Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 554-563, May 2009

Unrelated Donor Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: Long-Term Outcomes

  • Koen van Besien

      Affiliations

    • University of Chicago Medical Center, Chicago, Illinois
    • Corresponding Author InformationCorrespondence and reprint requests to: Koen van Besien, MD, University of Chicago, Section of Hematology/Oncology Rm 1209, 5841 South Maryland Avenue, Chicago, IL, 60637.
    • ,
  • Jeanette Carreras

      Affiliations

    • Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
    • ,
  • Philip J. Bierman

      Affiliations

    • University of Nebraska Medical Center, Omaha, Nebraska
    • ,
  • Brent R. Logan

      Affiliations

    • Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
    • ,
  • Arturo Molina

      Affiliations

    • Cougar Biotechnology, Los Angeles, California
    • ,
  • Roberta King

      Affiliations

    • National Marrow Donor Program, Minneapolis, Minneapolis
    • ,
  • Gene Nelson

      Affiliations

    • National Marrow Donor Program, Minneapolis, Minneapolis
    • ,
  • Joseph W. Fay

      Affiliations

    • Baylor University Medical Center, Dallas, Texas
    • ,
  • Richard E. Champlin

      Affiliations

    • M.D. Anderson Cancer Center, Houston, Texas
    • ,
  • Hillard M. Lazarus

      Affiliations

    • University Hospitals Case Medical Center, Cleveland, Ohio
    • ,
  • Julie M. Vose

      Affiliations

    • University of Nebraska Medical Center, Omaha, Nebraska
    • ,
  • Parameswaran N. Hari

      Affiliations

    • Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin

Received 22 October 2008; accepted 14 January 2009. published online 09 March 2009.

Article Outline

Abstract 

We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.

Key Words: Lymphoma, Unrelated donor, Myeloablative

 

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Introduction 

In 1993, the National Marrow Donor Program (NMDP) reported on 462 patients undergoing unrelated donor hematopoietic cell transplantation (HCT). The large majority of these patients suffered from leukemia, only 8 patients with lymphoma were included [1]. Since then, unrelated donor HCT has become a standard form of treatment for patients with acute leukemia 2, 3, 4. Advances in HLA-typing have permitted more accurate identification of compatible donor-recipient pairs, and many recent series suggest that the outcomes of HLA-identical unrelated donor transplantation are virtually identical to that of HLA-identical sibling transplantation for leukemia 5, 6, 7. At the same time, allogeneic sibling HCT has become more widely used in lymphoma. It is widely accepted as an excellent treatment for relapsed follicular lymphoma (FL) 8, 9, 10, 11, and is often used as an alternative to autologous transplant in large cell lymphoma 12, 13, 14, 15, mantle cell lymphoma 16, 17, T cell lymphoma 18, 19, 20, 21, in high-grade lymphomas 22, 23, in patients with lymphoma who have failed prior autologous transplantation [24]. Unrelated donor HCT is increasingly used in NHL 8, 12, 16, 25, 26, 27, 28, and single-institution studies report similar outcomes after related and unrelated donor transplantation for lymphoma [29], but large series are lacking. This report describes cure rates and treatment complications in a large patient cohort with very high-risk characteristics undergoing unrelated allogeneic HCT for non-Hodgkin lymphoma (NHL) facilitated by the NMDP. Because the large majority of the patients received total body irradiation (TBI)-based conditioning, this dataset does not address questions regarding relative superiority of various transplant conditioning regimens.

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Patients and Methods 

Data Sources 

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR), and the NMDP that comprises a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on consecutive allogeneic and autologous transplants to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee or the NMDP Coordinating Center in Minneapolis. Participating centers are required to report all consecutive transplants; compliance is monitored by on-site audits. Subjects are followed longitudinally, with yearly follow-up. Computerized checks for errors, physicians’ review of submitted data, and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are done with a waiver of informed consent and in compliance with HIPAA regulations as determined by the Institutional Review Board and the Privacy Officer of the Medical College of Wisconsin.

Patients 

The outcomes of patients with NHL who underwent myeloablative unrelated allogeneic bone marrow or peripheral blood HCT facilitated by the NMDP between 1991 and 2004 are reported. The policies and procedures of the NMDP have been described previously 2, 3. All donors signed written statements of informed consent prior to donation. Patients with a prior autologous HCT and recipients of cord blood grafts (n = 5) were excluded from analysis. Central histology review was not performed.

Study Endpoints 

Outcomes analyzed included engraftment, acute and chronic graft-versus-host disease (aGVHD, cGVHD), treatment-related mortality (TRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). The incidence and stage of acute skin, liver, and intestinal GVHD were measured by standard criteria [30]. cGVHD was classified according to the standard criteria in use prior to the recent consensus statement [31]. Lymphoma histology was classified according to the World Health Organization (WHO) classification [32]. The day of engraftment was defined as the first of 3 consecutive days on which the absolute neutrophil count (ANC) exceeded 0.5 × 109/L or time to neutrophil count >3 × 109/L on 1 occasion.

TRM was defined as death within 28 days posttransplant or death without lymphoma progression, and summarized using the cumulative incidence estimate with progression or relapse as the competing risk. Progression was defined as progressive lymphoma posttransplant or lymphoma recurrence. It could follow a period of “stable” disease posttransplant, or a partial or complete remission. Progression represents new or larger areas of lymphoma (≥25% increase in largest diameter) compared to the state of best posttransplant response. Progression was summarized by the cumulative incidence estimate with TRM as the competing risk. For PFS, subjects were considered treatment failures at the time of lymphoma progression or death from any cause. Subjects alive without evidence of lymphoma progression were censored at last follow-up and the PFS event was summarized by a survival curve. The OS interval variable was defined as time from the date of transplant to the date of death or last contact and summarized by a survival curve.

A variety of HLA typing methods were utilized over the period of study for matching donor recipient pairs. These included serologic typing, or molecular typing techniques. Donor recipient pairs were therefore reclassified as well matched, partially matched, or mismatched according to recent criteria proposed by Weisdorf et al. [33].

Statistical Analysis 

Subject-, disease-, and transplant-related variables for subjects were described. Univariate probabilities of developing TRM and lymphoma relapse/progression were calculated using cumulative incidence curves to accommodate corresponding competing risks [33]. Probabilities of OS and PFS were calculated using Kaplan-Meier estimator [34]. Confidence intervals (CI) were calculated with a log-transformation.

The effect of pretransplant variables on the outcomes of TRM, lymphoma progression, PFS, and survival after transplantation, was compared using Cox proportional hazards model incorporating pretransplant variables of interest [35]. Covariates that influenced outcomes were identified by stepwise forward selection multivariate model. Any covariate with a value of P ≤ .05 was considered significant. The proportionality assumption for Cox regression was tested by adding a time-dependent covariate for each risk factor and each outcome. Tests indicated that all variables met the proportional hazards assumption. Results were expressed as relative risks (RR) or the relative rate of occurrence of the event. The following variables (summarized in Table 1) were considered in multivariate analyses: age at transplant, sex, Karnofsky Performance Status (KPS) at transplant, lymphoma histology, disease status, and chemosensitivity at transplant, time from diagnosis to transplant, TBI-based conditioning, T cell depletion, donor-recipient HLA match, donor-recipient CMV status, and year of transplant. There were no statistically significant center effects [36]. Analyses were performed using SAS software, version 8.2 (SAS Institute, Cary, NC).

Table 1. Variables Tested in Cox Proportional Hazards Regression Models

Patient-related variables:

Age: ≤20∗ versus 21-40 versus ≥40

Sex: male∗ versus female

Karnofsky performance status: <90%∗ versus ≥90%

Disease-related variables

Histology: follicular∗ versus DLCL/immunoblastic versus lymphoblastic/Burkitts/Burkitt-like versus mantle cell versus peripheral T cell versus others

Disease status at transplant: chemosensitive CR∗ versus chemosensitive PR versus chemoresistant

Treatment-related variables:

Time from diagnosis to transplant: TBD (will look for optimal cutoff point)

TBI conditioning: no∗ versus yes

T cell depletion: no∗ versus yes

Type of donor: well-matched∗ versus others

Donor age: 11-20∗ years versus 21-30 years versus 31-40 years versus 41-50 years versus 51-60 years

Donor type: well matched versus others

CMV status: +/+ versus +/− versus −/+ versus −/− versus not tested

Year of transplant: 1991-1994∗ versus 1995-1999 versus 2000-2004

CR indicates complete remission; PR, partial remission; TBI, total body irradiation; TBD, to be determined; CMV, cytomegalovirus.

∗Reference group.

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Results 

Patient Characteristics 

Two hundred eighty-three NHL patients were identified who received unrelated allogeneic bone marrow transplants at 63 transplant centers between 1991 and 2004. Fifty-six percent of these transplants occurred between 2000 and 2004. The median follow-up for surviving patients is 5.1 years (0.7-12.1). The median time interval between diagnosis and transplant was 1.4 (range: 0.9-16) years. Patient characteristics are summarized in Table 2.

Table 2. Characteristics of Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for NHL and Reported to the CIBMTR between 1991 and 2004
VariableN evalN (%)
Number of patients 283
Number of centers 63
Age, median (range), years28337 (2-65)
Age at transplant, years283
≤10 16 (6)
11-20 34 (12)
21-30 62 (22)
31-40 58 (20)
41-50 84 (30)
51-60 27 (9)
≥61 2 (1)
Male sex283188 (66)
Karnofsky score pretransplant270
<90 100 (37)
≥90 170 (63)
Histology283
Follicular 62 (22)
DLCL/Immunoblastic 73 (26)
Lymphoblastic/Burkitts/Burkitt-like 68 (24)
Mantle Cell 20 (7)
Peripheral T cell 19 (7)
Others∗ 41 (14)
Disease status at transplant269
CR1 41 (15)
CR2+ 30 (11)
PIF resistant 74 (28)
PIF sensitive 57 (21)
REL resistant 27 (10)
REL sensitive 40 (15)
Extranodal sites of disease at transplant51
1 5 (10)
2 1 (2)
No extranodal involvement 45 (88)
Disease stage at diagnosis283
I-II 59 (21)
III-IV 206 (73)
Unknown 18 (6)
Interval from diagnosis to transplant, median (range), months28317 (1-192)
Conditioning regimen283
TBI + Cy ± other 212 (75)
TBI ± other 26 (9)
Bu + Cy ± other 38 (13)
Cy ± other 3 (1)
Others† 4 (2)
Fludarabine106
Yes 5 (5)
No 101 (95)
T cell depletion‡283
Yes 78 (28)
No 205 (72)
Donor age, median (range), years28236 (20-54)
Donor age at transplant, years282
11-20 7 (2)
21-30 76 (27)
31-40 121 (43)
41-50 70 (25)
51-60 8 (3)
Type of donor§283
Well-matched 153 (54)
Partially matched 111 (39)
Mismatched 17 (6)
Unknown 2 (1)
Graft type283
Bone marrow 223 (79)
Peripheral blood 60 (21)
Donor-recipient sex match283
M-M 132 (47)
M-F 57 (20)
F-M 56 (20)
F-F 38 (13)
Donor/recipient CMV status283
+/+ 31 (11)
+/− 24 (8)
−/+ 82 (29)
−/− 109 (39)
Not tested 37 (13)
GVHD prophylaxis283
MTX + CsA ± other 127 (45)
CsA ± other 12 (4)
MTX + FK506 ± other 76 (27)
FK506 ± other 12 (4)
T cell depletion ± other 52 (18)
Others§ 4 (2)
Year of transplant283
1991-1994 11 (4)
1995-1999 114 (40)
2000-2004 158 (56)
Median follow-up of survivors, months7361 (8-145)

Follow-up completeness index = 98%.

NHL indicates non-Hodgkin lymphoma; CR, complete remission; CIBMTR, Center for International Blood and Marrow Transplant Research; Cy, cyclophosphamide; TBI, total body irradiation; CsA, cyclosporine; GVHD, graft-versus-host disease; MTX, methotrexate; CMV, cytomegalovirus; DLCL, diffuse large cell lymphoma; PIF, prolactin release-inhibiting factor; REL, ring enhancing lesion; Bu, busulfan; MM, multiple myeloma.

†Other conditioning regimen includes (N = 4):

1.Bu + L-PAM (n = 2)

2.Carboplatin + Thiotepa + other (n = 2)

‡T cell depletion includes:

1.26 received in vivo T cell depletion with antithymocyte globulin (ATG) or Campath.

2.40 grafts were in vitro T cell depleted with various antibody based methods.

3.12 grafts were in vitro T cell depleted with antibody based methods combined with in vivo administration of ATG.

§Type of donor defined as:

Well-matched includes: 1,7,10,16 (see below)

Partially matched includes: 2,3,8,11,13,21 (see below)

Mismatched includes 5,6,9 (see below)
HLA GroupsN
1Matched 8/8 at high-res HLA-A, -B, -C, and -DRB1112
2Single allele MM (7/8) at high-res HLA-A, -B, -C, and -DRB117
3Single antigen MM (7/8) at high-res HLA-A, -B, -C, and -DRB126
5≥2 MM with 1 antigen MM (<7/8) at high-res HLA-A, -B, -C, and -DRB113
6≥2 MM with 2 or more antigen MM (<7/8) at high-res HLA-A, -B, -C and -DRB12
7Matched 8/8 at high-res HLA-A, -B, and -DRB1 and low-res at HLA-C5
8Single MM (7/8) at high-res HLA-A, -B, and -DRB1 and low-res at HLA-C2
9≥2 MM (<7/8) at high-res HLA-A, -B, and -DRB1 and low-res at HLA-C2
10Matched 8/8 at low-res HLA-A, -B and -C and high-res at HLA-DRB130
11Single MM (7/8) at low-res HLA-A, -B, and -C and high-res at HLA-DRB17
16Matched 6/6 at high-res HLA-A, -B, and -DRB1 (HLA-C unknown)6
21Matched 6/6 at low-res HLA-A and -B and high-res at HLA-DRB1 (HLA-C unknown)59

§Other GVHD prophylaxis includes (N = 4)

1. MTX ± other (n = 1)

2. GVHD given, not specified (n = 2)

3. None (n = 1)

∗Others histology includes (N = 41):

1.NHL, not otherwise stated (NOS) (n = 3)

2.NHL other, not specified (n = 35)

3.Extranodal marginal zone B cell of MALT (n = 1)

4.Nodal marginal zone B cell (n = 2)


The median age at the time of transplant was 37 (range: 2-65) years. Sixty-six percent of patients were male. Twenty-two percent of patients had FL 26% diffuse large B cell lymphoma, 24% lymphoblastic, Burkitt's or Burkitt-like lymphoma, 7% mantle cell lymphoma, and 7% had peripheral T cell lymphoma. Fourteen percent were classified as other. This group includes patients where no specific histology was provided, but also some with rare histologies (Table 2, footnote ∗). Thirty patients were reported as having transformed lymphoma. For analysis they were categorized under the histologic diagnosis at the time of transformation. Only 15% of patients underwent transplant in first complete remission and 11% in second or subsequent remission. The majority of patients were not in remission at transplant: 49% with primary induction failure, 15% with sensitive relapse, and 10% with resistant relapse. Overall, 38% patients were chemotherapy refractory at the time of transplant. The large majority of patients (84%) received TBI containing regimens. The donor grafts were non-T depleted in 72% of cases and they were mostly bone marrow grafts. Standard GVHD prophylaxis that is, a calcineurin inhibitor plus methotrexate (MTX) was used in 72% of cases. Donors were well matched in 54%, partially matched in 39%, and mismatched in 6% of cases. The matching for 2 donors (1%), was unknown.

Outcomes 

Outcomes are summarized in Table 3. Ninety percent of patients engrafted, and almost all of these had reached an ANC of >0.5 by day 28. The overall 100-day mortality was 39%. TRM was 44% by 1 year and increased to 52% by 5 years. The cumulative incidence of grade iii-iv aGVHD was 25% and the cumulative incidence of cGVHD increased to 32% at 5 years. The risk for disease progression was 25% at 1 year, with no change in subsequent years. PFS at 1 year was 31% and decreased to 22% at 5 years. OS was 36% at 1 year and decreased to 24% at 5 years (Figure 1).

Table 3. Univariate Probabilities of Transplant Outcomes among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for NHL
Outcome eventNProb (95% CI)∗
100-day mortality28339 (33-45)
ANC>0.5 × 109/L283
@ 28 days 89 (86-93)
@ 100 days 90 (87-93)
Acute GVHD @ 100 days, grades (3-4)28125 (20-30)
Chronic GVHD280
@ 1 year 27 (22-32)
@ 3 years 31 (26-37)
@ 5 years 32 (26-37)
TRM283
@ 1 year 44 (38-49)
@ 3 years 49 (43-55)
@ 5 years 52 (45-57)
Progression/relapse283
@ 1 year 25 (20-30)
@ 3 years 26 (21-32)
@ 5 years 26 (21-32)
PFS283
@ 1 year 31 (26-37)
@ 3 years 25 (20-30)
@ 5 years 22 (17-28)
OS283
@ 1 year 36 (31-42)
@ 3 years 28 (22-33)
@ 5 years 24 (19-30)

NHL indicates non-Hodgkin lymphoma; CI, confidence interval; ANC, absolute neutrophil count; GVHD, graft-versus-host disease; TRM, treatment-related mortality; PFS, progression-free survival, OS, overall survival.

∗Probabilities of neutrophil, acute and chronic GVHD (aGVHD, cGVHD), TRM, and progression/relapse were calculated using the cumulative incidence estimate. 100-day mortality, PFS, and OS were calculated using the Kaplan-Meier product limit estimate.

Multivariate Analysis 

Multivariate analyses for the outcomes of TRM, relapse/progression, PFS, and OS are summarized in Table 4, Table 5, Table 6, Table 7.

Table 4. Multivariate Analysis Comparing Treatment-Related Mortality among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for NHL
VariablesNRelative Risk (95% CI)P-Value
Age at transplant
≤20461.00∗P†overall = .003
21-401051.76 (0.97-3.20).062
≥401052.82 (1.51-5.28).001
Karnofsky performance status
≥901621.00∗
<90941.53 (1.07-2.18).018
Histology
Follicular521.00∗P†overall = .021
DLCL/Immunoblastic701.91 (1.15-3.16).012
Lymphoblastic/Burkitts/Burkitt-like611.97 (1.11-3.48).020
Mantle cell202.23 (1.15-4.31).017
Peripheral T cell150.61 (0.21-1.76).360
Others381.50 (0.80-2.80).204

CI indicates confidence interval; DLCL, diffuse large cell lymphoma; NHL, non-Hodgkin lymphoma.

∗Reference group.

†2 degrees of freedom.

Table 5. Multivariate Analysis Comparing Progression/Relapse among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for NHL
VariablesNRelative Risk (95% CI)P-Value
Disease status at transplant
Within 3 months posttransplant∗
Chemosensitive CR671.00†P‡overall = .008
Chemosensitive PR934.42 (1.46 - 13.34).008
Chemoresistant965.74 (1.90 - 17.36).002
Histology
Follicular521.00†P‡overall = .020
DLCL/Immunoblastic701.69 (0.72-4.00).231
Lymphoblastic/Burkitts/Burkitt-like613.53 (1.53-8.14).003
Mantle cell202.46 (0.74-8.21).143
Peripheral T cell150.37 (0.05-2.96).349
Others382.49 (1.02-6.10).046

CI indicates confidence interval; DLCL, diffuse large cell lymphoma; NHL, non-Hodgkin lymphoma.

∗Time-dependant covariates. The effect of disease status at transplant differs with the length of time after transplant. Patients transplanted with chemoresistant disease had no different progression/relapse rates than patients transplanted with chemosensitive disease, when considering time period beyond 3 months after transplant. However, when considering the first 3 months after transplant patients transplanted with chemoresistant disease had higher rates of progression/relapse.

†Reference group.

‡2 degrees of freedom.

Table 6. Multivariate Analysis Comparing Progression-Free Survival among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for NHL
VariablesNRelative Risk (95% CI)P-Value
Karnofsky performance status
≥901621.00∗
<90941.39 (1.03-1.87).031
Histology
Follicular521.00∗P†overall <.001
DLCL/Immunoblastic701.56 (1.02-2.39).041
Lymphoblastic/Burkitts/Burkitt-like611.92 (1.23-2.99).004
Mantle cell202.62 (1.48-4.66).001
Peripheral T cell150.43 (0.17-1.11).083
Others381.41 (0.86-2.32).170
Disease status at transplant
Within 3 months post transplant‡
Chemosensitive CR671.00∗P§overall = <.001
Chemosensitive PR932.13 (1.20-3.78).010
Chemoresistant963.25 (1.86-5.70)<.001

CI indicates confidence interval; DLCL, diffuse large cell lymphoma; CR, complete remission; PR, partial remission.

∗Reference group.

†4 degress of freedom.

‡Time-dependant covariates. The effect of disease status at transplant differs with the length of time after transplant. Patients transplanted with chemoresistant disease had no different progression/relapse or death rates than patients transplanted with chemosensitive disease, when considering time period beyond 3 months after transplant. However, when considering the first 3 months after transplant patients transplanted with chemoresistant disease had higher rates of progression/relapse or death.

§2 degrees of freedom.

Table 7. Multivariate Analysis Comparing Survival among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning For NHL
VariablesNRelative Risk (95% CI)P-Value
Age at transplant
≤20461.00∗P†overall = .025
21-401051.12 (0.73-1.74).596
≥401051.72 (1.07-2.75).025
Karnofsky performance status
≥901621.00∗
<90941.38 (1.02-1.87).037
Histology
Follicular521.00∗P‡overall = <.001
DLCL/immunoblastic701.91 (1.23-2.99).004
Lymphoblastic/Burkitts/Burkitt-like612.25 (1.38-3.67).001
Mantle cell202.16 (1.20-3.88).010
Peripheral T cell150.44 (0.15-1.27).128
Others381.67 (0.99-2.80).054
Disease status at transplant
Within 3 months post transplant§
Chemosensitive CR671.00∗P†overall = <.001
Chemosensitive PR931.70 (0.90-3.24).103
Chemoresistant962.99 (1.62-5.52)<.001

CI indicates confidence interval; CR, complete remission; DLCL, diffuse large cell lymphoma; PR, partial remission; NHL, non-Hodgkin lymphoma.

∗Reference group.

†2 degrees of freedom.

‡4 degrees of freedom.

§Time-dependent covariates. The effect of disease status at transplant differs with the length of time after transplant. Patients transplanted with chemoresistant disease had no different death rates than patients transplanted with chemosensitive disease, when considering time period beyond 3 months after transplant. However, when considering the first 3 months after transplant patients transplanted with chemoresistant disease had higher rates of death.

Treatment-related mortality 

After adjustment for covariates the relative risk of TRM was 3.02 for those over the age of 40 years (P < .001) compared to patients aged 20 years or younger. KPS of <90 was also associated with a 50% increased risk for TRM (RR = 1.43, P = .05). Compared to those with FL or those with peripheral T cell lymphoma, patients with diffuse large cell, lymphoblastic/Burkitt, or mantle cell lymphoma had significantly worse TRM.

Lymphoma relapse/progression 

The risk for disease recurrence was increased 5-fold (RR = 5.74, P = .002) for those undergoing transplant with refractory disease and 4-fold (RR = 4.42, P = .008) for those undergoing transplant in partial remission compared to those undergoing transplant in complete remission. Lymphoblastic or Burkitt's histology was also associated with increased disease recurrence (RR = 3.53, P = .003).

PFS and treatment failure 

PFS was adversely associated with lower performance status, aggressive disease histology, and chemotherapy resistance. KPS <90 was associated with a higher risk of treatment failure (RR = 1.39, P = .03). Patients with diffuse large cell, lymphoblastic/Burkitt's/Burkitt-like, or mantle cell histology were at higher risk of treatment failure than those with follicular or peripheral T cell lymphoma. Patients in partial remission at transplant (RR = 2.13, P = .01) or those with chemotherapy resistant disease (RR = 3.25, P < .001) were at higher risk of treatment failure within 3 months of transplant.

Survival 

Survival was superior for younger patients, those with better performance status, those with FL or peripheral T cell lymphoma, and those with chemotherapy sensitive disease. Figure 2 shows survival curves by disease histology. Figure 3 illustrates the impact of KPS on survival, and Figure 4 the impact of disease stage.

Causes of death 

Two hundred ten patients died with 29% of the deaths (29%) attributable to progressive lymphoma. Organ failure (19%), infection (15%), pulmonary syndrome (13%), and GVHD (12%) were the other major causes of mortality. Relapse accounted for 39% of deaths in patients with lymphoblastic or Burkitt's lymphoma (P < .01 versus all others).

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Discussion 

Multiple prospective and observational studies have demonstrated the curative potential of sibling transplantation in a variety of lymphoma subtypes and have established it as a reasonable alternative to autologous transplantation 8, 9, 10, 11, 12, 13, 14, 16, 17, 19, 20, 21, 22, 23, 37, 38, 39. Our analysis is the first large-scale report on outcome of unrelated donor transplantation in patients with lymphoma. These patients were transplanted over a 14-year period between 1991 and 2004. Many of the patients had chemotherapy refractory disease and many had a decreased performance score. Ninety percent engrafted, and 26% of patients survived free of disease for up to 5 years. Thus, unrelated donor transplantation can be considered a beneficial and curative procedure for a fraction of patients with NHL. Disconcertingly, the TRM was as high as 50%, and was variably caused by organ toxicity, GVHD, and infections (Table 8). This is reminiscent of the very high TRM observed in early studies of HLA-identical transplantation for low-grade lymphoma where small numbers of patients were reported from multiple institutions [40]. Baseline patient and disease-related adverse risk factors should be considered when assessing candidacy for unrelated donor transplantation. Those risk factors included the chemotherapy refractory nature of the disease and a decreased performance status in many patients. Disease status 9, 16, 41, 42 and performance score 9, 40, 43, 44, 45 have previously been identified as predictors of outcome. With better patient selection, it is to be expected that outcomes would be much improved. As in previous studies, older age and, particularly, age of over 40 years was another independent predictor for outcome, because of increased TRM associated with increasing age 8, 29, 40, 46. It is likely that older patients, in part because of comorbidities, are less tolerant of the intensive conditioning regimens, and that they would benefit from reduced intensity conditioning (RIC) as was recently shown by the Seattle group [42].

Table 8. Causes of Death among Patients Who Underwent Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning For NHL
Causes of DeathN evalN (%)
Number of patients210
Primary disease 60 (29)
GVHD 25 (12)
Pulmonary syndrome 27 (13)
Infection 32 (15)
Organ failure 41 (19)
Others∗ 25 (12)

NHL indicates non-Hodgkin lymphoma; GVHD, graft-versus-host disease.

∗Others include (N = 25)

1.New malignancy (n = 3)

2.Hemorrhage (n = 11)

3.Vascular (n = 1)

4.Acute cardiac infarct (n = 1)

5.Failure to thrive (n = 1)

6.TTP (n = 1)

7.Metabolic abnormalities (n = 1)

8.Nonbacterial thrombotic (n = 1)

9.Status epilepticus (n=1)

10.Other, not specified (n = 4)

The marked influence of disease histology on TRM and on disease recurrence is also consistent with numerous prior observations. Patients with FL and those with peripheral T cell lymphoma had the lowest risk of TRM and of disease recurrence. The low recurrence rate in FL is also consistent with previous observations. A relatively low rate of TRM mortality has by many been attributed to the use of RIC 11, 47. In registry analysis, however, the TRM of myeloablative transplantation for FL has also decreased over time and is not different than that associated with reduced intensity conditioning 9, 48, 49. The relatively good outcome in the small group of 15 PTCL patients, 12 of whom had recurrent or refractory disease, is gratifying, and adds support to emerging data on the role of allogeneic transplantation in this otherwise difficult to treat disorder 21, 50. Having aggressive B cell lymphomas was a independent risk factor for disease recurrence, and also for TRM. Although disease relapse can be attributed to disease biology, it is more difficult to understand how disease histology could relate directly to TRM. We speculate that patients with aggressive B cell lymphomas either because of disease biology or more intensive prior treatment present to transplant with a more pro-inflammatory host milieu, markers of which have been repeatedly shown to be associated with TRM 51, 52. Donor matching is an increasingly important determinant of outcome of unrelated donor transplantation, particularly in patients with favorable disease stages [2]. Because so many patients in the current study had advanced disease, it is not surprising that no impact of HLA typing on outcome could be detected.

In summary, unrelated donor HCT induced long-term survival in approximately 25% of patients with lymphoma transplanted between 1991 and 2004. The outcomes are poor for those with refractory disease and decreased performance status, but encouraging in patients with FL and T cell lymphoma. It is likely that with better patient and donor selection, improved supportive care, and changes in conditioning and GVHD prophylaxis, current results are superior, as was shown in single institution studies and in registry studies of sibling transplant for FL 42, 49.Unrelated donor transplantation should be considered a treatment alternative for patients with high risk, recurrent, or refractory lymphoma, particularly for those with good performance status and chemotherapy sensitive disease.

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Acknowledgments 

Financial disclosure: This work was supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation, Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Association of Medical Microbiology and Infectious Disease Canada; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gambro BCT, Inc.; Gamida Cell, Ltd.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka Pharmaceutical Development & Commercialization, Inc.; Pall Life Sciences; PDL BioPharma, Inc.; Pfizer Inc.; Pharmion Corporation; Saladax Biomedical, Inc.; Schering Plough Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex; Teva Pharmaceutical Industries; The Marrow Foundation; THERAKOS, Inc.; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government. This research has also been supported by funding from the National Marrow Donor Program, the Health Resources and Services Administration #240-97-0036, and the Office of Naval Research N00014-93-0658 to the National Marrow Donor Program.

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 Financial disclosure: See Acknowledgments on page 561.

PII: S1083-8791(09)00055-X

doi:10.1016/j.bbmt.2009.01.012

Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 554-563, May 2009

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