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Long-Term Follow-Up of High-Risk Allogeneic Peripheral-Blood Stem-Cell Transplant Recipients: Graft-Versus-Host Disease and Transplant-Related Mortality

From the Department of Internal Medicine, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO.

Address reprint requests to Randy A. Brown, MD, Washington University School of Medicine, 660 South Euclid, Box 8007, St. Louis, MO 63110; email rbrown{at}im.wustl.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the risks of graft-versus-host disease (GVHD) and transplant-related mortality after allogeneic peripheral-blood stem-cell (PBSC) transplantation.

PATIENTS AND METHODS: Between December 1994 and July 1996, 50 consecutive patients with high-risk hematologic malignancies in first remission or relapse received high-dose therapy followed by transplantation of granulocyte colony-stimulating factor–mobilized, allogeneic PBSCs collected from HLA-identical siblings. GVHD prophylaxis included cyclosporine and corticosteroids.

RESULTS: As of April 1, 1998, 18 patients (36% ± 13%) survived with a median follow-up period of 767 days (range, 602 to 1,127 days). The actuarial probability of grades 2-4 acute GVHD was 0.37 ± 0.14 (95% confidence interval). Of 36 assessable patients, 26 (72% ± 15%) developed chronic GVHD. The actuarial probability of chronic GVHD 2 years after transplantation was 0.87 ± 0.15. Of 14 progression-free survivors, 11 (79% ± 22%) have active, chronic GVHD. All 11 patients require ongoing immunosuppression, and nearly two thirds have extensive disease. Thirteen patients died as a result of transplant-related mortality (26% ± 12%), six (12%) before and seven (14%) after day +100.

CONCLUSION: We observed a high risk of chronic GVHD after allogeneic PBSC transplantation, which compromised the performance status of most long-term survivors and resulted in a relatively high risk of late transplant-related mortality. Approximately 75% of transplant-related deaths were associated with GVHD; thus, reduction in transplant-related mortality after allogeneic PBSC transplantation will require more effective strategies for the prophylaxis and/or treatment of GVHD.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DESPITE ADVANCES in supportive care, infection continues to be a major cause of transplant-related mortality after allogeneic bone marrow transplantation (BMT).¹ Our group and others have shown that transplantation of cytokine-mobilized, allogeneic peripheral-blood stem cells (PBSCs) results in rapid hematologic recovery.^2-4 This could reduce the risk of posttransplantation infection. However, patients who undergo PBSC transplantation receive approximately one log more T cells than do patients who undergo BMT, and this could increase the risk of graft-versus-host disease (GVHD). Several groups have shown that the risk of acute GVHD after allogeneic PBSC transplantation is similar to that observed among historic BMT controls.^5-7 Preliminary data from an ongoing randomized trial also demonstrated a similar risk of acute GVHD after PBSC transplantation or BMT.⁸ However, most groups have reported data with relatively short follow-up, thus the risk and time course of chronic GVHD and the risk of transplant-related mortality after allogeneic PBSC transplantation remain unclear.

In December 1994, our group initiated a trial in which patients with hematologic malignancies in relapse or at high risk for recurrence received dose-intensive therapy followed by transplantation of granulocyte colony-stimulating factor (G-CSF)–mobilized, allogeneic PBSCs collected from HLA-identical siblings. Our primary objective was to determine the impact of PBSC transplantation on the risk of GVHD and transplant-related mortality. We now report the outcome for 50 consecutive patients treated on this trial, with minimum follow-up for patients at risk for chronic GVHD exceeding 2 years.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patient characteristics are listed in Table 1. Eligibility criteria included the following: hematologic malignancy resistant to standard chemotherapy, or in first complete remission if at high-risk for relapse; estimated likelihood of cure with conventional chemotherapy less than or equal to 20% and excluding patients with chronic myelocytic leukemia in stable phase; age 10 to 65 years; Eastern Cooperative Oncology Group performance status of 0 to 2; no severe medical problems other than those related to malignancy; absence of uncontrolled infection; negative serology for human immunodeficiency virus and human T-cell leukemia virus I; informed consent. Donor eligibility criteria included the following: HLA-identical sibling; age 9 years or older; no significant medical problems within the prior year; negative serology for human immunodeficiency virus and human T-cell leukemia virus I; normal complete blood cell count; for menstruating females, negative pregnancy test within 2 weeks of mobilization; informed consent. The Washington University Human Studies Committee approved this protocol.

Treatment and Follow-Up
Details regarding mobilization and collection of PBSCs and treatment with busulfan/cyclophosphamide or etoposide/cyclophosphamide and total-body irradiation have been previously described.² Donors received G-CSF 10 µg/kg as a single, daily subcutaneous injection, with 20-L apheresis commencing on the fifth day and continuing until 2.0 x 10⁶ CD34+ cells/kg of recipient weight were collected. Donors who did not achieve this target after three aphereses underwent bone marrow harvesting. All PBSC products were administered fresh, without processing, within 6 hours of collection. Patients received G-CSF 10 µg/kg as a single, daily subcutaneous injection, from day +1 until absolute neutrophil count was greater than 1,500/µL on 3 consecutive days. GVHD prophylaxis included methylprednisolone 0.5 mg/kg/d started on day +7 and increased 1 week later to 1.0 mg/kg/d. In the absence of GVHD, methylprednisolone was tapered off between days +28 and +56. Cyclosporine 3 mg/kg/d was given as a 10-hour intravenous infusion bid (10 hours on and 2 hours off, twice daily) starting on day -1 and was changed to oral administration when possible. In the absence of toxicity, the cyclosporine dose was adjusted to maintain a whole blood level of 250 to 350 ng/mL. In the absence of GVHD, cyclosporine was tapered off between days +100 and +180. Acute GVHD was treated by escalating the corticosteroid dose, and corticosteroid-resistant cases were treated with antithymocyte globulin (15 to 30 mg/kg/d x 3 to 4 days). Chronic GVHD was treated with cyclosporine, methylprednisolone, and/or azathioprine (25 to 150 mg/d based on myelosuppression). No other modalities were used to treat chronic GVHD.

Bone marrow aspiration and biopsy were routinely carried out between days +90 and +110. Chimerism was assessed at that time and at 6 to 12 months after transplantation by evaluation of variable tandem repeats or restriction fragment length polymorphism.^9,10 Patients were assessed weekly for GVHD through day +100 and then at least every 3 months thereafter. This included physical examination and blood work that included creatinine level and liver enzyme assessment.

Definitions and Statistics
Acute GVHD was graded as per Glucksberg et al¹¹ and chronic GVHD was graded as per Shulman et al.¹² Biopsies were not routinely performed; diagnoses of GVHD were based on clinical manifestations. The technique of Kaplan-Meier¹³ was used to calculate all actuarial probabilities. For acute GVHD, patients who died before day +21 without evident GVHD were not considered assessable, whereas patients who died 21 to 100 days after transplantation who were without GVHD were censored on the day of death. We did not observe any cases of chronic GVHD before day +90, and we chose survival to that time with evidence of engraftment as criteria for assessability for this end point. Patients who died without chronic GVHD and patients who were alive without GVHD at last follow-up were censored. The actuarial probability of transplant-related mortality was calculated from day 0, with censoring at last follow-up appointment or at relapse. The actuarial probability of progression-free survival was calculated from day 0, with censoring at last follow-up appointment if the patient was alive and free of disease progression. One patient was censored on the day of his death, which was caused by an unrelated lung cancer. The actuarial probability of survival was calculated from day 0, with surviving patients being censored on the last day of follow-up. Follow-up is through April 1, 1998. Data analysis was performed using the StatView program (Version 4.5, Abacus Concepts Inc, Berkeley, CA).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Patient characteristics are listed in Table 1. Between November 1994 and July 1996, 50 patients were treated. All underwent transplantation for hematologic malignancies that were resistant to conventional chemotherapy or at high risk for relapse. Two patients had relapsed after autologous transplantation and one patient had relapsed after allogeneic transplantation. The latter patient received stem cells from the same donor with both transplants. Of 22 patients with acute leukemia, 16 (73%) had been treated unsuccessfully with conventional chemotherapy (13 patients relapsed, three experienced induction failure). The other six patients underwent transplantation in first complete remission because of a preceding hematologic disorder (four patients) or adverse cytogenetics (two patients). All 12 patients with non–Hodgkin's lymphoma had been treated unsuccessfully with conventional chemotherapy, with nine patients (75%) having failed to achieve at least a partial response to conventional salvage chemotherapy immediately before transplantation.

Of 50 donors, 43 (86%) achieved the target of greater than 2 x 10⁶ CD34+ cells/kg in a single collection, whereas five donors required two aphereses and one donor required three aphereses. One donor failed to achieve the target after three aphereses, and the recipients received both PBSCs and bone marrow. Content of PBSC products is listed in Table 1.

Current Status
As of April 1, 1998, 18 patients survived (36% ± 13%, 95% confidence interval [CI]) with a median follow-up period of 767 days (range, 602 to 1,127 days). Of these, four patients were alive in relapse and 14 (28% ± 12%) were free of disease progression. Median follow-up of progression-free survivors was 789 days (range, 630 to 1,116 days). Of the 18 surviving patients, 16 had developed chronic GVHD at some time during their course, so that only two patients remained at risk for GVHD on days +750 and +1,032 after transplantation. The actuarial probabilities of progression-free and overall survival 2 years after transplantation were 0.30 ± 0.14 and 0.34 ± 0.14, respectively (Fig 1).

View larger version (14K): [in this window] [in a new window]   Fig 1. Actuarial probabilities of (A) progression-free and (B) overall survival 2 years after transplantation were 0.30 ± 0.14 (95% CI) and 0.34 ± 0.14, respectively. Circles represent censored observations. Eighteen patients survive with median follow-up of 767 days (range, 602 to 1,127 days).

Acute GVHD
All progression-free survivors were completely chimeric (> 95% donor cells) when assessed 90 to 110 days and 6 to 12 months after transplantation. The actuarial probabilities of grade 2-4 and grade 3-4 acute GVHD were 0.37 ± 0.14 and 0.12 ± 0.09, respectively. Of 17 patients with grade 2-4 acute GVHD, skin was the most common site of significant involvement, followed by gastrointestinal and hepatic involvement.

Chronic GVHD
Thirty-six patients survived for at least 90 days and were assessable for chronic GVHD, which occurred a median of 120 days after transplantation (range, 100 to 707 days). Chronic GVHD occurred in 26 patients (72% ± 15%), with five patients having limited-stage disease and 21 (58%) having extensive-stage disease (Table 2). Two years after transplantation, the actuarial probability of chronic GVHD was 0.87 ± 0.15 (Fig 2). Of 10 assessable patients who did not develop chronic GVHD, seven died of recurrent disease (median, day +101; range, 90 to 132 days), one died as a result of liver failure on day +155, and two were alive and disease-free on days +750 and +1,032. Of 36 assessable patients, eight (22%) developed chronic GVHD de novo, without having developed preceding acute GVHD.

View larger version (16K): [in this window] [in a new window]   Fig 2. Two years after transplantation, the actuarial probability of chronic GVHD for 36 assessable patients was 0.87 ± 0.15. (*) indicates censored patients (death without GVHD or alive without GVHD). Two patients survive without chronic GVHD on days +750 and +1,032.

Sites of involvement by chronic GVHD are listed in Table 2. Chronic GVHD was most commonly manifested by lichenoid changes and/or ulceration of the buccal mucosa (19 of 26 patients; 73%) (Table 2). Isolated disease was uncommon, with involvement of the mouth and skin in one third of patients and of the mouth and liver in 11 patients (42%).

At last follow-up, 11 of 14 (79%) progression-free survivors had active, chronic GVHD (Table 3). All 11 remained on immunosuppression, with nine patients (64%) having moderately impaired performance status (Karnofsky performance status of 70 to 80) and one patient hospitalized and severely ill (Karnofsky performance status of 40) after an infection, which complicated chronic GVHD. Chronic GVHD contributed to the death of six patients (12% ± 9%), three with bronchiolitis obliterans and three with infection (two with viral pneumonia and one with pulmonary aspergillus).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The demonstration that transplantation of G-CSF–mobilized autologous PBSCs results in rapid and durable engraftment with a reduction in treatment-related morbidity led to initial trials of allogeneic PBSC transplantation. These have shown that transplantation of allogeneic PBSCs results in rapid hematologic recovery, comparable to that which follows autologous PBSC transplantation.^2-4,6,7,14 Five trials have compared the risk of acute GVHD after allogeneic PBSC transplantation with that observed among BMT historic controls, and in each there was no significant difference.^5-7,14,15 In the current series, the actuarial probability of grade 2-4 acute GVHD (0.37 ± 0.14) is similar to that reported by the International Bone Marrow Transplant Registry for more than 2,000 recipients of HLA-identical sibling bone marrow transplants (0.46 ± .02).¹⁶

The first report asserting that transplantation of peripheral-blood cells might be associated with an increased risk of chronic GVHD was published by Storb et al¹⁷ in 1982. In that trial, patients with severe aplastic anemia who underwent allogeneic BMT followed by infusion of unmobilized, donor buffy coat cells had a significantly higher risk of chronic GHVD than did historic BMT controls. Table 4 summarizes data from the current trial as well as from four articles that reported at least 20 assessable patients who received allogeneic PBSCs and that also reported information about length of follow-up.^18-21 Of note, two of these articles reported data with less than 1 year of follow-up. The effect of incomplete follow-up is illustrated by two reports from Seattle in which the risk of GVHD among 23 patients who had undergone allogeneic PBSC transplantation was compared with the risk among matched, historic BMT controls. In the initial report,⁶ the median duration of follow-up was 285 days, at which time the risk of chronic GVHD was similar for PBSC and BMT controls (59% v 61%, respectively). However, with longer follow-up (median, 682 days), the risk of chronic GVHD among PBSC recipients increased and was significantly greater than that observed in BMT controls (87% v 52%; P = .04) (Table 2).²¹

To our knowledge, the current trial is the most mature to date and is the first to provide detailed information regarding the status of long-term survivors of allogeneic PBSC transplantation. Median follow-up exceeds 2 years, with only two patients remaining at risk for chronic GVHD on days +750 and +1,032. Of 36 assessable patients, 26 (72%) developed chronic GVHD, with the actuarial risk of chronic GVHD 2 years after transplantation being 0.87 ± 0.15 (Fig 2). This is one of the highest risks ever reported for chronic GVHD after HLA-identical sibling allogeneic transplantation. In fact, only two of 26 patients (8%) who survived disease free for at least 180 days remain free of chronic GVHD. Only the Seattle group has reported results of allogeneic PBSC transplantation with comparable follow-up, and as previously discussed, that trial demonstrated a similarly high risk for chronic GVHD.²¹ In the current trial, the impact of chronic GVHD was demonstrated by the fact that nearly 80% of patients who survive disease free have active chronic GVHD and require ongoing immunosuppression (Table 3). Most have extensive-stage disease, which compromised performance status (Karnofsky performance status < 90). Only 20% have been able to return to work full time as a result of complications of chronic GVHD.

The use of corticosteroids and cyclosporine for GVHD prophylaxis has been associated with an increased risk of chronic GVHD after allogeneic BMT,²² and this may have contributed to the high risk observed in the present series. However, as presented in Table 4, two groups have reported a high risk of chronic GVHD after allogeneic PBSC transplantation, despite the use of cyclosporine and methotrexate for prophylaxis.^19,21 Increasing age has been associated with an increased risk of chronic GVHD.²³ The median age of patients in the present series is greater than that of patients in most prior reports of allogeneic BMT. However, in the current report, the risk of chronic GVHD did not seem to be age dependent, with the actuarial probability of chronic GVHD in patients older than the median age of 43 years being 0.79 versus 0.89 for younger patients (data not shown). Transplants from parous female donors to male recipients have also been associated with an increased risk of chronic GVHD.²³ However, in the current series, exclusion of these patients did not change the risk of chronic GVHD (0.90; 95% CI, 0.7 to 1.0).

In addition to the current trial, two of the other four studies listed in Table 4 have reported a risk for chronic GVHD exceeding 70%.^19,21 Four other trials published in abstract form and that together included more than 100 assessable patients have also reported a risk of chronic GVHD after allogeneic PBSC transplantation that exceeded 70%.^15,24-26 Taken together, these observations indicate that allogeneic PBSC transplantation is associated with a high risk of chronic GVHD. This risk is greater than that which is commonly reported after HLA-identical sibling BMT for adults with hematologic malignancy,^23,27-30 suggesting that the risk of chronic GVHD after allogeneic PBSC transplantation may be greater than that which follows BMT. Therefore, until the time when mature data are available from ongoing randomized trials, allogeneic PBSC transplantation should be undertaken with caution, particularly in the setting of unrelated-donor or mismatched related-donor transplantation.

Differences in absolute cell numbers or cell functions between allogeneic PBSCs and bone marrow could account for the increased risk of chronic GVHD with the former. Allogeneic PBSC products contain approximately one log more T cells than does bone marrow,³¹ and this could result in an increased risk of chronic GVHD. Several groups have also shown that mobilization of PBSCs with G-CSF alters peripheral-blood T-cell subsets. In a murine model, Pan et al³² found that mobilization of donors with G-CSF resulted in polarization of donor T cells toward type 2 cytokine production, and this was associated with a reduced risk of acute GVHD. Our group demonstrated a predominance of type 2 cytokine expression during the first 6 months after allogeneic PBSC transplantation followed by a shift to type 1 cytokines.³³ These changes could result in an increased risk of chronic GVHD without increasing the risk of acute GVHD. Another possible explanation for this pattern of GVHD after allogeneic PBSC transplantation involves the observations of Talmadge et al,³⁴ who described a population of suppressor cells among the peripheral-blood leukocytes of patients who underwent mobilized, autologous PBSC transplantation. These cells inhibited the response of T cells to mitogens and were only present during the first 20 days posttransplantion. Additional work indicates that these suppressor cells are monocytes, which may induce apoptosis of T cells.³⁵

In the current trial, chronic GVHD produced significant long-term morbidity and contributed to a substantial risk of late (> 100 days) mortality (14%). However, as a result of relatively low early mortality (12%), the overall risk of death from transplant-related causes compares favorably with that previously reported by our group and by the International Bone Marrow Transplant Registry for patients with resistant hematologic malignancy who have undergone BMT.^36-38 Perhaps as a result of the fact that all patients recovered neutrophils greater than 500/µL by day +15,² only one patient died of infection while neutropenic. However, approximately 75% of transplant-related mortality was associated with GVHD, indicating that a significant reduction of transplant-related mortality after allogeneic PBSC transplantation will depend on the development of more effective strategies for preventing and treating GVHD.

Chronic GVHD has been associated with reduced relapse risk after allogeneic BMT.³⁹ Therefore, the high risk of persistent chronic GVHD after allogeneic PBSC transplantation could have a favorable effect on progression-free survival, particularly among patients at high risk of relapse. This issue can only be resolved by trials in which patients with similar malignancies are randomized to receive allogeneic PBSC transplantation versus BMT.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 25, 1998; accepted November 18, 1998.

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