Clinical trial NCT00818961: Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer
Official title: Reduced Intensity Allogeneic Stem Cell Transplantation With Matched Unrelated Donors for Patients With Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
adult AML with 11q23 (MLL) abnormalities
blastic phase chronic myelogenous leukemia
chronic myelomonocytic leukemia
chronic phase chronic myelogenous leukemia
prolymphocytic leukemia
recurrent adult T-cell leukemia/lymphoma
refractory chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
stage I adult T-cell leukemia/lymphoma
stage I chronic lymphocytic leukemia
stage II adult T-cell leukemia/lymphoma
stage II chronic lymphocytic leukemia
stage III adult T-cell leukemia/lymphoma
stage III chronic lymphocytic leukemia
stage IV adult T-cell leukemia/lymphoma
stage IV chronic lymphocytic leukemia
recurrent adult Hodgkin lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
cutaneous B-cell non-Hodgkin lymphoma
recurrent cutaneous T-cell NHL
stage I cutaneous T-cell NHL
stage II cutaneous T-cell NHL
stage III cutaneous T-cell NHL
stage IV cutaneous T-cell NHL
extranodal marginal zone B-cell lymphoma of mucosal tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
contiguous st II adult diffuse large cell lymphoma
contiguous st II adult diffuse mixed cell lymphoma
contiguous st II adult diffuse sm cleaved cell lymphoma
contiguous st II grade 1 follicular lymphoma
contiguous st II grade 2 follicular lymphoma
contiguous st II grade 3 follicular lymphoma
contiguous st II mantle cell lymphoma
contiguous st II marginal zone lymphoma
contiguous st II small lymphocytic lymphoma
stage I adult diffuse large cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage I grade 1 follicular lymphoma
stage I grade 2 follicular lymphoma
stage I grade 3 follicular lymphoma
stage I mantle cell lymphoma
stage I marginal zone lymphoma
stage I small lymphocytic lymphoma
noncontiguous st II adult diffuse large cell lymphoma
noncontiguous st II adult diffuse mixed cell lymphoma
noncontiguous st II adult diffuse sm cleaved cell lymphoma
noncontiguous st II grade 1 follicular lymphoma
noncontiguous st II grade 2 follicular lymphoma
noncontiguous st II grade 3 follicular lymphoma
noncontiguous st II mantle cell lymphoma
noncontiguous st II marginal zone lymphoma
noncontiguous st II small lymphocytic lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult gr III lymphomatoid granulomatosis
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
de novo MDS
previously treated MDS
secondary myelodysplastic syndromes
Waldenstrom macroglobulinemia
myelodysplastic/myeloproliferative disease
Lead sponsor: Northside Hospital, Inc.
Sponsor class: OTHER
Collaborators: name: Blood and Marrow Transplant Group of Georgia
First posted: 2009-01-08
Enrollment: 36
Sex: ALL
Minimum age (years): 40
Maximum age (years): 72
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 a monoclonal antibody, such as alemtuzumab, before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of donor stem cell transplant and to see how well it works in treating patients with high-risk hematologic cancer.

Detailed description: OBJECTIVES:

* To evaluate the safety and toxicity of a reduced-intensity conditioning regimen followed by allogeneic bone marrow or peripheral blood stem cell transplantation from an HLA-matched unrelated donor in patients with high-risk hematologic malignancies.
* To evaluate engraftment by peripheral blood chimerism analysis.
* To determine the incidence and severity of acute and chronic graft-versus-host disease following the transplant.
* To examine the possibility of controlling hematologic malignancies by induction of a graft-versus-leukemia/tumor effect.
* To determine the disease-free survival, relapse, transplant-related mortality, and death from all causes.

OUTLINE:

* Reduced-intensity conditioning regimen: Patients receive 1 of 2 conditioning regimens according to diagnosis.

  * Regimen 1 (acute leukemia, myelodysplastic syndromes, myeloproliferative syndrome, or chronic myelogenous leukemia): Patients receive fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -6 to -3 or orally 4 times daily on days -7 to -3.
  * Regimen 2 (lymphoproliferative malignancies): Patients receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 1 hour on days -5 to -3. Patients with CD20+ malignancies also receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8.
* Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive low-dose alemtuzumab subcutaneously on days -11 to -9 and tacrolimus IV over 24 hours beginning on day -3 and then orally twice daily beginning on day 14 and continuing until day 60, followed by a taper until day 180 in the absence of clinically significant GVHD. Patients also receive methotrexate on days 1, 3, and 6.

Patients who exhibit persistent mixed chimerism or disease relapse/progression despite full withdrawal of immunosuppression may receive up to 3 donor lymphocyte infusions.

Blood samples are taken on days 30, 60, and 100 and then every 4 weeks thereafter for chimerism studies by PCR analysis.

After completion of study therapy, patients are followed periodically for up to 60 months.

Eligibility criteria: * Diagnosis of one of the following hematological malignancies:

  * CML, with 1 of the following:

    * In first CP AND failed imatinib mesylate therapy, defined as failure to obtain a hematologic remission at 3 months or a major cytogenetic response (i.e., Ph+ cells \< 35%) at 6 months or demonstrated clonal evolution or disease progression during therapy
    * In accelerated phase with \< 15% blasts
    * In blast crisis that has entered into a second CP following induction chemotherapy
  * AML, with 1 of the following:

    * In second or subsequent complete remission (CR) (i.e., \< 5% blasts by morphology, no residual leukemia by flow cytometry, and absence of cytogenetic abnormalities)
    * Failed primary induction chemotherapy, but subsequently entered into a CR with ≤ 2 subsequent re-induction chemotherapy treatment(s)
    * In first CR with intermediate-risk or poor-risk cytogenetics
  * ALL with 1 of the following:

    * In second or subsequent CR
    * In first CR AND presence of t(9;22)
  * MDS, with the following:

    * High-risk disease, defined by IPSS score of ≥ 1.5 at diagnosis AND meets 1 of the following criteria:

      * ≤ 10% blasts at diagnosis
      * In morphologic CR (\< 5% blasts) following cytoreductive chemotherapy
  * CMML, with 1 of the following:

    * ≤ 10% blasts at diagnosis
    * In morphologic CR (\< 5% blasts) following cytoreductive chemotherapy
  * CLL/PLL with the following:

    * Rai stage I-IV disease
    * Failed ≥ 1 prior chemotherapy regimen (including fludarabine phosphate) or ASCT
    * Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as \< 20% bone marrow involvement AND lymph node size \< 3 cm in axial diameter
    * No bulky tumor masses, elevated lactate dehydrogenase (LDH), B symptoms, or progressive disease prior to transplant
  * Low-grade non-Hodgkin lymphoma (NHL) (i.e., small lymphocytic lymphoma, follicular center lymphoma \[grade 1 or 2\], marginal zone lymphoma, or B-cell lymphoma), with the following criteria:

    * Failed ≥ 1 prior chemotherapy regimen or ASCT
    * Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as \< 20% bone marrow involvement AND lymph node size \< 3 cm in axial diameter
    * Received ≤ 3 prior chemotherapy regimens (monoclonal antibody therapy and involved-field radiotherapy are not considered a prior regimen)
    * No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
  * Mantle cell lymphoma, with the following:

    * Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
    * Responsive or stable disease to most recent prior therapy
    * No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
  * Intermediate-grade NHL (i.e., follicular center lymphoma \[grade 3\] or diffuse large cell lymphoma), meeting the following criteria:

    * Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
    * Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
    * No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
  * Hodgkin lymphoma, with the following:

    * Relapsed after prior ASCT OR after ≥ 2 combination chemotherapy regimens and ineligible for ASCT
    * Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
    * No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
  * Peripheral T-cell NHL, with the following:

    * Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
    * Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
    * No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant
* Myeloproliferative syndrome with poor risk features, meeting 1 of the following criteria:

  * \< 55 years old AND Lille score of 1
  * Lille score of 2
  * HgB \< 10 g/dL AND abnormal karyotype
* High-risk disease, with 1 of the following:

  * Age 40-72 years
  * Any age AND deemed to be at significantly increased risk of morbidity and death following a standard, myeloablative unrelated donor stem cell transplant (e.g., received extensive prior therapy, including ASCT)
* HLA-matched unrelated donor available, with 1 of the following:

  * 8/8 match at HLA-A, B, C, or DR loci by high-resolution genotyping
  * Single allelic mismatch at either the HLA-B or HLA-C loci donor by high-resolution molecular typing

    * No single allelic mismatch at HLA-A or HLA-DR loci
* KPS 80-100%
* Adapted weighted Charlson Comorbidity Index \< 3
* Serum creatinine ≤ 2.0 mg/dL
* AST or ALT \< 3 times upper limit of normal (ULN)
* Total bilirubin \< 1.5 times ULN
* LVEF ≥ 45%
* DLCO \> 50%
* No hypoxia at rest with oxygen saturation \< 92% on room air (corrected with bronchodilator therapy)
* No other severe pulmonary function abnormalities
* No HIV infection
* No active hepatitis B or C infection that, in the opinion of a gastroenterologist or the transplant committee, places the patient at moderate to high risk for developing severe hepatic disease
* No active opportunistic infection (e.g., fungal pneumonia, tuberculosis, or viral infection)

Primary outcomes:
measure: Survival at Day 100
timeFrame: 100 day
Secondary outcomes:
measure: Overall Survival at 1 Year
timeFrame: 1 year
measure: Non-relapse Mortality at Day 100
timeFrame: Day 100
measure: Non-relapse Mortality at 1 Year Post-transplant
timeFrame: 1 year
measure: Complete Donor Chimerism
timeFrame: 2 years
measure: Neutrophil Recovery
timeFrame: Day 100
measure: Platelet Engraftment
timeFrame: Day 100
measure: Number of Patients Requiring the Use of Donor Leukocyte Infusion (DLI) for Early Mixed T-cell Chimerism
timeFrame: Day 100
measure: Number of Patients Experiencing Grade 2-4 Acute Graft-versus-host Disease Post-transplant
timeFrame: patients were followed for 2 years
measure: Number of Patients Experiencing Chronic Graft Versus Host Disease
timeFrame: >100 days post-transplant
measure: Number of Patients Experiencing Veno-occlusive Disease (VOD) Post-transplant
timeFrame: 4 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Blood and Marrow Transplant Group of Georgia
state: Georgia
Study officials:
affiliation: Blood and Marrow Transplant Group of Georgia
name: Scott R. Solomon, MD
role: PRINCIPAL_INVESTIGATOR
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