Abstract

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-α (IFN-α), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-α results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-α on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-α therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-α, whereas 22, 23, and 25 patients received IFN-α for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-α therapy administered for ≥6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2.1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-α therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight ≥110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-α for less than 6 months before transplant, who were ≤50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% ± 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-α when the patient is ≤50 years of age and has an HLA-compatible unrelated volunteer donor.

INTERFERON-α (IFN-α) has demonstrated activity against chronic myelogenous leukemia (CML) and in most randomized studies has offered benefit when instituted in early chronic phase (CP).1-3 Cytogenetic responses (≤90% Philadelphia chromosome-positive metaphases) occurred in 20% to 60% of patients, becoming apparent after a median of 12 months of treatment.4 Major cytogenetic responses (<35% Philadelphia chromosome-positive metaphases) were achieved in 10% to 40% of patients,5-8 but molecular remissions, defined by the absence of bcr-abl mRNA determined by polymerase chain reaction, have rarely been described.9 Survival at 4 years was 90% for patients achieving a major cytogenetic response after 12 months of therapy with IFN-α, 75% for patients achieving a partial cytogenetic response (35% to 90% Philadelphia chromosome-positive metaphases),4 and 10% to 50% for those failing to achieve a cytogenetic response.4,7 Median overall survival for patients treated with IFN-α alone varies from 5 to 6 years,1-3,6-8 compared with 3 to 4.5 years for hydroxyurea or busulfan therapy.1-3,10,11 IFN-α combined with cytarabine has significantly improved cytogenetic response and survival compared with IFN-α alone.12 

Allogeneic transplantation from an HLA-identical sibling donor offers curative treatment for the majority of patients with CML in CP and a 5-year survival of 65% to 90%, depending on the interval from diagnosis to transplant.13 Survival is similar after transplantation in CP from a single locus HLA-A or B mismatched family donor,14,15 whereas survival after transplantation from a family member mismatched for a single HLA-DR antigen is worse (∼50% at 5 years).16 Only 35% of patients have an HLA-identical sibling donor, whereas a further 5% benefit from an extended family search.14 The recruitment of a large number of volunteer donors has resulted in the availability of HLA-A, B, DR serologically matched unrelated donors (URD) for up to 75% of Caucasian patients in the US National Marrow Donor Program and other registries worldwide. Recent studies have demonstrated the importance of donor matching for DRB117 and DQB118 to reduce the risk of severe acute graft-versus-host disease (GVHD) and donor matching for HLA-A, B and C19 alleles to decrease the risk of graft failure. Although early studies suggested inferior survival after URD compared with sibling donor transplantation,20-24 better prevention of cytomegalovirus (CMV) and fungal disease has substantially improved outcome after URD transplantation.25 

In the absence of an available sibling donor, physicians are often faced with the choice of either treating patients in early CP with IFN-α or an URD transplant. Some investigators recommend an initial 12-month trial of IFN-α, followed by an URD transplant if there is no cytogenetic response to IFN-α therapy.4 Previous reports have evaluated the impact of IFN-α on outcome of related donor transplants26,27 with contradictory conclusions, reflecting differences in sample size and duration of IFN-α therapy considered. Others point out the many unanswered questions in this choice.28 The aim of this study was to assess the impact of pretransplant therapy with IFN-α on patient outcome after URD transplantation.

PATIENTS AND METHODS

Study patients.

Between January 1988 and December 1994, 184 consecutive patients with Philadelphia chromosome-positive CML in CP underwent URD transplantation at the Fred Hutchinson Cancer Research Center. Treatment protocols were approved by the Institutional Review Board, and written informed consent was obtained from all patients or their legal guardians. The diagnosis and disease stage were confirmed by hematological and cytogenetic evaluations performed within 14 days before admission for transplantation.29 The protocol exclusion criteria were age greater than 55 years; availability of a HLA identical sibling or a one HLA-A, B or DR antigen incompatible family member; life expectancy severely limited by a disease other than malignancy; cardiac disease requiring therapy; severe hepatic disease including acute hepatitis; severe pulmonary disease including fibrosis; creatinine greater than 2 times normal; leukoencephalopathy; brain irradiation with greater than 3,000 cGy; chest irradiation with greater than 1,500 cGy; and positive human immunodeficiency virus (HIV) serology.

Pretransplant treatment of CML.

Details of pretransplant treatment were obtained from patient history and referring physician notes and flow sheets. Patients were classified as IFN-α recipients if they received therapy at doses of ≥9 × 106 U/m2/wk for at least 4 weeks. Treatment intervals in which the patient received ≥9 × 106U/m2/wk of IFN-α were added, with the total duration of pretransplant IFN-α calculated to the nearest month. The time period between the last dose of IFN-α and the day of transplant was calculated to the nearest month. Evaluation was made by chart review, with the observer (A.J.M.) blinded to patient transplantation outcomes.

HLA typing and donor matching.

The analysis of HLA matching was based on typing for HLA-A and B antigens by serological methods and typing of HLA-DRB1 and HLA-DQB1 alleles by DNA hybridization with sequence-specific oligonucleotide probes (SSOP). The population of 184 URD transplants included 129 HLA matched pairs, 15 pairs mismatched for HLA-A (n = 7) or HLA-B (n = 8), 28 pairs mismatched for HLA-DRB1 (n = 12) or HLA-DQB1 (n = 16), and 12 pairs multiply mismatched, including 7 pairs mismatched for HLA-A or B and HLA-DRB1 or DQB1 and 5 pairs mismatched for HLA-DRB1 and HLA-DQB1.

Transplant procedure and supportive care.

Conditioning for the 184 patients included cyclophosphamide (60 mg/kg on each of 2 consecutive days) and fractionated total body irradiation (TBI), with 80% of patients receiving 12 Gy and the others receiving exposures varying from 13.2 to 15.75 Gy. All patients received unmodified bone marrow and short course methotrexate in conjunction with cyclosporine for GVHD prophylaxis, as previously published.30 CMV-seronegative patients received blood products from CMV-seronegative donors or leukocyte-depleted blood products from CMV-seropositive donors. From November 16, 1990 until August 5, 1991, CMV-seropositive patients were randomized to receive ganciclovir or placebo at the time of engraftment to prevent CMV disease.31,32 Subsequently, CMV-seropositive patients received ganciclovir at the time of engraftment. Since December 17, 1993, CMV-seronegative recipients have been treated with ganciclovir at the first sign of CMV antigenemia as detected by fluorescence assay. Patients receiving ganciclovir prophylaxis at engraftment or at the first signs of CMV antigenemia and donor/recipient pairs in which both were CMV seronegative were coded as receiving CMV prophylaxis. From July 1990 to March 1992, patients were randomized to receive fluconazole or placebo from the pretransplant period until day +75 posttransplant for fungal prophylaxis.33 After March 1992, all patients received fluconazole prophylaxis. Acyclovir was administered to herpes simplex virus (HSV)-seropositive patients from the pretransplant period until day +30 or discharge from the in-patient unit. Fifty-nine patients received granulocyte-macrophage colony-stimulating factor (GM-CSF; 250 μg/m2/d)34,35 starting on day 0 as part of a phase II or phase III trial, whereas 32 patients received granulocyte colony-stimulating factor (G-CSF; 5 μg/kg/d) due to the absence of neutrophil recovery at day +21.

Engraftment.

Patients were evaluable for graft failure when survival exceeded 28 days. Graft failure was defined by the following: (1) the absolute neutrophil count did not surpass 500/μL at any time before second transplant, relapse or death; (2) the absolute neutrophil count decreased to less than 100/μL for at least three consecutive determinations at least 1 day apart after initial engraftment and did not recover before relapse, second transplant, or death; or (3) absence of donor T cells as documented by informative variable number tandem repeat polymorphisms or by fluorescent in situ hybridization with a Y-chromosome–specific probe in gender mismatched transplants. Platelet independence was defined as the maintenance of an unsupported platelet count exceeding 20,000/μL for 7 consecutive days.

GVHD.

Acute GVHD was assessed in patients surviving at least 14 days, excluding patients with primary graft failure. Severity of acute GVHD was graded by the Glucksberg criteria.36,37 Acute GVHD grades II-IV was treated with prednisone 2 mg/kg for 14 days and then tapered at 0.2 mg/kg every 5 days based on response.38 GVHD response to prednisone therapy over the first 80 days posttransplant was graded as follows: sensitive, indicating GVHD improvement in one or more organs without recurrence on the standard prednisone taper; dependent, indicating GVHD recurring on prednisone taper before day 80; and refractory, indicating GVHD progression after 7 days of prednisone therapy or failure to improve in one or more organs after 14 days of prednisone therapy. Patients were assessed for chronic GVHD between day +80 and day +100 and graded by standard criteria.39 

Relapse.

Relapse was defined by the persistence of any Philadelphia chromosomes in metaphases after day +50 on two occasions at least 1 month apart and after an attempt had been made to withdraw any immunosuppressive therapy, or by the presence of frank hematological relapse. Censors were defined as the day of last contact.

Statistical analysis.

Clinical endpoints included times to reach an absolute neutrophil count greater than 500/μL and a self sustaining platelet count greater than 20,000/μL, graft failure, cumulative incidence of severe acute and clinical extensive chronic GVHD, time to relapse, and survival. Continuous covariates were compared by two-sided Wilcoxon rank-sum tests, whereas differences between categorical variables were compared by two-tailed Fisher's exact tests. Cumulative incidence40estimates were used to measure the incidence of acute GVHD, clinical extensive chronic GVHD, relapse, and transplant-related mortality. Survival estimates were obtained by the method of Kaplan and Meier. The χ2 test was used to test for homogeneity of event distribution across strata for events in which the duration of follow-up exceeded the time to the last occurrence of complications such as acute GVHD and clinical extensive chronic GVHD. The log-rank test was used to test homogeneity of time to event distributions across strata in which follow-up of all subjects failed to exceed the last time point that an event occurred in the study population, such as relapse, nonrelapse mortality, and survival. The independence of covariates with significance levels less than 10% in the univariable analyses was tested by logistic regression or by Cox regression. Covariates were added to the models in a stepwise fashion based on their significance in univariable analyses. All covariates that added information to the model at the .05 significance level as measured by the likelihood ratio test were included in the final model.

Variables examined in all analyses included patient and donor age, donor/patient gender match, donor parity, parous female donor/male recipient pairing, donor/patient CMV match, CMV and fungal prophylaxis, disease duration, pretransplant weight ≥110% of ideal body weight, HLA match, pretransplant busulfan, pretransplant IFN-α, time off IFN-α pretransplant, uncorrected marrow cell dose, and TBI dose. Duration of therapy with IFN-α before transplant was initially categorized as none, 1 to 5 months, 6 to 12 months, and greater than 12 months. After examination of the data, the duration of therapy with IFN-α before transplant was subsequently categorized as 0 to 5 and ≥6 months based on the similarity of outcome for 0 and 1 to 5 months of pretransplant IFN-α, and the similarity of outcome for 6 to 12 and greater than 12 months of pretransplant IFN-α. All evaluations were based on data available as of December 31, 1996. Statistical analyses were performed using STATA statistical software 5.0 (Stata Corp, College Station, TX).

RESULTS

Patient characteristics.

Demographic and treatment characteristics are shown in Table 1. One hundred fourteen patients (62%) did not receive IFN-α, whereas 70 (38%) were treated with IFN-α before transplantation for a median of 10 months (range, 1 to 64 months): 22 for 1 to 5 months, 23 for 6 to 12 months, and 25 for greater than 12 months. IFN-α was discontinued a median of 2 months (range, 0 to 47 months) before URD transplantation for the following reasons: lack of compliance with IFN (n = 21), patient or physician preference for transplantation (n = 19), lack of cytogenetic remission by 1 year of treatment (n = 16), or uncontrolled blood cell counts (n = 14). Five of 70 (7%) patients had developed chronic toxicity attributed to IFN: psoriasis (n = 2), hypothyroidism (n = 2), or immune hemolytic anemia (n = 1). Based on the analysis of the association between posttransplant survival and duration of treatment with IFN-α in 4 patient groups, classified as no IFN-α and IFN-α for 1 to 5, 6 to 12, or greater than 12 months, subsequent analyses of GVHD, relapse, and mortality considered the two categories of pretransplant therapy with IFN-α for 0 to 5 months or ≥6 months. Patients receiving IFN-α for ≥6 months were less likely to weigh ≥110% of their ideal body weight, had lower serum albumin, had lower performance status score, had longer disease duration at the time of transplant, and were transplanted in the later years of the study period.

Table 1.

Patient Demographics

Variable Category or Value IFN 0-5 mo (n = 136) IFN ≥6 mo (n = 48) P Value
  No. of Patients (%)  
HLA compatibility  Match  95 (69%)  34 (70%) .3  
 A or B mismatch  9 (7%)  6 (13%)  
 DRB1 or DQB1 mismatch  24 (18%)  4 (9%)  
 Multiple mismatch* 8 (6%)  4 (8%)  
Patient age (yr)  <20 10 (7%)  4 (9%)  .7  
 20-35  60 (44%) 19 (41%)  
 36-50  62 (46%)  22 (46%)  
 >50  4 (3%)  3 (6%)  
Gender match  (donor to patient)   .5  
 M to M  37 (27%) 12 (25%)  
 M to F  42 (31%)  11 (23%)  
 F to M  30 (22%)  11 (23%)  
 F to F  27 (22%) 14 (29%)  
Donor parity  F to M  19 (14%)  7 (15%) .9  
Patient weight ≥10% above ideal   75 (55%) 17 (35%)  .02  
Busulfan   25 (19%)  7 (15%) .6  
CMV prophylaxis-151  98 (72%)  37 (77%)  .4 
Fungal prophylaxis-151  69 (51%)  31 (65%)  .1 
CML duration (yr)  (diagnosis to transplant)    .001 
 ≤1  60 (44%)  6 (13%)  
 1-3  54 (40%) 23 (49%)  
 >3  22 (16%)  19 (40%) 
Transplant year  1988-90  54 (40%)  10 (21%)  .04 
 1991-92  41 (30%)  22 (46%)  
 1993-94 41 (30%)  16 (33%)  
  g/dL  
Serum albumin  Median (range) 3.8 (2.4, 4.6)  3.3 (2.6, 4.5)  .03  
  Percent score  
Kernofsky status  Median (range)  100 (70, 100)  90 (70, 100)  .007  
  Years  
Donor age  Median (range) 38 (20, 57)  38 (23, 53)  .5  
  No. of cells × 108/kg  
Marrow cell dose  Median (range)  3.3 (0.65, 14.3) 3.4 (1.7, 11.4)  .6 
Variable Category or Value IFN 0-5 mo (n = 136) IFN ≥6 mo (n = 48) P Value
  No. of Patients (%)  
HLA compatibility  Match  95 (69%)  34 (70%) .3  
 A or B mismatch  9 (7%)  6 (13%)  
 DRB1 or DQB1 mismatch  24 (18%)  4 (9%)  
 Multiple mismatch* 8 (6%)  4 (8%)  
Patient age (yr)  <20 10 (7%)  4 (9%)  .7  
 20-35  60 (44%) 19 (41%)  
 36-50  62 (46%)  22 (46%)  
 >50  4 (3%)  3 (6%)  
Gender match  (donor to patient)   .5  
 M to M  37 (27%) 12 (25%)  
 M to F  42 (31%)  11 (23%)  
 F to M  30 (22%)  11 (23%)  
 F to F  27 (22%) 14 (29%)  
Donor parity  F to M  19 (14%)  7 (15%) .9  
Patient weight ≥10% above ideal   75 (55%) 17 (35%)  .02  
Busulfan   25 (19%)  7 (15%) .6  
CMV prophylaxis-151  98 (72%)  37 (77%)  .4 
Fungal prophylaxis-151  69 (51%)  31 (65%)  .1 
CML duration (yr)  (diagnosis to transplant)    .001 
 ≤1  60 (44%)  6 (13%)  
 1-3  54 (40%) 23 (49%)  
 >3  22 (16%)  19 (40%) 
Transplant year  1988-90  54 (40%)  10 (21%)  .04 
 1991-92  41 (30%)  22 (46%)  
 1993-94 41 (30%)  16 (33%)  
  g/dL  
Serum albumin  Median (range) 3.8 (2.4, 4.6)  3.3 (2.6, 4.5)  .03  
  Percent score  
Kernofsky status  Median (range)  100 (70, 100)  90 (70, 100)  .007  
  Years  
Donor age  Median (range) 38 (20, 57)  38 (23, 53)  .5  
  No. of cells × 108/kg  
Marrow cell dose  Median (range)  3.3 (0.65, 14.3) 3.4 (1.7, 11.4)  .6 

*Multiple mismatch denotes donor and recipient incompatibility for one antigen at HLA-A or B plus one at DRB1 or DQB1 or one at DRB1 plus one at DQB1.

F0-151

CMV and fungal prophylaxis are defined in the Patients and Methods.

Engraftment.

Twelve patients (6.7%) failed to engraft or developed late graft failure. There was no detectable association between pretransplant therapy with IFN-α and graft failure (P = .8). Median time to achieve an absolute neutrophil count greater than 500/μL was 22 days (range, 14 to 38 days) and platelet transfusion independence was 22 days (range, 5 to 167 days). Neutrophil and platelet recovery were not affected by pretransplant IFN-α. Platelet recovery was delayed by the presence of any HLA disparity between patient and donor (P = .04) and was accelerated for patients less than 20 years old (P = .02).

GVHD.

One hundred thirty-eight of 175 evaluable patients (79%) developed grades II-IV acute GVHD and 69 of 175 evaluable patients (39%) developed grades III-IV acute GVHD. Pretransplant treatment with IFN-α for ≥6 months was not associated with the development of grades II-IV acute GVHD (79% v 79%, P = 1). Conversely, the incidence of grades III-IV acute GVHD was 55% in patients treated with IFN-α for ≥6 months pretransplant, compared with 34% for those treated for less than 6 months (P = .009; Fig 1). Pretransplant patient performance status score and serum albumin levels were not associated with increased GVHD. By multivariate analysis, pretreatment with IFN-α for ≥6 months (relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and multiple HLA mismatches (RR, 6.1; 95% CI, 1.5 to 25; P = .01) were associated with an increased risk of grades III-IV acute GVHD, whereas CMV prophylaxis was protective (RR, 0.3; 95% CI, 0.2 to 0.7; P = .002). Restricting the multivariate analysis to HLA matched URD transplants, ≥6 months of IFN-α remained predictive for the development of grades III-IV acute GVHD (55% v 28%; RR, 3.4; 95% CI, 1.5 to 8.1;P = .005).

Fig. 1.

Cumulative incidence of grades III-IV acute GVHD after unrelated donor transplant. (A) 0 to 5 months of IFN-α pretransplant (cumulative incidence, 0.34; n = 128), (B) ≥6 months of IFN-α pretransplant (cumulative incidence, 0.55; n = 47) (P = .01, by the χ2 test).

Fig. 1.

Cumulative incidence of grades III-IV acute GVHD after unrelated donor transplant. (A) 0 to 5 months of IFN-α pretransplant (cumulative incidence, 0.34; n = 128), (B) ≥6 months of IFN-α pretransplant (cumulative incidence, 0.55; n = 47) (P = .01, by the χ2 test).

Acute GVHD was prednisone-dependent or refractory in 50 of 175 (29%) evaluable patients. Patients who had received pretransplant treatment with IFN-α for ≥6 months were at increased risk of prednisone-dependent or refractory acute GVHD (43% v 23%,P = .01). Multivariate analysis identified three factors predictive for the development of prednisone-dependent or refractory acute GVHD: multiple HLA mismatches (RR, 12; 95% CI, 2.9 to 52;P = .001), CMV prophylaxis (RR, 0.3; 95% CI, 0.1 to 0.6;P = .001), and ≥6 months of IFN-α (RR, 2.9; 95% CI, 1.3 to 6.5; P = .008). When the analysis was restricted to HLA-matched URD transplants, ≥6 months of pretransplant IFN-α remained predictive for the development of prednisone-dependent or refractory acute GVHD (37% v 18%; RR, 3.1; 95% CI, 1.2 to 8.1;P = .02).

One hundred two of 142 (72%) patients who were engrafted and in cytogenetic remission at day +100 developed clinical extensive chronic GVHD. The incidence of clinical extensive chronic GVHD was similar for patients treated pretransplant with IFN-α for 0 to 5 months (76/104 [73%]) or ≥6 months (26/38 [68%]).

Relapse.

Eight of 172 (5%) durably engrafted patients developed cytogenetic relapse of CML at a median of 311 days posttransplant (range, 56 to 1,090 days). Pretransplant therapy with IFN-α was not associated with the development of relapse posttransplant.

Survival.

One hundred six patients remain alive with an actuarial 5-year survival of 55% ± 4% and a median follow-up of 1,474 days (range, 609 to 3,028 days). Survival was significantly worse for those patients who had received pretransplant IFN-α for ≥6 months (43% ± 8%) than for those treated with IFN-α for 0 to 5 months (60% ± 5%; Fig 2; P = .05). There was no difference in survival for patients treated with IFN-α for 1 to 5 months pretransplant (67% ± 10%) and those not treated with IFN-α (59% ± 5%; P = .7). By multivariate analysis, IFN-α therapy for ≥6 months pretransplant was independently associated with an increased risk of posttransplant death (RR, 2.1; 95% CI, 1.3 to 3.5; P = .003). Pretransplant patient performance status score and serum albumin levels were not associated with decreased survival. In the multivariable model, time from diagnosis to transplantation did not achieve significance, did not significantly alter the log likelihood ratio (Table 2), and did not change the regression coefficient or confidence interval associated with therapy with IFN-α for ≥6 months (not shown). There was no apparent effect of time from diagnosis to transplant for the 114 patients who had not received treatment with IFN-α pretransplant. In relation to time interval from diagnosis to transplant ≤1 year, the relative risk was 0.9 for the interval greater than 1 to ≤3 years (P = .9), and the relative risk was 1.0 (P = .9) for the interval greater than 3 years. Treatment with IFN-α for ≥6 months before transplant remained associated with increased mortality (RR, 2.0; 95% CI, 1.1 to 3.7; P = .03) when the analysis was restricted to HLA-matched URD transplants. The association between pretransplant IFN-α for ≥6 months and survival was independent of the time interval between the last treatment with IFN-α and transplantation (P = .4).

Fig. 2.

Product-limit estimate of survival categorized by duration of pretransplant IFN-α. (A) 0 to 5 months of IFN-α pretransplant, 5-year survival 60% ± 5%, (n = 136). (B) ≥6 months of IFN-α pretransplant, 5-year survival 43% ± 8% (n = 48) (P = .05, by the log-rank test).

Fig. 2.

Product-limit estimate of survival categorized by duration of pretransplant IFN-α. (A) 0 to 5 months of IFN-α pretransplant, 5-year survival 60% ± 5%, (n = 136). (B) ≥6 months of IFN-α pretransplant, 5-year survival 43% ± 8% (n = 48) (P = .05, by the log-rank test).

Table 2.

Association Between Pretransplant Factors and Mortality After URD Transplantation

Factor Category Hazard Ratio 95% CI PValue
HLA  Match  1  
Compatibility  A or B mismatch 1.0  0.4, 2.4  1  
 DRB or DQB mismatch  2.1 1.1, 3.8  .02  
 Multiple mismatch  3.5  1.6, 7.4 .002  
CMV and  Neither  2  1.1, 3.6  .02  
Fungal Either  1  
Prophylaxis* Both  0.6  0.3, 1  .05 
Age  >50 yr  5.3  2.1, 13  <.001  
Weight ≥10% above IBW  1.8  1.1, 3.0  .02  
Disease  ≤1 yr  1  
Duration  >1 and ≤3 yr  0.8  0.5, 1.5  .6 
 >3 yr  1.5  0.8, 2.8  .2  
IFN-α  ≥6 m 2.1  1.2, 3.6  .007 
Factor Category Hazard Ratio 95% CI PValue
HLA  Match  1  
Compatibility  A or B mismatch 1.0  0.4, 2.4  1  
 DRB or DQB mismatch  2.1 1.1, 3.8  .02  
 Multiple mismatch  3.5  1.6, 7.4 .002  
CMV and  Neither  2  1.1, 3.6  .02  
Fungal Either  1  
Prophylaxis* Both  0.6  0.3, 1  .05 
Age  >50 yr  5.3  2.1, 13  <.001  
Weight ≥10% above IBW  1.8  1.1, 3.0  .02  
Disease  ≤1 yr  1  
Duration  >1 and ≤3 yr  0.8  0.5, 1.5  .6 
 >3 yr  1.5  0.8, 2.8  .2  
IFN-α  ≥6 m 2.1  1.2, 3.6  .007 

*Because of considerable overlap in the introduction of policies for CMV and fungal prophylaxis, the regimens were grouped based on no CMV or fungal prophylaxis (n = 40), CMV or fungal prophylaxis (n = 53: fungal only n = 9, CMV only n = 44), and CMV and fungal prophylaxis (n = 91).

The cumulative incidence of transplant-related mortality was significantly higher for those patients receiving IFN-α for ≥6 months than those receiving IFN-α for 0 to 5 months before transplant (56% v 38% at 5 years; P = .05). Mortality from causes other than relapse during the first 100 days was 15% in patients who had received IFN-α for ≥6 months before transplant and 13% in patients who had received IFN-α for 0 to 5 months (P= .7). Increased nonrelapse mortality occurred between day 100 and day 365 posttransplant in patients who had received IFN-α ≥6 months before transplant (37% v 15%, P = .003; Fig 3) and was limited to those patients who developed prednisone-dependent or refractory acute GVHD (Table 3). The difference between the two patient groups was due to deaths from refractory clinical extensive chronic GVHD with or without infection. There was no difference in the rates of subsequent nonrelapse mortality for patients alive at 1 year posttransplant. Nonrelapse mortality between 1 and 5 years was 16% in patients who had received pretransplant IFN-α for 0 to 5 months and 18% in patients who had received IFN-α for ≥6 months (P = .8).

Fig. 3.

Cumulative incidence of nonrelapse mortality categorized by duration of therapy with IFN-α pretransplant. (A) 0 to 5 months of IFN-α pretransplant, 0.38 (n = 136). (B) ≥6 months of IFN-α pretransplant, 0.56 (n = 48) (P = .05, by the log-rank test).

Fig. 3.

Cumulative incidence of nonrelapse mortality categorized by duration of therapy with IFN-α pretransplant. (A) 0 to 5 months of IFN-α pretransplant, 0.38 (n = 136). (B) ≥6 months of IFN-α pretransplant, 0.56 (n = 48) (P = .05, by the log-rank test).

Table 3.

Association Between Pretransplant IFN-α for ≥6 Months and Mortality From Day 100 to Day 365 Posttransplant, Stratified According to Severity of Acute GVHD

Acute GVHD Prednisone Response IFN-α 0-5 mo (no. died/total) IFN-α ≥6 mo (no. died/total) PValue (χ2 test)
No prednisone  2/33 (6%) 1/11 (9%)  .7  
Prednisone-sensitive 8.62 (13%)  2/16 (13%)  
Prednisone-dependent  or refractory  8/24 (33%) 12/14 (86%)  .002  
Total  18/119 (15%) 15/41 (37%)  .003 
Acute GVHD Prednisone Response IFN-α 0-5 mo (no. died/total) IFN-α ≥6 mo (no. died/total) PValue (χ2 test)
No prednisone  2/33 (6%) 1/11 (9%)  .7  
Prednisone-sensitive 8.62 (13%)  2/16 (13%)  
Prednisone-dependent  or refractory  8/24 (33%) 12/14 (86%)  .002  
Total  18/119 (15%) 15/41 (37%)  .003 

For those patients treated with IFN-α for 0 to 5 months pretransplant, who were ≤50 years of age, received a HLA-A, B, DRB1, DQB1 matched URD transplant for CML in CP, and received CMV and fungal prophylaxis after transplantation (n = 48), the cumulative incidence of grades III-IV acute GVHD was 21%, the estimated 5-year survival was 87% ± 5%, and the 5-year survival free of cytogenetic relapse was 74% ± 6% (Fig4).

Fig. 4.

Five-year survival, survival free from cytogenetic relapse, and cytogenetic relapse after HLA-A, B, DRB1 and DQB1-matched unrelated donor transplantation for patients ≤50 years old, who received IFN-α for 0 to 5 months before transplant, and received CMV and fungal prophylaxis after transplant (n = 48). (A) 5-year survival 87% ± 5%. (B) 5-year survival free from cytogenetic relapse 74% ± 6%. (C) 5-year cumulative incidence of relapse 13%. Four of 6 relapses followed graft failure and autologous reconstitution. The median follow-up of surviving patients is 1,128 days.

Fig. 4.

Five-year survival, survival free from cytogenetic relapse, and cytogenetic relapse after HLA-A, B, DRB1 and DQB1-matched unrelated donor transplantation for patients ≤50 years old, who received IFN-α for 0 to 5 months before transplant, and received CMV and fungal prophylaxis after transplant (n = 48). (A) 5-year survival 87% ± 5%. (B) 5-year survival free from cytogenetic relapse 74% ± 6%. (C) 5-year cumulative incidence of relapse 13%. Four of 6 relapses followed graft failure and autologous reconstitution. The median follow-up of surviving patients is 1,128 days.

DISCUSSION

The aim of this study was to evaluate the impact of pretransplant therapy with IFN-α on the outcome of marrow transplantation from URDs for CML in CP. After adjusting for other pretransplant risk factors previously shown to be associated with survival,25 we found that IFN-α administered for ≥6 months was associated with lower survival. This was due to an increase in the incidence of severe acute GVHD that was difficult to control with prednisone therapy. Increased mortality occurred between day 100 and day 365 and was due to complications of chronic GVHD that was refractory to treatment.

The effect of treatment with IFN-α for ≥6 months on the development of severe acute GVHD and survival was independent of the time interval from the last treatment with IFN-α to the transplant. Thus, pretransplant IFN-α therapy has a long-lasting effect that predisposes to the development of severe acute GVHD after transplantation. Interferons are known to enhance HLA class I gene expression and therefore the presentation of major and minor histocompatibility antigens,41,42 which in turn could lead to more severe GVHD reactions. However, the effect of IFN-α on HLA gene expression is expected to be transient and is unlikely to explain the long-lasting effect of IFN after its discontinuation. Reasons for the long-lasting effect of IFN-α after its discontinuation are not clear. Prolonged treatment with IFN-α results in chronic toxicity, including depression, fatigue, anorexia, and weight loss.43We found that patients treated with IFN-α for 6 or more months had lower body weight, lower serum albumin levels, and lower performance status scores than patients treated with IFN-α for less than 6 months. It is conceivable that the weakened physical condition from chronic IFN-α toxicity contributed an increased risk of transplant-related complications, including death.

In a previous analysis of URD transplantation for CML at our institution, we found that prolonged time from diagnosis to transplantation was an adverse prognostic factor for survival.25 The current study has also considered the impact of pretransplant treatment with IFN-α. Because time from diagnosis and length of treatment with IFN-α are correlated, it can be difficult to determine whether these variables act independently on survival or interact in some way. When time from diagnosis was added to the multivariable model already considering the variable IFN-α for ≥6 months, the likelihood ratio test indicated that the model was only marginally improved (P = .06). On the other hand, the addition of the variable IFN-α for ≥6 months significantly improved the model that was already considering the effect of time from diagnosis (P = .007). Furthermore, there was no association between time from diagnosis and survival for the 114 patients who were not treated with IFN-α pretransplant. Therefore, the association between pretransplant administration of IFN-α and posttransplant outcome is independent of the effect of time from diagnosis to transplant. In addition, our study suggests that the association between prolonged interval from diagnosis to transplant and poor survival may be due to pretransplant therapy with IFN-α.

Two previous reports have evaluated the impact of pretransplant IFN-α on the posttransplant course. A study from the M.D.Anderson Cancer Center26 reviewed 77 patients undergoing HLA-identical sibling transplantation, including 41 patients in CP, 23 who were treated with IFN-α for 9 to 343 weeks before transplant. The study found no statistically detectable differences in the rate of grades II-IV acute GVHD or 3-year survival. The investigators noted a suggestion towards improved survival for patients who had not been treated with IFN-α before transplant (66% ± 13% v 56% ± 10%), with an initial separation of the survival curves during the first 12 months after transplant. Beelen et al27included 133 patients with CML in CP who received transplants from HLA-identical siblings (n = 103) or alternative donors (n = 30). Pretransplant IFN-α was categorized as ≤12 months or greater than 12 months based on the median time to observe a cytogenetic response. No difference was seen in the incidence of grades II-IV acute GVHD, but survival was reduced in patients treated with IFN-α for greater than 12 months. The investigators noted an increased risk of death from infectious causes after day 120 for patients treated with IFN-α for greater than 12 months, similar to our results. They also noted a high rate of graft failure after alternate donor transplantation if the recipients were treated with IFN-α before transplantation.27 We were unable to confirm an association between patient treatment with IFN-α before transplant and marrow graft dysfunction.

In keeping with previous reports, we found that a single mismatch for HLA-A or B did not increase the risk of grades III-IV acute GVHD or decrease survival as compared with fully HLA-matched URD transplants.44 These patients were all less than 36 years of age and 14 of 15 were mismatched within cross-reactive antigen groups. In contrast, a single HLA-DRB1 or HLA-DQB1 mismatch was associated with worse outcome. Poorest survival followed multiple mismatched transplants. These results confirm previous observations regarding the importance of allele matching for HLA-DRB1 and DQB1 in URD transplantation.17,18 

The survival of patients treated with IFN-α for 0 to 5 months before transplant, who were 50 years of age or less, received a HLA-matched URD transplant, and received CMV and fungal prophylaxis was 87% ± 5% at 5 years, similar to survival after HLA-identical sibling transplantation and comparable to the survival described for patients achieving a major cytogenetic response to treatment with IFN-α. With no relapses observed after 3 years, it is likely that most of the patients alive 5 years after an URD transplant are cured of CML. The data presented here provide a rationale for immediate transplantation in preference to prolonged treatment with IFN-α when the patient is 50 years of age or less and has available a HLA-matched or HLA-A or B mismatched URD.

Supported in part by National Institutes of Health Grants No. CA 15704, CA 18029, CA 18221, and A1 33484. A.J.M. is the recipient of a grant from the Leukemia Foundation of Queensland, Australia.

Address correspondence to Claudio Anasetti, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.

© 1998 by the American Society of Hematology.

REFERENCES

1
Italian Cooperative Group on Chronic Myeloid Leukemia
Interferon α-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia.
N Engl J Med
330
1994
820
2
German CML Study Group
Randomized comparison of interferon-α with busulfan and hydroxyurea in chronic myelogenous leukemia.
Blood
84
1994
4064
3
Allan NC Richards
SM
Shepherd
PC
UK Medical Research Council randomized, multicenter trial of interferon-α for chronic myeloid leukemia: Improved survival irrespective of cytogenetic response.
Lancet
345
1995
1392
4
Kantarjian
HM
Smith
TL
O'Brien
S
Beran
M
Pierce
S
Talpaz
M
Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-α therapy.
Ann Intern Med
122
1995
254
5
Talpaz
M
Kantarjian
HM
McCredie
K
Trujillo
JM
Keating
MJ
Gutterman
JU
Hematologic remission and cytogenetic improvement induced by recombinant human interferonA in chronic myelogenous leukemia.
N Engl J Med
314
1986
1065
6
Talpaz
M
Kantarjian
H
Kurzrock
R
Trujillo
JM
Gutterman
JU
Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia.
Ann Intern Med
114
1991
532
7
Kloke
O
Niederle
N
Qiu
JY
Wandl
U
Moritz
T
Nagel-Hiemke
M
Hawig
I
Opalka
B
Seeber
S
Becher
R
Impact of interferon alpha-induced cytogenetic improvement on survival in chronic myelogenous leukemia.
Br J Haematol
83
1993
399
8
Ozer
H
George
SL
Schiffer
CA
Rao
K
Rao
PN
Wurster-Hill
DH
Arthur
DD
Powell
B
Gottlieb
A
Peterson
BA
Rai
K
Testa
JR
LeBeau
M
Tantravachi
R
Bloomfield
C
Prolonged subcutaneous administration of recombinant α2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival: Cancer and Leukemia Group B Study 8583.
Blood
82
1993
2975
9
Opalka
B
Wandl
UB
Becher
R
Kloke
O
Nagel-Hiemke
M
Moritz
T
Beer
U
Seeber
S
Niederle
N
Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon α-2b alone or in combination with interferon γ.
Blood
78
1991
2188
10
Sokal
JE
Cox
EB
Baccarani
M
Tura
S
Gomez
G
Robertson
J
Tso
CY
Braun
TJ
Clarkson
BD
Cervantes
F
Rozman
C
the Italian Cooperative CML Study Group
Prognostic discrimination in good risk chronic granulocytic leukemia.
Blood
63
1984
789
11
Kantarjian
HM
Keating
MJ
Smith
TL
Talpaz
M
McCredie
KB
Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia.
Am J Med
68
1990
1
12
Guilhot
F
Chastang
C
Michallet
M
Guerci
A
Harousseau
J
Maloisel
F
Bouabdallah
R
Guyotat
D
Cheron
N
Nicolini
F
Abgrall
J
Tanzer
J
Interferon alpha-2B combined with cytarabine versus interferon alone in chronic myelogenous leukemia.
N Engl J Med
337
1997
223
13
Appelbaum
FR
Clift
RG
Radich
J
Anasetti
C
Buckner
CD
Bone marrow transplantation for chronic myelogenous leukemia.
Semin Oncol
22
1995
405
14
Beatty
PG
Clift
RA
Mickelson
EM
Nisperos
BB
Flournoy
N
Martin
PJ
Sanders
JE
Stewart
P
Buckner
CD
Storb
R
Thomas
ED
Henson
JA
Marrow transplantation from related donors other than HLA-identical donors.
N Engl J Med
313
1985
765
15
Anasetti
C
Beatty
PG
Storb
R
Martin
PJ
Mori
M
Sanders
JE
Thomas
ED
Hansen
JA
Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after bone marrow transplantation for patients with leukemia or lymphoma.
Human Immunol
29
1990
79
16
Anasetti
C
Etzioni
R
Petersdorf
EW
Martin
PJ
Hansen
JA
Marrow transplantation from unrelated volunteer donors.
Annu Rev Med
46
1995
169
17
Petersdorf
EW
Longton
GM
Anasetti
C
Martin
PJ
Mickelson
EM
Smith
AG
Hansen
J
The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation.
Blood
86
1995
1606
18
Petersdorf
EW
Longton
GM
Anasetti
C
Mickelson
EM
Smith
A
Martin
PJ
Hansen
JA
Definition of HLA-DQ as a transplantation antigen.
Proc Natl Acad Sci USA
93
1996
15358
19
Petersdorf
EW
Longton
GM
Anasetti
C
Mickelson
EM
McKinney
SK
Smith
A
Martin
PJ
Hansen
JA
Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors.
Blood
89
1997
1818
20
Beatty
PG
Ash
R
Hows
JM
McGlave
PB
The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: Experience of four marrow transplant centers.
Bone Marrow Transplant
4
1989
287
21
McGlave
PB
Beatty
PG
Ash
R
Hows
JM
Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: Results in 102 cases.
Blood
75
1990
1728
22
McGlave
P
Bartsch
G
Anasetti
C
Ash
R
Beatty
P
Gajewski
J
Kernan
N
Unrelated donor marrow transplantation for chronic myelogenous leukemia: Initial experience of the National Marrow Donor Program.
Blood
81
1993
543
23
Marks
DI
Cullis
J
Ward
KN
Lacey
S
Szydlo
R
Hughes
T
Schwarer
AP
Lutz
E
Barrett
AJ
Hows
JM
Batchelor
JR
Goldman
JM
Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors.
Ann Intern Med
119
1993
207
24
Drobyski
WR
Ash
RC
Casper
JT
McAuliffe
T
Horowitz
M
Lawton
C
Keever
C
Baxter-Lowe
LA
Camitta
B
Garbrecht
F
Pietryga
D
Hansen
R
Chitambar
CR
Anderson
T
Flomenberg
N
Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease free survival in unrelated marrow transplantation for chronic myelogenous leukemia.
Blood
83
1994
1980
25
Hansen
J
Gooley
T
Martin
PJ
Appelbaum
F
Chauncey
TR
Clift
RA
Petersdorf
EW
Radich
J
Sanders
JE
Storb
R
Sullivan
KM
Anasetti
C
Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.
N Engl J Med
338
1998
962
26
Giralt
SA
Kantarjian
HM
Talpaz
M
Rios
MB
Giglio
AD
Andersson
BS
Przepiorka
D
Diesseroth
AB
Champlin
RE
Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia.
J Clin Oncol
11
1993
1055
27
Beelen
DW
Graeven
U
Elmaagacli
AH
Niederle
N
Kloke
O
Opalka
B
Schaefer
UW
Prolonged administration of interferon-α in patients with chronic phase chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome.
Blood
85
1995
2981
28
Goldman
J
Optimizing therapy for chronic myeloid leukemia.
N Engl J Med
337
1997
270
29
Thomas
ED
Clift
RA
Fefer
A
Appelbaum
FR
Beatty
P
Bensinger
WI
Buckner
CD
Cheever
MA
Deeg
HJ
Doney
K
Flournoy
N
Greenberg
P
Hansen
JA
Martin
P
McGuffin
R
Ramberg
R
Sanders
JE
Singer
J
Stewart
P
Storb
R
Sullivan
K
Weiden
PL
Witherspoon
R
Marrow transplantation for the treatment of chronic myelogenous leukemia.
Ann Intern Med
104
1986
155
30
Storb
R
Deeg
HL
Whitehead
J
Appelbaum
FR
Beatty
P
Bensinger
W
Buckner
CD
Clift
RA
Doney
KC
Farewell
V
Hansen
JA
Hill
R
Strout
P
Sullivan
KW
Witherspoon
RP
Yee
G
Thomas
ED
Methotrexate and cyclosporinee compared with cyclosporinee alone for prophylaxis of acute graft-versus-host disease after bone marrow transplantation for leukemia.
N Engl J Med
314
1986
729
31
Goodrich
JM
Bowden
RA
Fisher
L
Keller
C
Schoch
G
Meyers
JD
Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant.
Ann Intern Med
118
1993
173
32
Goodrich
JM
Boeckh
M
Bowden
R
Strategies for the prevention of cytomegalovirus disease after marrow transplantation.
Clin Infect Dis
19
1994
287
33
Slavin
MA
Osborne
B
Adams
R
Levenstein
MJ
Schoch
G
Feldman
AR
Meyers
JD
Bowden
RA
Efficacy and safety of fluconazole for fungal infections after marrow transplant—A prospective, randomized, double-blind study.
J Infect Dis
171
1995
1545
34
(abstr, suppl 1)
Anasetti
C
Anderson
G
Appelbaum
F
Buckner
D
Martin
P
Nemunaitis
J
Singer
J
Storb
R
Sullivan
K
Thomas
ED
Hansen
J
Phase III study of rh GM-CSF in allogeneic marrow transplantation from unrelated donors.
Blood
82
1993
1799a
35
Nemunaitis
J
Anasetti
C
Buckner
CD
Appelbaum
FR
Shannon-Daucy
K
Hansen
J
Dinger
JW
Long-term follow-up of 103 patients who received recombinant human granulocyte-macrophage colony stimulating factor after unrelated donor bone marrow transplantation.
Blood
84
1994
865
36
Glucksberg
H
Storb
R
Fefer
A
Buckner
CD
Neiman
PE
Clift
RA
Lerner
KG
Thomas
ED
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.
Transplantation
18
1974
295
37
Thomas
ED
Storb
R
Clift
RA
Fefer
A
Johnson
JL
Neiman
PE
Lerner
KG
Glucksberg
H
Buckner
CD
Bone-marrow transplantation (second of two parts).
N Engl J Med
292
1975
895
38
Doney
KC
Weiden
PL
Storb
R
Thomas
ED
Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: A randomized trial comparing antithymocyte globulin and corticosteroids.
Am J Hematol
11
1981
1
39
Sullivan
KM
Shulman
HM
Storb
R
Weiden
PL
Witherspoon
RP
McDonald
GB
Schubert
MM
Atkinson
K
Thomas
ED
Chronic graft versus host disease in 52 patients. Adverse natural course and successful treatment with combination immunosuppression.
Blood
57
1981
267
40
Pepe
M
Longton
G
Pettinger
M
Moro
M
Fisher
L
Storb
R
Summarizing data on survival, relapse and chronic graft-versus-host disease after bone marrow transplantation: motivation for and description of new methods.
Br J Haematol
83
1993
602
41
Baron
S
Tyring
S
Fleischmann
W
Coppenhaver
DH
Niesel
DW
Klimpel
GR
Stanton
GJ
Hughes
TK
The interferons. Mechanism of action and clinical applications.
JAMA
266
1991
1375
42
Schmidt
H
Kellermann-Kegreiss
E
Steiert
I
Walz
J
Zinser
R
Muller
CA
Differential regulation of human leukocyte antigen class I genes by interferon in vivo and in vitro.
J Immunother
14
1993
169
43
Quesada
JR
Talpaz
M
Rios
A
Kurzrock
R
Gutterman
JU
Clinical toxicity of interferons in cancer patients: a review.
J Clin Oncol
4
1986
234
44
(suppl 1)
Hansen
J
Petersdorf
E
Yoon Choo
S
Martin
PJ
Anasetti
C
Marrow transplantation from HLA partially matched relatives and unrelated donors.
Bone Marrow Transplant
15
1995
128