Conditioning Regimens

A prognostic model for prolonged event-free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin's disease

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Summary:

There are several prognostic models for Hodgkin's disease (HD) patients, but none evaluating patient characteristics at time of blood and marrow transplantation (BMT). We developed a prognostic model for event-free survival (EFS) post-BMT based on HD patient characteristics measured at the time of autologous (auto) or allogeneic (allo) BMT. Between 1/1991 and 12/2001, 64 relapsed or refractory HD patients received an auto (n=46) or allo (n=18) BMT. A multivariate prognostic model was developed measuring time to relapse, progression or death. Median follow-up was 51.7 months; median EFS for auto and allo BMT was 36 and 3 months, respectively (P=0.001). Significant multivariate predictors of shorter EFS were chemotherapy-resistant disease, KPS <90 and 3 chemotherapy regimens pre-BMT. Patients with two to three adverse factors had significantly shorter EFS at 2 years (58 vs 11% in auto; 38 vs 0% in allo BMT patients). Despite a selection bias favoring auto BMT, the model was valid in both auto and allo BMT groups. We were able to differentiate patients at high vs low risk for adverse outcomes post-BMT. This prognostic model may prove useful in predicting patient outcomes and identifying high-risk patients for novel treatment strategies. Validation of this model in a larger cohort of patients is warranted.

Main

Relapsed or refractory Hodgkin's disease (HD) patients have a poor prognosis with standard salvage chemotherapy, yielding a cure rate of 20% or less.1, 2, 3, 4 High-dose therapy followed by autologous blood or marrow transplantation (auto BMT) has become a standard treatment for patients refractory to or relapsing after induction therapy.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 The role of allogeneic BMT (allo BMT) in relapsed or refractory HD has not been fully determined,18, 19, 20, 21, 22, 23, 24, 25, 26 although the existence of a graft-versus-lymphoma (GVL) effect has been suggested.20, 21, 22, 23, 24, 25

Prognostic models based on presentation features in HD patients have been proposed for predicting the outcome.26, 27, 28, 29, 30, 31, 32, 33, 34, 35 These models have proven quite useful for predicting the outcome in newly diagnosed HD patients, however, not all HD patients have these prognostic factors evaluated at diagnosis, which can be difficult to obtain in patients referred for BMT often years after diagnosis. There have been three prognostic scoring systems reported in the last 3 years for auto BMT patients. Stiff et al36 developed a prognostic score based on 72 patients treated from 1990 to 1995 in the SWOG 9011 trial of cyclophosphamide, etoposide and carmustine vs cyclophosphamide, etoposide and total body irradiation as conditioning for auto BMT. Significant multivariate predictors of overall survival (OS) were >2 prior regimens, relapse in a previously radiated field and extranodal disease. Patients with two to three adverse factors had a significantly inferior OS compared to those with zero to one factor (38 vs 60%, P=0.05).

Moskowitz et al37 proposed a two-step risk-adapted treatment strategy for 65 relapsed and refractory HD patients enrolled from 1994 to 1998, of whom 57 underwent auto BMT at the Memorial Sloan-Kettering Cancer Center (MSKCC) based on a prognostic model of factors evaluated at the initiation of salvage chemotherapy. The three prognostic factors identified by the MSKCC model were B symptoms at the time of salvage chemotherapy, extranodal involvement at the time of salvage chemotherapy and CR duration <1 year or primary refractory disease. Patients with zero to one adverse factors had significantly superior EFS (83%) compared to those with two (27%) or three (10%) adverse factors (P<0.001).

Josting et al38 developed a prognostic score based on the relapse characteristics of 422 eligible relapsed HD patients from the German Hodgkin's Lymphoma Study Group (GHSG) treated between 1988 and 1998 with salvage chemotherapy plus autologous transplant (n=140) vs salvage chemotherapy alone (n=228) vs salvage radiation therapy alone (n=54). Significant multivariate adverse predictors of OS and freedom from second failure (FF2F) were <12 months from the end of induction therapy to relapse, stage III or IV at relapse, and hemoglobin <12 g/dl in males or <10.5 g/dl in females at relapse. Relapsed HD patients <60 years old with a KPS 90 and zero, one, two or three of these factors treated with autologous transplant had an OS of 100, 73, 55 and 50%, respectively (P<0.0001).

We intended to develop a prognostic model for event-free survival based on factors measured at the time of transplant rather than at salvage therapy that would be applicable to both autologous and allogeneic BMT patients. In the current study, we also present our validation of the MSKCC prognostic model in our auto and allo BMT patient population. The model presented herein may allow for more rapid validation using autologous and allogeneic transplant registry data.

Patients and methods

Patients

A total of 64 patients with relapsed or refractory HD underwent auto and/or allo BMT at the Roswell Park Cancer Institute between January 1991 and December 2001. Standard eligibility criteria included age 60 for allo BMT, 70 for auto BMT and adequate cardiac, pulmonary, hepatic and renal function. A total of 68 BMT procedures were performed (18 allo BMT and 50 auto BMT). Four patients received two transplants at our center during this time period, all of whom had an allo BMT after a failed auto BMT. To avoid violating the statistical assumption of independent samples, only one transplant per patient (the second BMT) was included in the analysis; therefore, four first auto BMTs were excluded from the analysis, yielding 64 transplants on 64 patients. Of the 64 patients, 11 had prior transplants (see Table 1), seven of which were performed at other centers. Only transplants performed at RPCI were included and analyzed in this study. A sensitivity analysis of the multivariate model was conducted, in which the study population was restricted to the first BMT patients only (see results section). All allo BMT patients had HLA-matched (at A, B and DRB1 antigens) related (n=16) or unrelated (n=2) donors. All patients received myeloablative conditioning regimens. All patients were treated on multiple Institutional Review Board approved protocols and signed informed consent. All individual patient data presented in this report have been de-identified.

Table 1 Patient characteristics

Treatment

Four patients did not receive any salvage therapy prior to BMT. All others were treated with etoposide-, or platinum-based salvage chemotherapy regimens and/or radiation therapy at the discretion of the referring physician. Patients were prioritized to receive an auto BMT and only received an allo BMT after a failed auto BMT or in the setting of a high risk of relapse at the discretion of the transplant team and contingent on the availability of a suitable donor.

Myeloablative conditioning regimens for patients undergoing allo BMT included thiotepa 450 mg/m2 × 2 days and carboplatin 400 mg/m2 × 4 days (TtCp) (n=12),39 thiotepa 300 mg/m2 × 2 days and 1000-1200 cGy TBI over 3 days (TtTBI) (n=3),39 busulfan 1 mg/kg every 6 h for 16 doses and cyclophosphamide 50 mg/kg × 2 days (BuCy) (n=1),40 etoposide 1800 mg/m2 × 1 day, cyclophosphamide 60 mg/kg × 3 days and TBI 1000 cGy in 5 fractions over 3 days (n=1),41 or fludarabine 25 mg/m2 × 5 days and melphalan 70 mg/m2 × 2 days (n=1).42 Auto BMT patients received etoposide 2400 mg/m2 × 1 day, cyclophosphamide 1800 mg/m2 × 4 days, and BCNU 600 mg/m2 × 1 day (VCB) (n=28),43 TtCp with the above schedule (n=10), TtTBI with the above schedule (n=4), thiotepa 300 mg/m2 × 3 days and cyclophosphamide 60 mg/kg × 3 days (n=2)39 or BuCy as busulfan 1 mg/kg every 6 h for 16 doses and cyclophosphamide 50 mg/kg × 2 or 4 days (n=2).40, 44 Conditioning regimen-related toxicity (RRT) was graded according to published criteria.45

Graft-versus-host disease (GVHD) prophylaxis for patients undergoing allo BMT consisted of combinations of cyclosporine (CSA) and methotrexate (n=4),46 CSA, methotrexate and methylprednisone (MP) (n=1),47 CSA and MP (n=3),48 or CSA, MP and OKT3 (n=10)49 based on the institutional protocols available at the time of BMT. CSA was switched to FK506 in three patients due to CSA toxicity. Acute GVHD was defined according to standard criteria.50, 51

Statistical considerations

The primary outcome was event-free survival (EFS) after transplant. Progression-free survival (PFS), overall survival (OS) and regimen-related toxicity (RRT) were analyzed as secondary end points. Analysis of variance (ANOVA) of independent samples was performed to compare means and the χ2 test (with Fisher's exact test, where applicable) was used to compare proportions. Tests of significance were two-sided, with P<0.05 considered statistically significant. All analyses were conducted using the intent-to-treat principle. Kaplan–Meier survival curves were calculated from the date of hematopoietic stem cell infusion (day 0).52 Differences in survival between the prognostic factor risk groups were determined by the log rank test. Survival was last updated on 1/15/2004. For EFS, all patients are included in the analysis and were censored only at the time of last follow-up if disease progression did not occur; events were disease relapse, progression or death due to any cause. For PFS, all patients were included in the analysis and were censored at the time of last follow-up if disease progression did not occur or at death if disease progression did not occur; events were disease relapse or progression. For OS, all patients were included in the analysis and were censored at the time of last follow-up; events were death due to any cause. No patients developed a secondary malignancy post-BMT. Landmark analysis at 2 years post-BMT was performed to provide a comparison with other reported studies; only three additional events occurred between 3 and 4 years post-transplantation. The prognostic model of EFS at 2 years used a Cox proportional hazards model with forward stepwise selection conditional on the likelihood ratio with P<0.1 to enter and P>0.05 to remove each factor from the model.53

Complete response was defined as complete disappearance of all known disease with the exception of persistent scan abnormalities of unknown significance for 4 weeks; partial response was defined as 50% reduction in the greatest diameter of all sites of known disease and no new sites of disease development. Patients who achieved a complete or partial response to salvage therapy were categorized as chemotherapy-sensitive, those who underwent BMT directly without salvage therapy and those who received salvage therapy but were not evaluated for disease response were categorized as not evaluated (NE), all others were defined as having chemotherapy-resistant disease. Disease progression post-transplantation was defined as (1) evidence of relapse in patients with a documented complete response after BMT, (2) evidence of new areas of disease post-BMT, (3) evidence of tumor growth in areas of persistent disease post-BMT or (4) death due to disease.

For the validation of the MSKCC model, the prognostic factors evaluated were B symptoms at the time of initiation of last salvage chemotherapy before BMT, extranodal involvement (defined as involvement of a noncontiguous extranodal site, including bone marrow, or direct extension to an adjacent organ from a nodal mass) at the time of last salvage chemotherapy before BMT, and CR duration 1 year or primary refractory disease. For the four patients who did not receive salvage chemotherapy for their most recent relapse before BMT, we collected the prognostic factors at the time of last disease relapse pre-BMT.

Results

Patient characteristics

Pretransplant patient demographics and disease characteristics of the 64 patients (46 auto BMT, 18 allo BMT) treated for relapsed or refractory HD are summarized in Table 1. A significantly higher proportion of allo BMT patients had B symptoms at the time of salvage chemotherapy, more chemotherapy-resistant disease at the time of transplant, 3 standard chemotherapy regimens before transplant, received a prior transplant and received bone marrow as the source of stem cells than auto BMT patients. There was also a significantly longer time from diagnosis of HD to BMT in the allo BMT group.

Engraftment

The median times to absolute neutrophil count (ANC) 500/mm3 and platelets 20 000/mm3 were similar in both the auto and allo BMT groups (Table 2). Two auto BMT patients died before neutrophil recovery on days +14 and +26. Six auto BMT patients died before platelet recovery on days +14 to 1384 (median 236 days); two auto BMT patients never dropped platelet counts below 20 000/mm3. One auto BMT patient has not yet achieved platelet recovery on day +572. Three allo BMT patients died before achieving neutrophil recovery on days 0 to +4. In all, 11 allo BMT patients died before achieving platelet recovery on days +0 to 215 (median 59 days).

Table 2 Transplant outcomes

Toxicity and causes of death

In the allo BMT group, 10 patients (56%) developed acute GVHD, five (29%) developed chronic GVHD, four of whom were previously diagnosed with acute GVHD. There were 14 early transplant-related deaths within the first 100 days following BMT; five (11%) in the auto BMT group and eight (44%) in the allo BMT (P=0.006). Treatment-related mortality (TRM) in the allo BMT group was attributable to RRT (n=5), acute GVHD (n=2) and infection (n=1). TRM in the auto BMT group was due to RRT (n=3) and infection (n=2). Overall, 28 patients (62%) died within the follow-up period (13 auto vs 15 allo). Causes of death for the auto BMT group were underlying disease (n=8), RRT (n=3) and infection (n=2), and for the allo BMT group were RRT (n=5), infection (n=4), GVHD (n=3) and underlying disease (n=3).

Survival

A total of 24 patients (38%) were alive and in CR at the time of analysis at a median follow-up for surviving patients of 51.7 months. Of those, two (11%) were in the allo BMT and 22 (48%) were in the auto BMT group. All survival parameters, except PFS, were significantly superior in the auto BMT group (see Table 2). The median PFS has not yet been reached in either group.

The 2-year landmark univariate analysis yielded several factors at BMT that were associated with shorter EFS (Table 3). The multivariate analysis of prognostic factors found chemotherapy-resistant disease at BMT, KPS<90 at BMT, and 3 chemotherapy regimens prior to BMT as statistically significant indicators of disease progression or death (inferior EFS) at 2 years post-BMT (Table 4). Donor relation (auto vs allo), stem cell type (BM vs PB vs PB+BM), second BMT (yes vs no) and conditioning regimen (VCB vs TtCp vs other) were not prognostic for EFS. Extranodal disease at the time of salvage chemotherapy was significant in the univariate analysis; however, it was not included as a factor in the multivariate analysis, since we aimed to develop a predictive model based on pre-transplant characteristics. Two sensitivity analyses were performed on the multivariate model. Extranodal disease at the time of salvage chemotherapy was considered as a factor in the multivariate analysis; however, it failed to reach statistical significance as an independent predictor. The multivariate analysis was also repeated, while restricted to patients receiving their first BMT (second BMT patients were excluded), yielding the same predictive factors with similar relative risks.

Table 3 Univariate analysis of prognostic factors for favorable event-free survival at 2 year landmark
Table 4 Multivariate analysis of prognostic variables for favorable EFS at 2 years post BMT

Development of the prognostic model

Each significant factor in the multivariate analysis had a similar relative risk, therefore, each was given 1 point. All patients were assigned a prognostic score based on their total number of points. Table 5 shows the number of auto and allo BMT patients with 0, 1, 2 or 3 factors. EFS curves were nearly identical for zero vs one factor and two vs three factors, therefore, the patients were grouped as low risk if they had one point or less, and high risk if they had two points or more. EFS was significantly prolonged in low-risk patients compared to high-risk patients, as defined by our prognostic model when applied to both the auto and allo BMT groups (Figure 1a–c). In the auto BMT group, the 4-year EFS estimates were 58% for the low-risk and 11% for the high-risk group (P<0.0001). The 4-year EFS estimates in the allo BMT group were 38 and 0% in low-risk and high-risk groups (P=0.0022).

Table 5 Prognostic score for autologous and allogeneic BMT patients
Figure 1
figure1

(a) Event-free survival by the RPCI prognostic model, autologous and allogeneic BMT patients combined. The low-risk group has zero to one, the high-risk group has two to three risk factors listed in Table 4 (P<0.0001). The 4-year EFS±the standard error and number of patients are stated for each risk group. Tick marks are patients alive with no disease progression. (b) Event-free survival by the RPCI prognostic model, autologous BMT patients only. The low-risk group has zero to one, the high-risk group has two to three risk factors listed in Table 4 (P=0.0001). The 4-year EFS±the standard error and number of patients are stated for each risk group. Tick marks are patients alive with no disease progression. (c) Event-free survival by the RPCI prognostic model, allogeneic BMT patients only. The low-risk group has zero to one, the high-risk group has two to three risk factors listed in Table 4 (P=0.0022). The 4-year EFS±the standard error and number of patients are stated for each risk group. Tick marks are patients alive with no disease progression.

Validation of existing prognostic scoring systems

We were unable to attempt a validation of the SWOG and GHSG prognostic models due to the unavailability of one prognostic factor from each system. For the SWOG model, we were unable to obtain complete and accurate information regarding prior radiation therapy fields on the majority of patients and therefore unable to determine if the sites of relapse were in or out of a prior RT field.36 For the GHSG model, laboratory data from the time of relapse are not routinely collected from outside oncologists when a patient is referred for transplant.38 As most patients lacked one data point, we were unable to investigate the applicability of these two scoring systems to our patient population. In addition, the SWOG and GHSG scores were developed to predict OS, whereas the MSKCC model was developed to predict the same end point, EFS, as our proposed model. It was difficult but possible to obtain information on all three prognostic factors identified in the MSKCC model, therefore, we attempted to validate the MSKCC prognostic scoring system.37

The prognostic factors identified in the MSKCC model were B symptoms at the time of salvage chemotherapy, extranodal disease at time of salvage chemotherapy, and CR 1 year or primary refractory disease.37 Patients who had zero or one factor were considered group A (good risk), two factors group B (intermediate) and three factors group C (poor risk). When we applied this model to our patient population including auto and allo BMT patients, the EFS estimates were 51, 24 and 20% for groups A, B and C, respectively (P=0.0091, Figure 2), and thus predictive of outcome. The MSKCC model in only auto BMT patients yielded EFS estimates of 83, 27 and 10% in groups A, B and C, respectively (P<0.001).37 The difference in EFS estimates for groups A, B and C was not statistically significant when stratified by auto vs allo BMT (data not shown), probably due to small numbers in the prognostic groups; however, they showed the same trends.

Figure 2
figure2

Event-free survival by MSKCC prognostic groups in the RPCI patient cohort, including all patients (autologous and allogeneic). Group A has zero to one, Group B two, and Group C three of: B symptoms at the time of salvage chemotherapy, extranodal disease at the time of salvage chemotherapy, and CR <1 year or primary refractory disease (P=0.0091). The 4-year EFS±the standard error and number of patients are stated.

Discussion

There have been several effective prognostic models to predict outcomes in newly diagnosed HD patients.26, 27, 28, 29, 30, 31, 32, 33, 34, 35 A reliable prognostic system is still needed for HD patients undergoing BMT. This is particularly problematic for patients treated at BMT referral centers because pre-BMT and/or diagnostic laboratory and/or clinical information may not be available or complete. Therefore, we developed a prognostic model based on factors that are easily available at the time of transplant, identified by multivariate analysis of refractory and relapsed HD patients undergoing auto and allo BMT. We found that chemotherapy-resistant disease at BMT, poor performance status and three or more chemotherapy regimens prior to BMT were independent predictors of poor outcome. Since these three factors had very similar relative risks in the multivariate analysis (range 2.5–3.2), we gave them equal weight in the development of the predictive model.

We validated the MSKCC model in our patient cohort, which confirms a prior validation of this model in autologous BMT patients by another group.54 However, the MSKCC model did not evaluate the three prognostic factors from our model that were predictive of EFS. In contrast to the MSKCC study in which all patients received identical salvage therapy followed by auto BMT,37 our patients were more heterogeneously treated; yet our model was equally significant in both the auto and allo BMT groups (Figure 1a–c). The major limitations of this study include the relatively small sample size of the auto and allo BMT groups, and the heterogeneity of the treatment regimens within each donor group. Therefore, it is important to further validate both models in larger patient populations treated at other institutions. The RPCI model may be more rapidly tested using data from registries such as the International Bone Marrow Transplant Registry or the Autologous Blood and Marrow Transplant Registry because reported patient factors are assessed at the time of BMT rather than at the time of salvage chemotherapy. In order to validate the MKSCC model using Registry data, additional requests for data would be required from all Registry sites, whereas the RPCI model could be validated using Registry data with no further data collection.

We acknowledge that the allo BMT group was biased due to a higher rate of poor prognostic features compared to the auto BMT group. These unfavorable factors had a significant confounding effect on the EFS and OS rates and any potential benefits of allo BMT have been offset by the poor disease characteristics of these patients. However, donor type (auto vs allo) was not significant in the multivariate analysis, probably because the poor prognostic features of the allo patients exhibited a stronger effect on outcome than their type of BMT. Therefore, a risk-adapted approach derived from our model can be applied to these patients with poor prognostic features. Nonmyeloablative allo BMT following less intensive conditioning regimens has been shown to offer sustained clinical responses with less RRT and lower peri-transplant mortality rates compared to standard myeloablative conditioning regimens.55, 56, 57, 58 High-risk patients should be considered for novel salvage therapies prior to nonmyeloablative allo BMT or other alternative therapies (ie, auto BMT followed by a nonmyeloablative allo BMT), since a myeloablative allo BMT has unacceptably high toxicity and an auto BMT alone is ineffective in controlling disease in these poor prognosis patients.

The results of this study support previous reports favoring the use of auto BMT in refractory and relapsed HD patients with good prognostic features. We could not demonstrate a beneficial role for myeloablative allo BMT in this patient population which had poor survival outcomes due to severe post-transplant complications. The RPCI prognostic model predicting shorter EFS in patients with chemotherapy-resistant disease, poor performance status, and three or more chemotherapy regimens prior to BMT will require validation with larger patient numbers.

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Acknowledgements

We thank Dr James Kepner, Chair of Biostatistics, Roswell Park Cancer Institute, for reviewing and commenting on the manuscript, the clinical services, data managers and transplant co-ordinators for help with data collection, and Ms Dorothy Macchio for editorial assistance.

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Correspondence to T Hahn.

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Hahn, T., Benekli, M., Wong, C. et al. A prognostic model for prolonged event-free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin's disease. Bone Marrow Transplant 35, 557–566 (2005) doi:10.1038/sj.bmt.1704789

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Keywords

  • prognostic model
  • Hodgkin's disease
  • autologous BMT
  • allogeneic BMT

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