Histologic transformation of follicular lymphoma

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) 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 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab; 75 percent), R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab; 22 percent), or R-FCM (fludarabine, cyclophosphamide, and mitoxantrone plus rituximab; 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]

●"Diffuse large B-cell lymphoma-like" pattern on genome sequencing [11]

In three studies, whether the patient received immediate or delayed treatment did not affect the risk of development of HT [4,12,13], while in a fourth study those who received delayed treatment had a higher risk of HT (HR 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 (SUV) >10 or >20 [14]. Similarly, the range of SUVs 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 [15]. HT is thought to develop through expansion of an aggressive clone that may have been very small at the time of presentation [15,16]. 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 [17]. 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 [18]. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

A large number of other nonrandom secondary cytogenetic abnormalities have been described in FL [19,20]. 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 [21].

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 [22]. (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 [23-25]. These include alterations in genes regulating proliferation, control of the cell cycle, deoxyribonucleic acid (DNA) damage response, and programmed cell death.

Mutations of the TP53 gene have been reported in approximately 25 to 80 percent of cases of transformed FL [26,27]. TP53 is similarly inactivated in approximately 20 percent of transformed mucosa-associated lymphoid tissue (MALT) lymphomas by deletion or mutation [28]. In a report of serial biopsies from patients with FL, TP53 mutations were observed in 28 percent of cases [29]. 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 [30,31]. 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 [32]. 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 [33]. BCL-2 mutations at diagnosis were associated with an increased risk of transformation (hazard ratio 3.6) and a 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 rearrangements ("double-hit" lymphoma) [34]. 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. (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")'.)

Cell of origin — Cell of origin can be assessed using gene expression profiling (GEP), immunohistochemistry algorithms (eg, Tally and Hans), and the Lymph2Cx platform. When assessed at the time of transformation, the most cases (approximately 80 percent) will have a pattern consistent with a germinal center B (GCB) cell of origin, the prognostic impact of which has not been clearly established [34]. (See "Prognosis of diffuse large B cell lymphoma", section on 'Cell of origin studies'.)

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 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 (NHL), 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 (eg, standardized uptake value [SUV] >10)  

●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 [35]:

●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 an SUV >10 have a higher likelihood of transformation [36,37].

Only an excisional biopsy of an intact node consistently allows sufficient tissue for histologic, immunologic, and 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 NHL 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 ("double-hit" lymphoma), or precursor lymphoid neoplasms (blastic/blastoid transformation) [38,39]. 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, which are indicators of a high proliferative index [40]. (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 [35,41-44]. 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. 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.

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. While patients may be cured of the aggressive component, they are usually not cured of the indolent component (ie, FL). 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 [cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab], R-pola-CHP [rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone], EPOCH-R [etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab], R-ICE [rituximab, ifosfamide, carboplatin, and etoposide])

●Lenalidomide

●Polatuzumab vedotin (anti-CD79b antibody-drug conjugate)

●Anti-CD20 antibodies, including CD20 x CD3 bispecific monoclonal antibodies (eg, glofitamab, epcoritamab)

●Anti-CD19 antibodies (eg, tafasitamab)

●Loncastuximab tesirine (an anti-CD19 antibody-drug conjugate)

●CD19-directed chimeric antigen receptor (CAR)-T cell therapy

●High-dose therapy followed by autologous hematopoietic cell transplantation (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.

Outside of a clinical trial, our preferred therapy depends upon:

●Prior treatment

●Tumor aggressiveness (eg, histology and molecular markers)

●International Prognostic Index (IPI) (calculator 1)

●Response to chemoimmunotherapy

●Patient fitness and comorbidities

●Patient values and preferences

This approach is generally consistent with that of major guidelines, including those from the National Comprehensive Cancer Network and the British Society for Haematology [45,46].

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. Since FL frequently presents in older adults, many patients will not be able to tolerate some of the more aggressive treatment options.

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.

Patients with HT have a risk of central nervous system (CNS) recurrence of approximately 2 to 5 percent and usually do not warrant CNS prophylaxis. 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'.)

Prior chemoimmunotherapy

Induction chemoimmunotherapy — Approximately one-half of patients will have received prior chemoimmunotherapy for FL (eg, bendamustine plus rituximab, R-CHOP) [47]. For such patients, a different chemotherapy regimen is given to control the aggressive component prior to consolidation with either CD-19-directed CAR-T cell therapy or autologous HCT.

The preferred chemoimmunotherapy regimen 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. Based on extrapolation of data from studies in follicular lymphoma, obinutuzumab-based combinations (eg, O-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone plus obinutuzumab]) 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 aggressive lymphoma, which are described separately.

●Diffuse large B cell lymphoma-like HT without exposure to R-CHOP or O-CHOP – For most patients with HT resembling diffuse large B cell lymphoma (DLBCL) without prior exposure to R-CHOP or O-CHOP, we offer therapy akin to that used for previously untreated DLBCL. Typically, we offer six cycles of either:

•R-CHOP (table 4), or

•R-pola-CHP

R-pola-CHP may be preferred over R-CHOP for those with an IPI ≥2 based on the worse prognosis of such patients and initial results of a randomized trial (POLARIX) that suggested superior efficacy and similar toxicity with R-pola-CHP when compared versus R-CHOP for the initial treatment of de novo DLBCL (trial excluded patients with HT) [48]. However, R-CHOP remains a reasonable alternative, especially given that a high percentage of patients with IPI ≥2 may have a germinal center B cell-like subtype of DLBCL, a subgroup that did not demonstrate a clear benefit from R-pola-CHP on exploratory analysis of POLARIX. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Initial therapy'.)

●Double-hit HT without exposure to R-CHOP or O-CHOP – For younger, fit patients with double-hit HT (those with both MYC and BCL-2 rearrangement), we suggest six cycles of dose-adjusted EPOCH-R (table 5) rather than R-CHOP or R-pola-CHP. This preference is based on extrapolation of data from a meta-analysis of 11 studies of de novo double-hit HT that demonstrated improved progression-free survival (PFS) yet greater toxicity with EPOCH-R or CODOX-M with IVAC (rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine) when compared with R-CHOP [49]. R-CHOP, R-pola-CHP, or R-mini-CHOP (reduced dose of CHOP with conventional dose of rituximab) 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")'.)

●Diffuse large B cell lymphoma-like or double-hit HT with prior exposure to R-CHOP or O-CHOP – For patients with HT resembling DLBCL or double-hit HT who have received prior R-CHOP or O-CHOP, we offer a regimen used for relapsed DLBCL (eg, R-ICE [rituximab, ifosfamide, carboplatin, and etoposide], R-DHAP [rituximab, dexamethasone, high-dose cytarabine, cisplatin], R-ESHAP [rituximab, etoposide, methylprednisolone, cytarabine, cisplatin]). We assess response after two or three cycles. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Selection of salvage chemotherapy'.)

●High-grade B-cell lymphoma, NOS – For those with HT resembling high-grade B-cell lymphoma, not otherwise specified (previously "Burkitt-like" lymphoma), we offer six cycles of dose-adjusted EPOCH-R. While CODOX-M with IVAC has demonstrated superior outcomes in young patients with de novo Burkitt lymphoma, patients with HT are older than those with de novo Burkitt lymphoma. Selected younger adults and/or those with CNS involvement may be candidates for the more aggressive CODOX-M with IVAC regimen. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

Consolidation with chimeric antigen receptor T or transplant — Approximately one-half of patients will have received prior chemoimmunotherapy for FL (eg, bendamustine plus rituximab, R-CHOP, O-CHOP) [47]. For such patients, we suggest treatment with a different chemoimmunotherapy followed by consolidation with either CAR-T cell therapy or autologous HCT rather than chemoimmunotherapy alone (algorithm 1). While many will achieve a complete response (CR) with chemoimmunotherapy, a high percentage will relapse in a short period if no further therapy is given. Consolidation attempts to postpone relapse and improve overall survival (OS). CAR-T cell therapy is preferred for those who do not achieve a CR. Either CAR-T cell therapy or autologous HCT is a reasonable option for patients achieving a CR.

Our preference to proceed with consolidation is based on 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 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 [50,51]. There is little information regarding the outcomes of patients with HT previously treated with bendamustine plus rituximab. While we proceed with consolidation in this population, other experts might reasonably suggest observation.

The use of CAR-T cell therapy and autologous HCT in HT is based on small studies of these modalities in patients with HT and extrapolation of larger studies of these modalities in relapsed aggressive lymphoma, many of which included a small population of patients with HT.

In those who achieve a CR with chemoimmunotherapy, either approach may be effective. Retrospective analyses have suggested that autologous HCT improves PFS and potentially OS in patients with chemotherapy-sensitive disease. Further details regarding efficacy and eligibility requirements for autologous HCT are presented separately. (See 'Autologous transplant' below and "Determining eligibility for autologous hematopoietic cell transplantation".)

In those who do not achieve a CR with chemoimmunotherapy, we prefer CAR-T cell therapy based on extrapolation of data from randomized trials that have shown an OS advantage for CAR-T cell therapy over autologous HCT in patients with early first relapse (<12 months) of DLBCL or primary refractory DLBCL [52,53]. Patients with FL with transformation to DLBCL were included in these trials, although they constituted a small percentage of patients enrolled. Further details regarding efficacy are presented separately. (See 'Chimeric antigen receptor T cells' below.)

If CAR-T cell therapy is not available, patients with exposure to multiple lines of systemic therapy are also candidates for targeted therapies, including other antibody-based therapies. A choice among these is individualized. (See 'Multiply relapsed or refractory disease' below.)

Allogeneic HCT is only rarely used for HT because of substantial treatment-related mortality and toxicity. However, if CAR-T cell therapy and antibody-based treatments are not available or were previously administered, allogeneic HCT may be considered for select medically fit patients who achieve a CR or near-CR with salvage chemotherapy. It may also be an option for patients who are not felt to be candidates for autologous HCT due to poor stem cell reserve or quality. (See 'Multiply relapsed or refractory disease' below.)

Little or no prior therapy — Approximately one-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) [47]. 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 are largely extrapolated from studies of those with de novo lymphoma, which are described separately.

●For most patients with HT resembling DLBCL, we suggest a regimen used for the initial treatment of advanced-stage DLBCL. Typically, we offer six cycles of either R-CHOP (table 4) or R-pola-CHP. R-pola-CHP is preferred for those with an IPI ≥2 based on extrapolation of data from patients with de novo DLBCL. (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 risk-adapted 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 both MYC and BCL-2 rearrangement or both), we offer regimens used for double-hit large cell lymphoma, typically six cycles of dose-adjusted EPOCH-R (table 5) rather than R-CHOP or R-pola-CHP. (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 high-grade B-cell lymphoma, not otherwise specified (previously "Burkitt-like" lymphoma), we suggest six cycles of dose-adjusted EPOCH-R rather than R-CHOP. While CODOX-M with IVAC has demonstrated superior outcomes in young patients with de novo Burkitt lymphoma, patients with HT are older than those with de novo Burkitt lymphoma. Selected younger adults and/or those with CNS involvement may be candidates for the more aggressive CODOX-M with IVAC regimen described separately. (See "Treatment of Burkitt leukemia/lymphoma in adults".)

Further management depends on the response to chemoimmunotherapy (algorithm 1):

●Partial or no response – Those who have a partial response or no response are offered CAR-T cell therapy based on extrapolation of data from randomized trials that have shown an OS advantage for CAR-T cell therapy over autologous HCT in patients with early first relapse (<12 months) of DLBCL or primary refractory DLBCL [52,53]. Patients with FL with transformation to DLBCL were included in these trials, although they constituted a small percentage of patients enrolled. (See 'Chimeric antigen receptor T cells' below.)

●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 [5,47,50,51,54,55]. 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 [3,5,47,50,56]. 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 [35].

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 [47]. There was no demonstrated benefit from autologous HCT. In another retrospective analysis, rituximab maintenance did not have a significant impact on PFS or OS [57]. 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, we favor the following approach:

●Young, fit patients are evaluated for cellular therapies (CAR-T or allogeneic HCT). For most patients, CAR-T cell therapy is preferred over allogeneic HCT based on extrapolation of studies in DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'CD19-directed chimeric antigen receptor-T cell therapy'.)

●Patients who are not candidates for cellular therapy are offered serial regimens used for relapsed DLBCL with a plan to perform autologous HCT in those with an at least partial response. Bispecific antibodies and novel agents (eg, targeted therapies) are preferred over cytotoxic chemotherapies.

For many targeted therapies, regulatory approval for DLBCL includes approval for large cell lymphoma transformed from indolent lymphoma (eg, epcoritamab, glofitamab, tafasitamab plus lenalidomide, loncastuximab tesirine, and selinexor). (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit".)

The targeted therapies have not been directly compared; however, of these, we favor the bispecific antibodies epcoritamab and glofitamab and the combination of tafasitamab plus lenalidomide over others as they are well tolerated and highly active in HT.

●Palliative care is a reasonable alternative for patients who progress despite or are not candidates for these cellular and targeted therapies. (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 relapse within 12 months of first-line chemoimmunotherapy. As described below, CRs are seen in up to one-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 approximately 5 percent [58]. CAR-T cell therapy is not approved for other histologic subtypes of HT. (See 'Chimeric antigen receptor 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 [59]. 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 hematopoietic cell transplantation' below and "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Responses to regimens used for relapsed DLBCL alone are short. As an example, the median PFS was 7.7 months in a phase II study of 23 patients with HT treated with single-agent lenalidomide [60]. 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 [61]. For the group as a whole, the 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'.)

Chimeric antigen receptor T cells — 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 relapse within 12 months of first-line chemoimmunotherapy (algorithm 1). We offer CAR-T cell therapy to all eligible patients with HT except those with no or limited therapy prior to transformation who achieve a CR with induction therapy.

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 CAR 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 one-half of patients with refractory B cell lymphoma achieve 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 [52,62-64]. 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 [63]. 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 lymphodepletion and the condition of the T cells from which they are produced.

CAR-T therapy is associated with serious complications, including rare 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, 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. Axicabtagene ciloleucel and lisocabtagene maraleucel are 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 axicabtagene ciloleucel, 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 [52,53,65]. 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 'Chimeric antigen receptor T cell therapy'.)

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 an option for 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 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 autologous HCT. In general, we offer autologous HCT or CAR-T cell therapy to patients who have been exposed to chemoimmunotherapy prior to HT who achieve a CR to chemoimmunotherapy directed at the HT (algorithm 1). (See 'Consolidation with chimeric antigen receptor T or transplant' above.)

We do not offer autologous HCT to patients who achieve less than a CR or 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) [56]. 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 following estimated rates were reported by modality:

●Chemoimmunotherapy alone – 61 percent OS and 40 percent PFS at five years.

●Autologous HCT – 65 percent OS and 55 percent PFS at five years. Transplant-related mortality 5 percent.

●Allogeneic HCT – 46 percent OS and 46 percent PFS at five years. Transplant-related mortality 23 percent.

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. However, this cohort predated the availability of CAR-T cell therapy and other targeted therapies (eg, bispecific antibodies) that are expected to improve outcomes in those treated without HCT [66].

Additional retrospective analyses that predated CAR-T cell therapy reported outcomes after autologous HCT in patients with chemotherapy-sensitive disease and a good performance status after HT of FL [56,67-77]. With this approach, approximate four- to five-year disease-free survival ranged from 30 to 60 percent, and OS rates ranged from 40 to 65 percent. However, these values likely underestimate outcomes with modern therapy. As an example, a retrospective study of 147 HCT-eligible patients in first CR, some of whom had access to CAR-T cell therapy, reported an estimated four-year OS of 91 percent [66]. While autologous HCT was associated with delayed progression, an OS benefit was not demonstrated.

The use of high-dose therapy and autologous HCT in patients with relapsed DLBCL with chemosensitive disease is discussed in detail separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Autologous hematopoietic cell transplantation'.)

Allogeneic hematopoietic cell transplantation — Allogeneic HCT is only rarely used for HT because of substantial treatment-related mortality and toxicity. However, if CAR-T cell therapy and antibody-based treatments are not available or were previously administered, allogeneic HCT may be considered for select medically fit patients with prior exposure to chemoimmunotherapy who achieve a CR or near-CR with induction chemoimmunotherapy.

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 [59]. 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 [56]. 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 [78]. 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 hematopoietic cell transplantation'.)

PROGNOSIS AND PROGNOSTIC FACTORS — Patients with HT historically had a poor prognosis, with a median overall survival (OS) of approximately one to two years [7]. However, outcomes have improved with the availability of rituximab, other targeted therapies, and advances in supportive care surrounding transplantation and chimeric antigen receptor T cell therapy [4,5,47,50,56,75,79-82]. 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 OS 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 had improved survival (40.5 versus 11 months), with the following good prognostic features [8]:

●Prior complete remission for treatment of indolent lymphoma

●Absence of prior treatment

●Complete remission 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 (cyclophosphamide, doxorubicin, vincristine, and prednisone) 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 [83].

In another study, attainment of complete remission was associated with the extent of disease at HT, while prior therapy was not [84]. The median survival for patients achieving complete remission 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).

SUMMARY AND RECOMMENDATIONS

●Disease scope – Histologic transformation (HT) refers to the histologic evolution of a clinically indolent non-Hodgkin lymphoma (NHL) subtype (eg, follicular lymphoma [FL]) to a clinically aggressive subtype (eg, diffuse large B cell lymphoma [DLBCL]). 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 typically biopsy at progression to confirm relapse and evaluate for HT. We sample a lymph node with the highest activity on fluorodeoxyglucose (FDG) positron emission tomography; lesions with a standardized uptake value >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, 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 NHL 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. (See 'Pretreatment evaluation and staging' above.)

●Management – Whenever possible, patients should be encouraged to enroll on clinical trials. Palliative care alone is a reasonable alternative, especially for 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 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) or R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone).

-For patients with HT resembling high-grade B-cell lymphoma, not otherwise specified (previously "Burkitt-like" lymphoma) or double-hit HT DLBCL (those with both MYC and BCL-2 rearrangement), we suggest dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab) (table 5) (Grade 2C).

Further management depends on response:

-For those who achieve a complete response (CR), we suggest observation (Grade 2C).

-For those with a partial response or no response, we suggest chimeric antigen receptor (CAR)-T cell therapy (Grade 2C).

•Prior chemoimmunotherapy – For patients with HT to DLBCL, we offer R-CHOP or R-pola-CHP, provided that it was not previously administered. For patients who have received prior R-CHOP or O-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus obinutuzumab), we proceed with second-line therapy such as that used for refractory DLBCL (eg, R-ICE [rituximab, ifosfamide, carboplatin, and etoposide]) (algorithm 1). (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Chemoimmunotherapy regimens'.)

For those who achieve a CR, we suggest consolidation with either autologous hematopoietic cell transplantation (HCT) or CAR-T cell therapy rather than chemoimmunotherapy alone or allogeneic HCT (Grade 2C). For those who do not achieve a CR, we suggest consolidation with CAR-T cell therapy rather than autologous HCT (Grade 2C). (See 'Prior chemoimmunotherapy' above and 'Autologous transplant' above.)

•Multiply refractory disease – For those with multiply refractory disease, we suggest CAR-T cell therapy rather than allogeneic HCT (Grade 2C), for eligible patients.

Patients who are not candidates for cellular therapy are offered serial regimens used for relapsed DLBCL with a plan to perform autologous HCT in those with an at least partial response. Bispecific antibodies and novel agents are preferred over cytotoxic chemotherapies. Palliative care is a reasonable alternative for most patients who progress despite or are not candidates for these cellular and targeted therapies. (See 'Multiply relapsed or refractory disease' above.)