Originally published as JCO Early Release 10.1200/JCO.2006.09.3260 on May 7 2007

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Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Silvia Montoto, Andrew John Davies, Janet Matthews, Maria Calaminici, Andrew J. Norton, John Amess, Sarah Vinnicombe, Rachel Waters, Ama Z.S. Rohatiner, T. Andrew Lister

From the Cancer Research UK Medical Oncology Unit, Barts and the London, Queen Mary's School of Medicine and Dentistry; Departments of Cellular Pathology, Haematology, and Radiology, Barts and the London NHS Trust, London; and the Cancer Research UK Medical Statistics Group, University of Oxford, Oxford, United Kingdom

Address reprint requests to Silvia Montoto, MD, Institute of Cancer, Centre for Medical Oncology, St Bartholomew's Hospital, 45 Little Britain, London EC1A 7BE, United Kingdom; e-mail: silvia.montoto{at}cancer.org.uk

	ABSTRACT

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Purpose: To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL).

Patients and Methods: From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew's Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%.

Results: The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed.

Conclusion: Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.

	INTRODUCTION

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The clinical course of follicular lymphoma (FL) is characteristically that of a progressing and regressing disease, apart from a group of patients with very early-stage disease treated with irradiation and even fewer who may be cured with allogeneic transplant. Responsiveness to therapy and duration of response both decline with repeated treatments, particularly after documented transformation, with death generally resulting from the disease.^1,2

The reported incidence of histologic transformation (HT) ranges from 16% to 60% depending on length of follow-up and rebiopsy/autopsy policy.^1,3-5 Also critical is the definition of transformation, which, in addition to being diagnosed on cytology alone or clinical data,^6-8 has in the past included progression (grade 1/2 to grade 3 FL) or development of a diffuse pattern, with persistence of follicular morphology. All of these have sometimes been combined with frank transformation to diffuse large B-cell lymphoma (DLBCL) or, rarely, Burkitt's lymphoma.

The purpose of this study was to document the frequency of HT to DLBCL and presenting features, both at diagnosis and at progression, which predict for it, in a large series of patients with FL and a high repeat biopsy rate at progression, using a strict definition of HT, always based on a biopsy and restricted to patients with a biopsy demonstrating features diagnostic of DLBCL.

	PATIENTS AND METHODS

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Patient Population
From January 1972 to December 1999, 325 patients with FL were treated at St Bartholomew's Hospital (London, United Kingdom; Table 1). Duration of symptoms and date of diagnosis was known in all cases. Histologic diagnosis was reviewed in all cases by A.S.,⁹ A.N., or M.C. Patients with grade 3b FL or composite lymphoma were excluded. Staging included clinical examination, bone marrow (BM) biopsy, and hilar tomography with lymphangiography until 1976, and, subsequently, computed tomography scanning.^2,9 For the purpose of classifying the patients according to the Follicular Lymphoma International Prognostic Index (FLIPI)¹⁰ and the International Prognostic Index (IPI),¹¹ hydroxybutyrate dehydrogenase (HBD; until 1989) and lactate dehydrogenase (LDH; since 1989) have been assumed to have equivalent significance.^12,13

Management at Recurrence/Progression
Patients were fully restaged at progression, including lymph node (LN) and BM biopsy whenever possible. An image-guided core-needle biopsy was performed in the absence of peripheral lymphadenopathies or when the main site of progression was the retroperitoneum or within the viscera.¹⁴ Treatment was administered according to protocols used at that time, including myeloablative therapy with stem-cell rescue¹⁵ (57 patients) and other investigational protocols.^16,17 Patients in whom the response was considered suboptimal ([poor partial response] [poor PR]⁹) at a given event almost always received further treatment until achievement of best response (complete or maximal response).

Definition of Transformation
The diagnosis of transformation was always based on histology. Transformation was defined by the histological features of DLBCL as opposed to cytologic progression with an increase in the proportion of large cells (from grade 1/2 to grade 3 FL).

Assessment of Response
Response was categorized according to local criteria used at the time.^2,9 Complete response (CR) was defined as in the consensus statement throughout¹⁸; [good partial remission] as the presence of minimal residual abnormalities on radiographic investigation, BM examination or clinical suspicion of splenomegaly and [poor PR] is comparable to PR. For the purpose of this analysis, CR and good partial remission were grouped together. Stable disease after treatment, progression less than 3 months after finishing treatment, and treatment-related deaths were considered treatment failures (no response [NR]).

Definitions
Performance status was retrospectively documented and FLIPI retrospectively assigned on the basis of examination of patients’ records, including computed tomography (CT) scan report review. Hence, it was not possible to accurately record the FLIPI because of missing observation before 1976. Patients were assigned a performance status of 0 if, according to their medical records, they were ambulatory and asymptomatic and 1 if they had minor symptoms and were ambulatory, whereas it was 2 to 4 for the remainder.

An [episode] of disease was defined as recurrence (after CR) or progression (in patients in PR) after achievement of best response –irrespective of the number of lines of treatment needed. For the sake of simplicity, [recurrence] is used to encompass both. For a given episode, transformation was considered at the time of recurrence (hereafter, [at recurrence]), at progression after expectant management ([after expectant management]), or at progression in NR patients ([at progression]).

Overall survival (OS) was measured from date of diagnosis to date of last follow-up or death.¹⁸ Time from first recurrence (in CR patients) or first progression (in PR patients) to death was analyzed as survival from progression, in an attempt to identify prognostic factors that influence outcome at the time of first recurrence/progression. Time to transformation was taken from diagnosis to date of biopsy confirming transformation, with death treated as a censoring event in those in whom HT did not occur. Survival from transformation was the time from transformation to death.

Statistical Analysis
Survival analysis was performed by the Kaplan-Meier¹⁹ method using the log-rank statistic²⁰ to test for significant associations where appropriate. Cox²¹ regression was used with stepwise selection to build a multivariate model for survival times; where incomplete data made it impractical to include all variables, only those with P < .2 from log-rank tests were included. Models were fitted twice, once using the FLIPI and IPI categories and once using the individual risk factors instead. Risk factors were treated as binary variables throughout the analysis; transformation was treated as a time-varying covariate in survival models. For multivariate modeling of survival from progression, patients experiencing transformation before first recurrence were excluded. Risk factors from either index were tested for association with transformation at progression using the ² test, or Fisher's exact test where expected cell frequencies fell below 5. No adjustments were made for multiple testing, although it is acknowledged that some spurious relationships will be found because of the number of tests performed. Median follow-up was calculated for patients alive at last follow-up only.

	RESULTS

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Response to Treatment and Duration of First Response
Response after first therapy in 301 assessable patients is detailed in Table 1. The median follow-up was 15 years. One hundred eighty-six patients developed recurrent lymphoma, the median duration of first response being 2.7 years (range, 0.1 to 31 years). Response rates at first, second, third, fourth, and fifth recurrence were 70%, 59%, 63%, 45%, and 50%, respectively.

Overall Survival, Survival From Progression, and Causes of Death
Two hundred twenty-eight patients (70%) have died. The median OS was 9.5 years (range, 0.07 to 34 years). In 104 cases (46%), death was caused by disease progression; in 38 (17%), by treatment-related complications (including deaths related to symptomatic treatment to those with active disease late in the illness); in 31 (14%), by a second malignancy; and in 37 (16%), by causes not attributed to FL or therapy. Eighteen patients (8%) died as a result of unknown causes, progression not having been documented. The median survival from progression in 186 patients who had progression after CR or PR after first treatment was 4.8 years (range, 0 to 30.5 years).

Biopsy Rate
Sixty-four percent of the patients had a repeat LN biopsy at the time of first recurrence (119 of 186) and 146 (78%) a BM biopsy. A further 17 of 186 had an LN biopsy when the disease progressed after expectant management, with a total of 73% of patients with a repeat biopsy at first recurrence. The corresponding figures for second, third, and fourth recurrence were 77%, 64%, and 57%, respectively, giving a total biopsy rate of 70%. Clinical characteristics of patients with progression are shown in Table 2, according to whether biopsy was performed and, if so, the result. Survival from progression for patients who had a biopsy that showed recurrent FL at that time was similar to that of patients who did not have a repeat biopsy.

Risk of Transformation
The risk of transformation by 5, 10, and 15 years was 17% (95% CI, 13% to 22%), 28% (95% CI, 23% to 34%), and 37% (95% CI, 30% to 44%), respectively. HT was not observed after 16.2 years of follow-up, the rate of transformation remaining at 39% from that point onward (Fig 1).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative incidence of histologic transformation in 325 patients with follicular lymphoma.

Outcome for Patients With HT
Twelve of 88 patients in whom HT was documented are alive, whereas 76 patients died, 38 (43%) at the episode of HT. Eighty-one patients were treated with intent to prolong survival, the response rate being 61%. Two patients died less than 1 month after HT without being treated, and five received palliative treatment. Treatment administered for HT and response is shown in Table 1. Eight patients (2 CR, 6 PR) received high-dose therapy (HDT) with stem-cell rescue as consolidation of remission. Five are alive (four in CR or PR after HDT without further progression; one is being treated with expectant management after recurrence after HDT), with three developing progression and dying (because of a secondary malignancy in one case). Thirty-six of 48 patients who responded to treatment for HT had further recurrences at a median of 0.5 years (range, 0.08 to 13 years), 32 dying with progression.

The median survival from transformation was 1.2 years (range, 0.1 to 25 years; Fig 2). Table 3 shows the variables that were predictive for shorter survival from transformation. Patients in CR after salvage therapy had a longer survival than did the remainder (median, 5.6 v 1 and 0.4 years for patients in PR and NR, respectively). Given the number of patients with missing data (especially regarding LDH/HBD), it was not possible to obtain a reliable multivariate model for survival from transformation.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Survival from transformation in 88 patients with histologic transformation.

Survival From First Recurrence
Survival from progression was shorter among patients in whom transformation was diagnosed at first or subsequent recurrences in comparison with that of patients in whom HT was not diagnosed (median, 3.4 v 5.6 years). The variables that predicted for survival from progression on univariate analysis were HT (P < .0001), LDH/HBD level (P = .004), age (P < .0001), performance status (P < .0001), IPI (P = .002), and FLIPI (P = .02). On multivariate analysis, HT retained predictive value for survival from progression (P < .0001), together with performance status (P = .0002) and age (P = .0009; Table 3).

Characteristics of 59 Patients With No Transformation After Long Follow-Up
HT was not diagnosed in 59 patients (of whom 19 have died) with a minimum follow-up of 16.2 years (median, 24 years). Clinical characteristics are described in Table 4. A total of 58 episodes of recurrence were documented, eight of them more than 16 years after diagnosis, with a biopsy (showing FL) performed in five of the eight.

	DISCUSSION

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The overall frequency and rate of transformation are entirely consistent with the published literature, minor differences almost certainly reflecting differences in biopsy and autopsy policy and the length of follow-up.^1,6,8 The intriguing finding that the risk of transformation declines very substantially after 15 years is supported by another study, albeit with shorter follow-up.⁶ The hypothesis that this reflects the existence of two distinct subtypes of FL is gaining some support from molecular studies,^22,23 but more data will be required before the case can be made with confidence.

An unexpected finding is the higher risk of transformation in patients treated with expectant management at diagnosis, contrasting with the data from Stanford University.¹ This finding, however, should be taken cautiously in that it is counterintuitive and difficult to explain. In the current study, patients not treated at diagnosis did not have prognostic features that might explain their higher risk of transformation, but the missing data precluded a good multivariate model to test for the independency of this variable. However, in the Stanford series, the proportion of patients with progression undergoing repeat biopsy was lower (45%) in patients who had been managed expectantly than those treated ab initio (65%), possibly allowing for underdiagnosis of HT in the former group, which might have accounted for the differences between the two studies. A recent paper suggested a reduced risk of HT for patients treated with an anthracycline-based chemotherapy at diagnosis.²⁴ The small proportion of patients receiving such a first-line treatment in this series prevented the analysis of its impact in the risk of HT.

The grave prognostic significance of HT is clear, both from the very poor outlook for the majority of the patients in whom it occurs, and the global comparison of survival of those in whom it was diagnosed with those in whom it did not occur. The latter has been previously reported in some series,^5,8 although questioned in others with a shorter follow-up.^3,25 These findings and the correlation between the risk of transformation and the IPI and FLIPI scores at diagnosis suggest strongly that both scores are actually predicting for the transformation event, for which treatment is currently most unsatisfactory.

The issue of the clinical features that accompany transformation at the time of a particular event was addressed in the current study by analysis of outcome at first recurrence (not possible at later events because of small numbers). Some studies have in the past reported clinical factors^2,26-28 that predict for a shorter survival at the time of recurrence, but only two included HT in the analysis, and none demonstrated an impact of HT on survival from progression, possibly because of the small number of patients with HT.^2,28 It is clear from the multivariate analysis in the present study, including both histology (transformation or not) and clinical features, particularly performance score and age, that both are independently highly significant. It might therefore be argued that therapeutic decisions based on the clinical situation might obviate the need for a biopsy, undoubtedly good for the patient and for health care economics. However, although there is a close correlation between clinical evidence of a change in pace of the disease and HT, it is not absolute. Thus, the performance score was satisfactory in two thirds of patients and the LDH normal in one third of patients at the time of HT. As therapeutic decisions are based on both clinical and pathologic data, it seems reasonable to conclude that it is advisable to have both.

The observations discussed herein and conclusions of their relevance are based on data generated during an era before the finding that chemoimmunotherapy, both at the initial therapy of FL and at first progression has altered progression-free and overall survival.^29-31 The results of vaccine therapy are awaited. It remains to be demonstrated whether these new therapeutic interventions will alter the clinical course of the disease by averting the risk of transformation. Time will tell. Meanwhile, it behooves us to gain the maximum information available to manage FL optimally.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Silvia Montoto, Andrew John Davies, T. Andrew Lister

Provision of study materials or patients: Maria Calaminici, Andrew J. Norton, Sarah Vinnicombe, Ama Z.S. Rohatiner, T. Andrew Lister

Collection and assembly of data: Silvia Montoto, Andrew John Davies, Janet Matthews, Maria Calaminici, Andrew J. Norton, Ama Z.S. Rohatiner

Data analysis and interpretation: Silvia Montoto, Andrew John Davies, Janet Matthews, Rachel Waters

Manuscript writing: Silvia Montoto, Andrew John Davies, Ama Z.S. Rohatiner, T. Andrew Lister

Final approval of manuscript: Silvia Montoto, Andrew John Davies, Janet Matthews, Maria Calaminici, Andrew J. Norton, John Amess, Sarah Vinnicombe, Rachel Waters, Ama Z.S. Rohatiner, T. Andrew Lister

Other: Maria Calaminici [Histologic diagnosis], Andrew J. Norton [Histologic diagnosis], John Amess [Responsibility for the hematological laboratory support of the patients reported in this study]

	Appendix

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	ACKNOWLEDGMENTS

 
We thank the patients and the medical and nursing staff of the Medical Oncology Unit; and J. Connors, MD, for his helpful comments on the manuscript. This work was supported by Cancer Research UK and by the family of Olivia Walduck (S.M.).

	NOTES

 
published online ahead of print at www.jco.org on May 7, 2007.

Presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted September 26, 2006; accepted March 19, 2007.

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