Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer

Lymphoma Clinical Trial

Official title:

Reduced Intensity Allogeneic Stem Cell Transplantation With Matched Unrelated Donors for Patients With Hematologic Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00818961
• Other study ID #: CDR0000630617
• Secondary ID: BMTGG-NSH-756
• Status: Terminated
• Phase: Phase 2
• First received: January 7, 2009
• Last updated: October 28, 2013
• Start date: May 2005
• Est. completion date: March 2012

Study information

• Verified date: October 2013
• Source: Northside Hospital, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 36
• Est. completion date: March 2012
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 72 Years

Eligibility

• 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)

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Lymphoma
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Diseases
• Myeloproliferative Disorders
• Preleukemia

Intervention

Biological:
• alemtuzumab
43 mg subcutaneously over 3 days (3 mg on day -11, 10 mg on day -10, 30 mg on day -9)
• graft-versus-tumor induction therapy
curative potential of allogeneic transplant results from the immune anti-tumor effect of donor cells or GVT/GVL
• rituximab
in patients with Cd20+ malignancies: rituximab 375 mg/m*2 day -13. rituximab 1000 mg/m*2 on days, -6, +1, +8.

Drug:
• busulfan
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.
• cyclophosphamide
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
• fludarabine phosphate
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.
• methotrexate
5 mg/m2 administered on days +1, +3 and +6
• tacrolimus
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

Procedure:
• allogeneic bone marrow transplantation
Recipients will receive an allogeneic transplant on day 0 after receiving high-dose chemotherapy. This trial uses matched unrelated donor stem cells.

Locations

Country	Name	City	State
United States	Blood and Marrow Transplant Group of Georgia	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 (23)

Anderson JE, Anasetti C, Appelbaum FR, Schoch G, Gooley TA, Hansen JA, Buckner CD, Sanders JE, Sullivan KM, Storb R. Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia. Br J Haematol. 1996 Apr;93(1):59-67. — View Citation

Byrne JL, Stainer C, Cull G, Haynes AP, Bessell EM, Hale G, Waldmann H, Russell NH. The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia. Bone Marrow Transplant. 2000 Feb;25(4):411-7. — View Citation

Champlin RE, Passweg JR, Zhang MJ, Rowlings PA, Pelz CJ, Atkinson KA, Barrett AJ, Cahn JY, Drobyski WR, Gale RP, Goldman JM, Gratwohl A, Gordon-Smith EC, Henslee-Downey PJ, Herzig RH, Klein JP, Marmont AM, O'Reilly RJ, Ringdén O, Slavin S, Sobocinski KA, Speck B, Weiner RS, Horowitz MM. T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Blood. 2000 Jun 15;95(12):3996-4003. — View Citation

Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT, Nademanee A, Noreen H, King R, Confer D, Kernan NA. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program. Blood. 2000 Dec 15;96(13):4096-102. — View Citation

Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004 Sep 1;104(5):1550-8. Epub 2004 May 18. — View Citation

Escalón MP, Champlin RE, Saliba RM, Acholonu SA, Hosing C, Fayad L, Giralt S, Ueno NT, Maadani F, Pro B, Donato M, McLaughlin P, Khouri IF. Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol. 2004 Jun 15;22(12):2419-23. — View Citation

Faulkner RD, Craddock C, Byrne JL, Mahendra P, Haynes AP, Prentice HG, Potter M, Pagliuca A, Ho A, Devereux S, McQuaker G, Mufti G, Yin JL, Russell NH. BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients. Blood. 2004 Jan 15;103(2):428-34. Epub 2003 Sep 11. — View Citation

Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Kørbling M, Keating M, Kantarjian H, Champlin R. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997 Jun 15;89(12):4531-6. — View Citation

Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998 Apr 2;338(14):962-8. — View Citation

Izutsu K, Kanda Y, Ohno H, Sao H, Ogawa H, Miyazaki Y, Kawa K, Kodera Y, Kato S, Morishima Y, Hirai H; Japan Marrow Donor Program. Unrelated bone marrow transplantation for non-Hodgkin lymphoma: a study from the Japan Marrow Donor Program. Blood. 2004 Mar 1;103(5):1955-60. Epub 2003 Nov 6. — View Citation

Jones RJ, Ambinder RF, Piantadosi S, Santos GW. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood. 1991 Feb 1;77(3):649-53. — View Citation

Kernan NA, Bartsch G, Ash RC, Beatty PG, Champlin R, Filipovich A, Gajewski J, Hansen JA, Henslee-Downey J, McCullough J, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med. 1993 Mar 4;328(9):593-602. — View Citation

Khouri IF, Lee MS, Saliba RM, Andersson B, Anderlini P, Couriel D, Hosing C, Giralt S, Korbling M, McMannis J, Keating MJ, Champlin RE. Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. Exp Hematol. 2004 Jan;32(1):28-35. — View Citation

McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R, Antin JH, Kernan NA, King R, Weisdorf DJ. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Blood. 2000 Apr 1;95(7):2219-25. — View Citation

Mehta J, Singhal S. Graft-versus-myeloma. Bone Marrow Transplant. 1998 Nov;22(9):835-43. Review. — View Citation

O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. — View Citation

Pérez-Simón JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, García-Conde J, Milligan DW, Schey S, Urbano-Ispizua A, Parker A, Leon A, Yong K, Sureda A, Hunter A, Sierra J, Goldstone AH, Linch DC, San Miguel JF, Mackinnon S; Spanish and United Kingdom Collaborative Groups for Nonmyeloablative Transplantation. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002 Nov 1;100(9):3121-7. — View Citation

Porter DL, Connors JM, Van Deerlin VM, Duffy KM, McGarigle C, Saidman SL, Leonard DG, Antin JH. Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol. 1999 Apr;17(4):1234. — View Citation

Shaw BE, Peggs K, Bird JM, Cavenagh J, Hunter A, Alejandro Madrigal J, Russell NH, Sirohi B, Towlson K, Williams CD, Marks DI; Clinical Trials Committee of the British Society of Blood and Marrow Transplantation. The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma. Br J Haematol. 2003 Dec;123(5):886-95. — View Citation

Sierra J, Storer B, Hansen JA, Martin PJ, Petersdorf EW, Woolfrey A, Matthews D, Sanders JE, Storb R, Appelbaum FR, Anasetti C. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant. 2000 Aug;26(4):397-404. — View Citation

Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood. 2004 Aug 15;104(4):961-8. Epub 2004 Apr 27. — View Citation

Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L, Buckner CD, Anasetti C, Appelbaum FR, Badger C, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989 May 1;73(6):1720-8. Erratum in: Blood 1989 Aug 15;74(3):1180. — View Citation

Weisdorf DJ, Billett AL, Hannan P, Ritz J, Sallan SE, Steinbuch M, Ramsay NK. Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood. 1997 Oct 15;90(8):2962-8. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival at Day 100	Survival at Day 100	100 day	No
Secondary	Overall Survival at 1 Year	Evaluation of overall survival at 1 year (# of patients who are alive at 1 year post-transplant)	1 year	No
Secondary	Non-relapse Mortality at Day 100	patients are evaluable for their cause of death at Day 100	Day 100	Yes
Secondary	Non-relapse Mortality at 1 Year Post-transplant	Number of patients who died of non-relapse causes at one year. this is in clusive of all patients who were transplanted on study even though only 10 patients died at by 1 year time point. This outcome will be referenced in the donor chimerism outcome. Only 26/36 patients were eligible for this time point as that is all that were alive.	1 year	Yes
Secondary	Complete Donor Chimerism	Complete donor chimerism (defined as >/= 95% donor cells in peripheral blood CD3+ and CD33+ was measured.	2 years	No
Secondary	Neutrophil Recovery	The number of patients experiencing neutrophil recovery post transplant	Day 100	Yes
Secondary	Platelet Engraftment	The number of patients experiencing platelet engraftment post-transplant	Day 100	Yes
Secondary	Number of Patients Requiring the Use of Donor Leukocyte Infusion (DLI) for Early Mixed T-cell Chimerism	DLI is used for patients with mixed chimerism following transplant	Day 100	No
Secondary	Number of Patients Experiencing Grade 2-4 Acute Graft-versus-host Disease Post-transplant	patients experiencing acute graft versus host disease post-transplant	patients were followed for 2 years	Yes
Secondary	Number of Patients Experiencing Chronic Graft Versus Host Disease		>100 days post-transplant	Yes
Secondary	Number of Patients Experiencing Veno-occlusive Disease (VOD) Post-transplant	Patients will be evaluated up to 4 years post transplant	4 years	Yes