	Percentage of participants achieving full-donor chimerism in unsorted peripheral blood.
Chimerism in CD3+ Sorted Peripheral Blood	Day 60	Percentage of participants achieving full-donor chimerism in CD3+ sorted peripheral blood

Secondary Outcome Measures

Name	Time	Method
Incidence of Graft-versus-host-disease (GVHD)	1 year	Percentage of participants experiencing acute and chronic GVHD. Acute GVHD is graded by Przepiorka criteria. Chronic GVHD is graded by NIH consensus criteria and Seattle criteria.
Progression-free Survival	1 year	Percentage of participants alive without disease relapse or progression.
Non-relapse Mortality	1 year	Percentage of participants who died due to BMT-related reasons
Overall Survival	1 year	Percentage of participants alive
Graft Failure	Day 60	Percentage of participants who failed to engraft.
Incidence of Relapse	1 year	Percentage of participants experiencing disease relapse or progression