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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


Phase 2
18 Years
60 Years
Open (Enrolling)
Both
Chronic Leukemia, Acute Leukemia, Hodgkin's Disease, Non-Hodgkin's Lymphoma, Myelodysplastic Syndrome

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Trial Information

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


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.


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
- 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
- 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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Number of patients experiencing hemorrhagic cystitis post transplant

Outcome Description:

1.1 To estimate the incidence of hemorrhagic cystitis following a TBI-based myeloablative haploidentical HSCT in patients with high risk hematologic malignancies. For this study, HC will be defined as the development of late-onset (post-engraftment) macroscopic hematuria and dysuria, associated with positive urine PCR for BK virus or adenovirus. Asymptomatic viruria, with or without microscopic hematuria, will not be considered an episode of HC.

Outcome Time Frame:

6 months

Safety Issue:

Yes

Principal Investigator

Scott R Solomon, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Blood and Marrow Transplant Group of Georgia

Authority:

United States: Institutional Review Board

Study ID:

NSH 922

NCT ID:

NCT01336712

Start Date:

April 2011

Completion Date:

August 2014

Related Keywords:

  • Chronic Leukemia
  • Acute Leukemia
  • Hodgkin's Disease
  • Non-Hodgkin's Lymphoma
  • Myelodysplastic Syndrome
  • CML
  • CLL
  • AML
  • ALL
  • MDS
  • HD
  • NHL
  • MFB
  • P.vera
  • Essential Thrombocytosis
  • Hematologic Diseases
  • Hodgkin Disease
  • Leukemia
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Myelodysplastic Syndromes
  • Preleukemia
  • Chronic Disease

Name

Location

Northside HospitalAtlanta, Georgia  30342