Transformed Follicular Lymphoma: Is Early Autologous Stem Cell Transplantation Indicated in the Modern Era?

Research Article

Ann Hematol Oncol. 2014;1(1): 1002.

Transformed Follicular Lymphoma: Is Early Autologous Stem Cell Transplantation Indicated in the Modern Era?

Amie E Jackson1, Jingxia Liu2, Nancy L Bartlett3 and Amanda F Cashen3*

1Division of Hematology and Medical Oncology, Mayo Clinic, USA

2Division of Biostatistics, Washington University School of Medicine, USA

3Division of Oncology, Washington University School of Medicine, USA

*Corresponding author: Amanda F Cashen, Division of Oncology, Washington University School of Medicine, 660 South Euclid Ave, Box 8007, St. Louis, MO63110, USA

Received: August 04, 2014; Accepted: August 27, 2014; Published: August 29, 2014

Abstract

Transformation of follicular lymphoma (FL) is associated with an aggressive course and rapid decline in survival. Inclusion of auto logous stem cell transplant (auto-SCT) in the initial treatment of transformed FL (tFL) has been investigated; but most studies pre-date the widespread use of rituximab. The role of early auto- SCT in the current immunotherapy era is not established. This study reports the outcomes of 105 patients with tFL treated at a single institution between 1994 and 2009. 24 patients underwent auto-SCT in first remission. Rituximab was part of the initial therapy for tFL in 86%, and 56% were chemotherapy naïve at transformation. Median follow-up was 44 months. The 2-year and 5-year overall survival (OS) rates for all patients were 78% and 65%, respectively. Survival did not differ among those patients who underwent auto-SCT (PFS 42% and OS 74% at 5 years) compared to those who did not (PFS 30% and OS 63% at 5 years). Age over 60 was associated with worse OS. In conclusion, we did not observe a benefit in PFS or OS when auto-SCT was included in the initial therapy of tFL.

Keywords: Autologous stem cell transplantation; Diffuse large B-cell lymphoma; Follicular lymphoma; Transformed lymphoma; Rituximab

Introduction

Follicular lymphoma (FL) is an indolent malignancy with a historic median overall survival (OS) of 8-12 years, and even better outcomes with modern therapies [1-4]. Transformation to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), can occur at any point in the disease course. A recent review estimates the risk of clinically significant transformation as 20%at 5 years and 30%at 10 years [5].

Prognosis following transformation is poor, with a historical median survival of less than 1 year [6-8]. Recent studies report modestly longer median OS rates, likely reflecting new treatment options, especially rituximab, as well as better supportive care [2,9- 15]. The subset of patients with transformed FL (tFL) who achieve complete remission (CR) following therapy have a prolonged median OS of40 to 81 months [2,7,10-15]. There is no reproducible prognostic index for tFL. Variably predictive factors include no prior chemotherapy [15], limited stage disease [9], low international prognostic index (IPI), and age less than 60 years [12]. The relatively small population of tFL patients has precluded prospective trials, and patients are frequently excluded both from FL and DLBCL studies. Consequently, treatment is usually based on results of de novo DLBCL trials. As with FL, the addition of rituximab improves outcomes in patients with both de novo and transformed DLBCL, and R-CHOP (rituximab, Cyclophosphamide, adriamycin, vincristine, prednisone) is now considered first-line therapy for tFL [16,17]. Because of the poor reported median survivals for patients with tFL, consolidative autologous stem cell transplant (auto-SCT) is often considered. Small cohorts, non-randomized design, and variable inclusion criteria and length of follow-up limit interpretation of reports of auto-SCT in tFL, and most of the published series do not reflect the now standard use of rituximab. Recent reports from transplant registries include larger patient cohorts, but they did not focus on initial therapy of patients diagnosed with transformed follicular lymphoma [18,19]. Consequently, the benefit and optimal timing of auto-SCT fort FL in the current immunotherapy era is not established.

We conducted a retrospective analysis of patients with tFL who were treated at our institution over a 15 year period to evaluate the impact of auto-SCT on survival. We limited our study population to patients with FL that transformed to DLBCL. Both patients with histologic transformation and those with clinical transformation who did not undergo biopsy were included, as previous reports indicate that these patients have similar survival [9]. Eighty-six percent of patients received rituximab as part of the initial therapy for tFL.

Methods

Study design

Patients treated for tFL between Jan 1, 1994 and March 31, 2009 was identified through a search of institutional clinical and surgical pathology databases. We performed a retrospective review of the medical records if patients had a pathologic diagnosis of both FL and DLBCL according to the 2008 WHO Classification definitions [20]. If biopsy results were not available at suspected transformation, we used criteria previously adopted by other authors to define clinical transformation, including a sudden rise in LDH, rapid localized nodal growth, new extra nodal sites of disease, hypocalcaemia, or the development of B symptoms [9,10]. Patients were excluded if no clinical information was available or if they were lost to follow-up prior to receiving therapy for tFL (n=7).

We grouped patients into 5 categories for analysis: 1) an initial biopsy demonstrated FL and biopsy from a later date demonstrated DLBCL; 2) initial biopsies had evidence of both FL and DLBCL; 3) initial biopsy demonstrated DLBCL, and subsequent biopsy demonstrated FL (in these cases, date of transformation was defined as date of DLBCL diagnosis); 4) DLBCL occurred in the CNS; 5) biopsy proven FL and clinical evidence of transformation as defined above.

For descriptive purposes, chemotherapy at the time of tFL diagnosis was divided into four groups: 1) CHOP; 2) R-CHOP; 3) platinum-based regimens; 4) other chemotherapy. Rituximab use, both for FL and at the time of transformation was also recorded. Response was determined using standard criteria and was documented by PET in 43 patients (41%) [21].

Statistical analysis

Progression free survival (PFS) was calculated from the date of DLBCL diagnosis (date of transformation) to the date of documented lymphoma progression, death or date the patient was last documented to be alive and free of progression. OS was calculated from the date of diagnosis of DLBCL until last contact or death. For patients who were lost to follow-up, PFS was calculated from date of last contact. Date of death, if available, was obtained from the Social Security Death Index database and used in OS calculations; otherwise date of last contact was used.

Categorical variables were compared by the chi-square or Fisher's exact test as appropriate and continuous variables were compared by the Kruskal-Wallis test. The survival probability was estimated using the Kaplan-Meier method and compared between treatment groups with the log-rank test. A Cox proportional regression model was used to evaluate factors which may be associated with OS and PFS after transformation. All statistical tests were 2-sided and statistical significance was indicated at p value <0.05. The statistical package SAS 9.3 was used for all the statistical analysis (SAS Institute Inc., Cary, NC). This study was approved by the institutional review board at Washington University in Saint Louis.

Results

Patient characteristics

Categorical variables were compared by the chi-square or Fisher's exact test as appropriate and continuous variables were compared by the Kruskal-Wallis test. The survival probability was estimated using the Kaplan-Meier method and compared between treatment groups with the log-rank test. A Cox proportional regression model was used to evaluate factors which may be associated with OS and PFS after transformation. All statistical tests were 2-sided and statistical significance was indicated at p value <0.05. The statistical package SAS 9.3 was used for all the statistical analysis (SAS Institute Inc., Cary, NC). This study was approved by the institutional review board at Washington University in Saint Louis.