INTRODUCTION — Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the clinically indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. Histologic transformation (HT) refers to the evolution of a clinically indolent NHL (eg, FL) to a clinically aggressive lymphoma (eg, diffuse large B cell lymphoma [DLBCL]) defined as those lymphomas in which survival of the untreated patient is measured in months.
HT of FL occurs at a rate of approximately 1 to 2 percent per year and is associated with rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, elevated serum lactate dehydrogenase, hypercalcemia, and often a poor prognosis.
The largest body of information dealing with HT is related to its occurrence in FL, which will be the focus of this review. HT has also been observed in other clinically indolent B cell lymphoproliferative disorders, including marginal zone lymphoma, lymphoplasmacytic lymphoma, and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). HT that occurs in patients with SLL/CLL has been termed Richter transformation. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)
The epidemiology, diagnosis, and treatment of HT in patients with FL will be discussed here. Richter transformation is discussed separately, as is the diagnosis and management of FL that has not undergone HT.
●(See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)
●(See "Initial treatment of stage I follicular lymphoma".)
●(See "Initial treatment of stage II to IV follicular lymphoma".)
EPIDEMIOLOGY
Frequency of transformation — Approximately 15 percent of patients with FL will undergo HT during their disease course at an estimated annual rate of 1 to 2 percent [1-6].
Since not all patients undergo biopsy at the time of progression, studies have tried to estimate rates of HT using both biopsy-proven cases and clinical HT. Clinical HT includes patients with a sudden rise in lactate dehydrogenase (LDH) to twice the upper limit of normal, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new unexplained systemic B symptoms (fever, weight loss, night sweats), and/or the development of hypercalcemia.
In a prospective observational series of over 600 patients with newly diagnosed FL followed for a median of five years, 60 patients (11 percent) developed clinical or biopsy-proven HT, at an estimated rate of 2 percent per year [3]. In this study, 85 percent of HT was biopsy-proven.
The frequency of HT was also analyzed in the Primary Rituximab and Maintenance (PRIMA) study, which included over 1000 patients with previously untreated FL who had demonstrated an initial response to chemoimmunotherapy with R-CHOP (75 percent), R-CVP (22 percent), or R-FCM (3 percent) [4]. After a median follow-up of six years, 463 patients had progressive disease. Among the 194 patients who had histologic confirmation of relapse, 40 patients (21 percent) demonstrated HT and 154 patients (79 percent) had untransformed FL. Median time to recurrence was shorter in those with transformed FL (9.6 versus 22.8 months).
Risk factors for transformation — Risk factors for the ultimate development of HT at the time of initial presentation of FL were evaluated among over 2600 patients prospectively enrolled in the National LymphoCare Study [5]. After a median follow-up of 6.8 years, HT was identified clinically or pathologically in 14 percent. The following factors were associated with an increased risk of confirmed or suspected HT:
●>1 extranodal site – hazard ratio (HR) 1.39
●Eastern Cooperative Oncology Group (ECOG) performance status >1 – HR 2.12
●Increased serum level of LDH – HR 1.57
●Systemic "B" symptoms (fevers, night sweats, weight loss) – HR 1.35
Risk factors reported in other studies have included:
●Stage III or IV disease [7]
●Increased serum level of LDH [4,5,7]
●Beta-2 microglobulin level >3 mg/L [8]
●Serum albumin <3.5 g/dL [8]
●Grade III histology [4,9]
●High Follicular Lymphoma International Prognostic Index (FLIPI) (table 1) [4,9] or International Prognostic Index (IPI) (table 2) [4,7]
●Lack of complete remission following initial treatment [8]
●Early treatment failure (eg, progression within 24 months of chemoimmunotherapy) [4,10]
In three studies, whether the patient received immediate or delayed treatment did not affect the risk of development of HT [4,11,12], while in a third study those who received delayed treatment had a higher risk of HT (hazard ratio 1.9; 95% CI 1.2-2.9) [7].
While positron emission tomography (PET) imaging can guide the selection of an appropriate biopsy site in suspected HT, increased uptake on pretreatment PET imaging does not appear to predict future HT. A retrospective analysis of patients with previously untreated advanced stage FL enrolled on the prospective GALLIUM study did not detect higher rates of HT in patients with baseline maximum standardized uptake value (SUVmax) >10 or >20 [13]. Similarly, the range of SUV values at baseline was not predictive of future HT. Importantly, patients with biopsy-proven HT at the time of FL diagnosis were excluded from this study. As such, these results do not address the role of PET in assessing suspected HT at the time of diagnosis or beyond.
PATHOBIOLOGY — HT is a nonlinear evolution of the FL tumor population. At the time of diagnosis, most cases of FL are comprised of multiple clones [14]. HT is thought to develop through expansion of an aggressive clone that may have been very small at the time of presentation [14,15]. The following sections describe the pathobiology of HT. The pathobiology of FL and diffuse large B cell lymphoma (DLBCL) are presented in detail separately. (See "Pathobiology of follicular lymphoma" and "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma".)
Cytogenetics — While the acquisition and accumulation of additional genetic abnormalities are commonly seen in HT, no single cytogenetic abnormality appears to be solely responsible for this transformation. The overwhelming majority of cases of DLBCL evolving from FL are clonally related [16]. In contrast, in histologic (Richter) transformation of chronic lymphocytic leukemia (CLL), the CLL clone and the transformed clone are related in only 60 percent of cases [17]. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)
A large number of other nonrandom secondary cytogenetic abnormalities have been described in FL [18,19]. Although many of these accompany disease progression in which follicular architecture is retained, as well as following HT, detailed analysis has demonstrated widespread secondary chromosomal abnormalities at initial diagnosis and during the course of FL [20].
The most common translocation in FL is t(14;18) (bcl-2/IgH), being present in 85 percent of patients. Following HT, the bcl-2/IgH rearrangement persists in virtually all cases, with identical nucleotide sequences in the original FL and the DLBCL samples [21]. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Cytogenetics'.)
Gene alterations — Specific genetic lesions have been identified in HT and provide insight into its pathogenesis [22-24]. These include alterations in genes regulating proliferation, control of the cell cycle, DNA damage response, and programmed cell death.
Mutations of the TP53 gene have been reported in 26 percent and 80 percent of cases of transformed FL [25,26]. TP53 is similarly inactivated in approximately 20 percent of transformed mucosa-associated lymphoid tissue (MALT) lymphomas by deletion or mutation [27]. In a report of serial biopsies from patients with FL, TP53 mutations were observed in 28 percent of cases [28]. Although TP53 mutations were not present at diagnosis, in subsequent biopsies where the histology remained FL, 14 percent of cases had mutations, providing evidence that TP53 mutations can precede HT, occurring from six months to four years prior to transformation.
Given the central role of the B cell lymphoma 6 (BCL-6) gene in DLBCL, investigators have examined BCL-6 alterations in HT [29,30]. In one study, BCL-6 translocations or deletions were reported in 39 percent of patients with FL who went on to develop HT, versus 14 percent in those that did not transform [31]. However, both loss and gain of BCL-6 translocations were observed, suggesting that BCL-6 translocation is not required for HT. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant BCL6 expression' and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Alterations in BCL6'.)
FL is associated with the overexpression of the oncogene B cell leukemia/lymphoma 2 (BCL-2), located on chromosome band 18q21. Overexpression is typically due to a translocation between the long arm of chromosome 18 and one of the three immunoglobulin genes. In one study, mutations in the BCL-2 coding sequence were found in 12 percent of cases at diagnosis and 53 percent at HT [32]. BCL-2 mutations at diagnosis were associated with an increased risk of transformation (hazard ratio 3.6) and shorter median survival (9 versus 20 years).
At the time of transformation, approximately one-quarter of cases meet criteria for high grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements ("double-hit" lymphoma) [33]. While "double-hit" lymphoma is associated with a worse prognosis than newly diagnosed DLBCL, the prognostic impact of these mutations on HT is not well established. However, as in de novo cases, for patients with double-hit HT we favor more aggressive chemotherapy regimens (eg, da-EPOCH-R) rather than standard R-CHOP. (See "Prognosis of diffuse large B cell lymphoma", section on 'Double hit lymphoma' and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit")'.)
Gene expression profiling — The gene expression profile (GEP) is a powerful tool to identify genes and pathways that are aberrantly expressed during carcinogenesis or transformation. GEP has been used in FL to better understand the pathogenesis of HT and to develop prognostic models to identify patients with aggressive or more indolent disease at the time of presentation [34-37]. When assessed at the time of transformation, the majority of cases (approximately 80 percent) will have a pattern consistent with a germinal center B cell (GCB) cell of origin, the prognostic impact of which has not been clearly established [33]. (See "Prognosis of diffuse large B cell lymphoma", section on 'Cell of origin studies'.)
In one study, the GEP of FL samples identified a "pluripotency" signature that may predict HT [38]. Such "pluripotency" signatures were rich in the expression of genes that are typically expressed by embryonic stem cells and had reduced expression of genes typically expressed by stromal cells. This suggests that patients with a FL GEP closer to an embryonic stem cell may be more likely to transform into a more aggressive non-Hodgkin lymphoma subtype.
Another study examined paired specimens from 12 patients with HT of FL using GEP [39]. Of the known genes, only one oncogene, c-myc, previously associated with HT was identified. Fifteen c-myc-regulated genes were also significantly altered in expression. Further analysis found that cases segregated into groups with increased or decreased expression of c-myc-regulated genes and a group with no significant change in these genes. Since c-myc controls proliferation as well as programmed cell death, increased expression of c-myc-regulated genes may enhance proliferation, whereas decreased expression may impede programmed cell death contributing to HT via other mechanisms [40]. (See "Pathobiology of Burkitt lymphoma", section on 'Consequences of MYC overexpression'.)
The predictive value of GEP for patients with newly diagnosed FL is currently unknown. The predictive value of GEP may be limited if HT is not inherent at initial diagnosis of FL, but rather reflects the progressive accumulation of additional genetic changes leading to a histologically and clinically distinct entity.
CLINICAL PRESENTATION AND DIAGNOSIS
When to suspect HT — For patients with FL, we have a low threshold to biopsy at the time of progression prior to retreatment in order to confirm relapse and evaluate for HT. Imaging with a combined positron emission tomography/computed tomography (PET/CT) scan provides information about the anatomic areas of involvement and their metabolic activity. Biopsy should aim to sample a lymph node with the highest activity on PET. (See 'Evaluation' below.)
HT is clinically aggressive, and patients frequently display features commonly seen in patients initially presenting with a diagnosis of clinically aggressive non-Hodgkin lymphoma, such as diffuse large B cell lymphoma (DLBCL). These are described in more detail separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Clinical presentation'.)
The following findings raise the clinical suspicion for HT:
●Early treatment failure (eg, progression within 24 months of initial chemoimmunotherapy)
●Focal intense uptake on imaging with PET
●Rapid progression of lymphadenopathy
●Infiltration of uncommon extranodal sites (excluding the bone marrow)
●Systemic symptoms (eg, fever, weight loss, night sweats)
●Sudden decline in performance status
●Elevated serum lactate dehydrogenase (LDH)
●Hypercalcemia
A retrospective single center analysis of 325 patients with newly diagnosed FL, followed for a median of 15 years, had a cumulative incidence of HT by 10 years of 28 percent [7]. Of the 111 patients who underwent biopsy at first recurrence, 22 had HT. When compared with patients whose repeat biopsy showed FL without HT, patients with biopsy-proven HT were more likely to have the following findings:
●Elevated LDH (79 versus 17 percent)
●Hemoglobin <12 g/L (53 versus 23 percent)
●Age >60 years (68 versus 35 percent)
●High International Prognostic Index (IPI) score (calculator 1) (50 versus 20 percent)
In another study of 60 patients found to have HT at the time of diagnosis, the following adverse clinical characteristics were found at the time of presentation [41]:
●Disseminated disease – 97 percent
●Increased serum LDH levels – 55 percent
●More than one extranodal site involved – 50 percent
●Poor performance status – 33 percent
HT has been reported at high rates among patients with early treatment failure. As an example, in a retrospective study of approximately 300 patients with FL, clinical or biopsy-proven HT was reported in 76 percent of patients progressing within 24 months of initial treatment with bendamustine plus rituximab [10]. In another analysis of 194 patients with biopsy confirmation of progressive disease after chemoimmunotherapy in the Primary Rituximab and Maintenance (PRIMA) study, 79 percent had untransformed FL and 21 percent had HT [4]. Median time to progression was shorter in those with transformed FL (9.6 versus 22.8 months).
Evaluation — The initial evaluation of a patient with suspected HT aims to identify the best lymph node for biopsy. Imaging with a combined 18F-fluorodeoxyglucose (FDG) PET/CT scan provides information about the anatomic areas of involvement and their metabolic activity. Biopsy should aim to sample a lymph node with the highest activity on PET; lesions with a standardized uptake value (SUV) >10 have a higher likelihood of transformation [42,43].
Only an excisional biopsy of an intact node consistently allows sufficient tissue for histologic, immunologic, molecular biologic assessment, and classification by experienced hematopathologists. In general, lymph nodes larger than 2.25 cm2 (ie, a node with biperpendicular diameters of 1.5 x 1.5 cm) or 2 cm in a single diameter have the best diagnostic yields. Peripheral lymph nodes are generally preferred to other lymph nodes for diagnostic biopsy because they are easily accessed and have a relatively high diagnostic yield. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node selection'.)
Pathologic features — The diagnosis of HT requires a biopsy of involved tissue (usually a lymph node) that demonstrates loss of the follicular architecture and the accumulation of large tumor cells that resemble those of a clinically aggressive or highly aggressive non-Hodgkin lymphoma subtype. In most cases, the pathology is consistent with DLBCL. Less commonly, FL evolves into Burkitt lymphoma, high grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements ("double-hit" lymphoma), or into precursor lymphoid neoplasms (blastic/blastoid transformation) [44,45]. HT includes FL that evolves to grade 3b FL (sometimes called follicular large cell lymphoma). In contrast, tumors that evolve from a grade 1 to grade 2 or 3a are not considered HT. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Grade'.)
On histology, the tumor demonstrates loss of the follicular architecture as well as an accumulation of large cells (picture 1). These tumors resemble de novo DLBCL or other aggressive or highly aggressive histologies, and have high Ki-67 staining (picture 2) and transferrin receptor-related protein, indicators of a high proliferative index [46]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Immunophenotype'.)
Histology can vary greatly in different sections of the same lymph node. As such, careful examination of the sampled lymph node is key to determining whether a component of higher grade lymphoma is present. Discordant histologic features suggest HT of a previously undiagnosed FL [41,47-50]. As an example, FL may be identified in the bone marrow in a patient with DLBCL in a lymph node. The detection of areas of DLBCL within the lymph node denotes HT.
PRETREATMENT EVALUATION AND STAGING — Prior to initiating therapy, a pretreatment evaluation must establish the extent and sites of disease, and the performance status of the patient. The pretreatment evaluation for patients with HT is the same as that of patients with de novo diffuse large B cell lymphoma (DLBCL). This is discussed in more detail separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Pretreatment evaluation'.)
Most patients with HT will have advanced stage disease (usually stage III or IV (table 3)). While HT may occur at a single site, it is difficult to prove that other sites of FL have not transformed. As such, most patients with HT are treated as if they have advanced stage aggressive lymphoma. Rare cases of localized HT may be managed as limited stage aggressive lymphoma.
Patients with HT have a risk of central nervous system (CNS) recurrence of approximately 2 to 5 percent, and the decision to administer CNS prophylaxis should be decided on a case-by-case basis. The decision to administer CNS prophylaxis and the choice of regimen is discussed in more detail separately. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'CNS prophylaxis'.)
MANAGEMENT
Choosing a management approach — The goal of therapy for most patients is to eliminate the aggressive component of disease (ie, the histologically transformed cells) while minimizing toxicity. Therapy directed at the palliation of symptoms alone may be appropriate for patients unlikely to tolerate the toxicity of more aggressive treatment regimens.
Management incorporates one or more of the following (algorithm 1):
●Conventional chemoimmunotherapy (eg, R-CHOP, EPOCH-R, R-GDP)
●High dose therapy followed by autologous hematopoietic cell transplantation (HCT)
●Chimeric antigen receptor T (CAR-T) cells
●Allogeneic HCT
There is no agreed-upon standard treatment for HT. Management is largely guided by data from observational studies and retrospective analyses, and by extrapolation of data on the treatment of de novo aggressive histologies. Whenever possible, patients should be encouraged to enroll on clinical trials. A discussion about values and preferences can help to guide therapy. Palliative care alone may be in the patient's best interest, especially in the setting of multiply relapsed disease for which both the indolent and aggressive components may be particularly difficult to control.
Outside of a clinical trial, our preferred therapy depends upon prior treatments, the aggressiveness of the tumor (eg, histology and molecular markers), and response to chemoimmunotherapy, along with the patient's fitness and his or her values and preferences as described in the sections that follow. This approach is generally consistent with that of major guidelines, including those from the National Comprehensive Cancer Network (NCCN) and the British Society for Haematology [51,52]. Since FL frequently presents in middle-aged individuals and older adults, many patients will not be able to tolerate some of the more aggressive treatment options such as allogeneic HCT. Lenalidomide may be a less toxic alternative in such patients.
While patients may be cured of the aggressive component of disease, they are usually not cured of the indolent component with conventional treatment. Individuals differ in the value they place on the avoidance of toxicity and the delay of further anti-lymphoma treatment. Different patients who are equally informed of these risks and benefits are likely to make different treatment decisions.
Prior chemoimmunotherapy — Approximately half of patients will have received prior chemoimmunotherapy for FL (eg, bendamustine plus rituximab, R-CHOP-21) [53]. While many can achieve a complete response (CR) with chemoimmunotherapy, a high percentage will relapse in a short period if no further therapy is given. Autologous HCT has been offered to these patients in an attempt to decrease the rate of relapse and improve overall survival (OS).
For most patients who have received prior chemoimmunotherapy, our approach depends on what regimens the patient has been exposed to and the type of HT (algorithm 1). Either rituximab-based or obinutuzumab-based combination regimens may be used. Obinutuzumab-based combinations may provide greater disease control for the indolent component. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Obinutuzumab-based regimens'.)
Data supporting this choice are largely extrapolated from studies of those with de novo relapsed or refractory aggressive lymphoma, which are described separately.
●For most patients with HT resembling diffuse large B cell lymphoma (DLBCL), we offer four to six cycles of R-CHOP-21 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (table 4)) if the patient has not been exposed to this regimen in the past. A total of four cycles may be appropriate for patients who achieve a CR after two cycles, whereas six cycles are offered to those with only a partial response (PR). (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Initial therapy'.)
●For younger, fit patients with double-hit HT (those with c-MYC translocation plus gene rearrangement of BCL-2, BCL-6, or both), we suggest six cycles of dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab (table 5)) rather than R-CHOP-21. RCHOP-21 or R-mini-CHOP are acceptable alternatives for older or frail patients with double-hit HT. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit")'.)
●For patients with HT resembling DLBCL or double-hit HT who have received prior R-CHOP-21, we offer a regimen used for relapsed DLBCL (eg, R-GDP, R-ICE, R-DHAP, R-ESHAP). Of these, we prefer R-GDP (gemcitabine, dexamethasone, cisplatin, rituximab) based on its low cost, similar efficacy to other regimens, and outpatient administration. We assess response after two or three cycles. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Selection of salvage chemotherapy'.)
●For those with HT resembling Burkitt lymphoma, we offer six cycles of dose-adjusted EPOCH-R. Selected younger adults and/or those with central nervous system involvement may be candidates for the more aggressive CODOX-M with IVAC regimen described separately. (See "Treatment of Burkitt leukemia/lymphoma in adults".)
●Patients who are not candidates for aggressive regimens may respond to lenalidomide. An international phase II trial of single agent lenalidomide in patients with relapsed or refractory aggressive non-Hodgkin lymphoma included a subset analysis of 23 patients with HT of FL [54]. The overall response rate was 57 percent (26 percent complete) with a median progression-free survival (PFS) of 7.7 months.
Further management depends on the response to this chemoimmunotherapy. Those who have an at least PR proceed with high dose therapy and autologous HCT akin to what is offered to patients with relapsed DLBCL. (See 'Role for autologous transplant' below.)
Our preference to proceed with HCT is based upon retrospective studies and case series that have demonstrated inferior outcomes in patients with prior exposure to anthracyclines. In one report of 35 patients treated after HT with R-CHOP-21 or a similar therapy, OS at five years was worse among those who had received R-CHOP before HT (21 versus 66 percent) [3]. Similar survival rates were noted in other studies of patients with HT after prior anthracycline-based therapy [55,56]. As described in more detail below, retrospective analyses have suggested that autologous HCT improves PFS and potentially OS in patients with chemotherapy-sensitive disease. (See 'Role for autologous transplant' below.)
There is little information regarding the outcomes of patients with HT previously treated with bendamustine plus rituximab. While we proceed with HCT in this population, other experts might reasonably suggest observation.
Those with stable disease or progression are unlikely to benefit from autologous HCT. Such patients are candidates for cellular therapies (CAR-T or allogeneic HCT). (See 'Multiply relapsed or refractory disease' below.)
Little or no prior therapy — Approximately half of patients will present with HT after having received little prior therapy (eg, single agent rituximab or radiation therapy) or no prior therapy (eg, those presenting with transformation) [53]. For such patients, we suggest initial treatment with chemoimmunotherapy akin to that used for patients presenting with a de novo lymphoma of a similar histology (algorithm 1). Data supporting this choice is largely extrapolated from studies of those with de novo lymphoma, which are described separately.
●For most patients with HT resembling DLBCL, we suggest six cycles of R-CHOP-21 (table 4). (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Initial therapy'.)
●Rarely, patients with HT resembling DLBCL will have what appears to be localized transformation. While it is not possible to definitively rule out transformation at other sites, it is reasonable to offer such patients fewer cycles of R-CHOP-21 with or without radiation therapy akin to that used for limited stage DLBCL. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Initial treatment'.)
●For patients with double-hit HT (those with c-MYC translocation plus gene rearrangement of BCL-2, BCL-6, or both), we suggest six cycles of dose-adjusted EPOCH-R (table 5) rather than R-CHOP-21. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit")'.)
●For those with HT resembling Burkitt lymphoma, we suggest six cycles of dose-adjusted EPOCH-R rather than R-CHOP-21. Selected younger adults and/or those with central nervous system involvement may be candidates for the more aggressive CODOX-M with IVAC regimen described separately. (See "Treatment of Burkitt leukemia/lymphoma in adults".)
●As described above, patients who are not candidates for aggressive regimens may respond to lenalidomide [54]. (See 'Prior chemoimmunotherapy' above.)
Further management depends on the response to this chemoimmunotherapy:
●Complete response – We do not routinely offer maintenance or consolidation to patients who achieve a CR. Patients with little or no therapy prior to HT have a better prognosis than those who have been treated with chemoimmunotherapy and survival rates mirror those in the de novo DLBCL population [5,53,55-58]. Retrospective studies suggest that treatment of this group with chemoimmunotherapy alone results in CR rates over 80 percent and five-year survival rates of approximately 60 to 80 percent [3,5,53,55,59]. Unlike patients with de novo DLBCL, these patients are at risk for relapse of the indolent component, which was seen in 20 percent of patients in one study [41].
●Partial or no response – Those who have a PR or no response are treated with two cycles of another chemoimmunotherapy regimen (eg, R-GDP for DLBCL) with plans to proceed with high dose therapy and autologous HCT if they achieve an at least PR. In those who are not candidates for autologous HCT, we aim to administer at least two cycles beyond CR, usually a total of six cycles of chemotherapy. (See 'Role for autologous transplant' below.)
●Multiply refractory disease – Patients with multiply refractory disease are candidates for cellular therapies (CAR-T or allogeneic HCT). (See 'Multiply relapsed or refractory disease' below.)
There have been no prospective trials evaluating the use of maintenance therapy in patients with HT who attain a CR. In one multicenter retrospective analysis, rituximab maintenance improved PFS (94 versus 53 percent), but not OS in this population [53]. There was no demonstrated benefit from autologous HCT. In another retrospective analysis, rituximab maintenance did not have a significant impact on PFS or OS [60]. Maintenance rituximab is commonly employed after chemoimmunotherapy for newly diagnosed FL. In contrast, maintenance therapy does not appear to improve survival among patients who have completed initial chemoimmunotherapy for DLBCL. The use of maintenance rituximab in these two settings is discussed in detail separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Use of maintenance' and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Incorporation of rituximab'.)
Multiply relapsed or refractory disease — Patients with HT of FL who are resistant to initial therapy or who relapse following initial therapy have a high likelihood of either not responding to further chemoimmunotherapy or relapsing soon after responding. We encourage such patients to enroll on a clinical trial. Outside of a clinical trial, young, fit patients may be candidates for cellular therapies (CAR-T or allogeneic HCT). Palliative care is a reasonable alternative in the majority of patients who are not young and not fit (algorithm 1). (See 'Clinical trials' below.)
CAR-T cell therapy is an option for those with HT resembling DLBCL who have received two or more lines of systemic therapy, have disease that is refractory to first-line chemoimmunotherapy, or relapses within 12 months of first-line chemoimmunotherapy. As described below, CRs are seen in up to half of patients with refractory B cell lymphoma and responses have been sustained for more than three years. These potential benefits must be weighed against the risk of serious, potentially life-threatening toxicity around the time of infusion. Nonrelapse mortality (NRM) is less than 10 percent. CAR-T cell therapy is not approved for other histologic subtypes of HT. (See 'CAR-T cells' below.)
Both myeloablative and nonmyeloablative allogeneic HCT have been performed in patients with HT, although the data are limited. HT to DLBCL is listed as an indication for allogeneic HCT referral in guidelines from the American Society for Blood and Marrow Transplantation [61]. While long-term remissions may be attained, NRM can be as high as 25 to 30 percent. Eligibility for allogeneic HCT is discussed separately. (See 'Allogeneic HCT' below and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
Patients who are not candidates for CAR-T therapy or allogeneic HCT can be given serial regimens used for relapsed DLBCL with a plan to perform autologous HCT in those with an at least PR. Eligibility for autologous HCT is discussed separately. (See 'Role for autologous transplant' below and "Determining eligibility for autologous hematopoietic cell transplantation".)
Responses to regimens used for relapsed DLBCL alone are short. As an example, median PFS was 7.7 months in a phase II study of 23 patients with HT treated with single agent lenalidomide [54]. Similarly, in a phase II study of selinexor, responses were seen in 12 of 31 patients with HT and 23 of 94 patients with de novo DLBCL [62]. For the group as a whole, median PFS was 2.6 months. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically-unfit", section on 'Treatments'.)
Role for autologous transplant — A choice to proceed with high dose therapy and rescue with autologous HCT in patients with HT depends upon the response to therapy, risk of relapse, and ability to meet eligibility requirements. HCT is offered to patients with chemotherapy-sensitive disease who have a high risk of early relapse. Autologous HCT is not effective in those who have no response to chemoimmunotherapy.
While we know that a proportion of patients with HT will attain a sustained remission following chemoimmunotherapy alone, it is very difficult to identify these patients at the time of diagnosis. Experts differ in their selection of patients for HCT. In general, we offer HCT in the following situations (algorithm 1):
●All patients who have been exposed to chemoimmunotherapy prior to HT provided they demonstrate an at least PR to chemoimmunotherapy directed at the HT. (See 'Prior chemoimmunotherapy' above.)
●Patients who have not been exposed to chemoimmunotherapy prior to HT, but have a less than CR to chemoimmunotherapy directed at the HT, provided they demonstrate an at least PR to subsequent chemoimmunotherapy. (See 'Little or no prior therapy' above.)
We do not offer HCT to patients who present with HT after having received little prior therapy (eg, single agent rituximab or radiation therapy) or no prior therapy (eg, those presenting with transformation) and have a CR to chemoimmunotherapy directed at the HT.
Eligibility requirements for autologous HCT are presented separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)
No randomized trials have evaluated autologous HCT in this setting. A nonrandomized multicenter cohort study from the Canadian Blood and Marrow Transplant Group reported outcomes of patients with HT who underwent autologous HCT (46 patients), allogeneic HCT (22 patients), or were treated with rituximab-containing chemotherapy without HCT (53 patients) [59]. When compared with the other groups, patients who underwent allogeneic HCT were younger and were more heavily pretreated (including two patients who had progressed despite prior autologous HCT). The estimated rates of five-year OS after HT were 65, 46, and 61 percent, respectively, following autologous HCT, allogeneic HCT, and chemoimmunotherapy alone. Corresponding rates of PFS were 55, 46, and 40 percent, respectively. Transplant-related mortality at five years was 5 percent after autologous HCT and 23 percent after allogeneic HCT.
The lower transplant-related mortality rate and greater experience with autologous HCT in this setting supports our preference for autologous HCT rather than allogeneic HCT as consolidation therapy for most patients with advanced stage disease and/or those who have received extensive prior therapy.
Additional retrospective analyses have evaluated autologous HCT in patients with chemotherapy-sensitive disease and a good performance status after HT of FL [59,63-73]. With this approach, approximate four- to five-year disease-free survival and OS rates range from 30 to 60 and 40 to 65 percent, respectively:
●One analysis evaluated the outcomes of 87 patients with transformed indolent lymphoma included in a prospective trial of chemotherapy followed by autologous HCT for aggressive lymphoma [73]. Approximately half of the patients with HT responded to chemotherapy and proceeded with HCT. With a median follow-up of 53 months, the estimated rates of OS and event-free survival at four years following HCT were 65 and 45 percent, respectively.
●A series of 50 patients from the European Bone Marrow Transplant Registry who underwent autologous HCT for transformed low grade non-Hodgkin lymphoma reported OS and PFS rates at five years of 51 and 30 percent, respectively [65]. A subgroup of patients with residual chemotherapy-sensitive disease who attained a CR after high dose therapy had an OS rate at five years of 69 percent. All three patients with chemotherapy-resistant disease at the time of high dose therapy died of relapsed or progressive disease.
●In a retrospective analysis of 85 patients with HT, the addition of autologous HCT to chemoimmunotherapy in 54 patients was associated with superior PFS at five years (60 versus 30 percent) [72]. While not statistically significant, there was an increase in OS that would be clinically significant if true (67 versus 48 percent at five years).
Based on results of high dose therapy and autologous HCT in patients with relapsed DLBCL with chemosensitive disease, this strategy has also been successfully applied to patients with HT. This subject is discussed in detail separately.
CAR-T cells — Young, fit patients with HT of FL relapsed after two or more lines of systemic therapy are candidates for CAR-T cell therapy (algorithm 1). CAR-T cells are a form of genetically modified autologous immunotherapy that have shown activity against transformed FL. This customized treatment uses the patient's own T lymphocytes, which are genetically modified (transfected) with a gene that encodes a chimeric antigen receptor to direct the patient's T cells against the lymphoma cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy.
Approximately half of patients with refractory B cell lymphoma achieve complete remission (CR) in response to CAR-T cells directed against CD19; while the overall durability of these responses remains to be determined, some patients have remissions that are sustained for at least three years [74-77]. In a subgroup analysis of a single arm trial of CAR-T in FL, 6 of 13 patients (46 percent) with heavily pretreated HT of FL achieved CR, with a median duration of response of 10.2 months [76]. No relapses occurred after 15 months, with durable remissions observed for up to 39 months after CAR-T infusion. Various CAR-T constructs have subtle structural differences, even when directed against the same antigen, but they have not been directly compared and clinical effects of such differences are not yet clear. Other factors that might impact the efficacy of CAR-T cells include the intensity of the preparative regimen and the condition of the T cells from which they are produced.
CAR-T therapy is associated with serious complications, including some fatal neurologic events and cytokine release syndrome (CRS), which is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. CRS is observed in nearly all treated patients and may be life-threatening, but it typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids. Neurologic toxicities may also be severe or life-threatening. Other adverse events include hypersensitivity reactions, serious infections, prolonged cytopenias, prolonged hypogammaglobulinemia, and second malignancies. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
Axicabtagene ciloleucel (axi-cel), tisagenlecleucel, and lisocabtagene maraleucel are CD19-directed CAR-T immunotherapies that are approved by the US Food and Drug Administration (FDA) for treatment of adults with relapsed or refractory DLBCL after two or more lines of systemic therapy, including DLBCL arising from FL. Axi-cel is also FDA approved for large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy. CAR-T cells are only available in the United States through a risk evaluation and mitigation strategy (REMS), and the FDA labels carry a boxed warning for CRS and neurologic events. Facilities that dispense these agents require special certification, staff must be trained to recognize and manage adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin 6 receptor [IL-6R]) must be available for immediate administration.
The ZUMA-1 study of axi-cel, the JULIET study of tisagenlecleucel, and the TRANSCEND study of lisocabtagene maraleucel in relapsed or refractory DLBCL included patients with HT of FL, but subgroup specific data are limited [74,78,79]. These studies are discussed in more detail separately. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically-unfit", section on 'CAR-T cell therapy'.)
Allogeneic HCT — Both myeloablative and nonmyeloablative allogeneic HCT have been performed in patients with HT. Only small case series of highly selected patients have been reported using this approach. HT to DLBCL is listed as an indication for allogeneic HCT referral in guidelines from the American Society for Blood and Marrow Transplantation [61]. Only young, fit patients are candidates for allogeneic HCT.
A nonrandomized multicenter cohort study from the Canadian Blood and Marrow Transplant Group reported outcomes of 22 patients with HT who underwent allogeneic HCT [59]. The estimated five-year OS and PFS were both 46 percent. Transplant-related mortality at five years was 23 percent. In another report of 18 patients with HT who underwent reduced intensity conditioning allogeneic HCT, OS and PFS at four years were 60 and 61 percent, respectively [80]. With a median follow-up of 52 months, there were no relapses after one year suggesting long-term disease control. NRM at one year was 29 percent. Patients with chemotherapy refractory disease have high relapse rates following reduced intensity conditioning allogeneic HCT.
The use of allogeneic HCT for FL and DLBCL is discussed separately. (See "Allogeneic hematopoietic cell transplantation in follicular lymphoma" and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically-unfit", section on 'Allogeneic HCT'.)
PROGNOSIS AND PROGNOSTIC FACTORS — Patients with HT historically had a poor prognosis, with a median overall survival of approximately one to two years [7]. However, outcomes have improved with the availability of rituximab and advances in supportive care surrounding transplantation [4,5,53,55,59,71,81-84]. As an example, a prospective observational study of 631 patients with newly diagnosed FL followed for a median of 60 months identified 60 cases of HT with a median overall survival following HT of 50 months [3]. The estimated rate of survival at five years post-HT was higher for patients who had transformed more than 18 months after FL diagnosis when compared with those who had transformation detected earlier (66 versus 22 percent).
In another study, patients achieving complete remission (CR) had improved survival (40.5 versus 11 months), with the following good prognostic features [8]:
●Prior CR for treatment of indolent lymphoma
●Absence of prior treatment
●CR following treatment for HT
●Normal serum lactate dehydrogenase activity
●Absence of marrow involvement
●Absence of systemic "B" symptoms
●Limited stage disease
●Treatment with a CHOP-like regimen
In this study, the time from diagnosis and number of prior relapses did not have an impact on survival after HT. Similar good prognostic factors were noted in a second study [85].
In another study, attainment of CR was associated with the extent of disease at HT, while prior therapy was not [86]. The median survival for patients achieving CR was 6.8 years, suggesting that a limited subset of patients with HT treated with CHOP-like regimens experience long survival in remission.
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SUMMARY AND RECOMMENDATIONS
●Disease scope – Histologic transformation (HT) refers to the histologic evolution of a clinically indolent non-Hodgkin lymphoma subtype (eg, follicular lymphoma [FL]) to a clinically aggressive subtype (eg, diffuse large B cell lymphoma [DLBCL]). In patients with FL, HT occurs at a rate of approximately 1 to 2 percent per year. (See 'Frequency of transformation' above.)
●Importance of biopsy for diagnosis – For patients with FL, we have a low threshold to biopsy at the time of progression prior to retreatment in order to confirm relapse and evaluate for HT. Biopsy should aim to sample a lymph node with the highest activity on fluorodeoxyglucose (FDG) positron emission tomography (PET); lesions with a standardized uptake value (SUV) >10 have a higher likelihood of transformation. Other clinical findings that increase the suspicion of HT include rapid progression of lymphadenopathy, infiltration of uncommon extranodal sites, development of systemic symptoms (eg, fever, weight loss, night sweats), elevated serum lactate dehydrogenase, and/or hypercalcemia. (See 'When to suspect HT' above.)
The diagnosis of HT requires a biopsy of involved tissue (usually an excisional biopsy of a lymph node) that demonstrates loss of the follicular architecture and the accumulation of large tumor cells that resemble those of a clinically aggressive or highly aggressive non-Hodgkin lymphoma subtype. Importantly, FL that evolves from low to higher grade (eg, grade 1 to grade 2 or 3a) is not considered HT. (See 'Clinical presentation and diagnosis' above and 'Pathologic features' above.)
●Pretreatment evaluation – Prior to initiating therapy, a pretreatment evaluation must establish the extent and sites of disease and the performance status of the patient. Most patients with HT are treated as if they have advanced stage aggressive lymphoma. (See 'Pretreatment evaluation and staging' above.)
●Management – Management is largely guided by data from observational studies and retrospective analyses, and by extrapolation of data on the treatment of de novo aggressive histologies. Whenever possible, patients should be encouraged to enroll on clinical trials. Palliative care alone is a reasonable alternative, especially in the setting of multiply relapsed disease.
Outside of a clinical trial, our preferred therapy depends upon prior treatments, the aggressiveness of the tumor (eg, histology and molecular markers), and response to chemoimmunotherapy (algorithm 1):
•Little or no prior therapy – For most patients who have received little (eg, single agent rituximab or radiation therapy) or no prior therapy (eg, presenting with transformation), we offer chemoimmunotherapy used for treatment of de novo cases of the specific aggressive or highly aggressive lymphoma. (See 'Little or no prior therapy' above.)
As examples:
-For most patients with HT resembling DLBCL, we offer R-CHOP-21 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) (table 4).
-For patients with HT resembling Burkitt lymphoma or double-hit HT (those with c-MYC translocation plus gene rearrangement of BCL-2, BCL-6, or both), we offer dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab) (table 5).
Further management depends on the response to this chemoimmunotherapy:
-For those who achieve a complete response, we suggest observation rather than autologous hematopoietic cell transplantation (HCT) or maintenance.
-For those with a partial response or no response, we offer another chemoimmunotherapy regimen with plans to proceed with high dose therapy and autologous HCT if they achieve an at least partial response.
•Prior chemoimmunotherapy – For most patients who have received prior chemoimmunotherapy, we suggest treatment with chemoimmunotherapy followed by high dose therapy and autologous HCT for those with chemotherapy-sensitive disease rather than chemoimmunotherapy alone or allogeneic HCT. The choice of chemoimmunotherapy given depends upon what regimens the patient has been exposed to and the type of HT. (See 'Prior chemoimmunotherapy' above and 'Role for autologous transplant' above.)
•Multiply refractory disease – Young, fit patients with multiply refractory disease are candidates for cellular therapies (chimeric antigen receptor T [CAR-T] cell therapy or allogeneic HCT). Those with HT resembling DLBCL who have received two or more lines of systemic therapy are candidates for CAR-T cell therapy. Although data are limited, we suggest CAR-T cell therapy rather than allogeneic HCT for eligible patients based on early studies that suggest it is an effective and relatively safe option (Grade 2C). In contrast, palliative care is appropriate for the majority of patients who are not young and not fit. (See 'Multiply relapsed or refractory disease' above.)
