Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure

Article Outline

• Abstract
• Introduction
• Methods
  • Data Sources
  • Patient Population
  • Outcomes
  • Statistical Analysis
• Results
  • Patient Characteristics
  • Graft Source Type and Cell Dose
    • Engraftment
  • Survival Outcomes and Relapse
  • Causes of Death
• Discussion
• Acknowledgments
• References
• Copyright

Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of ≥500/μL without recurrent disease. Patients were transplanted for leukemia (n = 83), myelodysplastic disorders (n = 16), severe aplastic anemia (n = 20), and other diseases (n = 3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival (OS) after second transplant was 11%, with 10 patients alive at last follow-up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure.

Key Words: Graft failure, Second transplant, Nonengraftment

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Introduction 

Primary graft failure after hematopoietic cell transplantation (HCT) is a life- threatening complication whose reported incidence is as high as 11% 1, 2, 3. Treatment approaches including growth factors, manipulation of immunosupressant doses, or infusion of additional autologous or allogeneic stem cells with or without preparative regimens are among the strategies that have been attempted to overcome nonengraftment [4]. Unfortunately, available data on outcomes after a subsequent transplantation for treatment of primary graft failure is limited and heterogeneous. Studies published to date commonly combine primary and secondary graft failures, related and unrelated donors, and often include second transplants for treatment of early posttransplant relapse 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16.

Patients with primary graft failure typically have a number of high risk factors, which makes a second transplant challenging. These include being pancytopenic for weeks, often with active infections and poor performance status. Furthermore, recipients of unrelated donor grafts face additional logistic challenges with donor procurement, not seen with sibling transplants. This may not only prolong the time to the second transplant, it also results in increased demands on volunteer donors.

Considering the emotional and financial burden on patients, their families, transplant centers, as well as the resources required for donor procurement for subsequent transplantation, it is important to characterize the outcomes carefully. Here, we describe the results of 122 patients reported to the National Marrow Donor Program (NMDP), which received second unrelated donor transplantation for treatment of primary graft failure.

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Methods 

Data Sources 

This observational study uses data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database on unrelated donor transplants facilitated by the NMDP. The CIBMTR comprises a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive HCT to a Statistical Center at the Medical College of Wisconsin in Milwaukee and the NMDP Coordinating Center in Minneapolis. Participating centers are required to report all transplants consecutively; compliance is monitored by on-site audits. The CIBMTR maintains an extensive database on detailed patient-, transplant-, and disease-related information for transplants performed worldwide, and prospectively collects data longitudinally with yearly follow-ups. Computerized checks for discrepancies, physicians' review of submitted data, and on—site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with the Privacy Rule (HIPAA) as a Public Health Authority, and in compliance with all applicable federal regulations pertaining to the protection of human research participants as determined by continuous review of the institutional review boards of the National Marrow Donor Program and the Medical College of Wisconsin since 1985.

Patient Population 

We reviewed the records of 14,564 patients reported from 1990 to 2005, who underwent an unrelated bone marrow (BM) or mobilized peripheral blood progenitor cells (PBPC) HCT, facilitated by the NMDP. Nine hundred eighty-one patients (6.7%) were reported by the transplant center as having primary graft failure, that is, not achieving a minimum absolute neutrophil count (ANC) of 500/μL without evidence of disease relapse (Figure 1). Among the 817 patients with primary graft failure who had no information on second transplants, 808 (99%) died within the first year, with the majority (N = 707) dying within 30 days from the first HCT; 7 patients were lost to follow-up, but were alive 1 year after transplantation, and 2 patients died 3 years after transplant. Among 164 patients who received a second HCT, 122 received BM or PBPC grafts from unrelated donors, 26 from a previously cryopreserved autologous graft, 10 from a related donor, 4 received an umbilical cord blood graft, and 2 patients received donor lymphocyte infusion (DLI).

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• Figure 1 

  Selection criteria and study population according to donor type and graft source status. Abreviations: DLI, donor lymphocyte infusion; HCT, hematopoietic cell transplantation; UCD, umbilical cord blood; URD, unrelated donor.

Patients who had evidence of engraftment prior to the second HCT, who received umbilical cord blood grafts or DLIs, or patients who had a period >180 days between the HCTs were excluded. Data on the 122 patients who received a second graft from an unrelated donor, reported from 47 centers worldwide, were analyzed for this study.

Outcomes 

Outcomes analyzed include 30-day and 100-day mortality, overall survival (OS), neutrophil engraftment, disease-free survival (DFS), treatment-related mortality (TRM), and relapse for patients with malignant diseases. Disease relapse was defined as clinical or hematologic evidence of disease recurrence. DFS was analyzed as time from second HCT to relapse or death from any cause. For analysis of OS, failure was death from any cause; surviving patients were censored at date of last contact. Time to neutrophil engraftment was defined as the time to achieve a sustained ANC of ≥500 cells/μL for 3 consecutive days after the second transplant.

Statistical Analysis 

Probabilities of DFS, OS, and 30-day and 100-day mortality were calculated using the Kaplan-Meier estimator, with the variance estimated by the Greenwood's formula. Probabilities of TRM, relapse, neutrophil engraftment were calculated using cumulative incidence rates to accommodate for competing risks. All computations were performed using the statistical package SAS version 9.1.

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Results 

Patient Characteristics 

Patient characteristics and demographics are summarized in Table 1. The median age at time of second HCT was 30 years (range: 2-62) and one-third of the patients were ≤20 years of age. Karnofsky performance scores (KPS) were available on 63 patients at the time of second HCT. Of these, 62% had a KPS of ≤50. Most patients had acute leukemia as their primary diagnosis. The median time from first to second HCT was 48 days, with a range of 18 to 126 days. Eighty-seven percent of patients received an ablative conditioning regimen for the first HCT (Table 2). Details on the conditioning regimen for the second transplant are unavailable in 23% of patients. Among patients with available conditioning regimen data for second HCT, 38% received a myeloablative conditioning regimen and 11% received no conditioning regimen. Thirty-one percent of patients received antithymocyte globulin (ATG) as part of the first HCT, whereas 61% of patients with available data reported use of ATG for the second HCT. T cell-depleted grafts were used in 42% and 10% of patients for the first and second HCT, respectively. The median follow-up of survivors from the second HCT was 77 months (range: 2-144) (Table 2).

Table 1. Demographic and Disease Characteristics of Patients Who Received a Second Unrelated Hematopoietic Cell Transplantation for Primary Graft Failure Reported to the NMDP 1990 and 2005

Characteristics of Patients	N Eval	N (%)
Patient related:
Number of patients		122
Age, median (range), years∗	122	30 (2-62)
≤20		41 (33)
21-40		45 (38)
>40		36 (18)
Male sex	122	79 (65)
Disease related:
Disease Indication for first transplant	122
Acute myelogenous leukemia		18 (15)
Acute lymphoblastic leukemia		13 (11)
Other leukemia†		3 (2)
Chronic myelogenous leukemia		49 (40)
Myelodysplastic/myeloproliferative disorders		16 (13)
Severe aplastic anemia		20 (16)
Other nonmalignant indications‡		3 (1)
Disease status prior to first transplant	122
Early		51 (42)
Intermediate		26 (21)
Advanced		14 (11)
Non-malignant		23 (19)
Unknown§		8 (7)
Time from diagnosis to first transplant, median (range), months	121	13 (2-175)
Time from first transplant to second transplant, median (range), days	122	48 (18-126)
Year of second transplant	122
1990-1992		8 (7)
1993-1995		32 (26)
1996-1998		28 (23)
1999-2001		27 (22)
2002-2004		18 (15)
2005		9 (7)
Donor age for second transplant, median (range), years	122	37 (19-59)
Number of total transplants	122
2		110 (90)
3		11 (9)
Median follow-up of survivor after second transplant, (range) months	10	77 (2-144)

Table 2. Transplant Characteristics from the First and Second Transplant in Patient Who Received Second Unrelated Donor Hematopoietic Cell Transplantation for Treatment of Graft Failure

	First Transplant		Second Transplant
Transplant Characteristics	N Eval	N (%)	N Eval	N (%)
Nucleated cell dose, median (range), 108/kg∗	121	2 (<1-23)	122	2 (<1-50)
<2.5		74 (60)		48 (39)
2.5-4.5		29 (24)		24 (20)
≥4.5		18 (15)		17 (14)
Missing		1 (<1)		33 (27)
Preparative regimen type	122		122
Myeloablative		106 (87)		36 (30)
Nonmyeloablative/RIC		16 (13)		44 (36)
No conditioning received		—		14 (11)
Missing		—		28 (23)
ATG-based conditioning	122		80
Yes		38 (31)		49 (61)
No		84 (69)		31 (39)
Conditioning regimen	122		122
Cy + TBI ± other		61 (50)		5 (4)
Bu + Cy ± other		38 (31)		—
Bu ± other		2 (2)		—
Cy ± other		9 (7)		33 (27)
Fludarabine ± other		12 (10)		24 (20)
ATG ± other		—		15 (12)
Other†		—		2 (2)
None		—		15 (11)
Missing		—		28 (23)
HLA match‡	122		122
Well matched		19 (16)		14 (12)
Partially matched		50 (41)		53 (43)
Mismatched		53 (43)		52 (43)
Non evaluable		—		3 (2)
ABO compatibility at transplant§	121		121
Major ABO-incompatible		38 (31)		37 (31)
Minor ABO-incompatible		33 (27)		30 (25)
Matched ABO		50 (41)		54 (44)
Graft-versus-host disease prophylaxis	122		94
T cell depletion		51 (42)		9 (10)
Cyclosporine + methotrexate ± other		42 (35)		18 (19)
CNI + mycophenolate		9 (8)		14 (15)
Cyclosporine only		6 (5)		25 (26)
Tacrolimus + methrotrexate ± other		14 (4)		4 (4)
Other¶		—		17 (19)
None		—		7 (7)
Graft type	122		122
Bone marrow		102 (84)		62 (51)
Peripheral blood		20 (16)		60 (49)

HLA indicates human leukocyte antigen; RIC, reduced-intensity conditioning; GVHD, graft-versus- host disease; ATG, antithymocyte globulin; TBI, total body irradiation; Bu, busulfan; Cy, cyclophosphamide; CNI, calcineurin inhibitor.

Graft Source Type and Cell Dose 

Bone marrow was the graft source in 51% of second HCT and 84% of first HCT. Ninety-eight patients received a second HCT from the same donor, whereas 24 patients had a different unrelated donor. Among patients who received cells from the same donor, 28 patients received a cryopreserved product. The median nucleated cell dose infused was 2.5 × 10⁸/kg for both first and second HCT, although data was missing in 27% of patients for the second transplant.

Complete report information on engraftment after second HCT was only available on 79 patients. The cumulative incidence (CI) for neutrophil engraftment at 28 and 100 days was 66% [95% CI, 55-76] and 74% (95% CI, 64-84), respectively (Figure 2).

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• Figure 2 

  Neutrophil engraftment after second unrelated donor hematopoietic cell transplantation for primary graft failure.

Survival Outcomes and Relapse 

The 30-day and 100-day mortality rates were 39% (95% CI, 31-48) and 75% (95% CI, 67-82), respectively. Among patients with malignant disease, TRM, relapse, and DFS at 1 year after second HCT were 86% (95% CI, 79-92), 7% (95%, CI 2-12), and 7% (95% CI,3-12), respectively (Table 3). Ten patients (8%) were alive and disease free at time of last follow-up (Figure 3). Patients who failed to engraft after the second transplant had a median survival of less than 1 month. Univariate comparisons of post transplant outcomes were similar between same versus different donor, fresh versus cryopreserved grafts, and cell doses below versus above the median cell dose infused (Table 4).

Table 3. Univariate Probabilities of Outcomes after Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure

Outcome of Interest	N Eval	Probability (95% CI)
∗Treatment-related mortality @ 1 year	99	86 (79-92) %
∗Relapse @ 1 year	99	7 (3-13) %
∗Disease-free survival @ 1 year	99	7 (2-12) %
30-day mortality	48/121	39 (31-48) %
100-day mortality	91/122	75 (67-82) %
Overall survival
@ 6 months	122	13 (9-20) %
@ 1 year	122	11 (6-17) %

CI indicates confidence interval.

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• Figure 3 

  Probability of OS after second allogeneic unrelated donor transplant for “nonengraftment.”

Table 4. Overall Survival Probabilities after a Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure According to Graft Status and Donor Type

HCT indicates hematopoietic cell transplantation; CI, confidence interval.

Causes of Death 

Table 5 shows the causes of death, reported to the CIBMTR by the treating center, in patients who underwent a second transplant. Graft failure was considered the primary cause of death for 38 patients (34%). Among 32 of the reported 38 patients, who died of graft failure and had available information on secondary causes of death, 57% died from an infection-related cause. Infection without graft failure was the reported cause of death in 17 (15%) patients. Other reported causes of death include end organ failure (15%), graft-versus-host disease (GVHD) (13%), idiopathic pneumonia syndrome (9%), and hemorrhage (4%), among others. Together, graft failure and infection accounted for 47% of all deaths.

Table 5. Causes of Death after Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure

Causes of Death	N (Eval)	N (%)
Number of patients	112
Graft rejection/failure∗		38 (34)
Infection		17 (15)
Organ failure		17 (15)
GVHD		15 (13)
Idiopathic pneumonia syndrome		10 (9)
Primary disease		7 (6)
Hemorrhage		4 (4)
Other†		4 (4)

GVHD indicates graft-versus-host disease.

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Discussion 

This study presents the largest experience to date of a second transplant with unrelated donor grafts as salvage in patients with primary graft failure without disease relapse. The incidence of primary graft failure in this cohort of patients who received unrelated donor HCT from 1990 to 2005 is 6.7%. Interestingly, this incidence decreased during the 15-year study period with 8.2%, 6.9%, and 3.6% of patients experiencing this complication from 1990 to 1995, 1996 to 2000, and 2001 to 2005, respectively. Improvements in HLA matching with utilization of high-resolution typing and better donor selection or the increased use of PBPC may account for the drop of primary graft failure incidence over time.

Survival after a second unrelated donor HCT as a rescue from initial nonengraftment is dismal, with only 11% of patients being alive and disease free at 1 year. The results suggest that this strategy as currently practiced is ineffective. Moreover, this group represents a small minority of those 981 patients who were identified by the treating center as having primary graft failure. The 1-year OS of the 981 with primary graft failure after the first HCT is <1%.

Results from this study are similar to previous published reports. It is important to highlight that cross-study comparisons are difficult based on the heterogeneity of study populations. The French multicenter study analyzed the outcomes of second HCT for graft failure in 82 patients with malignant diseases and severe aplastic anemia [8]. Twenty-eight patients had primary graft failure as defined in this study, and 12 patients received an unrelated donor graft. Median survival of this population was 3 months and estimated 3-year survival was 30%. The study did not analyze primary graft failure, which generally has a worse prognosis separately. The German Bone Marrow Center Database (DKMS) reported on 70 patients with malignant diseases undergoing a second unrelated donor HCT for primary graft failure (N = 34) or disease relapse (N = 36) [11]. Half of the patients with primary graft failure received no conditioning prior to a second transplant, and virtually all received PBPC as the graft source for their second transplant. There was no benefit noted for those patients receiving prior conditioning versus stem cell infusion alone. The OS after the second HCT for primary graft failure was 37%, with a median follow-up of 33 months. Patients older than 50 years of age faired particularly poorly with only 8% surviving in the first year after the second transplantation. Although the estimated OS was superior to this report, the median survival was <5 months. The French study also demonstrated that patients younger (age <34 years) were twice as likely to be alive at 3 years from the second HCT [8]. Other smaller studies suggest better outcomes in the pediatric population, with a larger proportion of patients being alive at 1 year after the second HCT 6, 7, 13. In our analysis, recipient's age had no impact on survival outcomes (data not shown).

Additional factors were analyzed to determine their impact on survival, and showed no differences, including same or different donor, fresh or cryopreserved product, and cell dose. Small numbers and few survivors hinder the identification of subgroups with better outcomes.

The second HCT successfully reestablished hematopoiesis, and the cumulative incidence of neutrophil engraftment prior to day 100 was 74%. Similar engraftment rates were observed in other series of salvage second transplants, which included related donor transplants 8, 13. It is important to note in the current study that the mortality rate after neutrophil engraftment was high. Among 58 patients who successfully engrafted prior to day 100, 37 died from the time of engraftment to day 100.

The most common causes of death were directly related to bone marrow failure, such as infection and hemorrhage. Even among those patients who engrafted, the OS was dismal (19%, 95 CI, 10%-29%), highlighting the generally poor prognosis of this patient population.

Diagnosis of primary graft failure occurs when patients failed to engraft within 28 days from stem cell infusion, and, in our series, the median time to a second transplant was 48 days. Identification of prognostic factors for primary graft failure might assist with earlier donor procurement. Leukocyte count ≤200/μL on day 16 posttransplant was shown to be a powerful predictor for primary graft failure [17]. Identification of other predicators for graft failure have the potential to significantly alter the median time to second transplant, which may lead to earlier engraftment, reducing the pancytopenic period and mortality related to infection.

Utilization of a backup product, that is, autologous or unrelated cord blood, is another strategy to reduce time to graft procurement, although the data remains limited. Practices of storing an autologous product as a backup prior to an unrelated donor HCT are common in Europe [18] . Analysis of 25 patients who received autologous backup for treatment primary graft failure resulted on a 16% 1-year OS [15]. Among the patients reported to the NMDP, 26 received a backup autologous graft, 24 of whom died within 6 months of their second transplant. Two patients with chronic myelogenous leukemia remain alive 158 and 14 months following the second transplant. Small series have looked at umbilical cord blood as salvage for graft failure. One report, 3 of 4 patients were alive beyond 12 months after salvage transplant using double cord units [19]. In 4 of such patients reported to the CIBMTR, 2 were alive at 12 and 5 months posttransplant. It might be advantageous to have cord blood units identified early in the process as a backup for potential use.

Patients who have primary graft failure represent a very complex problem. Most patients will die before being able to receive a second HCT. Our study suggests that, in practice, primary graft failure is an uncommon complication, and it is decreasing in recent years. Survival after the second transplant for primary graft failure remains unacceptably poor, and despite retransplantation, nearly all patients died of infections and complications of prolonged pancytopenia. Strategies to improve outcomes include identifying risk factors for primary graft failure to potentially avoid this complication and using early predictors for graft failure to initiate early procurement of alternative grafts to be used for salvage.

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Acknowledgments 

Financial disclosure: The CIBMTR is 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; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; 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 America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; 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 Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.

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