Comparable Outcomes after Nonmyeloablative Hematopoietic Cell Transplantation with Unrelated and Related Donors

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Eligibility Criteria
  • Preparative Regimens, Hematopoietic Cell Sources, and Supportive Care
  • Prophylaxis Against GVHD
  • Categorization of Patients According to Their Predicted Risks of NRM and Recurrent Malignancy
  • Statistical Analysis
• Results
  • Patient Characteristics
  • HCT CI and Relapse Risk Categories
  • NRM
  • Recurrent Malignancy
  • Overall Mortality
  • GVHD
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

We sought to determine whether patients with hematologic malignancies treated by nonmyeloablative hematopoietic cell transplantation (HCT) at a single institution between December 1997 and June 2006 had worse outcomes with grafts from unrelated donors (URDs) (n = 184) compared with HLA-identical related donors (n = 221). The nonmyeloablative preparative regimen consisted of 2 Gy of total body irradiation (TBI) with (78%) or without (22%) fludarabine, along with posttransplantation mycophenolate mofetil (MMF) and cyclosporine (CSa). After adjusting for the HCT comorbidity index, relapse risk, patient age, stem cell source, preparative regimen, previous cytomegalovirus (CMV) infection, and sex mismatch of donor and recipient in multivariate analysis, we found no statistically significant differences between unrelated and related HCT recipients in terms of risk of nonrelapse mortality (NRM; hazard ratio [HR] = 0.98; 95% confidence interval = 0.6-1.6; P = .94), relapse (HR = 1.04; 95% confidence interval = 0.7-1.5; P = .82), or overall mortality (HR = 0.99; 95% confidence interval = 0.7-1.4; P = .94). Overall rates of severe acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) also were not significantly different between the 2 groups. We conclude that within the limitations of a retrospective study, these results indicate that candidates for nonmyeloablative HCT without suitable related donors may expect similar outcomes with grafts from URDs.

Key Words: Transplantation, Nonmyeloablative, Related, Unrelated, Hematologic malignancies

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Introduction 

Most patients with hematologic malignancies who might benefit from treatment by allogeneic hematopoietic cell transplantation (HCT) lack HLA-identical related donors (MRDs) [1]. For these patients, unrelated volunteers (URDs) are being increasingly used as donors. Historically, HCT from URDs after conditioning with myeloablative preparative regimens has been associated with increased risk of nonrelapse mortality (NRM) and, consequently, decreased overall survival (OS) compared with results for MRDs 2, 3, 4, 5, 6. These differences have been attributed primarily to the greater degree of genetic disparity between URD–recipient pairs compared with related pairs. With the advent of high-resolution HLA typing and the resulting improved matching between URDs and their recipients, outcomes after URD transplantation have improved 7, 8, 9, 10. This improvement has been ascribed to decreased rates of graft-versus-host disease (GVHD) and accelerated immune reconstitution [11]. Even with high-resolution HLA typing, URD–recipient pairs may have greater disparity for numerous minor histocompatibility antigens compared with related pairs, which may contribute to the persistently higher rates of GVHD and, consequently, NRM after HCT from URDs compared with MRDs [12].

In nonmyeloablative HCT, graft-versus-tumor (GVT) effects have replaced high-dose cytotoxic therapy as the conceptual basis for treating underlying malignancies 13, 14, 15, 16, 17. The use of potent pregrafting and postgrafting immunosuppression has allowed a major reduction in pretransplantation cytotoxic therapy without compromising engraftment of hematopoietic donor cells. The use of nonmyeloablative conditioning avoids major regimen-related toxicities, making it possible to treat older and medically infirm patients who are at greater risk for complications after treatment with conventional transplantation regimens 13, 16, 18, 19. The immunobiology of nonmyeloablative HCT differs from that of myeloablative HCT in several important aspects. Compared with myeloablative HCT, nonmyeloablative HCT is associated with (a) decreased release of inflammatory cytokines resulting from limited tissue damage during administration of the conditioning regimen 20, 21, 22, 23, 24, (b) a transient and potentially tolerogenic state of mixed donor/host chimerism 25, 26, and (c) the use of novel regimens for immunosuppression after HCT 13, 14, 27, 28. These differences might account for the lower rates of severe GVHD after unrelated HCT with nonmyeloablative conditioning compared with myeloablative conditioning 29, 30, 31.

In this retrospective study, we investigated whether outcomes in patients who underwent HCT with nonmyeloablative conditioning also differed according to donor type. After adjusting for factors known to influence outcome after allografting in multivariate analysis, we found that the use of URDs did not appear to increase either NRM or overall mortality after HCT with nonmyeloablative conditioning.

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Patients and Methods 

Eligibility Criteria 

Patients who underwent nonmyeloablative HCT from MRDs or URDs for treatment of hematologic malignancies at the Fred Hutchinson Cancer Research Center between December 1997 and June 2006 were screened for study eligibility. The patients had signed forms approved by the Institutional Review Board documenting informed consent to participate in the clinical trials and to allow the use of protected health information for research. To be included in the analysis, all related donors were HLA-matched siblings based on family studies [8].

Sequence-specific oligonucleotide hybridization and/or sequencing-based typing methods were used to define exons 2 and 3 of HLA-A, B, and C alleles and exon 2 of DRB1 and DQB1 alleles in all donor–recipient pairs. Unrelated pairs were defined as matched if donors and recipients had identical probe hybridization patterns. The 82 DQB1∗03 and 06-positive donor–recipient pairs with identical exon 2 oligonucleotide probe patterns potentially representing 2 different DQB1∗0302, 0303, 0602, or 0603 alleles (1 frequent and the other very rare) were considered to be matched. The analysis included 405 patients with follow-up as of January 2007. Of these 405 patients, 184 patients had URDs (45%) and 221 had MRDs (55%).

Preparative Regimens, Hematopoietic Cell Sources, and Supportive Care 

Patients received low-dose total body irradiation (TBI; 2 Gy) alone (22%) or in combination with fludarabine (30 mg/m² body surface area/day, for 3 consecutive days) (78%) 13, 27. Most recipients (98%) were given granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs); 2% were given bone marrow grafts. Antimicrobial and cytomegalovirus (CMV) prophylaxis and blood product support were administered as described previously [30].

Prophylaxis Against GVHD 

Postgrafting immunosuppression included mycophenolate mofetil (MMF) and cyclosporine (CSP) as described previously 13, 27. Fifty unrelated recipients (27%) received MMF 15 mg/kg every 12 hours, and 134 (73%) received MMF 15 mg/kg every 8 hours [32]. Grading and treatment of GVHD were done as described previously [30].

Categorization of Patients According to Their Predicted Risks of NRM and Recurrent Malignancy 

Outcomes with unrelated versus related grafts were also compared in subgroups of patients according to their predicted risks of NRM and recurrent malignancy after HCT. Patients were grouped according to HCT comorbidity indices (CIs) assigned at the time of transplantation (scores 0, 1-2, and ≥ 3), which serve as strong predictors for NRM 18, 33, 34, and their estimated rates of recurrent malignancy per year [35]. In brief, the risks of recurrent malignancy were categorized as follows:

Statistical Analysis 

Survival curves were estimated by the Kaplan-Meier method. Cumulative incidence curves were estimated as described previously [36]. Hazard ratios for each endpoint were estimated from Cox regression models, with NRM and relapse treated as competing risks for analysis of these endpoints. Multivariate analyses were adjusted for relapse risk category, HCT CI, patient age, patient/donor sex mismatch, previous CMV infection, and stem cell source. Every patient with a URD received a conditioning regimen of fludarabine and low-dose TBI, whereas some patients with MRDs received low-dose TBI alone. Therefore, analyses were also adjusted for the absence of fludarabine in the conditioning regimen. Modifying effects of comorbidity and relapse risk were evaluated by interaction terms for donor relation with HCT CI (0 vs 1-2 vs ≥ 3) or relapse risk (low vs intermediate vs high). All P values were based on Wald statistics derived from hazard ratio (HR) analyses and were 2-sided. Adjusted survival curves were estimated based on methods derived from Makuch et al. [37]; in brief, the adjusted survival curve for the group of patients with URDs represents a model-based estimate of survival for a group of patients having the baseline hazard function estimated for patients with URDs, but with the covariate characteristics of the group of patients with MRDs. These estimates were derived from Cox regression models stratified on donor relation, with other adjustment factors incorporated as covariates. Curves were estimated for each set of covariates from the related donor group and then averaged to yield the adjusted survival curve.

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Results 

Patient Characteristics 

Details regarding patient characteristics are listed in Table 1. The median patient age was 54.5 years (range, 20-72 years) for patients with MRDs and 55.9 years (range, 5-75 years) for those with URDs. The distributions across HCT CI and relapse risk categories were similar in the 2 groups. Among the URD transplants, 13% of donor–recipient pairs were mismatched for a single HLA-A, -B or -C allele. All patients with URDs were prepared with 2 Gy TBI and fludarabine, whereas 40% of those with MRDs were prepared with TBI alone. The median follow-up time among surviving patients was 36.6 months (range, 3.3-98.7 months) for those receiving MRDs and 28.1 months (range, 2.6-71.8 months) for those receiving URDs.

Table 1. Patient characteristics

	MRDs (n = 221)	URDs (n = 184)
Patient age, years
Median (range)	54.5 (20.4-72.7)	55.9 (5.1-74.6)
< 50, n (%)	76 (34)	60 (33)
≥ 50, n (%)	145 (66)	124 (67)
Diagnosis, n (%)
ALL	2 (1)	13 (7)
AML	29 (13)	50 (27)
MDS	26 (12)	22 (12)
CML	6 (3)	11 (6)
MM	61 (28)	19 (10)
NHL	46 (21)	33 (18)
Hodgkin disease	18 (8)	16 (9)
CLL	27 (12)	17 (9)
Other	6 (3)	3 (2)
Relapse risk category, n (%)
Low	46 (21)	42 (23)
Intermediate	111 (50)	83 (45)
High	64 (29)	59 (32)
HCT CI score, n (%)
0	65 (29)	40 (22)
1-2	69 (31)	57 (31)
3+	87 (39)	87 (47)
Previous HCT, n (%)
Autologous	39 (18)	64 (35)
Allogeneic	5 (2)	5 (3)
Preparative regimen, n (%)
TBI 2 Gy	89 (40)	0
TBI 2 Gy + fludarabine	132 (60)	184 (100)
Stem cell source, n (%)
PBSCs	221 (100)	176 (96)
Bone marrow	0	8 (4)
Donor–recipient single allele mismatch at HLA-A, -B or -C, n (%)
No	221 (100)	160 (87)
Yes	0	24 (13)
Donor–recipient sex mismatch, n (%)
No	105 (48)	103 (56)
Yes	116 (52)	81 (44)
Patient CMV serostatus, n (%)
Negative	96 (43)	84 (46)
Positive	125 (57)	100 (54)

PBSCs indicates peripheral blood stem cells.

HCT CI and Relapse Risk Categories 

HCT CI categories separated patients into groups with different risks of NRM (9%, 14%, and 29% at 2 years for HCT CI scores of 0, 1-2, and ≥ 3, respectively), whereas the risk of recurrent malignancy did not correlate with HCT CI (36%, 38% and 41% at 2 years for low, intermediate, and high risk, respectively) (Table 2; Figure 1A and B). Conversely, the relapse risk categories separated patients into groups with different risks of recurrent malignancy (20%, 36%, and 56% at 2 years for low, intermediate, and high risk, respectively), whereas the risk of NRM did not correlate with these categories (24%, 15%, and 23% at 2 years for HCT CI scores of 0, 1-2, and ≥ 3, respectively) (Table 2; Figure 1C and D). Therefore, these risk categorizations were applied in the analysis of outcomes with unrelated versus related HCT.

Table 2. Multivariate analysis of transplantation outcomes in 405 patients after nonmyeloablative HCT

		Overall mortality		NRM		Relapse/progression
	n	HR (95% confidence interval)	P	HR (95% confidence interval)	P	HR (95% confidence interval)	P
Donor
MRD	221	1.0		1.0		1.0
URD	184	1.01 (0.7-1.4)	.95	0.98 (0.6-1.6)	.93	1.10 (0.8-1.6)	.60
Comorbidity category [34]
HCT CI 0	105	1.0		1.0		1.0
HCT CI 1-2	126	1.61 (1.0-2.5)		1.89 (0.9-3.9)		1.20 (0.8-1.8)
HCT CI ≥ 3	174	2.65 (1.8-4.0)	< .0001	3.93 (2.0-7.7)	< .0001	1.25 (0.8-1.9)	.52
Relapse risk category [35]
Low	88	1.0		1.0		1.0
Intermediate	194	1.31 (0.9-2.0)		0.76 (0.4-1.3)		1.82 (1.1-2.9)
High	123	2.94 (1.9-4.5)	< .0001	1.46 (0.8-2.5)	.05	3.80 (2.3-6.2)	< .0001
Age at transplantation, years
<50	136	1.0		1.0		1.0
≥50	239	1.38 (1.0-1.9)	.04	1.61 (1.0-2.7)	.06	1.04 (0.7-1.4)	.83
Sex mismatch
No	208	1.0		1.0		1.0
Yes	197	1.39 (1.0-1.8)	.02	1.64 (1.1-2.5)	.03	1.29 (1.0-1.8)	.10
Stem cell source
PBSCs	397	1.0		1.0		1.0
Bone marrow	8	1.36 (0.5-3.4)	.53	0.96 (0.2-4.1)	.96	1.86 (0.7-5.2)	.28
Patient CMV status
Negative	180	1.0		1.0		1.0
Positive	225	1.23 (0.9-1.6)	.16	1.71 (1.1-2.7)	.02	1.19 (0.9-1.6)	.29
Fludarabine in the preparative regimen
Yes	316	1.0		1.0		1.0
No	89	0.76 (0.5-1.2)	.20	0.86 (0.4-1.6)	.64	0.99 (0.6-1.5)	.95

PBSCs indicates peripheral blood stem cells.

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• Figure 1 

  Cumulative incidence of recurrent malignancy and NRM according to HCT CI and relapse risk categories. The combined groups of patients with MRDs and URDs were categorized according to the presence of pretransplantation comorbidities (HCT CI: 0, 1-2, or ≥ 3) [18] (A, B) and the predicted risk of recurrent malignancy (low, intermediate, or high) [35] (C, D). The cumulative incidence rates of recurrent malignancy (A, C) and NRM (B, D) are shown for respective subgroups of patients.

NRM 

The HRs of NRM for patients receiving URDs versus those receiving MRDs showed no statistically significant difference in univariate analysis (HR 1.22: 95% confidence interval = 0.8-1.9; P = .36) (Figure 2A; Table 3). This conclusion remained unchanged after adjusting for HCT CI, relapse risk category, use of fludarabine in the preparative regimen, patient age, stem cell source, previous CMV infection, and sex mismatch of the donor and recipient in multivariate analysis (HR = 0.98; 95% confidence interval = 0.6-1.6; P = .94) (Figure 2A; Table 3). The hazard of NRM for patients with URDs versus MRDs also showed no statistically significant difference across HCT CI subgroups (Table 3), although the statistical power of this analysis was limited by the smaller numbers of patients in these subgroups.

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• Figure 2 

  NRM, relapse or progression, and OS according to donor type. Cumulative incidence of NRM (A) and relapse or progression (B), and Kaplan-Meier survival estimates (C) in patients with HLA-identical sibling donors (“MRD,” n = 221) compared with those with URDs (“URD,” n = 184; P = .08). The third curve in each panel (“URD adjusted”) shows the projected survival with URDs after adjusting for HCT CI, relapse risk category, patient age, stem cell source, previous CMV infection, and donor–recipient sex mismatch.

Table 3. Outcomes after transplantation from HLA-matched URDs compared with HLA-identical sibling donors^∗

			Overall mortality		NRM		Relapse/progression
	MRD n	URD n	HR (95% confidence interval)	P	HR (95% confidence interval)	P	HR (95% confidence interval)	P
Univariate	221	184	1.29 (1.0-1.7)	.08	1.22 (0.8-1.9)	.36	1.17 (0.9-1.6)	.32
Multivariate∗	221	184	1.01 (0.7-1.4)	.95	0.98 (0.6-1.6)	.93	1.10 (0.8-1.6)	.60
Comorbidity category [34]
HCT-CI 0	65	40	1.07 (0.5-2.3)		1.23 (0.3-4.4)
HCT-CI 1-2	69	157	1.28 (0.7-2.2)	Trend†	1.03 (0.4-2.5)	Trend†
HCT-CI ≥3	87	87	0.87 (0.6-1.3)	.42	0.92 (0.5-1.7)	.66
Relapse risk category [35]
Low	46	42	1.22 (0.6-2.5)				0.49 (0.2-1.2)
Intermediate	111	83	1.07 (0.7-1.7)	Trend†			0.85 (0.5-1.4)	Trend†
High	64	59	0.91 (0.6-1.4)	.47			1.76 (1.1-2.9)	.007
Patient age
<50 years	76	60	1.10 (0.6-1.9)		0.65 (0.3-1.6)		1.70 (1.0-3.0)
≥50 years	145	124	0.98 (0.7-1.4)	.70	1.11 (0.7-1.9)	.29	0.89 (0.6-1.4)	.06

An HR > 1.0 indicates a more favorable outcome with related donors.

Recurrent Malignancy 

The hazard of recurrent malignancy for patients with URDs versus those with MRDs showed no statistically significant difference in univariate analysis (HR = 1.17; 95% confidence interval = 0.9-1.6; P = .32) or multivariate analyses (HR = 1.10; 95% confidence interval, 0.8-1.6; P = .60) (Figure 2B; Table 3). There were also no statistically significant differences in the risk of relapse between recipients of URDs versus those of MRDs across subgroups with different risks of recurrent malignancy (Table 3). Again, the statistical power of this analysis was limited by the smaller numbers of patients in these subgroups.

Overall Mortality 

The hazard of overall mortality for patients with URDs versus those with MRDs showed no statistically significant difference in univariate analysis (HR = 1.29; 95% confidence interval = 1.0-1.7; P = .08) or multivariate analyses (HR = 1.01; 95% confidence interval = 0.7-1.4; P = .95) (Figure 2C; Table 3). There were also no statistically significant differences in the risk of overall mortality between recipients of URDs versus those of MRDs across subgroups with different HCT CI scores or risks of recurrent malignancy (Table 3). Additional adjustment for presence of single-allele mismatches at HLA class I between URD donors and recipients did not change the results (not shown).

GVHD 

Table 4 shows the distribution of patients with aGVHD and cGVHD according to donor type. Even though patients with URDs had a higher incidence of grade II aGVHD compared with those with MRDs (59% vs 37%; P < .0001), the overall incidence of grade III-IV aGVHD did not differ between the 2 groups (15% vs 15%). The overall incidence of cGVHD requiring systemic immunosuppressive therapy was 67% after unrelated HCT and 68% after related HCT (P = .55). In Cox regression analysis, the adjusted hazard of grade II–IV aGVHD was higher in recipients of URDs compared with recipients of MRDs (HR = 1.93; 95% confidence interval = 1.5-2.5; P < .0001), but the risks of developing grade III–IV aGVHD (HR = 1.03; 95% confidence interval = 0.8-1.4; P = .84) and cGVHD requiring systemic immunosuppressive therapy (HR = 1.21: 95% confidence interval = 0.9-1.6; P = .15) were similar in the 2 groups.

Table 4. Incidence of acute and chronic GVHD according to donor type

	MRD (n = 221)		URD (n = 184)
	n	%	n	%
Acute GVHD
Grade 0	86	39	38	21
Grade I	19	9	10	5
Grade II	82	37	109	59
Grade III	24	11	23	13
Grade IV	8	4	4	2
Grade III-IV	22	15	27	15
Chronic GVHD∗	221	68	184	67

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Discussion 

The results of this retrospective analysis demonstrate that compared with nonmyeloablative HCT for hematologic malignancies from MRDs, transplantation from URDs did not increase the risks of NRM and overall mortality. In addition to factors known to influence outcome after allogeneic HCT (including patient age, stem cell source, type of preparative regimen, previous CMV infection, and sex mismatch of donor and recipient), our overall analysis was also adjusted for HCT CI (a powerful predictor of NRM) 18, 33, 34 and for relapse risk categories [35]. Two different systems were used to categorize patients according to their predicted risks of NRM [34] and recurrent malignancy [35], because—in contrast to the experience with myeloablative HCT—a single categorization system equally predictive for both outcomes could not be defined for nonmyeloablative HCT.

Decades of experience with allogeneic myeloablative HCT has shown that transplantation from URDs is associated with a greater risk of overall mortality than HCT from MRDs 12, 38, 39, 40, 41. The net detrimental effect associated with unrelated grafts is largely mediated by an increased risk of GVHD and the resulting increased risk of NRM, which typically is not outweighed by the more potent immunologic effects of unrelated grafts against malignant cells. With improved HLA-typing technology and better matching between URDs and their recipients, however, outcomes after URD transplantation have improved substantially [7], and—at least for certain patient groups—may approach those observed with MRDs 42, 43, 44, 45, 46.

The similar risks of NRM and OS with unrelated and related donors after nonmyeloablative conditioning found in our analysis could reflect the similar risks of developing grade III-IV aGVHD (HR = 1.03; P = .84). We speculate that despite the greater genetic disparity between unrelated and related donor–recipient pairs, decreased tissue damage and decreased release of inflammatory cytokines, transient mixed donor–host chimerism, or differences in the pharmacologic immunosuppressive regimen associated with nonmyeloablative HCT might have diminished the activation and clonal expansion of cells that cause clinical GVHD. This conclusion was supported by results of earlier studies demonstrating that the onset of GVHD occurred later and the incidence was lower after HCT with nonmyeloablative conditioning compared with HCT with myeloablative conditioning 29, 30, 31.

The findings observed in our study population might not apply to other populations treated with possibly more toxic nonmyeloablative conditioning regimens. It is conceivable that more severe gastrointestinal tissue damage or differences in postgrafting immunosuppression associated with other nonmyeloablative preparative regimens might translate into differences in NRM that could affect OS.

Only 30% of patients with hematologic malignancies who might benefit from treatment by HCT have MRD. For older patients (particularly those over age 60 years), the availability of suitable sibling donors is further limited by the concordant increased age of their siblings. Even though older patients are typically ineligible for myeloablative HCT, they often can be considered for a nonmyeloablative transplantation approach. In this context, our findings of comparable outcomes with MRDs and URDs in patients prepared with our nonmyeloablative regimen are important, because they suggest that in the absence of suitable MRDs, well-matched URDs may offer a very reasonable alternative that does not appear to be associated with a detrimental outcome.

Retrospective designs have many limitations, including the possibility of selection bias. In this study, URDs were used only when MRDs were not available, and baseline characteristics of the 2 cohorts were similar. Nonetheless, other types of bias could have been present, but one ordinarily would expect any such bias to have an unfavorable effect on outcomes among patients with URDs. Despite the absence of statistically significant differences between outcomes for patients with URDs versus those with MRDs in the overall study population, it is possible that further studies could identify specific subgroups in which unrelated grafts are disadvantageous.

In summary, except for an increased risk of mild aGVHD, outcomes after HCT with nonmyeloablative conditioning appear to be similar with HLA-matched URDs and MRDs. We conclude that the lack of a suitable related donor should not pose an obstacle to considering HCT with nonmyeloablative conditioning for patients with hematologic malignancies.

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Acknowledgments 

This work was supported in part by National Institutes of Health grants CA78902, CA18029, CA15704, HL36444, DK064715, and K99-HL088021. We thank research nurses Mary Hinds and John Sedgwick and the staff of the Long-Term Follow-Up Program for their invaluable assistance with data collection. We also thank Helen Crawford and Bonnie Larson for their help with manuscript preparation. We acknowledge the excellent care provided to patients and families by the inpatient and outpatient physicians, physician's assistants, nursing teams, and support staff at the Fred Hutchinson Cancer Research Center and the University of Washington Medical Center.

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