Clinical trial NCT00303719: Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy
Official title: Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Kidney Cancer
Leukemia
Lymphoma
Multiple Myeloma
Plasma Cell Neoplasm
Myelodysplastic Syndromes
Keywords: leukemia
lymphoma
myeloma
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2006-03-17
Enrollment: 342
Sex: ALL
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.

Detailed description: OBJECTIVES:

* Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation.
* Determine the safety of this nonmyeloablative transplantation regimen in these patients.
* Determine the risk of graft-versus-host-disease in patients treated with this regimen.
* Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen.
* Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high).
* Preparative regimen\*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)\*\* IV every 12 hours on days -6 to -4. Patients who receive ATG\* include the following:

  * Related donor recipients who have not received combination chemotherapy within the past 6 months
  * Unrelated donor recipients who have not received combination chemotherapy within the past 3 months
  * Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: \*\*Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG.
* Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0.
* Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30.
* Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours.

After completion of study treatment, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Eligibility criteria: Inclusion Criteria:

Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with aplasia) will be considered separately in Arm 7.

* Age and Graft criteria (all patients)

  * Patient's \< or = 75 years old with a 5/6 or 6/6 related donor match are eligible.
  * Patient's \< or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match are eligible.
* Disease Criteria (standard risk patients)

  * Acute myelogenous leukemia
  * Acute lymphocytic leukemia
  * Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible).
  * Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating chemosensitive disease
  * Acquired bone marrow failure syndromes
  * Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS categories if severe pancytopenia, transfusion requirements not responsive to therapy, or high risk cytogenetics. Blasts must be less than 5%. If \>5% requires therapy (induction or Hypomethylating agents) pre-transplant to decrease disease burden.
  * Renal cell cancer,
  * Chronic myeloproliferative disorder, i.e. myelofibrosis
* Disease Criteria (High risk patients on Arm 7)

  * Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately in Arm 7.
* Adequate organ function and performance status (all patients)

Exclusion Criteria:

* Pregnancy or breast feeding
* Evidence of HIV infection or known HIV positive serology
* Active serious infection
* Congenital bone marrow failure syndrome
* Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI)
* Chronic myelogenous leukemia (CML) in refractory blast crisis
* Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky.
* Multiple Myeloma progressive on salvage chemotherapy.

DONOR ELIGIBILITY

* Related will undergo apheresis - if donor is unable to undergo apheresis, a bone marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone marrow harvest or apheresis.
* All donors must be able to give informed consent.
* Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for suitability of the apheresis procedure. Informed consent must be obtained from parent or guardian as applicable for minors.

Primary outcomes:
measure: Neutrophil and Donor Cell Engraftment
timeFrame: Day 42 and Day 100
Secondary outcomes:
measure: Serious Adverse Events
timeFrame: Day 100
measure: Transplant Related Mortality
timeFrame: Day 100
measure: Overall Survival
timeFrame: 1 year
measure: Acute Graft-Versus-Host Disease
timeFrame: Day 100
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Erica Warlick, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Warlick E, Ahn KW, Pedersen TL, Artz A, de Lima M, Pulsipher M, Akpek G, Aljurf M, Cahn JY, Cairo M, Chen YB, Cooper B, Deol A, Giralt S, Gupta V, Khoury HJ, Kohrt H, Lazarus HM, Lewis I, Olsson R, Pidala J, Savani BN, Seftel M, Socie G, Tallman M, Ustun C, Vij R, Vindelov L, Weisdorf D. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era. Blood. 2012 Apr 26;119(17):4083-90. doi: 10.1182/blood-2012-02-409763. Epub 2012 Mar 9.
citation: Warlick ED, DeFor TE, Bejanyan N, Holtan S, MacMillan M, Blazar BR, Dusenbery K, Arora M, Bachanova V, Cooley S, Lazaryan A, McGlave P, Miller JS, Rashidi A, Slungaard A, Vercellotti G, Ustun C, Brunsein C, Weisdorf D. Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up. Biol Blood Marrow Transplant. 2019 Jan;25(1):56-62. doi: 10.1016/j.bbmt.2018.07.038. Epub 2018 Aug 1.
citation: Bachanova V, Burke MJ, Yohe S, Cao Q, Sandhu K, Singleton TP, Brunstein CG, Wagner JE, Verneris MR, Weisdorf DJ. Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant. 2012 Jun;18(6):963-8. doi: 10.1016/j.bbmt.2012.02.012. Epub 2012 Mar 16.
citation: Bachanova V, Sandhu K, Yohe S, Cao Q, Burke MJ, Verneris MR, Weisdorf D. Allogeneic hematopoietic stem cell transplantation overcomes the adverse prognostic impact of CD20 expression in acute lymphoblastic leukemia. Blood. 2011 May 12;117(19):5261-3. doi: 10.1182/blood-2011-01-329573. Epub 2011 Mar 14.
citation: Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009 Mar 26;113(13):2902-5. doi: 10.1182/blood-2008-10-184093. Epub 2009 Jan 28.