Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer
Condition: Leukemia; Lymphoma; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases
MeSH terms: Lymphoma; Leukemia; Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases
Intervention: alemtuzumab; graft-versus-tumor induction therapy; rituximab; busulfan; cyclophosphamide; fludarabine phosphate; methotrexate; tacrolimus; allogeneic bone marrow transplantation
Intervention description: 43 mg subcutaneously over 3 days (3 mg on day -11, 10 mg on day -10, 30 mg on day -9); curative potential of allogeneic transplant results from the immune anti-tumor effect of donor cells or GVT/GVL; in patients with Cd20+ malignancies: rituximab 375 mg/m*2 day -13. rituximab 1000 mg/m*2 on days, -6, +1, +8.; For patients with AML, CML, MDS, MPS and ALL only: IV or oral busulfan may be given IV busulfan: 130 mg/m2 over 3 hours once daily on days -6, -5, -4 and -3 Oral busulfan: taken every 6 hours x 15 doses beginning on day -7 at 6pm and continuing through day -3 at 6am. 1 mg/kg test dose will be given prior to day -7 and PK samples will be drawn to calculate AUC.; 750 mg/m2 infused over 1 hour once daily on days -5, -4 and -3. Cyclophosphamide will be started approximately 4 hours after the start of Fludarabine; For patients with CLL, NHL & HD: 30 mg/m2 infused over 30 minutes once daily on days -5, -4 and -3 For patients with AML, CML, MDS, MPS and ALL: 40 mg/m2 infused over 30 minutes once daily on days -6, -5, -4 and -3.; 5 mg/m2 administered on days +1, +3 and +6; 0.03mg/kg/day infused over 24 hours starting on day -1 and switched to oral (twice daily divided dose) on day 14 or when able to tolerate PO; Recipients will receive an allogeneic transplant on day 0 after receiving high-dose chemotherapy. This trial uses matched unrelated donor stem cells.
Intervention MeSH terms: Cyclophosphamide; Busulfan; Rituximab; Methotrexate; Fludarabine; Fludarabine phosphate; Alemtuzumab; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 40 Years
Maximum age: 72 Years
Healthy volunteers: No
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

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.
    

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)