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Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases

Phase 2
2 Years
80 Years
Open (Enrolling)
Hematologic Disease, Lymphoma, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Disorder

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Trial Information

Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases

Patients with malignant and non-malignant hematologic diseases including severe aplastic
anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS),
acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma can
now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has been
ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone marrow
effect of the allograft. Dose intensification of conditioning regimens in attempts to
reduce disease recurrence has been largely unsuccessful because of increased toxicity and
mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal
modality leading to the complete eradication of both malignant and non-malignant host
hematopoietic cells.

The assumption that successful allogeneic BMT relies on the myeloablative effect of
intensive but hazardous chemo-radiotherapy has largely restricted this therapeutic modality
to patients with malignant or life-threatening hematologic disorders under the age of 55
years. Treatment-related mortality increases substantially with age, prior intensive
treatment with chemo-radiotherapy, worsening performance status, and co-morbid medical
conditions. An unacceptable risk of death from conventional BMT renders many patients
ineligible for what may otherwise be curative therapy.

Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8
positive lymphocytes with specific reactivity for the patient's leukemia. These cells
provide a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in
patients with CML relapsing after bone marrow transplantation, where a single infusion of
donor lymphocytes has been shown to induce complete remission. In addition to the potent
anti-leukemia effect of these cells, there is now strong evidence that donor T-cells are
capable of completely eradicating residual host hematopoietic cells in a non-myeloablative
transplant setting (graft-versus-marrow) leading to successful and complete donor
hematopoietic engraftment.

Non-myeloablative allogenic peripheral blood stem cell transplants are currently being
investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
transplant centers. Preliminary data, including our own experience with greater than 150
patients undergoing this type of procedure, have shown a high rate of complete donor
engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative
allo-transplantation in standard risk patients revealed an extremely low rate of
transplant-related complications and mortality.

The decreased risk of transplant-related complications associated with non-myeloablative
transplants expands the eligibility of transplant candidates as well as opens the
possibility to evaluate non-myeloablative regimens in patients at high risk for
complications with standard transplantation. Besides hematologic malignancies, allogeneic
BMT has been shown to be curative in a number of debilitating hematologic diseases which may
behave in a relatively indolent fashion, such as PNH and refractory anemia (RA) or
refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of
treatment-related mortality with standard myeloablative allotransplantation usually
precludes these patients from potentially curative therapy, because of concerns about
shortening life in patients with these disorders. In this protocol we investigate
non-myeloablative allogeneic PBSC transplantation in two groups of subjects where standard
allogeneic transplantation is considered to have unacceptable toxicity.

Group A: Subjects with hematologic malignancies with factors putting them at high risk for
transplant related complications and mortality, including prior intensive chemo-radiotherapy
and co-morbid diseases.

Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with
reasonable longevity not currently considered for allogeneic BMT because of prohibitive
procedural mortality with conventional BMT (Enrollment closed October 2010).

In this protocol, eligible subjects are treated with an allogeneic peripheral blood stem
cell transplant from an HLA identical or single HLA antigen-mismatched family donor, using
an intensive immunosuppressive regimen without myeloablation in an attempt to decrease the
transplant related toxicities while preserving the anti-malignancy and/or anti-host marrow
effect of the graft. The low intensity non-myeloablative conditioning regimen should
provide adequate immunosuppression to allow stem cell and lymphocyte engraftment. T-cell
replete, donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral
blood stem cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution.
We will add back lymphocytes in recipients with less than 100% donor T-cell chimerism in an
attempt to prevent graft rejection and enhance a graft-versus-malignancy effect.

The primary endpoint of this study is transplant related mortality (200 day survival).
Other end points include engraftment, degree of donor-host chimerism, incidence of acute and
chronic graft versus host disease (GVHD), transplant related morbidity as well as
disease-free and overall survival.

Inclusion Criteria


Group A: Subjects at high risk for transplant related complications and mortality as
defined below:

Ages 10 to 75 (both inclusive) with a history of one of the following:

- Treatment with dose intensive chemotherapy and/or radiotherapy

- Previous history of allo/auto transplant

- History of multiple myeloma or extramedullary plasmacytoma

- Chronic disease or co-morbid medical condition including subjects with symptoms or
signs of significant pulmonary disease, hepatic disease, kidney disease, cardiac
disease or disease of other organ systems which would result in increased risk of
morbidity or death from a standard myeloablative transplant.

Diseases to be included:

- Chronic myelogenous leukemia (CML) chronic phase

- Acute lymphoblastic leukemia (ALL), all subjects in complete or partial remission.

- Acute myelogenous leukemia (AML): AML in first complete or partial remission
Exceptions: AML with good risk karyotypes: AML M3 t(15:17), AML M4Eo (inv. 16), AML
t(8;21). All AML in second or subsequent complete remission.

- Myelodysplastic syndromes: refractory anemia with excess blasts (RAEB), or chronic
myelomonocyte leukemia (CMML).

- Myeloproliferative diseases associated with either cytopenia or uncontrolled

- Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with bulky or
progressive disease despite prior treatment with chemotherapy which includes purine

- Non-Hodgkin's lymphoma (NHL)

A) Intermediate or high grade relapsed or progressive despite treatment with standard
therapy ineligible for autologous PBSC transplant.

B) Non-Hodgkin's intermediate or high grade relapsing despite prior autologous transplant.

C) Low grade follicular or small lymphocytic lymphoma (1) high risk patients who have
relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or
PBSC transplant, or (3) chemo resistant disease.

D) Mantle cell lymphoma

E) Non-Hodgkin's lymphoma intermediate or high grade with concurrent BCL2 and MYC
translocations who are at high risk for relapsed and who have low survival with
conventional chemotherapy.

- Hodgkin's disease, relapsed after prior autologous transplant or after 2 or more
combination chemotherapy regimens and ineligible for autologous PBSC transplant.

- EBV driven lymphoproliferative disorders progressing despite standard therapies.

Group B: (Closed to enrollment Oct 2010) Subjects with hematologic diseases associated
with reasonable longevity, shown to be curable by allogeneic BMT but where concern for a
high procedural mortality with conventional BMT may delay or prevent such treatment.

Ages 8 to 80 (both inclusive) with a history of one of the following

- Paroxysmal nocturnal hemoglobinuria (PNH) associated with either life-threatening
thrombosis, cytopenia, transfusion dependence or recurrent and debilitating hemolytic

- Aplastic anemia or pure red cell aplasia (acquired or congenital) in subjects
associated with transfusion dependence and/or neutropenia who are not candidates for
or who have failed immunosuppressive therapy

- Refractory anemia (RA) or RARS MDS subjects who have associated transfusion
dependence and/or neutropenia.

Ability to comprehend the investigational nature of the study and provide informed
consent. The procedure will be explained to subjects age 8-17 years with formal consent
being obtained from parents or legal guardian.

Availability of HLA identical or single HLA locus mismatched family donor


HLA identical or single HLA mismatched family donor

Age greater than or equal to 2 up to 80 years old

Weight greater than or equal to 18 kg

Ability of donor or guardian of donor to comprehend the investigational nature of the
study and provide informed consent.

EXCLUSION CRITERIA - Recipient - any of the following:

Pregnant or lactating

Group A: age less than 10 or greater than 75 (multiple myeloma age less than 10 or greater
than 65); Group B: Age less than 8 or greater than 80 years.

ECOG performance status of 3 or more. Psychiatric disorder or mental deficiency severe as
to make compliance with the BMT treatment unlikely and making informed consent impossible.

Major anticipated illness or organ failure incompatible with survival from PBSC transplant

Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.

Left ventricular ejection fraction: less than 30%.

Serum creatinine greater than 2.5 mg/dl or creatinine clearance less than 50 cc/min by 24
hr urine collection

Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of

Other malignant diseases liable to relapse or progress within 5 years.

EXCLUSION CRITERIA - Donor - any of the following:

Pregnant or lactating

Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of
congestive heart failure or unstable angina, thrombocytopenia)

HIV positive donor. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or
human T-cell lymphotropic virus (HTLV I/II) will be used at the discretion of the
investigator following counseling and approval from the recipient

Type of Study:


Study Design:

Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate engraftment by bone marrow chimerism analysis.

Principal Investigator

Richard W Childs, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)


United States: Federal Government

Study ID:




Start Date:

February 1999

Completion Date:

December 2016

Related Keywords:

  • Hematologic Disease
  • Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndrome
  • Myeloproliferative Disorder
  • Graft-Versus-Leukemia
  • Peripheral Blood Stem Cells
  • Engraftment
  • Cyclophosphamide
  • Fludarabine
  • Donor Apheresis
  • Nonmyeloablative Bone Marrow Transplantation
  • Graft-Versus-Tumor
  • Graft-Versus-Host Disease
  • Multiple Myeloma
  • Extramedullary Plasmacytoma
  • Chronic Disease
  • Chronic Myelogenous Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myelogenous Leukemia
  • Myeloproliferative Disease
  • Chronic Lymphocytic Leukemia
  • Paroxysmal Nocturnal Hemoglobinuria
  • Aplastic Anemia
  • Myelodysplastic Syndrome (MDS)
  • Chronic Myelomoncytic Leukemia
  • Non-Hodgkin's Lymphoma (NHL)
  • Hodgkin Disease
  • Pure Red Cell Aplasia
  • Hematologic Diseases
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892