Inferior Outcomes with Cyclosporine and Mycophenolate mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation

Betty K Hamilton; Ying Liu; Michael T Hemmer; Navneet Majhail; Olle Ringden; Dennis Kim; Luciano Costa; Robert Stuart; Amin Alousi; Joseph A Pidala; Daniel R Couriel; Mahmoud Aljurf; Joseph H Antin; Christopher Bredeson; Jean-Yves Cahn; Mitchell Cairo; Sung Won Choi; Christopher Dandoy; Robert Peter Gale; Usama Gergis; Peiman Hematti; Yoshihiro Inamoto; Rammurti T Kamble; Margaret MacMillan; David I Marks; Eneida Nemecek; Taiga Nishihori; Ayman Saad; Bipin N Savani; Jeff Schriber; Sachiko Seo; Gérard Socié; Takanori Teshima; Leo F Verdonck; Edmund K Waller; Mona Wirk; Stephen R Spellman; Mukta Arora; Saurabh Chhabra

doi:10.1016/j.bbmt.2019.05.019

. Author manuscript; available in PMC: 2020 Sep 1.

Published in final edited form as: Biol Blood Marrow Transplant. 2019 May 31;25(9):1744–1755. doi: 10.1016/j.bbmt.2019.05.019

Inferior Outcomes with Cyclosporine and Mycophenolate mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation

Betty K Hamilton ¹, Ying Liu ², Michael T Hemmer ², Navneet Majhail ¹, Olle Ringden ³, Dennis Kim ⁴, Luciano Costa ⁵, Robert Stuart ⁶, Amin Alousi ⁷, Joseph A Pidala ⁸, Daniel R Couriel ⁹, Mahmoud Aljurf ¹⁰, Joseph H Antin ¹¹, Christopher Bredeson ¹², Jean-Yves Cahn ¹³, Mitchell Cairo ¹⁴, Sung Won Choi ¹⁵, Christopher Dandoy ¹⁶, Robert Peter Gale ¹⁷, Usama Gergis ¹⁸, Peiman Hematti ¹⁹, Yoshihiro Inamoto ²⁰, Rammurti T Kamble ²¹, Margaret MacMillan ²², David I Marks ²³, Eneida Nemecek ²⁴, Taiga Nishihori ²⁵, Ayman Saad ²⁶, Bipin N Savani ²⁷, Jeff Schriber ^28,²⁹, Sachiko Seo ³⁰, Gérard Socié ³¹, Takanori Teshima ³², Leo F Verdonck ³³, Edmund K Waller ³⁴, Mona Wirk ³⁵, Stephen R Spellman ³⁶, Mukta Arora ³⁷, Saurabh Chhabra ^38,³⁹

¹Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

²Medical College of Wisconsin, Milwaukee, WI

³Translational Cell Therapy Goup, CLINTEC( Clinical Science, Intervention and Technology) Karolinska Institutet, Stockholm Sweden

⁴Princess Margaret Cancer Center - BMT Program, Toronto, ON, Canada

⁵Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

⁶Medical University of South Carolina, Charleston, SC

⁷Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX

⁸H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

⁹Utah Blood and Marrow Transplant Program – Adults, Salt Lake City, Utah

¹⁰Department of Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia

¹¹Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

¹²The Ottawa Hospital Blood and Marrow Transplant Program and the Ottawa Hospital Research Institute, Ottawa, ON, Canada

¹³Department of Hematology, CHU Grenoble Alpes, Grenoble, France

¹⁴Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, New York Medical College, Valhalla, NY

¹⁵The University of Michigan, Ann Arbor, MI

¹⁶Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

¹⁷Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom

¹⁸Hematolgic Malignancies & Bone Marrow Transplant, Department of Medical Oncology, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY

¹⁹Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin, Madison, WI

²⁰Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

²¹Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX

²²University of Minnesota Blood and Marrow Transplant Program – Pediatrics/Adults, Minneapolis, MN

²³Adult Bone Marrow Transplant, University Hospitals Bristol NHS Trust, Bristol, United Kingdom;

²⁴Pediatric Blood & Marrow Transplant Program, Department of Pediatrics, Doernbecher Children’s Hospital and Oregon Health & Science University, Portland, OR

²⁵Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

²⁶Division of Hematology, Ohio State University, Columbus, OH

²⁷Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

²⁸Cancer Transplant Institute, Virginia G. Piper Cancer Center, Scottsdale, AZ

²⁹Arizona Oncology, Scottsdale, AZ

³⁰Department of haematology and Oncology, Dokkyo Medical University

³¹Department of Hematology, Hopital Saint Louis, Paris, France

³²Hokkaido University Hospital, Sapporo, Japan

³³Dept of Hematology/Oncology, Isala Clinic, Zwolle, The Netherlands

³⁴Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA;

³⁵Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, WA;

³⁶CIBMTR – Minneapolis, Minneapolis, MN

³⁷Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN

³⁸CIBMTR-Milwaukee, Milwaukee, WI

³⁹Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI

Authorship

Author Contribution: B.K.H. designed the study, analyzed results and wrote the manuscript; S.C., S.S., M.A., N.M., O.R., D.K., L.C., R.S. designed the study, analyzed results, and critically reviewed the manuscript; Y.L. and M.T.H. provided the statistical support; A.A., J.A.P., D.R.C., M.A, J.H.A., C.B., J-Y.C., M.C., S.W.C., C.D., R.P.G., U.G., P.H., Y.I., R.T.K., M.M., D.M., E.N., T.N., A.S., B.N.S., J.S., S.S., G.S., T.T., L.F.V., E.K.W., M.W. interpreted data and critically reviewed the manuscript. All authors approved the final manuscript.

^✉

Corresponding Author: Betty Ky Hamilton, MD, Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue CA 60, Cleveland, OH 44195, Phone: (216)-445-7580, Fax: (216)-444-9464, hamiltb2@ccf.org

PMCID: PMC7039394 NIHMSID: NIHMS1550134 PMID: 31158502

Abstract

The combination of a calcineurin inhibitor (cyclosporine [CSA] or tacrolimus [Tac]) and methotrexate (MTX) or mycophenolate mofetil (MMF) are widely used approaches to graft-versus-host disease (GVHD) prevention. There is limited and conflicting data, however, on the comparative effectiveness of MMF compared to MTX

We analyzed data from the CIBMTR for adult patients undergoing first myeloablative hematopoietic cell transplant (HCT) from an HLA-identical matched related (MRD) (N=3979) or matched unrelated donor (URD) (N=4163) using CSA+MMF, CSA+MTX, Tac+MMF or Tac+MTX for GVHD prevention from 2000–2013.

Within the MRD cohort, 2252 received CSA+MTX, 1391 Tac+MTX, 114 CSA+MMF, and 222 Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute grade 2–4 (HR 1.65, 95% CI 1.24–2.20, P<0.001) and grade 3–4 (HR 1.92, 95% CI 1.31–2.83, P<0.001) GVHD compared to Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR 2.31, 95% CI 1.73–3.09, P<0.001) due to higher transplant-related mortality (TRM) (HR 4.03, 95% CI 2.61–6.23, P<0.001) versus Tac+MTX. Within the URD cohort, 974 received CSA+MTX, 2697 Tac+MTX, 68 CSA+MMF, and 424 Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade 3–4 acute GVHD (HR 2.31, 95% CI 1.57–3.42, P<0001), worse OS (HR 2.36, 95% CI 1.67–3.35, P<0.001), and higher TRM (HR 3.09, 95% CI 2.00–4.77, P<0.001), compared to Tac+MTX, and other regimens.

This large retrospective comparison of MMF versus MTX in combination with CSA or Tac thus demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared to Tac+MTX.

Keywords: GVHD, MMF, MTX, myeloablative, allogeneic HCT

INTRODUCTION:

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT). While the combination of a calcineurin inhibitor (CNI), such as tacrolimus (Tac) or cyclosporine (CSA) with methotrexate (MTX) has been a standard practice over the past several decades for GVHD prevention, this treatment is associated with several unfavorable toxicities, including mucositis [1], delayed engraftment [2], and hepatic toxicities, primarily due to MTX [3]. Mycophenolate mofetil (MMF) was initially shown to have synergy with CSA in preventing GVHD and improving survival in experimental models, [4] and despite a limited number of prospective randomized trials comparing its efficacy to MTX, the combination of CNI and MMF is commonly used in both reduced-intensity conditioning (RIC) and myeloablative (MAC) transplants. [5–10]

While small prospective studies have suggested similar outcomes of MMF and MTX in MAC transplant with improved toxicity profiles, [8–11] others have demonstrated more severe acute GVHD, primarily in unrelated donor (URD) transplants [12, 13]. Previous retrospective studies evaluating MMF have also confirmed improved toxicity but with similar GVHD and survival outcomes compared to MTX; [14, 15] whereas a more recent retrospective study of 414 patients undergoing MAC and RIC HCT demonstrated a relatively high incidence of grade III-IV acute GVHD (22.3% in related and 36.5% in unrelated donors) and non-relapse mortality (NRM) (33.3% in related and 46.5% in unrelated donors).[16] In addition, a large Center for International Blood and Marrow Transplant Research (CIBMTR) analysis comparing bone marrow (BM) versus peripheral blood (PB) grafts in URD transplant demonstrated significantly worse outcomes in overall survival (OS), NRM, and acute (a) and chronic (c)GVHD with MMF compared to MTX, further raising the question of MMF’s efficacy compared to MTX in this setting.[17]

Given these conflicting results, we sought to determine the rates of GVHD and OS in patients undergoing first myeloablative transplant using MTX versus MMF in combination with CSA or Tac.

METHODS:

Data Source:

The CIBMTR is a combined research program of the Medical College of Wisconsin and the National Marrow Donor Program. The CIBMTR comprises a voluntary network of more than 420 transplantation centers worldwide that contribute data on consecutive allogeneic and autologous HCTs to a centralized statistical center. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. Protected health information used in the performance of such research is collected and maintained in the capacity of the CIBMTR as a public health authority under HIPPAA regulations. Additional details regarding the source have been previously described.[18]

Patients:

Patients age 18 years or older who underwent a first HLA-identical sibling or 8/8 or 7/8 HLA-matched unrelated donor HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) and received a CNI (CSA or Tac) in combination with MTX or MMF for GVHD prophylaxis reported to the CIBMTR from 2000–2013 were included. Transplants using anti-thymocyte globulin (ATG) were included, however ex-vivo T-cell depleted grafts, use of alemtuzumab, and post-transplant cyclophosphamide were excluded. Haploidentical, syngeneic and cord blood transplants were also excluded.

Study Endpoints and definitions:

The primary endpoints of this study are incidence of grade II-IV and III-IV aGVHD, cGVHD, and OS. Secondary endpoints include relapse, transplant-related mortality (TRM), and disease-free survival (DFS). The composite endpoint of GVHD-relapse-free survival (GRFS), including survival without grade 3–4 aGVHD, cGVHD requiring systemic treatment, relapse or death was also evaluated. GVHD was graded according to historical consensus criteria.[19, 20] Disease status was categorized into early, intermediate, and advanced.[21] Relapse was defined by hematologic criteria by submitting centers with non-relapse mortality as a competing event. TRM was defined as death without evidence of disease recurrence, relapse was considered a competing event. DFS was defined as time to treatment failure (death or relapse). For relapse, TRM, and DFS, patients alive in continuous complete remission were censored at last follow-up. For GVHD, death without the event was considered a competing event. HLA matching was defined as described previously.[22]

Statistical Analysis:

Patient, disease, and transplant-related variables for donor types were compared using chi-square statistics for categorical variables and the Kruskal-Wallis test for continuous variables. Probabilities for relapse, TRM, and GVHD were calculated using the cumulative incidence method to account for competing risks. Kaplan-Meier estimates were used to calculate the probability of DFS and OS. Multivariate Cox regression models were constructed to evaluate hazard ratios (HR) for endpoints of aGVHD, cGVHD, relapse, TRM, DFS and OS of GVHD prophylaxis regimens (CSA+MTX, CSA+MMF, Tac+MMF) compared with Tac+MTX as the reference. Pair-wise comparisons were also made between each combination of Tac or CSA and MTX or MMF. Analyses were performed separately in MRD and URD recipients given the known differences in GVHD between these groups as well as patterns of use of GVHD prophylaxis. Other variables in the multivariable model included: age at transplant, race, gender, Karnofsky performance status, Sorror HCT comorbidity index, disease diagnosis (AML, ALL, MDS, CML), disease status (early, intermediate, advanced), donor age (for URD), donor HLA match (7/8 versus 8/8, for URD), donor-recipient CMV match, donor-recipient sex match, graft source (PB versus BM, use of ATG, conditioning regimen, use of total body irradiation (TBI), and year of transplantation. The assumption of proportional hazards for each factor in the Cox model was tested using time-dependent covariates. When the test indicated differential effects over time (non-proportional hazards), models were constructed breaking the post-transplant time course into 2 periods, using the maximized partial likelihood method to find the most appropriate breakpoint, which may have been different for different outcomes. Several outcomes, including cGVHD, TRM and OS, demonstrated differential effects over time and are thus reported for different time-points. A backward stepwise procedure was used to identify all significant risk factors and develop models for each outcome, using a P value threshold of 0.05. Interactions between the main variable (GVHD prophylaxis) and adjusted covariates were tested at the significance level of 0.01.

RESULTS:

Transplantation from an HLA-identical related donor

Patient, Disease, and Transplant Characteristics

Patient characteristics are summarized in Table 1. In the MRD cohort, CSA+MTX was the most common GVHD prophylaxis regimen (N=2252), followed by Tac+MTX (N=1391), Tac+MMF (N=222) and CSA+MMF (N=114). Most patients receiving CSA+MTX (65%) were transplanted prior to 2005, reflected by a larger proportion of transplants for CML (29%). ATG was used infrequently, but more commonly in the CSA+MMF (11%) and Tac+MMF (14%) group compared to CSA+MTX (5%) and Tac+MTX (4%). The use of BM was more common in the CSA+MMF (28%) and CSA+MTX (36%) groups compared to Tac+MTX (8%) and Tac+MMF (7%).

Table 1:

Characteristics of patients receiving myeloablative transplant treated with Tac/CSA in combination with MTX or MMF

	Matched Related Donor					Matched Unrelated Donor

	CSA+MMF N=114	CSA+MTX N=2252	TAC+MMF N=222	TAC+MTX N=1391	P-Value	CSA+MMF N=68	CSA+MTX N=974	TAC+MMF N=424	TAC+MTX N=2697	P-Value

Age at transplant, years, median (range)	48 (19–69)	48 (18–72)	49 (18–70)	48 (18–71)	<0.001	42 (18–72)	40 (18–69)	46 (18–73)	45 (18–75)	<0.001

Race
Caucasian	95 (83)	1746 (78)	210 (95)	1142 (82)	<0.001	59 (87)	904 (93)	386 (91)	2475 (92)	0.05
Non-Caucasian	16 (14)	393 (17)	11(5)	166 (12)		7 (10)	39 (4)	30 (7)	160 (6)
Missing	3 (3)	113 (5)	1(<1)	83 (6)		2 (3)	31 (3)	8 (2)	62 (2)

Sorror co-morbidity index
Prior to 2007	57 (50)	2033 (90)	71 (32)	555 (40)		32 (47)	820 (84)	216 (51)	1354 (50)	<0.001
0–1	30 (26)	155 (7)	68 (31)	412 (30)		16 (24)	84 (9)	104 (25)	669 (25)
2+	25 (22)	52 (2)	82 (37)	419 (30)	<0.001	13 (19)	53 (5)	103 (24)	657 (24)
Missing	2 (2)	12 (<1)	1(<1)	5 (<1)		7 (10)	17 (2)	1 (<1)	17 (<1)

KPS prior to transplant
<90	36 (32)	441 (20)	71 (32)	455 (33)	<0.001	23 (38)	232 (24)	168 (40)	838 (31)	<0.001
≥ 90	67 (59)	1763 (78)	68 (31)	886 (64)		42 (62)	669 (69)	245 (58)	1666 (62)
Missing	11 (10)	48 (2)	82 (37)	50 (4)		0	73 (7)	11 (3)	193 (7)

Disease
AML	62 (54)	879 (43)	133 (60)	741 (53)	<0.001	41 (60)	451 (46)	245 (58)	1519 (56)	<0.001
ALL	12 (11)	490 (22)	42 (19)	271 (19)		12 (18)	226 (23)	70 (17)	479 (18)
CML	24 (21)	648 (29)	15 (7)	166 (12)		8 (12)	199 (20)	51 (12)	291 (11)
MDS	16 (14)	136 (6)	32 (14)	213 (15)		7 (10)	98 (10)	58 (14)	408 (15)

Disease status at transplant *	46 (40)	977 (43)	124 (56)	741 (53)	<0.001	27 (40)	470 (48)	195 (46)	1334 (49)	0.002
Early	35 (31)	881 (39)	34 (15)	323 (23)		19 (28)	278 (29)	90 (21)	635 (24)
Intermediate	29 (25)	377 (17)	60 (27)	309 (22)		21 (31)	216 (22)	136 (32)	691 (26)
Advanced	4 (4)	17 (<1)	4 (2)	18 (1)		1 (1)	10 (1)	3 (<1)	37 (1)
Missing

Donor type
HLA-identical sibling	114	2252	222	1391		0	0	0	0	<0.001
Unrelated, 8/8-matched	0	0	0	0		46 (68)	686 (70)	316 (75)	2130 (79)
Unrelated, 7/8-matched	0	0	0	0		22 (32)	288 (30)	108 (25)	567 (21)

Donor-recipient gender Match	40 (35)	750 (33)	78 (35)	429 (31)	0.96	25 (37)	341 (35)	174 (41)	1032 (38)	0.34
Male/Male	28 (25)	500 (22)	48 (22)	326 (23)		17 (25)	275 (28)	125 (29)	775 (29)
Male/Female	24 (21)	545 (24)	51 (23)	342 (25)		11 (16)	185 (19)	54 (13)	447 (17)
Female/Male	22 (19)	456 (20)	45 (20)	294 (21)		15 (22)	173 (18)	71 (17)	442 (16)
Female/Female	0	1 (<1)	0	0		0	0	0	1 (<1)
Missing

Donor-recipient CMV status	44 (39)	1247 (55)	77 (35)	558 (40)	<0.001	19 928)	164 (17)	108 (25)	567 (21)	0.003
Neg/Neg	16 (14)	208 (9)	25 (11)	142 (10)		9 (13)	102 (10)	44 (10)	263 (10)
Neg/Pos	19 (17)	273 (12)	63 (28)	331 (24)		24 (35)	339 (35)	138 (33)	948 (35)
Pos/Neg	32 (28)	430 (19)	54 (24)	337 (24)		15 (22)	306 (31)	122 (29)	801 (30)
Pos/Pos	3 (3)	94 (4)	3 (1)	23 (2)		1 (1)	64 (7)	12 (3)	118 (4)
Missing

Graf t type
Bone marrow	41 (36)	633 (28)	15 (7)	114 (8)	<0.001	17 (25)	479 (49)	53 (13)	813 (30)	<0.001
Peripheral blood	73 (54)	1619 (72)	207 (93)	1277 (92)		51 (75)	500 (51)	371 (88)	1884 (70)

ATG use
Yes	13 (11)	118 (5)	30 (14)	55 (4)	<0.001	23 (34)	146 (15)	144 (34)	718 (27)	<0.001
No	101 (89)	2134 (95)	192 (86)	1336 (96)		45 (66)	828 (85)	280 (66)	1979 (73)

TBI
Yes	30 (26)	834 (37)	99 (45)	600 (43)	<0.001	24 (35)	614 (63)	141 (33)	1128 (42)	<0.001
No	84 (74)	1418 (63)	123 (55)	791 (57)		44 (65)	360 (37)	283 (67)	1569 (58)

Conditioning regimen
Bu + Cy ± Others	54 (47)	1215 (54)	32 (14)	461 (33)	<0.001	25 (37)	284 (29)	64 (15)	688 (26)	<0.001
ATG+ Bu ± Cy ± Flu ±	11 (10)	88 (4)	8 (4)	49 (4)		15 (22)	60 (6)	101 (24)	533 (20)
Others	9 (8)	47 (2)	72 (32 )	248 (18)		2 (3)	11 (1)	98 (23)	288 (11)
Bu + Flu ± others	25 (22)	749 (33)	72 (32)	494 (36 )		16 (24)	516 (53)	88 (21)	897 (33)
TBI ± Cy ± others	1 (<1)	29 (1)	22 (10)	5 (<1)		6 (9)	85 (9)	41 (10)	177 (7)
ATG + TBI ± Cy ± others	4 (4)	65 (3)	5 (2)	101 (7)		2 (3)	12 (3)	12 (3)	54 (2)
TBI + Etop ± others	10 (9)	68 (3)	11 (5)	33 (2)		2 (3)	5 (<1)	20 (5)	60 (2)
Others

Year of transplant
2000–2004	41 (36)	1460 (65)	33 (15)	248 (18)	<0.001	11 (16)	560 (57)	49 (12)	506 (19)	<0.
2005–2008	29 (25)	635 (28)	82 (37)	464 (33)		34 (50)	321 (33)	219 (52)	1148 (43)	001
2009–2013	44 (39)	157 (7)	107 (48)	679 (49)		23 (34)	93 (10)	156 (37)	1043 (39)

Follow-up of survivors, months, median (range)	70 (3–168)	61 (1–194)	65 (3–150)	66 (3–174)	<0.001	76 (37–169)	97 (6–193)	72 (25-191)	72 (5–172)	<0.001

Open in a new tab

Tac- tacrolimus; CSA-Cyclosporine; MTX- methotrexate; MMF- mycophenolate mofetil; KPS- Karnofsky performance status; AML- acute myeloid leukemia; ALL- acute lymphoblastic leukemia; CML- chronic myeloid leukemia; MDS- myelodysplastic syndrome; CMV-cytomegalovirus; ATG- antithymocyte globulin; TBI- total body irradiation; Bu- busulfan; Cy- cyclophosphamide; Flu-fludarabine; Etop- etoposide

Engraftment and GVHD

Median time to neutrophil engraftment was 16 days for CSA+MTX (range, 1–72); followed by CSA+MMF 14 days (7–29); Tac+MTX 13 days (1–111); and Tac+MMF 12 days (98–25). Platelet recovery by day 28 was also low with CSA+MTX (75%) and CSA+MMF (76%) compared to Tac+MTX (82%) and Tac+MMF (98%) (Table 2)

Table 2:

Univariate Outcomes and Cause of Death in Myeloablative Related and Unrelated Donor Transplant

	Matched Related Donor (MRD)

	N eval	CSA+MMF Prob (95% CI)	N eval	CSA+MTX Prob (95% CI)	N eval	Tac+MMF Prob (95% CI)	N eval	Tac+MTX Prob (95% CI)	P-Value

Acute GVHD, II-IV
Day 100	114	44 (35–53%)	2218	34 (32–36%)	220	35 (28–41%)	1369	32 (20–35%)	0.07

Acute GVHD, III-IV
Day 100	114	26 (18–34%)	2203	18 (16–19%)	220	18 (13–23%)	1369	14 (12–16%)	0.005

Chronic GVHD
6 months	113	20 (13–28%)	2194	27 (25–29%)	219	28 (23–35%)	1372	26 (24–28%)	0.35
1 year		30 (21–39%)		41 (39–43%)		45 (39–52%)		46 (44–99%)	<0.001

Relapse
1 year	112	37 (28–46%)	2212	21 (19–23%)	219	28 (23–35%)	1368	30 (28–33%)	<0.001
2 years		40 (31–49%)		27 (25–29%)		45 (39–52%)		36 (34–39%)	<0.001

Transplant-related mortality
1 year	112	30 (22–39%)	2212	18 (16–19%)	219	14 (10–19%)	1368	13 (11–15%)	<0.001
2 years		35 (26–44%)		20 (18–21%)		17 (12–22%)		17 (15–19%)	<0.001

Disease-free survival
1 y ear	112	33 (25–42%)	2212	61 (59–63%)	219	54 (47–60%)	1368	57 (54–60%)	<0.001
2 years		25 (18–34%)		54 (52–56%)		45 (39–52%)		47 (44–49%)	<0.001

Overall Survival
1 year	114	46 (37–55%)	2252	69 (67–71%)	222	66 (59–72%)	1391	68 (66–71%)	<0.001
2 years		35 (26–44%)		61 (59–64%)		52 (45–59%)		55 (53–58%)	<0.001

GVHD-Relapse-free
Survival (GRFS)	114		2214		221		1377
1 year		16 (10–23%)		27 (25–29%)		20 (15–25%)		20 (18–22%)	<0.001

ANC recovery
14 days	113	46 (37–55%)	2228	30 (28–32%)	220	66 (60–72%)	1379	50 (48–53%)	<0.001

Platelet recovery
28 days	105	76 (68–84%)	2159	75 (74–77%)	201	89 (84–93%)	1349	82 (80–84%)	<0.001

Cause of Death	80		992		132		780
Primary disease		33 (41)		384 (39)		71 (54)		404 (52)
Graft failure		2 (3)		8 (<1)		1 (<1)		1 (<1)
GVHD		24 (30)		222 (22)		28 (21)		158 (20)
IPN		5 (6)		102 (10)		10 (8)		70 (9)
Infection		3 (4)		57 (6)		4 (3)		20 (3)
Organ failure		8 (10)		91 (9)		7 (5)		59 (8)
Secondary		0		14 (1)		2 (2)		10 (1)
malignancy		4 (5)		86 (9)		7 (5)		40 (5)
Other		1 (1)		28 (3)		2 (2)		18 (2)
Missing

	Unrelated donor (URD)

	N eval	CSA+MMF Prob (95% CI)	N eval	CSA+MTX Prob (95% CI)	N eval	Tac+MMF Prob (95% CI)	N eval	Tac+MTX Prob (95% CI)

Acute GVHD, II-IV
Day 100	68	57 (46–69%)	964	50 (47–53%)	419	55 (50–59%)	2678	49 (47–51%)	0.11

Acute GVHD, III-IV
Day 100	68	40 (28–52%)	965	23 (20–25%)	420	25 (21–30%)	2673	20 (19–22%)	0.001

Chronic GVHD
6 months	66	21 (12–32%)	962	35 (32–38%)	417	35 (30–40%)	2673	28 (27–30%)	<0.001
1 year		NE		48 (44–51%)		51 (46–56%)		45 (43–47%)	0.01

Relapse
1 year	64	23 (14–25%)	954	23 (20–25%)	415	28 (24–32%)	2652	27 (25–29%)	0.03
2 years		25 (15–36%)		27 (24–30%)		32 (28–37%)		31 (30–33%)	0.03

Transplant-related mortality
1 year	64	41 (29–53%)	954	26 (24–29%)	415	24 (20–28%)	2652	20 (19–22%)	<0.001
2 years		44 (32–56%)		30 (27–33%)		29 (25–34%)		24 (22–26%)	<0.001

Disease-free survival
1 y ear	64	36 (25–48%)	954	51 (48–54%)	415	48 (43–53%)	2652	53 (51–54%)	0.02
2 years		31 (21–43%)		43 (40–47%)		39 (34–43%)			0.02

Overall Survival
1 year	68	40 (28–52%)	974	57 (54–60%)	424	54 (49–59%)	2697	60 (58–62%)	0.001
2 years		34 (23–45%)		49 (46–52%)		44 (39–49%)		50 (48–52%)	0.005

GVHD-Relapse-free
Survival (GRFS)	67		968		422		2691
1 year		10 (4–19%)		16 (13–18%)		10 (7–13%)		17 (15–18%)	<0.001

ANC recovery
14 days	67	43 (32–55%)	970	26 (23–28%)	424	70 (65–74%)	2686	41 (39–43%)	<0.001

Platelet recovery
28 days	67	64 (52–75%)	960	59 (56–62%)	402	83 (79–86%)	2646	68 (67–70%)	<0.001

Cause of Death	48		628		293		1659
Primary disease		13 (27)		209 (33)		111 (38)		686 (41)
Graft failure		0		9 (1)		1(<1)		12 (<1)
GVHD		16 (33)		167 (27)		90 (31)		393 (24)
IPS		7 (15)		73 (12)		30 (10)		170 (10)
Infection		4 (8)		35 (6)		11(4)		66 (4)
Organ failure		5 (10)		69 (11)		22 (8)		169 (10)
Secondary		0		2 (<1)		3 (1)		15 (<1)
malignancy		3 (6)		58 (9)		17 (6)		120 (7)
Other		0		6 (<1)		8 (3)		29 (2)
Missing

Open in a new tab

CSA- cyclosporine; MMF- mycophenoalte mofetil; MTX- methotrexate; Tac- tacrolimus; GVHD- graft-versus-host diseae; ANC- absolute neutrophil count; IPN- idiopathic pneumonia syndrome

The cumulative incidence of grade II-IV and III-IV aGVHD at day 100 is shown in Table 2. In multivariable analysis (MVA), CSA+MMF (HR 1.65, P<0.001) and CSA+MTX (HR 1.17, P=0.010) were associated with worse grade II-IV aGVHD relative to reference Tac+MTX (Table 3, Figure 1A). CSA+MMF was also associated with more grade III-IV aGVHD (HR 1.92, P<0.001) versus Tac+MTX. While the primary analysis focused on comparisons of GVHD prophylaxis regimens relative to Tac+MTX as the reference, pairwise comparisons between each regimen was also evaluated and demonstrated a higher incidence of grade III-IV aGVHD with CSA+MMF relative to CSA+MTX (HR 1.71, 95% confidence interval [CI] 1.17–2.50, P=0.006). CSA+MMF also fared worse relative to CSA+MTX (HR1.41, 95% CI 1.06–1.86, P=0.017) and Tac+MMF (HR 1.57, 95% CI 1.10–2.22, P=0.012) for grade II-IV aGVHD, but did not reach our pre-defined level of significance (P=0.01). Complete MVA tables detailing additional patient, disease, and transplant-factors are in the Supplementary Tables.Given differential effects over time specific for this outcome, MVA for cGVHD were divided into those experiencing cGVHD <5 months and ≥ 5 months (median time to cGVHD onset: 5.6 months). Relative to Tac+MTX, CSA+MTX was associated with higher rates of cGVHD <5 months of transplant (HR 1.41, P<0.001), however ≥5 months of transplant, this association reversed (HR 0.74, P<0.001) (Table 3). Pairwise comparisons of each GVHD prophylaxis regimens relative to each other did not reveal any further significant associations (Supplementary Table)

Table 3:

Multivariate Outcomes in Myeloablative Related and Unrelated Donor Transplant

	Tac+MTX	CSA+MMF	CSA+MTX	Tac+MMF
Matched Related donor (MRD) HR (95% CI), P-value
aGVHD grade 2–4	Ref (1.00)	1.65 (1.24–2.20) P<0.001	1.17 (1.04–1.33) P=0.010	1.05 (0.83–1.34) P=0.661
aGVHD grade 3–4		1.92 (1.31–2.83) P<0.001	1.13 (0.92–1.37) P=0.283	1.19 (0.85–1.66) P=0.319
cGVHD^* <5 months		1.34 (0.83–2.17) P=0.233	1.41 (1.20–1.67) P<0.001	1.28 (0.94-.74) P=0.119
cGVHD^* ≥5 months		0.56 (0.34–0.95) P=0.030	0.74 (0.65–0.85) P<0.001	0.92 (0.71–1.19) P=0.512
TRM^* <5 months		4.03 (2.61–6.23) P<0.001	2.29 (1.78–2.95) P<0.001	1.17 (0.71–1.94) P=0.537
TRM^* ≥5 months		1.38 (0.78–2.44) P=0.275	0.83 (0.67–1.03) P=0.095	0.90 (0.59–1.36) P=0.609
Relapse		1.43 (1.05–1.93) P=0.022	0.86 (0.74–0.98) P=0.029	0.92 (0.73–1.14) P=0.444
OS^* <5 months		2.31 (1.73–3.09) P<0.001	1.27 (1.10–1.48) P=0.002	1.05 (0.81–1.37) P=0.704
OS^* ≥5 months		0.94 (0.62–1.43) P=0.767	0.74 (0.64–0.87) P<0.001	0.92 (0.70–1.20) P=0.530
Unrelated donor (URD) HR (95% CI), P-value
aGVHD, grade 2–4	Ref (1.00)	1.49 (1.08–2.07) P=0.016	1.00 (0.90–1.12) P=0.961	1.14 (0.99–1.32) P=0.066
aGVHD, grade 3–4		2.31 (1.57–3.42) P<0.001	1.02 (0.87–1.20) P=0.806	1.26 (1.02–1.56) P=0.030
cGVHD^* <4 months		1.54 (0.79–2.98) P=0.203	1.62 (1.35–1.93) P<0.001	1.34 (1.04–1.73) P=0.022
cGVHD^* ≥4 months		0.92 (0.52–1.63) P=0.779	0.85 (0.74–0.98) P=0.025	1.47 (1.24–1.75) P<0.001
TRM^* <4 months		3.09 (2.00–4.77) P<0.001	1.24 (1.02–1.51) P=0.030	1.02 (0.77–1.36) P=0.896
TRM^* ≥4 months		0.89 (0.42–1.90) P=0.763	1.00 (0.84–1.20) P=0.979	1.45 (1.16–1.81) P=0.001
Relapse		0.81 (0.50–1.32) P=0.398	0.97 (0.85–1.12) P=0.699	0.93 (0.78–1.12) P=0.449
OS^* <4 months		2.36 (1.67–3.35) P<0.001	1.23 (1.08–1.41) P=0.002	1.20 (1.01–1.44) P=0.044
OS^* ≥4 months		1.10 (0.64–1.89) P=0.730	0.91 (0.79–1.05) P=0.221	1.34 (1.12–1.61) P=0.001

Open in a new tab

Given differential effects over time (non-proportional hazards), models were constructed breaking the post-transplant time course into 2 periods, using the maximized partial likelihood method to find the most appropriate breakpoint.

Figure 1A. — Incidence of Acute Grade II-IV GVHD among GVHD Prophylaxis Regimens in Myeloablative Matched Related Donors

TRM

The incidence of TRM at 1-year was significantly higher for CSA+MMF (30%) compared to other GVHD regimens (Table 2). In MVA, both CSA+MMF (HR 4.03, P<0.001) and CSA+MTX (HR 2.29, P<0.001) were significantly associated with higher TRM compared to Tac+MTX <5 months of transplant, but not after 5 months given time varying effects (Table 3, Figure 2A). Pairwise comparisons between all GVHD prophylaxis regimens also demonstrate worse TRM<5 months of transplant with CSA+MMF compared to CSA+MTX (HR 1.76, 95% CI 1.17–2.65, P=0.007) and Tac+MMF (HR 3.43, 95% CI 0.77–3.03, P<0.001); and subsequently CSA+MTX relative to Tac+MMF (HR 1.96, 95% CI 1.19–3.22, P=0.0074) (Supplementary Table).

Figure 2A. — Incidence of Treatment-Related Mortality among GVHD Prophylaxis Regimens in Myeloablative Matched Related Donors

Relapse

The 1-year cumulative incidence of relapse for each regimen is shown in Table 2. In MVA, there was no significant difference in relapse between any GVHD prophylaxis regimen relative to Tac+MTX. Pairwise comparisons between all groups, however, demonstrate a higher association of relapse with CSA+MMF relative to CSA+ MTX (HR 1.67, 95% CI 1.23–2.27, P=0.001) (Supplementary Table).

DFS and OS

CSA+MMF recipients had poor DFS and OS compared to all other GVHD regimens (Table 2). One-year probabilities of GRFS confirmed significantly worse outcomes with CSA+MMF (10%) compared to CSA+MTX (27%), Tac+MMF (20%), and Tac+MTX (20%).

In MVA, CSA+MMF was associated with poor DFS (HR 1.64, P<0.001) relative to Tac+MTX. Pair-wise comparisons between each regimen also demonstrate inferior DFS with CSA+MMF versus CSA+MTX (HR 1.63, 95% CI 1.29–2.05, P<0.001) and Tac+MMF (HR 1.74, 95% CI 1.32–2.30, P<0.001) (Supplementary index).

Two-year OS within the CSA+MMF cohort was 48%, compared to 67% with CSA+MTX, 69% with Tac+MMF, and 71% for Tac+MTX. Adjusted OS curves are shown in Figure 3A. In MVA, CSA+MMF was significantly associated with worse outcome (HR 2.31, P<0.001) compared to Tac +MTX < 5 months of transplant. CSA+MTX was also associated with worse survival (HR 1.27, P=0.002) compared to Tac+MTX within the first 5 months, with a reversal of this association ≥5 months (HR 0.74, P=0.003) given non-proportional hazards over time (Table 3). Pairwise comparisons also demonstrated inferior survival of CSA+MMF relative to CSA+MTX (HR 1.82, 95% CI 1.36–2.42, P<0.001) and Tac+MMF (HR 2.17, 95% CI 1.53–3.12, P<0.0001) <5 months of transplant (Supplementary index)

Transplantation from an unrelated donor

Patient, Disease, and Transplant Characteristics

In the URD cohort, Tac+MTX was the predominant GVHD prophylaxis regimen (N=2697), followed by CSA+MTX (N=974), Tac+MMF (N=424), and CSA+MMF (N=68) (Table 1). Similar to MRD, there were more patients in the CSA+MTX (57%) cohort transplanted before 2005. The use of BM as a cell source was also more common in CSA+MTX group (49%) compared to other regimens—CSA+MMF (25%), Tac+MMF (13%), Tac+MTX (30%); while ATG was used less commonly with CSA+MTX (15%) relative to CSA+MMF (34%), Tac+MMF (34%), and Tac+MTX (27%).