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Patterns of Outcome Following Recurrence After Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma

From the ICRF Medical Oncology Unit, Department of Medical Oncology, Departments of Histopathology and Hematology, St. Bartholomew's Hospital, London; and ICRF Medical Statistics Group, Institute of Health Sciences, Oxford, England.

Address reprint requests to J. Apostolidis, MD, ICRF Medical Oncology Unit, Department of Medical Oncology, St. Bartholomew's Hospital, 45 Little Britain, West Smithfield, London EC1A 7BE, England; Email j.apostolidis{at}icrf.icnet.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess the patterns of recurrence, management, and survival following recurrence after myeloablative therapy with autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma (FL).

PATIENTS AND METHODS: Between June 1985 and October 1995, 99 patients with FL received cyclophosphamide and total-body irradiation with ABMT as consolidation of second or subsequent remission.

RESULTS: Median length of follow-up was 5 years, and 33 patients developed recurrent lymphoma a median of 14 months after ABMT. In 26 patients, the recurrence was overt; in seven, it was detected on surveillance investigation. Twenty-six patients presented with recurrence at previous sites of disease. Twenty-two patients (67%) had FL at the time of recurrence; in 11 (33%), there was evidence of transformation to diffuse large B-cell lymphoma. Eight patients were managed expectantly; five were alive 21 to 53 months later. Twenty-five patients have required treatment to date; eight remained alive 6 months to 10 years later, and five were in remission. The Kaplan-Meier estimate of patients alive 5 years after recurrence is 45% (95% confidence interval, 27% to 62%). In univariate and multivariate analyses, survival after recurrence and overall survival after diagnosis were similar to those of a historical control group who received conventional treatment, before the introduction of myeloablative therapy (adjusted hazard ratio [HR], 1.56, P = .3, and HR, 1.34, P = .4, respectively).

CONCLUSION: The survival pattern of patients with FL following recurrence after myeloablative therapy and ABMT suggests that this treatment does not compromise outcome in patients in whom it fails, reflecting the survival pattern of the disease when treated conventionally.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FOLLICULAR LYMPHOMA (FL), frequently referred to as "indolent" because of a relatively long natural history, remains a challenge for the clinician.¹ Although the pattern of survival is dominated by repeated response to treatment, death occurs either when resistance develops, the histology remaining unchanged, or when transformation to diffuse large B-cell (DLBC) lymphoma supervenes.^2-7

Recently, the use of myeloablative therapy with autologous hematopoietic stem-cell support has been evaluated in patients with FL, especially those with recurrent disease.^8-13 However, there has generally been a reluctance to use such therapy for FL because patients with this disease tend to be older, and the disease has a long natural history and usually involves the bone marrow. Furthermore conventional approaches have not altered the disease's natural course. In the experience of St. Bartholomew's Hospital (SBH) and the Dana Farber Cancer Institute, Boston, MA, myeloablative therapy prolongs remission duration.¹⁴ Although these results are promising, long follow-up will be required if any survival advantage for this approach is to be observed. Furthermore, an increasing concern in this experimental setting is the risk of developing secondary myelodysplasia (S-MDS), which must be considered seriously when potential advantages are being weighed against possible risks of the treatment.^15,16

However, the major problem after myeloablative therapy remains recurrence, with or without transformation to DLBC lymphoma; in several large series, failure-free survival ranged from 18% to 58%.^8-13 There are relatively few reports regarding outcome following recurrence after high-dose treatment.¹⁷ This analysis was therefore undertaken to review the patterns of recurrence, management, and survival in such patients treated at SBH over a 10-year period.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Original Patient Population and Treatment
Between June 1985 and October 1995, 99 patients with FL (and no history of transformation) in second or subsequent complete remission (CR) or good partial remission (GPR) (as defined for the purpose of this study⁹) received myeloablative therapy comprising cyclophosphamide (CY) 60 mg/kg x 2 days and fractionated total-body irradiation (TBI) 200 cGy bid x 3 days with autologous bone marrow transplantation (ABMT). The bone marrow from the first 74 patients was treated in vitro with the monoclonal antibody (mAb) anti-CD20 and baby rabbit complement as previously described.⁹ In the subsequent 25 patients, four mAbs (anti-CD10, anti-CD19, anti-CD20, and anti-B5) and complement were used as previously described by Gribben et al.¹⁸ All patients were subsequently seen in follow-up, monthly for the first 3 months and quarterly thereafter. Surveillance computed tomographic (CT) scans of the chest, abdomen, and pelvis and unilateral trephine biopsies were performed annually.

Analysis of Outcome
An investigation was undertaken of survival patterns, in patients who received CY + TBI + ABMT during second or subsequent remission and who later relapsed. In these patients, the impact of several factors on survival following recurrence after CY + TBI + ABMT was assessed. The factors investigated were number of prior treatment episodes, remission status (CR v GPR) at time of ABMT, interval from diagnosis to ABMT, clinical versus surveillance-detected recurrence, and transformation to DLBC lymphoma. For overall survival, the following factors were also assessed: age, stage, bulky disease and extranodal disease at diagnosis, and number of treatment episodes required to achieve first remission.

Survival of patients who received CY + TBI + ABMT during second remission but subsequently relapsed was also compared with that of a historical control group treated with conventional treatment. These patients would have been candidates for CY + TBI + ABMT during second remission had it been available at that time.

Historical Control Group
In a randomized study undertaken before 1985, patients with FL received chlorambucil (CB) or cyclophosphamide, vincristine, and prednisolone as first-line treatment. There was no difference in outcome.¹⁹ Subsequent newly diagnosed patients were therefore treated with CB. A second randomized comparison between CB and CB plus interferon did not show that there was any advantage to addition of interferon,²⁰ and therefore treatment again was reverted to CB. The CY + TBI + ABMT therapy was introduced in 1985, and since then, all patients less than 60 years of age in whom second or subsequent remission was achieved have been considered for myeloablative therapy.

Thirty consecutive patients less than 60 years of age, with FL (and no history of transformation) treated at SBH before the introduction of myeloablative therapy, made up a control group for the study group, 22 patients receiving CY + TBI + ABMT during second CR or GPR who subsequently relapsed. In all control cases, a second CR or GPR had been achieved with CB or cyclophosphamide, vincristine, and prednisolone. Subsequent recurrence was treated with conventional treatment. To test for differences between the patients in the study group and their historical counterparts, the following factors were compared: age, stage, bulky disease and extranodal disease at diagnosis; number of treatment episodes required to achieve first remission; duration of first remission; and time from diagnosis to achievement of second remission. The two groups were similar with respect to these potential prognostic factors (Table 1).

Definitions
A patient was considered to be in complete remission if he or she was in normal health with no abnormal physical findings; normal CT scans of the chest, abdomen, and pelvis; and bilateral iliac crest bone marrow aspirates and biopsy specimens showing neither morphologic nor phenotypic evidence of infiltration.

A patient was considered to have achieved good partial remission if he or she was in normal health with clinical or radiologic evidence of residual lymphadenopathy (lymph nodes up to 2 cm in diameter) at no more than three sites or equivocal CT abnormalities and/or bone marrow infiltration of up to 20% on a bone marrow biopsy.

A patient was considered in partial remission (PR) if he or she had a greater than 50% reduction in all measurable disease, as demonstrated by physical examination, CT scans, and bone marrow biopsy.

Recurrence was defined as biopsy-proven recurrence of FL or transformation to DLBC lymphoma. In two patients in whom biopsy (open or tru-cut needle²¹) was not possible, radiologic evidence of progression was considered evidence of progressive disease.

The phrase "episode of treatment" refers to one type of treatment, not to one cycle (eg, chlorambucil; cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]; or fludarabine).

Statistical Methods
Comparisons between the study group and their historical control counterparts were performed using the ² test for categoric data and otherwise using the Mann-Whitney U test. Survival was defined as the time from recurrence after CY + TBI + ABMT to the day of last follow-up or date of death from any cause. Overall survival was defined as the time from diagnosis to the day of last follow-up or date of death from any cause. Survival curves were estimated using the product-limit method of Kaplan and Meier,²² with confidence intervals (CIs) calculated using Greenwood's formula. Comparison of survival curves was done using the log-rank test. Factors were examined using a Cox proportional hazards regression model,²³ to identify prognostic variables for survival and overall survival.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Recurrence After ABMT
Median length of follow-up was 5 years (range, 1 month to 12 years). Thirty-three (33%) of 99 patients developed recurrent lymphoma. The pretransplant characteristics and presenting features at the time of recurrence are given in Tables 2 and 3, respectively. In 26 patients, the recurrence was overt, with patients presenting with symptoms or clinical findings related to the disease. In seven patients, recurrence was detected through surveillance, ie, the patient was asymptomatic and the recurrence was detected on an annual surveillance trephine biopsy, annual CT scan, or both.

Twenty-six of the 33 patients presented with recurrence at a previous site of disease, in four patients recurrence was detected at new sites, and in three patients recurrence was detected at both previous and new sites. Bone marrow biopsies were performed in all patients when recurrence was detected. Involved lymph node or other soft tissue biopsy specimens were obtained from 28 (93%) of 30 patients in whom recurrence was confined to sites other than the bone marrow. Twenty-two (67%) of the 33 patients were found to have FL at the time of recurrence; in 11 patients (33%) there was evidence of transformation to DLBC lymphoma.

Management at Recurrence
Patients managed expectantly. Thirteen patients were managed expectantly; five of these 13 patients progressed between 5 and 37 months and had treatment (see next section). Three of the remaining eight patients (one with poor graft function, one with recurrent episodes of infection related to severe immunoparesis, and one with low performance status) were not considered eligible for treatment and died from disease 3 to 45 months later. Five patients (one with clinical recurrence and four with recurrence detected through surveillance) did not require treatment; four patients (three with surveillance-detected recurrence) were alive and well with stable disease 21 to 45 months later. One patient with recurrence at a single site remained in CR 4 years after excision biopsy of the involved lymph node.

Patients treated for recurrence. Twenty-five patients received treatment at some point. Nineteen responded (six achieved CR and 13 achieved PR), five patients' disease progressed despite treatment, and there was one treatment-related death after treatment with CHOP.

One of the six patients in whom CR was achieved remained in continuous complete remission more than 8 years after treatment; the remaining five developed further recurrence and received treatment. One remained in CR at 6 years, one remained in PR at 10 years, and three died from disease between 3 and 5 years.

Two of the 13 patients in whom a PR was achieved maintained this state at 16 months (with concurrent myelodysplasia) and 6 years. Disease in the remaining 11 patients progressed 3 to 45 months later, and these patients required further treatment. In four of these 11 patients, a further PR was achieved; three remained alive with disease 16 to 33 months later and one died after 5 years, of myelodysplasia. Disease progressed in the remaining seven patients who eventually died from disease, at 4 months to 5 years.

Three of the five patients whose disease progressed despite treatment died from disease 2 to 5 months later; PR was achieved in the other two after alternative treatment, but they eventually died from toxicity related to CHOP, 6 months and 5 years later, after further progression.

Patterns of Outcome According to Histology
At the time of original diagnosis, all patients had follicular, predominantly small cleaved lymphoma (Working Formulation²⁴ [WF]) or follicular, follicle center lymphoma, grade I (International Lymphoma Study Group classification²⁵). A biopsy-proven recurrence was documented in 31 (94%) of 33 patients at the time of recurrence, whereas in two patients with a surveillance-detected recurrence, radiologic progression was considered evidence of progressive disease. In the latter two patients, histologic evidence was subsequently obtained at the time of clinical progression.

At the time of recurrence, in 22 of 33 patients, histology remained follicular, but in 11 patients there was evidence of transformation to DLBC lymphoma (WF G in 10 patients and H in one patient). In two of 22 patients with follicular histology, there was transformation to an intermediate phase of follicular growth, with increased numbers of blast cells (follicular, follicle center lymphoma, grade III). In four of these 22 patients (including the two patients with follicular, follicle center lymphoma, grade III), there was subsequent transformation to diffuse large-cell lymphoma.

Follicular histology at recurrence.
Eighteen of the 22 patients with follicular histology never had evidence of transformation after recurrence. Eleven remained alive; seven died (six because of disease progression, at 3 months to 5 years; and one from myelodysplasia, at 64 months, while in PR). The Kaplan-Meier estimate of the percentage of patients alive 5 years after recurrence for this patient population is 59% (95% CI, 35% to 77%) (Fig 1).

View larger version (11K): [in this window] [in a new window]   Fig 1. Survival after recurrence, according to histology at the time of recurrence. The P value represents the log-rank test for a difference between patients with evidence of transformation and patients without.

In four patients, there was subsequent transformation (4 to 64 months later), and three of these patients died because of disease progression, at 15 to 33 months. One patient died from sepsis 5 years after treatment with CHOP.

Transformation to diffuse large B-cell lymphoma.
In eight of the 11 patients with evidence of transformation to diffuse large-cell lymphoma, an extranodal site was involved (either at recurrence or subsequently), involving the CNS (two patients), bone (two patients), gastrointestinal mucosa (two patients), skin (one patient), and lung (one patient). Ten of the 11 patients were treated; CR was achieved in two (one remained in continuous CR 8 years later) and PR was achieved in four (one patient with immunoblastic lymphoma remained alive, after multiple episodes of treatment, 32 months after recurrence). Two of the 10 patients died from progressive disease and two died from treatment-related toxicity after receiving CHOP (one patient had concurrent myelodysplasia). The Kaplan-Meier estimate of the percentage of patients alive 5 years after recurrence for this patient population is 18% (95% CI, 3% to 44%) (Fig 1). Transformation to a DLBC lymphoma was associated with a poor prognosis (P = .01, log-rank test, Fig 1).

Survival
Overall, with a median length of follow-up from recurrence after ABMT of 35 months (range, 1 month to 10 years), 13 of 33 patients were alive at a median of 44 months (range, 6 months to 10 years), whereas 20 patients died a median of 31 months (range, 1 to 64 months) following recurrence after ABMT. The Kaplan-Meier estimate of the percentage of patients alive 5 years after recurrence is 45% (95% CI, 27% to 62%) (Fig 2).

View larger version (9K): [in this window] [in a new window]   Fig 2. Survival following recurrence after CY + TBI + ABMT.

Comparison with historical controls.
The survival after recurrence of patients who received myeloablative treatment during second CR or GPR was similar to that of equivalent patients who developed a second recurrence and received conventional therapy at SBH before the introduction of myeloblative treatment in 1985 (P = .4, log-rank test, Fig 3). In multivariate analyses, the HR for the patients treated with CY + TBI + ABMT compared with the historical controls was 1.56 (95% CI, 0.65 to 3.79; P = .3). Likewise, the overall survival for patients in whom myeloablative therapy failed was similar to that for patients who received conventional therapy at SBH before 1985 (P = .8, log-rank test, Fig 4). In multivariate analyses, the HR for the patients treated with CY + TBI + ABMT compared with the historical controls was 1.34 (95% CI, 0.64 to 2.82; P = .4).

View larger version (11K): [in this window] [in a new window]   Fig 3. Survival after second recurrence. Comparison of the study group who received CY + TBI + ABMT during second remission and the historical control group who did not. The P value represents the log-rank test for a difference between the two groups.

View larger version (11K): [in this window] [in a new window]   Fig 4. Survival after diagnosis. Comparison of the study group who received CY + TBI + ABMT during second remission and the historical control group who did not. The P value represents the log-rank test for a difference between the two groups.

Prognostic factors for survival.
In univariate analysis, factors found to have a significant adverse prognostic impact on survival following recurrence after CY + TBI + ABMT were older age at diagnosis (HR, 1.06; 95% CI, 1.00 to 1.13; P = .05), more than one treatment episode required to achieve first remission (HR, 3.72; 95% CI, 1.29 to 10.7; P = .02), and transformation to DLBC histology (HR, 3.06; 95% CI, 1.25 to 7.51; P = .01). For overall survival, in univariate analysis, both age at diagnosis (HR, 1.06; 95% CI 1.00 to 1.13; P = .04) and more than one treatment episode to achieve first remission (HR, 11.7; 95% CI 3.01 to 45.8; P < .001) were found to be significant. In a multivariate model, the same factors were all influential for both survival following recurrence after CY + TBI + ABMT and overall survival.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Because of the incurability of FL with conventional treatment, myeloablative therapy with autologous stem-cell support has been evaluated in younger patients. Preliminary data suggest an advantage in terms of remission duration⁹ and possibly an overall survival advantage.²⁶ However, a significant percentage of patients do not permanently benefit from myeloablative therapy. Recurrence and S-MDS or acute myelogenous leukemia (data not presented) have been the two major causes of treatment failure at SBH.

Patients who develop recurrent disease after myeloablative therapy for other lymphoid malignancies are generally treated with aggressive regimens, but only a small percentage become long-term survivors.¹⁷ These results show that relapse after failure of myeloablative therapy for FL does not necessarily lead to immediate death, that patients continue to respond to standard treatment, and that there are long-term survivors.

The majority of study patients presented with recurrence at previous sites of disease, which implies that myeloablative therapy failed to eradicate residual disease at these sites. The incidence of transformation in patients who developed recurrence was 45% (slightly higher than previously experienced^6,27), probably reflecting a specific policy to rebiopsy new lesions. The high incidence of extranodal disease was also in line with the observation that histologic progression is associated with tumor dissemination to extranodal sites.

Five patients remained alive without treatment 21 to 53 months after recurrence. This result indicates that patients may benefit from an expectant policy even at this point in the course of the illness. Nineteen of 25 patients responded to treatment with single agents, combination regimens, or radiotherapy. Although "fragility" of blood counts was observed in most patients receiving single agent or combination regimens, the majority tolerated treatment, with toxicity levels being acceptable. In most patients, hospitalization was avoided and quality of life was maintained.

The observation that failure of myeloablative therapy had no significant adverse impact on survival also reflects the prognostic factors for survival following recurrence after CY + TBI + ABMT and for overall survival. These factors are similar to those reported from SBH for patients with FL who received conventional treatment.^6,28 Although these factors were influential in both univariate and multivariate analyses, the latter should be treated with caution because of the small size of the patient population.

With a median length of follow-up of more than 5 years, 11% of the patients included in the original patient population developed S-MDS and six patients subsequently died. With long follow-up, it has become apparent that patients who receive myeloablative therapy for FL are at increased risk for developing S-MDS.^15,16 This significant late complication is of prime concern and has major implications for thesurvival of such patients, particularly those in whom there is no evidence of disease recurrence.²⁹

In conclusion, these results, reflecting the experience of a single center, confirm that reasonable survival is possible for patients who develop recurrent FL after myeloablative therapy. Although it has yet to be demonstrated that the improved freedom-from-recurrence pattern achieved with myeloablative chemoradiotherapy and ABMT translates into a survival advantage, these data suggest strongly that at least it does not compromise outcome in those in whom it fails.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted July 22, 1997; accepted September 23, 1998.

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