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Early Administration of ATG Followed by Cyclophosphamide, Busulfan and Fludarabine Before a Donor Stem Cell Transplant in Patients With Hematological Cancer

Information source: Northside Hospital, Inc.
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Myeloproliferative Disorders; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

Intervention: anti-thymocyte globulin (Biological); busulfan (Drug); cyclophosphamide (Drug); fludarabine phosphate (Drug); methotrexate (Drug); tacrolimus (Drug); nonmyeloablative allogeneic HSCT (Procedure)

Phase: Phase 2

Status: Completed

Sponsored by: Northside Hospital, Inc.

Official(s) and/or principal investigator(s):
Asad Bashey, MD, PhD, Principal Investigator, Affiliation: Blood and Marrow Transplant Group of Georgia


RATIONALE: Giving low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before the transplant and tacrolimus and methotrexate after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving antithymocyte globulin together with cyclophosphamide, busulfan, and fludarabine works in treating patients with hematological cancer or kidney cancer undergoing donor stem cell transplant.

Clinical Details

Official title: Pre-administration of Rabbit Antithymocyte Globulin to Optimize Donor T-Cell Engraftment Following Reduced Intensity Allogeneic Peripheral Blood Progenitor Cell Transplantation From Matched-Related Donors

Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Achievement of > 90% (Full) Donor Chimerism in the T-cell Lineage as Measured by PCR at Day 30 Post-transplantation

Secondary outcome:

T-cell and Myeloid Chimerism at Days 90 Post-transplantation (>90% Chimerism)

T-cell and Myeloid Chimerism at Days 180 Post-transplantation (>90%)

Number of Patients Who Experience Severe (Grade 3 or 4) Acute Graft-versus-host Disease

Number of Patients Experiencing Extensive Chronic Graft Versus Host Disease (GVHD)

Non-relapse Mortality (NRM) at Day 180 Post-transplantation

Disease-free Survival (DFS) at 24 Months

Overall Survival (OS) at 24 Months

Detailed description: OBJECTIVES:

- To assess the percentage of patients with hematological malignancies or renal cell

carcinoma who achieve > 90% donor T-cell chimerism at 30 days after treatment with reduced-intensity conditioning comprising low-dose anti-thymocyte globulin, low-dose cyclophosphamide, busulfan, and fludarabine phosphate followed by allogeneic peripheral blood progenitor cell transplantation from a matched related donor.

- To assess the incidence of severe (grade 3 or 4) acute graft-versus-host disease (GVHD)

and extensive chronic GVHD in these patients.

- To assess whether this regimen is associated with reduced transplant-related toxicity

and increased tolerability in these patients.

- To assess the overall safety of this conditioning regimen as measured by 6-month

transplant-related mortality in these patients.

- To determine the efficacy of this regimen in inducing durable remissions in these

patients. OUTLINE:

- Reduced-intensity conditioning (RIC): Patients receive anti-thymocyte globulin IV over

4-6 hours on day - 16 and over 6-8 hours on day -15, fludarabine phosphate IV over 30

minutes on days - 7 to -3, busulfan IV over 3 hours on days -4 and -3, and

cyclophosphamide IV over 1-2 hours on day - 2.

- Transplantation: Patients undergo allogeneic peripheral blood progenitor cell

transplantation on day 0.

- Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus every 12

hours on days - 1 to 90, followed by a taper until day 150. Patients also receive

methotrexate IV on days 1, 3, and 6. Blood samples are collected periodically for pharmacokinetic studies of anti-thymocyte globulin and PCR analysis for chimerism. After completion of study therapy, patients are followed periodically for up to 3 years.


Minimum age: N/A. Maximum age: 75 Years. Gender(s): Both.



- Histologically confirmed diagnosis of one of the following:

- Chronic myeloid leukemia (CML)

- Philadelphia chromosome (Ph)- and/or BCR-ABL-positive disease

- In chronic or accelerated phase

- Suboptimal response to imatinib mesylate (i. e., no hematologic complete

response by 3 months, no major cytogenetic response by 6 months, or no complete cytogenetic response by 1 year)

- CML in blastic transformation allowed provided patient achieved complete

remission (CR) or second chronic phase after treatment with imatinib mesylate or chemotherapy

- Chronic lymphocytic leukemia meeting one of the following criteria:

- Rai stage III or IV disease

- Rai stage I or II disease that failed standard therapy (i. e., disease is

progressing after ≥ 1 course of standard therapy)

- Non-Hodgkin lymphoma (NHL) meeting one of the following criteria:

- Indolent NHL

- Clinical stage III or IV disease or bulky stage II disease (i. e., ≥

one lymphoid mass > 5 cm in ≥ one dimension)

- Relapsed after primary therapy OR is refractory to therapy

- Aggressive NHL

- Is not considered curable with standard chemotherapy or autologous

stem cell transplantation (i. e., relapsed after autologous stem cell transplantation)

- Chemotherapy-responsive disease

- Multiple myeloma

- Durie-Salmon stage II or III disease

- Durie Salmon stage I disease allowed provided β2 microglobulin level >

3 mg/dL

- Acute myeloid leukemia or acute lymphocytic leukemia

- In CR (defined as < 5% blasts in bone marrow and no circulating blasts) AND

has any of the following poor prognostic features:

- WBC > 100,000/mm^3 at presentation

- In second or greater remission

- Adverse-risk cytogenetics (i. e., Ph1-positive, 11q23 translocation,

- 5, -7, complex translocations, or other recognized adverse-risk


- Renal cell carcinoma

- Stage IV disease

- Clear cell morphology

- Myelodysplastic syndromes

- Bone marrow blasts ≤ 10% on last bone marrow biopsy prior to


- Myeloproliferative disease

- Anticipated life expectancy on conventional therapy < 10 years

- No uncomplicated essential thrombocythemia or primary polycythemia

- Hodgkin lymphoma

- Relapsed after ≥ 1 standard-dose chemotherapy regimen

- Not considered curable by autologous stem cell transplantation

- No clinical evidence of active CNS involvement

- Previously treated leptomeningeal disease allowed provided CSF cytology is

negative at the time of assessment for transplantation

- Available 6/6 allele match (i. e., HLA-A, B, DRβ1)matched related donor


- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Bilirubin < 3 times normal (unless abnormality due to malignancy)

- AST and ALT < 3 times normal (unless abnormality due to malignancy)

- Creatinine ≤ 2. 0 mg/dL

- LVEF ≥ 40% by MUGA or ECHO

- DLCO ≥ 40% of predicted

- FEV-1 ≥ 50% of predicted

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Deemed to be an appropriate candidate for allogeneic SCT

- No evidence of myocardial infarction within the past 6 months

- No psychological or social condition that may interfere with study participation

- No serious uncontrolled localized or active systemic infection

- No second malignancy within the past 3 years except for completely excised

nonmelanotic skin cancer or in situ carcinoma of the cervix

- No chronic inflammatory disorder requiring the continued use of glucocorticoids or

other immunosuppressive medications

- No known HIV positivity

- No hypersensitivity to E. coli-derived proteins

Locations and Contacts

Blood and Marrow Transplant Group of Georgia, Atlanta, Georgia 30342, United States
Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Related publications:

Rao SS, Peters SO, Crittenden RB, Stewart FM, Ramshaw HS, Quesenberry PJ. Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment. Exp Hematol. 1997 Feb;25(2):114-21.

Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP, Leisenring W, Shulman H. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997 Apr 15;89(8):3048-54.

Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Kørbling M, Keating M, Kantarjian H, Champlin R. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997 Jun 15;89(12):4531-6.

Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63.

McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers ME, Georges GE, Grumet FC, Kiem HP, Torok-Storb B, Yu C, Blume KG, Storb RF. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001 Jun 1;97(11):3390-400.

Champlin R, Khouri I, Anderlini P, De Lima M, Hosing C, McMannis J, Molldrem J, Ueno N, Giralt S. Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation. Biology and current indications. Oncology (Williston Park). 2003 Jan;17(1):94-100; discussion 103-7. Review.

Platzbecker U, Ehninger G, Schmitz N, Bornhäuser M. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation in myeloid diseases. Ann Hematol. 2003 Aug;82(8):463-8. Epub 2003 Jun 21. Review.

Storb R. Non-myeloablative allogeneic transplantation -- state-of-the-art. Pediatr Transplant. 2004 Jun;8 Suppl 5:12-8. Review.

Starting date: April 2007
Last updated: August 29, 2012

Page last updated: August 20, 2015

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