Accepted Manuscript The graft-versus-myeloma effect: Chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation Michele L. Donato, David S. Siegel, David H. Vesole, Phyllis McKiernan, Themba Nyirenda, Andrew L. Pecora, Melissa Baker, Stuart L. Goldberg, Anthony Mato, Andre Goy, Scott D. Rowleyr PII:
S1083-8791(14)00267-5
DOI:
10.1016/j.bbmt.2014.04.027
Reference:
YBBMT 53450
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 20 January 2014 Accepted Date: 15 April 2014
Please cite this article as: Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL, Baker M, Goldberg SL, Mato A, Goy A, Rowleyr SD, The graft-versus-myeloma effect: Chronic graftversus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.04.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Succinct title: The graft-versus-myeloma effect: Chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation.
M AN U
Acknowledgments of research support for the study: This research was not supported by industry or grants.
SC
RI PT
Names of each author’s institution and an indication of each author's affiliation: Michele L. Donato, David S. Siegel, David H. Vesole, Phyllis McKiernan, Themba Nyirenda, Andrew L. Pecora, Melissa Baker, Stuart L. Goldberg, Anthony Mato, Andre Goy and Scott D. Rowley All authors affiliation: John Theurer Cancer Center Hackensack University Medical Center 92 Second Street Hackensack, NJ 07601
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Name, address, telephone and fax numbers, and e-mail address of the corresponding author: Michele L. Donato, MD FACP John Theurer Cancer Center Hackensack University Medical Center 92 Second Street, Hackensack, NJ 07601 551-996-4546 Fax: 551-996-0575 [email protected] Running head: Role of GVHD in allogeneic transplantation for multiple myeloma
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Disclaimers: None
EP
List of where and when the study has been presented in part elsewhere, if applicable: American Society of Hematology 2013 Annual Meeting
1
ACCEPTED MANUSCRIPT
The graft-versus-myeloma effect: Chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation
RI PT
Michele L. Donato, David S. Siegel, David H. Vesole, Phyllis McKiernan, Themba Nyirenda, Andrew L. Pecora, Melissa Baker, Stuart L. Goldberg, Anthony Mato, Andre Goy and Scott D. Rowley. John Theurer Cancer Center, Hackensack University Medical Center. Hackensack, NJ.
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Corresponding author: Michele Donato, MD, Department of Blood and Marrow Transplantation, John Theurer Cancer Center, 92 second Street, Hackensack, NJ, 07601; e-mail: [email protected]
M AN U
Abstract
Purpose We have conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters.
Patients and methods Fifty seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least
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one prior autologous transplant were included. Twenty six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed
EP
between related and unrelated.
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Results The median follow-up was 52 months. Thirty two (57.1%) patients achieved a CR. At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions (DLI) or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year OS for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared to 38% for the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (HR 4.05, p=0.0196), acute graft-versus-host disease (HR 2.99, p=0.034) and
2
ACCEPTED MANUSCRIPT
chronic graft-versus-host disease (cGVHD) which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR 0.17, p=0.008).
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Conclusion Our data show that allogeneic transplantation for multiple myeloma can lead to sustained remissions. Acute GVHD (aGVHD) is significantly deleterious to OS and PFS, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-
SC
myeloma effect. INTRODUCTION
M AN U
Over the past decade, outcomes for patients with MM have significantly improved. The incorporation of novel therapies, proteasome inhibitors (bortezomib,1 carfilzomib2) and immunomodulatory agents (lenalidomide,3 pomalidomide4), have improved the 5-year survival from 29% to 43%.5 Autologous transplantation remains a standard treatment. Multiple
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myeloma is the most common indication for autologous transplantation in North America and the number of autologous transplants has been steadily increasing over the past decade, including in older patients.6 Allogeneic transplantation has been received with less enthusiasm,
EP
mainly due to its inherent treatment-related mortality. Originally, allogeneic transplantation was applied in the context of very advanced disease and involved the use of toxic
AC C
myeloablative regimens, leading to a treatment-related mortality ranging from 20 to 40%.7 Since then, there has been improvement in supportive care, new preparative regimens have been developed, and treatment-related mortality has significantly decreased.8 Large United States and European trials have explored the role of allogeneic transplantation using nonmyeloablative regimens in tandem with a prior autologous transplantation.9, 10 The US trial did not show improvement over tandem autologous transplantation at 3 years median follow up. In
3
ACCEPTED MANUSCRIPT
contrast, the European trial failed to show improvement at 3 years but did show superiority of allogeneic transplantation with a 5-year median follow up. Thus, important questions remain such as the characteristics predicting for survival and the role of the graft-versus-myeloma
RI PT
effect. We report on the outcome of 57 patients with MM who received an allogeneic transplantation at our institution.
SC
PATIENTS AND METHODS Patients
M AN U
The study cohort included 57 consecutive patients with MM who received an allogeneic hematopoietic stem cell transplantation (HSCT) between November 2004 and June 2011. For the purpose of this analysis, only patients who had received at least one prior autologous transplant were included. All patients signed informed consents approved by our institutional
Preparative Regimens
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review board for data analysis and reporting, and for transplantation.
EP
Patients received either a non-myeloablative (NMA), a reduced intensity conditioning (RIC) or a myeloablative (MA) regimen. Regimen selection was based on physician preference,
AC C
protocol or treatment plan availability and eligibility at the time of transplantation. The NMA regimen consisted of low dose total body irradiation (TBI) 200cGy as a single dose for siblings administered on day 0, and low dose TBI 200cGy on day 0 with fludarabine 30 mg/m2 on days -5 to -3 for unrelated donors. The RIC regimen consisted of fludarabine 30 mg/m2 on days -5 to -3 (-6 to -3 for unrelated donors) and melphalan 140 mg/m2 on day -2, with the addition of low dose thymoglobulin 4 mg/kg in divided doses on days -3 to -1 for unrelated donors. The
4
ACCEPTED MANUSCRIPT
MA regimen was intravenous busulfan 130 mg/m2 on days -7 to -4 and melphalan 70 mg/m2 on days -2 and -1, with thymoglobulin 4 mg/kg in divided doses on days -3 to -1 for unrelated donors. All regimens have been previously described in the literature.9, 11, 12, 13 Graft-versus-
RI PT
host disease prophylaxis consisted of tacrolimus and mini-methotrexate,14 or cyclosporine and mycophenolate mofetil15 for patients receiving a non-myeloablative regimen. Patients received antibiotic prophylaxis with valacyclovir, fluconazole or voriconazole and
Definitions and terminology
M AN U
did not receive post transplantation maintenance therapy.
SC
ciprofloxacin. Pneumocystis jiroveci prophylaxis was administered post engraftment. Patients
The International Uniform Response Criteria for MM was used to define response, relapse and progression.16 Chronic GVHD diagnosis and staging was based on the 2005 NIH concensus.17
TE D
Patients were considered to have received allogeneic transplantation as consolidation if they had at least a partial remission (PR) to their first autograft and had not progressed prior to the allograft. Salvage transplantation was defined as allogeneic transplantation after disease
EP
progression or less than a PR following the first autologous transplant.
AC C
Statistical method
Continuous variables were summarized as mean or median (interquartile range) depending upon whether the data followed the normal distribution or not. Comparison of continuous variables between any two groups was conducted using a two-sided t-test or two-sided Wilcoxon rank sum test, as appropriate. Categorical variables were examined using Fisher’s exact test or Pearson’s Chi-Square test as appropriate. The end points of interest included
5
ACCEPTED MANUSCRIPT
progression free survival (PFS), overall survival (OS), incidence of chronic graft-versus-host disease, incidence of relapse and incidence of non-relapse mortality.
RI PT
Progression free survival (PFS) was the time measured from the date of allogeneic
transplantation to disease progression, death or last contact. Overall survival was measured from the date of allogeneic transplantation to death from any cause. PFS and OS were
SC
estimated using the Kaplan-Meier method. The cumulative incidence of chronic GVHD was estimated with relapse and death as competing risks. Chronic GVHD was also analyzed as a
M AN U
time-dependent variable. Non-relapse mortality (NRM) was considered a competing risk for incidence of relapse. Comparison of PFS and OS between any groups was performed using a two-sided log rank test. Examination of association between progression and all cause of death and potential risk factors was performed by fitting the Cox-proportional hazard regression
TE D
model. The assumption of proportional hazard was examined for each factor. The results of Cox regression analyses are presented as hazard ratio (HR), 95% confidence interval (CI) for HR, and p-value. Any p
S1083-8791(14)00267-5
DOI:
10.1016/j.bbmt.2014.04.027
Reference:
YBBMT 53450
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 20 January 2014 Accepted Date: 15 April 2014
Please cite this article as: Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL, Baker M, Goldberg SL, Mato A, Goy A, Rowleyr SD, The graft-versus-myeloma effect: Chronic graftversus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.04.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Succinct title: The graft-versus-myeloma effect: Chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation.
M AN U
Acknowledgments of research support for the study: This research was not supported by industry or grants.
SC
RI PT
Names of each author’s institution and an indication of each author's affiliation: Michele L. Donato, David S. Siegel, David H. Vesole, Phyllis McKiernan, Themba Nyirenda, Andrew L. Pecora, Melissa Baker, Stuart L. Goldberg, Anthony Mato, Andre Goy and Scott D. Rowley All authors affiliation: John Theurer Cancer Center Hackensack University Medical Center 92 Second Street Hackensack, NJ 07601
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Name, address, telephone and fax numbers, and e-mail address of the corresponding author: Michele L. Donato, MD FACP John Theurer Cancer Center Hackensack University Medical Center 92 Second Street, Hackensack, NJ 07601 551-996-4546 Fax: 551-996-0575 [email protected] Running head: Role of GVHD in allogeneic transplantation for multiple myeloma
AC C
Disclaimers: None
EP
List of where and when the study has been presented in part elsewhere, if applicable: American Society of Hematology 2013 Annual Meeting
1
ACCEPTED MANUSCRIPT
The graft-versus-myeloma effect: Chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation
RI PT
Michele L. Donato, David S. Siegel, David H. Vesole, Phyllis McKiernan, Themba Nyirenda, Andrew L. Pecora, Melissa Baker, Stuart L. Goldberg, Anthony Mato, Andre Goy and Scott D. Rowley. John Theurer Cancer Center, Hackensack University Medical Center. Hackensack, NJ.
SC
Corresponding author: Michele Donato, MD, Department of Blood and Marrow Transplantation, John Theurer Cancer Center, 92 second Street, Hackensack, NJ, 07601; e-mail: [email protected]
M AN U
Abstract
Purpose We have conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters.
Patients and methods Fifty seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least
TE D
one prior autologous transplant were included. Twenty six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed
EP
between related and unrelated.
AC C
Results The median follow-up was 52 months. Thirty two (57.1%) patients achieved a CR. At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions (DLI) or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year OS for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared to 38% for the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (HR 4.05, p=0.0196), acute graft-versus-host disease (HR 2.99, p=0.034) and
2
ACCEPTED MANUSCRIPT
chronic graft-versus-host disease (cGVHD) which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR 0.17, p=0.008).
RI PT
Conclusion Our data show that allogeneic transplantation for multiple myeloma can lead to sustained remissions. Acute GVHD (aGVHD) is significantly deleterious to OS and PFS, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-
SC
myeloma effect. INTRODUCTION
M AN U
Over the past decade, outcomes for patients with MM have significantly improved. The incorporation of novel therapies, proteasome inhibitors (bortezomib,1 carfilzomib2) and immunomodulatory agents (lenalidomide,3 pomalidomide4), have improved the 5-year survival from 29% to 43%.5 Autologous transplantation remains a standard treatment. Multiple
TE D
myeloma is the most common indication for autologous transplantation in North America and the number of autologous transplants has been steadily increasing over the past decade, including in older patients.6 Allogeneic transplantation has been received with less enthusiasm,
EP
mainly due to its inherent treatment-related mortality. Originally, allogeneic transplantation was applied in the context of very advanced disease and involved the use of toxic
AC C
myeloablative regimens, leading to a treatment-related mortality ranging from 20 to 40%.7 Since then, there has been improvement in supportive care, new preparative regimens have been developed, and treatment-related mortality has significantly decreased.8 Large United States and European trials have explored the role of allogeneic transplantation using nonmyeloablative regimens in tandem with a prior autologous transplantation.9, 10 The US trial did not show improvement over tandem autologous transplantation at 3 years median follow up. In
3
ACCEPTED MANUSCRIPT
contrast, the European trial failed to show improvement at 3 years but did show superiority of allogeneic transplantation with a 5-year median follow up. Thus, important questions remain such as the characteristics predicting for survival and the role of the graft-versus-myeloma
RI PT
effect. We report on the outcome of 57 patients with MM who received an allogeneic transplantation at our institution.
SC
PATIENTS AND METHODS Patients
M AN U
The study cohort included 57 consecutive patients with MM who received an allogeneic hematopoietic stem cell transplantation (HSCT) between November 2004 and June 2011. For the purpose of this analysis, only patients who had received at least one prior autologous transplant were included. All patients signed informed consents approved by our institutional
Preparative Regimens
TE D
review board for data analysis and reporting, and for transplantation.
EP
Patients received either a non-myeloablative (NMA), a reduced intensity conditioning (RIC) or a myeloablative (MA) regimen. Regimen selection was based on physician preference,
AC C
protocol or treatment plan availability and eligibility at the time of transplantation. The NMA regimen consisted of low dose total body irradiation (TBI) 200cGy as a single dose for siblings administered on day 0, and low dose TBI 200cGy on day 0 with fludarabine 30 mg/m2 on days -5 to -3 for unrelated donors. The RIC regimen consisted of fludarabine 30 mg/m2 on days -5 to -3 (-6 to -3 for unrelated donors) and melphalan 140 mg/m2 on day -2, with the addition of low dose thymoglobulin 4 mg/kg in divided doses on days -3 to -1 for unrelated donors. The
4
ACCEPTED MANUSCRIPT
MA regimen was intravenous busulfan 130 mg/m2 on days -7 to -4 and melphalan 70 mg/m2 on days -2 and -1, with thymoglobulin 4 mg/kg in divided doses on days -3 to -1 for unrelated donors. All regimens have been previously described in the literature.9, 11, 12, 13 Graft-versus-
RI PT
host disease prophylaxis consisted of tacrolimus and mini-methotrexate,14 or cyclosporine and mycophenolate mofetil15 for patients receiving a non-myeloablative regimen. Patients received antibiotic prophylaxis with valacyclovir, fluconazole or voriconazole and
Definitions and terminology
M AN U
did not receive post transplantation maintenance therapy.
SC
ciprofloxacin. Pneumocystis jiroveci prophylaxis was administered post engraftment. Patients
The International Uniform Response Criteria for MM was used to define response, relapse and progression.16 Chronic GVHD diagnosis and staging was based on the 2005 NIH concensus.17
TE D
Patients were considered to have received allogeneic transplantation as consolidation if they had at least a partial remission (PR) to their first autograft and had not progressed prior to the allograft. Salvage transplantation was defined as allogeneic transplantation after disease
EP
progression or less than a PR following the first autologous transplant.
AC C
Statistical method
Continuous variables were summarized as mean or median (interquartile range) depending upon whether the data followed the normal distribution or not. Comparison of continuous variables between any two groups was conducted using a two-sided t-test or two-sided Wilcoxon rank sum test, as appropriate. Categorical variables were examined using Fisher’s exact test or Pearson’s Chi-Square test as appropriate. The end points of interest included
5
ACCEPTED MANUSCRIPT
progression free survival (PFS), overall survival (OS), incidence of chronic graft-versus-host disease, incidence of relapse and incidence of non-relapse mortality.
RI PT
Progression free survival (PFS) was the time measured from the date of allogeneic
transplantation to disease progression, death or last contact. Overall survival was measured from the date of allogeneic transplantation to death from any cause. PFS and OS were
SC
estimated using the Kaplan-Meier method. The cumulative incidence of chronic GVHD was estimated with relapse and death as competing risks. Chronic GVHD was also analyzed as a
M AN U
time-dependent variable. Non-relapse mortality (NRM) was considered a competing risk for incidence of relapse. Comparison of PFS and OS between any groups was performed using a two-sided log rank test. Examination of association between progression and all cause of death and potential risk factors was performed by fitting the Cox-proportional hazard regression
TE D
model. The assumption of proportional hazard was examined for each factor. The results of Cox regression analyses are presented as hazard ratio (HR), 95% confidence interval (CI) for HR, and p-value. Any p
