Total Body Irradiation/Fludarabine Based Ablative Haploidentical Transplant for Hematologic Diseases

Myelodysplastic Syndrome Clinical Trial

Official title:

A Phase II Trial of Total Body Irradiation-Based Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01336712
• Other study ID #: NSH 922
• Status: Completed
• Phase: Phase 2
• First received: April 14, 2011
• Last updated: December 10, 2015
• Start date: April 2011
• Est. completion date: July 2015

Study information

• Verified date: December 2015
• Source: Northside Hospital, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

In this study, patients will receive a myeloablative preparative regimen consisting of fludarabine and total body irradiation (TBI), followed by a T cell replete, mobilized peripheral blood stem cell (PBSC) allograft from a partially matched related donor. All patients will receive post-transplant Cy in addition to standard post transplant immunosuppression with tacrolimus and MMF. The treatment protocol will be essentially identical to the prior study, with the exception of the substitution of TBI for Busulfan. The investigators hypothesize that this change will significantly reduce the risk of HC, while maintaining the efficacy of the transplant.

Description:

Historically, haploidentical HSCT has been associated with significant risks of graft rejection and severe graft versus host disease (GVHD), leading to high treatment related mortality and poor outcomes. The risk of engraftment failure and GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Recently, investigators from Johns Hopkins University demonstrated a new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative regimen, followed by a T cell-replete bone marrow infusion and post-transplantation immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and MMF. Clinical studies have shown this approach to be safe and effective with a low incidence of graft rejection, GVHD, and treatment-related mortality. Relapse represents the major cause of treatment failure in these patients, particularly with high-risk myeloid malignancies.

In order to decrease this relapse risk in high-risk patients, the investigators initiated a myeloablative haploidentical HSCT study in January 2009 utilizing Busulfan-based conditioning, post-transplant Cy, and PBSC, instead of BM, as the stem cell source. Outcomes of the 15 patients transplanted to date have been promising with 100% engraftment, low rates of treatment-related mortality, relapse and GVHD, and excellent survival rates. An unexpected outcome of the study was a higher-than-expected rate of BK virus-induced hemorrhagic cystitis (HC) occurring in 7 of 14 evaluable patients. Although there were no deaths attributable to HC, it was associated with significant morbidity in some patients.

HC is a recognized complication of allogeneic transplant therapy. Late onset HC, occurring after engraftment, is due almost exclusively to reactivation of the polyoma BK virus (BKV). Other important risk factors associated with HC include Busulfan-based conditioning, acute GVHD, HLA mismatched transplants, and use of bone marrow as the stem cell source. TBI-based conditioning, prior to myeloablative allogeneic transplant, has been associated with significantly less HC than Busulfan-based conditioning in both retrospective and prospective randomized trials.

Eighteen patients will be accrued to this study. The primary end point of this study is the incidence of HC. The investigators will also examine the incidence of acute and chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2015
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• No available matched related or unrelated donor OR a matched related or unrelated donor that is unavailable in the time frame necessary

• Availability of a 3/6 or 5/6 matched (HLA-A, B, DR) related donor

• Donor must have a negative HLA cross-match in the host vs. graft direction

• Donor must be willing to donate mobilized peripheral blood stem cells

• Age 18 to </=60 years

• Karnofsky Status >/= 70%

• Must have one of the following high-risk malignancies

• Chronic Myelogenous Leukemia (CML) in chronic phase, resistant and/or intolerant to TKI

• CML in accelerated phase

• CML blast crisis that has entered into 2nd Chronic phase following induction

• Acute Myelogenous Leukemia (AML) in 2nd or subsequent complete remission (CR)

• AML primary induction failure but subsequently in CR

• AML in 1st CR with poor risk cytogenetics or arising from preceding hematologic disease

• AML with marrow blasts <5% but persistence of minimal residual disease by flow cytometry, cytogenetics or FISH

• Myelodysplastic Syndrome (MDS) that is treatment related

• MDS that has monosomy 7 or complex cytogenetics

• MDS with IPSS score of 1.5 or greater

• Chronic myelomonocytic leukemia (CMML)

• Acute Lymphocytic Leukemia/lymphoblastic lymphoma (ALL) in 2nd or subsequent complete remission (CR)

• ALL with poor-risk karyotype [t(9;22) or bcr-abl fusion, t(4;11) or other MLL translocation] and in 1st CR

• ALL with marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics or FISH

• Chronic Lymphocytic Leukemia (CLL)/Prolymphocytic Leukemia (PLL) with previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy including purine analogs AND in the opinion of the transplant physician is unlikely to benefit from reduced intensity transplantation due to the presence of one or more high risk features (i.e. bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy)

• Hodgkin's or Non-Hodgkin's Lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse) with previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation AND in the opinion of the transplant physician is unlikely to benefit from reduced intensity transplantation due to the presence of one or more high risk features (i.e. bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy)

• Advance Myelofibrosis, Primary or Post-Polycythemia Vera/Essential Thrombocythemia. Patients must have one of more of the following accelerate phase features, which have been associated with a median overall survival of </= 15 months

• Blood or bone marrow blasts >/= 10%

• Platelets < 50 x 10*9/L

• Chromosome 17 aberrations

Exclusion Criteria:

• Patients will not be excluded on the basis of sex, racial or ethnic background

• Poor cardiac function: Left ventricular ejection fraction < 45%

• Poor pulmonary function: FEV1 and FVD < 60% predicted

• Poor liver function: bilirubin >/= 2.5 mg/dl (not due to hemolysis, Gilbert's or primary malignancy), AST/ALT > 3x ULN

• Poor renal function: Creatinine >/= 2.0 mg/dl or creatinine clearance (calculated creatinine clearance is permitted) < 40 mL/min based on Traditional Cockcroft-Gault formula: 140-age (yrs) x smaller of actual weight vs ideal body weight (kg)/72 x serum creatinine (mg/dl)

• HIV positive

• Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception

• Patients who have any debilitating medical or psychiatric illness which would preclude their giving informed consent or their receiving optimal treatment and follow-up.

• Prior irradiation therapy rendering patient ineligible for TBI

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Leukemia
• Chronic Leukemia
• Hodgkin Disease
• Hodgkin's Disease
• Leukemia
• Lymphoma, Non-Hodgkin
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Non-Hodgkin's Lymphoma
• Preleukemia

Intervention

Procedure:
• Peripheral Blood Stem Cell Transplant
Total Body Irradiation 1200cGy (150cGy given in 8 fractions twice a day six hours apart on days -4, -3, -2 and -1. Fludarabine 30 mg/m^2 given once a day for 3 days on days -7, -6 and -5 Cyclophosphamide 50mg/kg given one a day on days +3 and +4

Locations

Country	Name	City	State
United States	Northside Hospital	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Northside Hospital, Inc.	Blood and Marrow Transplant Group of Georgia

Country where clinical trial is conducted

United States, 

References & Publications (14)

Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, Clift R, Doney K, Martin PJ, Mickelson E, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989 Jan 26;320(4):197-204. — View Citation

Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE, Thomas ED, Hansen JA. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990 Oct;29(2):79-91. — View Citation

Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998 Oct 22;339(17):1186-93. — View Citation

Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005 May 20;23(15):3447-54. Epub 2005 Mar 7. — View Citation

Guinan EC, Boussiotis VA, Neuberg D, Brennan LL, Hirano N, Nadler LM, Gribben JG. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med. 1999 Jun 3;340(22):1704-14. — View Citation

Kanda Y, Chiba S, Hirai H, Sakamaki H, Iseki T, Kodera Y, Karasuno T, Okamoto S, Hirabayashi N, Iwato K, Maruta A, Fujimori Y, Furukawa T, Mineishi S, Matsuo K, Hamajima N, Imamura M. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991-2000). Blood. 2003 Aug 15;102(4):1541-7. Epub 2003 Apr 24. — View Citation

Kernan NA, Collins NH, Juliano L, Cartagena T, Dupont B, O'Reilly RJ. Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease. Blood. 1986 Sep;68(3):770-3. — View Citation

Kernan NA, Flomenberg N, Dupont B, O'Reilly RJ. Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation. 1987 Jun;43(6):842-7. — View Citation

Lang P, Greil J, Bader P, Handgretinger R, Klingebiel T, Schumm M, Schlegel PG, Feuchtinger T, Pfeiffer M, Scheel-Walter H, Führer M, Martin D, Niethammer D. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis. 2004 Nov-Dec;33(3):281-7. — View Citation

Mehta J, Singhal S, Gee AP, Chiang KY, Godder K, Rhee Fv Fv, DeRienzo S, O'Neal W, Lamb L, Henslee-Downey PJ. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004 Feb;33(4):389-96. — View Citation

Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, Chute J, Smith C, Gong JZ, Lagoo A, Niedzwiecki D, Dowell JM, Waters-Pick B, Liu C, Marshall D, Vredenburgh JJ, Gockerman J, Decastro C, Moore J, Chao NJ. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007 Feb 20;25(6):690-7. Epub 2007 Jan 16. — View Citation

Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH, Bradley BA, Casper JT, Flomenberg N, Gajewski JL, Gluckman E, Henslee-Downey PJ, Hows JM, Jacobsen N, Kolb HJ, Lowenberg B, Masaoka T, Rowlings PA, Sondel PM, van Bekkum DW, van Rood JJ, Vowels MR, Zhang MJ, Horowitz MM. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997 May;15(5):1767-77. — View Citation

Waller EK, Giver CR, Rosenthal H, Somani J, Langston AA, Lonial S, Roback JD, Li JM, Hossain MS, Redei I. Facilitating T-cell immune reconstitution after haploidentical transplantation in adults. Blood Cells Mol Dis. 2004 Nov-Dec;33(3):233-7. — View Citation

Zuckerman T, Rowe JM. Alternative donor transplantation in acute myeloid leukemia: which source and when? Curr Opin Hematol. 2007 Mar;14(2):152-61. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Patients Experiencing Hemorrhagic Cystitis Post Transplant	1.1 To estimate the incidence of BK virus-associated hemorrhagic cystitis following a TBI-based myeloablative haploidentical HSCT in patients with high risk hematologic malignancies.	6 months	Yes
Secondary	Survival	To obtain estimate of overall survival (OS)	2 year	Yes
Secondary	Percentage of Participatns With Donor Chimerism Post-transplant	Characterize donor hematopoietic chimerism in peripheral blood at day 30 after HSCT.	Day 30	Yes
Secondary	Disease Free Survival (DFS) Percentage		2 year	No
Secondary	Non-relapsed Mortality (NRM) Percentage		2 year	Yes
Secondary	Relapse Rate		2 year	No
Secondary	Cumulative Incidence of Chronic Graft-versus-host Disease		2 year	Yes