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Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma

Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma
Author:
Jennifer R Brown, MD, PhD
Section Editor:
Arnold S Freedman, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Oct 2022. | This topic last updated: Aug 23, 2022.

INTRODUCTION — Richter transformation (RT; Richter's syndrome) was first described in 1928 by Maurice Richter as the development of an aggressive large-cell lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although diffuse large B cell lymphoma is the most common histology seen in patients with RT, Hodgkin lymphoma and T cell lymphomas have also been reported less commonly. The clinical features, pathogenesis, and treatment of RT will be discussed here.

Evolution to a component of B cell prolymphocytic leukemia (B-PLL) during the natural history of relapsed CLL/SLL is also common but is not usually included under the rubric of RT. (See "Pathobiology of chronic lymphocytic leukemia", section on 'Prolymphocytoid transformation'.)

INCIDENCE AND CLINICAL FEATURES

Incidence — The incidence of Richter transformation (RT) from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to diffuse large B cell lymphoma (DLBCL) has been variously estimated at 2 to 9 percent [1-9], making it less common than histologic transformation of other low grade mature B cell malignancies (picture 1). The median time from the diagnosis of CLL/SLL to transformation has been in the range of two to five years [2,3,10,11]. For example, a series of 185 consecutive, previously untreated patients with CLL followed for a median of 47 months identified RT in 17 cases (9 percent) at a median of 23 months from diagnosis [5]. This group took an aggressive approach to repeat biopsy, which may explain the high rate of RT. In addition to those transforming to DLBCL, an additional 0.4 percent of patients will transform to Hodgkin lymphoma [12]. (See "Histologic transformation of follicular lymphoma", section on 'Clinical presentation and diagnosis'.)

Clinical features — The onset of RT is heralded by sudden clinical deterioration, characterized by a marked increase in lymphadenopathy at one or more sites (often abdominal), splenomegaly, and worsening "B" symptoms (ie, fever, night sweats, weight loss). The serum level of lactate dehydrogenase (LDH) is elevated in 50 to 80 percent of patients with RT compared with 8 percent of CLL patients [3,10,13]. Anemia with a hemoglobin <11 g/dL is seen in approximately 50 percent of cases, and thrombocytopenia with a platelet count <100,000/microL in 43 percent [13]. Symptoms are similar in the Hodgkin lymphoma variant. The clinical course of RT is rapidly progressive, with a median survival of five to eight months [1,3,14-16].

Risk factors — Risk factors for the development of RT remain poorly defined.

In a review of the MD Anderson experience between 1975 and 2005, RT occurred in 148 of 3986 patients with CLL (3.7 percent) [13]. In an earlier report of their experience, clinical features associated with RT included [3]:

Elevated serum LDH – 82 percent

Progressive lymphadenopathy – 64 percent

Systemic symptoms – 59 percent

Monoclonal gammopathy – 44 percent

Extranodal involvement – 41 percent

No clinical, chromosomal, or treatment groups were significantly associated with RT in this study. In a subsequent review of patients seen between 1992 and 2002, the incidence of RT was 5 percent overall, and was as high as 10 to 13 percent in those who had received three or more previous treatments [1].

Other suggested risk factors include the following:

An increasing number of prior therapies [3] and younger age [17] have both been associated with higher risk of RT.

One analysis found that advanced Rai stage, hemoglobin <12 g/dL, and elevated LDH and beta-2 microglobulin levels were associated with increased risk of RT [18].

A prospective cohort study of 185 patients identified lymph nodes >3 cm, absence of del 13q14, CD38 expression, and usage of IGHV4-39 as risk factors for RT [5]. Another analysis suggested that CLL with IGHV4-39 and stereotyped B cell receptors in subset 8 had a very high risk of RT (69 percent at five years) [19]. NOTCH1 mutation has been associated with RT [20-22], as well as with stereotyped B cell receptors [20], particularly subset 8 [23].

The G allele of a single nucleotide polymorphism (SNP) in the regulatory region of intron 1 of CD38 has been found to increase the upregulation of CD38 in response to interleukin (IL)-2, and this SNP when heterozygous or homozygous has been associated with the development of RT in a modest number of patients [24].

SNPs in BCL2 (rs4987852) and LRP4 (rs2306029) have also been associated with the risk of RT [25,26].

Although immunosuppression related to treatment with fludarabine has been suggested to promote RT, several studies have found that purine analogue therapy is not a risk factor [3,27,28].

The early studies of ibrutinib and venetoclax in high-risk relapsed refractory patient populations showed relatively high rates of RT (8.3 percent at 26 months in the phase 1b study of ibrutinib [29], and 25 percent in a single institution analysis of heavily pretreated patients enrolled on multiple venetoclax studies [30]). These high rates have not been demonstrated in subsequent randomized trials in earlier stage disease [31-33], but those patients who do develop RT while on targeted therapy appear to have an even poorer prognosis, with a median overall survival (OS) of 3.3 months [34,35]. In one study, risk factors for transformation on ibrutinib included increased number of prior therapies, BCL6 abnormalities, MYC abnormalities, del(17p), and complex karyotype, although only BCL6 abnormalities and complex karyotype remained significant in multivariable analysis [36]. A subsequent study implicated near tetraploidy as a risk factor for RT on ibrutinib [37]. For venetoclax, risk factors for progression included complex karyotype and fludarabine-refractory disease.

MAKING THE DIAGNOSIS

Image-directed biopsy — Biopsy of a likely site of transformation, usually a site of enlarging lymphadenopathy, is required to establish the diagnosis of Richter transformation (RT) (picture 1). We suggest using whole body 18F-2-deoxy-2-fluoro-D-glucose labelled positron emission tomography with computed tomography (FDG PET/CT) to determine the preferred biopsy site. If possible, the site of greatest FDG avidity should be biopsied. While an increased standardized uptake value (SUV) on FDG PET is suggestive of RT, histologic confirmation is necessary. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Positron emission tomography (PET)'.)

The ability of FDG PET to identify RT differs depending on the SUV cutoff chosen and may differ according to the treatment context. In one report of 37 patients that used a PET SUV cutoff >5, PET correctly identified 10 of 11 patients with RT; however, nine additional patients had false positive PET results [38]. A subsequent study from the same institution evaluated the correlation between FDG PET and histology in 332 patients with chronic lymphocytic leukemia (CLL) [39]. Of the 95 patients with RT, the median SUV was 17.6 and 88 percent had an SUV >5. Patients without RT on biopsy were subclassified as having histologically indolent or histologically aggressive CLL, with 34 and 72 percent having SUV >5, respectively. An SUV >10 was associated with poor survival. Similarly, a French-led retrospective study of 240 patients with CLL who underwent PET scan for clinical indications found that 90 percent of those with RT had a SUVmax ≥10, with sensitivity and specificity of PET for identifying RT of 91 and 95 percent [40].

However, as illustrated in the following studies, PET appears to be less sensitive and specific for RT in patients on a BCR inhibitor. This may reflect the clinically aggressive nature (and consequent higher uptake on PET) of CLL progressions on BCR inhibitors. The low specificity reinforces the importance of biopsy to confirm suspected RT in this setting, even in lymph nodes with a very high SUVmax.

As part of enrollment in a phase 2 study, 167 patients who had progressed after ibrutinib or idelalisib were screened for RT [41]. PET-based criteria for biopsy included patients with SUVmax ≥10 at any site, and patients with TP53 disruption, unmutated IGHV, ZAP70, and/or CD38 positivity who had SUVmax 4 to 10 plus B symptoms, elevated lactate dehydrogenase (LDH), or lymph node >5 cm. Biopsy was performed in 35 of the 57 patients meeting biopsy criteria and revealed RT (8 patients), CLL (25 patients), and another malignancy (2 patients). The sensitivity and specificity for RT of a SUVmax ≥10 were relatively poor at 71 and 50 percent.

In another study, 92 patients with CLL underwent PET scan to evaluate possible disease progression after a median of 14 months on a BCR inhibitor (90 on ibrutinib, 2 on idelalisib) [42]. SUVmax was between 5 and 10 in 37 percent, and >10 in 27 percent. Targeted biopsy was performed in 54 patients and revealed RT in 46 percent (21 DLBCL and 4 HL), CLL in 33 percent, and another malignancy in 17 percent. The best cutoff for predicting RT versus other pathology was SUVmax ≥9 or more, although sensitivity and specificity were both only 72 percent. This study recommended biopsy for SUVmax of ≥5, as the sensitivity was 96 percent and the negative predictive value was 86 percent.

Bone marrow — The malignant cells of RT can occasionally be seen in the bone marrow and only very rarely in the peripheral blood. An attempt was made to predict the presence of RT without a lymph node biopsy by studying bone marrow in a group of 78 randomly selected patients with CLL and 29 patients with histologically confirmed RT [43]. The presence of >7 percent "large cells" (greatest nuclear dimension more than twice that of a normal lymphocyte) in the bone marrow along with a serum beta-2 microglobulin level >5 mg/L in a patient with CLL predicted for a clinical outcome similar to that of patients with RT (median survival nine months). However, these findings could be explained by advanced progressive CLL even in the absence of RT, and therefore serve more as prognostic markers than as necessary predictors of RT.

Histology — The histologic diagnosis in patients with RT is usually that of a diffuse large B cell lymphoma (DLBCL) [13]. A minority have morphologic features of Hodgkin lymphoma (HL) [44-46]. In some cases, the CLL and RT cells had a common clonal origin [13,46,47], while in others the RT cells apparently arose de novo [48].

The diagnosis of RT can be challenging and review by an experienced hematopathologist is important. These challenges were highlighted in one study, in which central pathologic review confirmed RT in only 83 percent of cases previously identified as RT [49].

The diagnosis of DLBCL type RT can be difficult because progressive CLL may show an increased percentage of large cells in the absence of true RT. The diagnosis of RT should be restricted to cases with confluent sheets of centroblast- or immunoblast-like large neoplastic cells. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Clinical presentation'.)

Two subtypes of HL type RT have been proposed [50]. The type 1 category is characterized by scattered or clustered Reed-Sternberg cells in a background of CLL cells. In the type 2 category, the Reed-Sternberg cells are found within a polymorphous reactive background, thereby making it indistinguishable from de novo HL. Some have proposed restricting the diagnosis of HL type RT to cases with type 2 morphology [46]. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

PATHOGENESIS — The molecular pathogenesis of Richter transformation (RT) is a complex, multistep process leading to the replication of a malignant clone of germinal or post-germinal B cell origin manifesting as diffuse large B cell lymphoma (DLBCL) or, less commonly, Hodgkin lymphoma or another clinically aggressive lymphoma subtype.

There are two possible origins of the DLBCL clone:

DLBCL may arise from the underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

DLBCL may represent a new clone

Approximately 85 percent are clonally related to the underlying CLL/SLL, and 15 percent represent a new clone [3,20,46,47,51-54]. The clonal relationship has been confirmed using different methods, including analysis of immunoglobulin isotypes [10], immunoglobulin heavy chain variable region (IGHV) gene rearrangements [1,4,55], and chromosomal abnormalities [20], although the analysis of IGHV gene rearrangements is generally considered the gold standard. Significant differences in immunophenotype (eg, loss of CD5 or CD23) can occur in RT regardless of clonal relationship with the underlying CLL [46].

The acquisition of new cytogenetic abnormalities is common in the evolution of CLL/SLL with or without RT [52]. To better understand the key pathways involved, numerous studies have evaluated the genetic evolution of CLL/SLL to RT using paired samples [52,56-58].

One seminal study performed genome-wide DNA profiling on samples from patients with [57]:

CLL/SLL without RT (315 patients, median follow up 6 years)

CLL/SLL that later developed RT (28 patients)

CLL/SLL at the time of RT (59 patients)

de novo DLBCL (127 patients)  

Key findings included [57]:

The genomic complexity of RT was intermediate between CLL/SLL without RT and de novo DLBCL. The CLL/SLL phase preceding RT had similar genomic complexity to CLL/SLL cases that did not develop RT, but had a higher frequency of certain genetic lesions (eg, del17p, del15q, add2p).

At the time of RT, approximately 50 percent had inactivation of tumor suppressor p53 (TP53 mutation or del17p; typically acquired before transformation) or inactivation of cell cycle regulator CDKN2A/B (eg, del9q, typically acquired at the time of transformation). Activation of c-MYC (8q gain) primarily occurred in RT with TP53 inactivation.

At the time of RT, an additional approximately 30 percent had trisomy 12, typically in combination with NOTCH1 mutations. Cases with trisomy 12 were mutually exclusive to cases with inactivation of TP53 or CDKN2A.

This and other genetic studies have identified the following risk factors for RT that offer insight into its pathogenesis:

TP53 aberration and inactivation of CDKN2A/B – Aberration of the TP53 tumor-suppressor impairs DNA damage response and is associated with worse outcomes in patients with CLL/SLL and RT. TP53 mutations are more common in RT than CLL/SLL without transformation [57]. Mutations of INK4a/ARF, a possible upstream regulator of p53 activity, have been found in 29 percent of RT cases as compared with 4 percent of CLL/SLLs [59] and are often present when TP53 mutation is absent [60]. Together these mutations are present in about 60 percent of RT [1,57]. (See "Pathobiology of chronic lymphocytic leukemia", section on 'Impaired DNA damage response'.)

In mouse models of CLL/SLL, knockout of TP53 or ATM lead to a more aggressive CLL/SLL that rarely undergoes RT [61]. However, RT can be induced by simultaneous loss of TP53, CDKN2A, and CDKN2B in a mouse model [62].

IGHV mutation status CLL/SLL with unmutated IGHV is also associated with progressive disease and a poor prognosis. Several studies have found that many cases of RT appear to arise from CLL with unmutated IGHV [5,46,53,63]. One study found that 18 of 23 (78 percent) cases of DLBCL RT demonstrated clonality with the underlying CLL by IGHV sequence analysis, and of these, 73 percent of the underlying CLLs had unmutated IGHV genes [46]. Interestingly, four of the five RTs that were not clonal with the underlying CLL had mutated IGHV genes. (See "Pathobiology of chronic lymphocytic leukemia", section on 'Cell of origin'.)

A possible exception is the Hodgkin lymphoma variant of RT, which commonly has mutated IGHV. Hodgkin lymphoma is thought to arise from germinal center or post-germinal center B cells, which have undergone somatic hypermutation [64]. In one study, five of six cases of CLL associated with Hodgkin variant RT were found to have mutated IGHV genes [46]. In another study, three of four cases of Hodgkin variant RT lacked expression of ZAP-70 [64]; the lack of ZAP-70 expression usually correlates with mutated IGHV.

NOTCH1 mutations, trisomy 12 – A subset of CLL/SLL tumors have activating mutations in coding and noncoding regions of the NOTCH1 proto-oncogene, causing aberrant splicing events, increased NOTCH1 activity, and more aggressive disease. NOTCH1 mutations are associated with unmutated IGHV and trisomy 12. NOTCH1 mutation has been associated with a higher risk of RT [22]. (See "Pathobiology of chronic lymphocytic leukemia", section on 'Genetic abnormalities'.)  

PI3K/AKT signaling is initiated downstream of the BCR signaling pathway. CLL with NOTCH1 mutation, TP53 mutation, or del17p have an increased rate of constitutive phosphorylation of AKT. In a mouse model of CLL, genetic constitutive activation of AKT led to expansion of CD4 T cells in the microenvironment and upregulation of NOTCH1, and high rates of RT [65].

BCR stereotypy, particularly subset 8 – CLL/SLL cells express BCRs with a limited immunoglobulin repertoire characterized by restricted heavy and light chain usage (referred to as BCR stereotypy). An individual BCR stereotype reflects a group of CLL/SLL cases with essentially identical BCRs, a finding that is vanishingly unlikely by chance, and therefore likely reflects selection potentially by a common antigen(s). Different subsets presumably have different biological backgrounds, prognosis, and response to treatment [66]. Stereotyped subset 8, which is also associated with NOTCH1 mutation, is an independent risk factor for RT [5,19]. (See "Pathobiology of chronic lymphocytic leukemia", section on 'BCR stereotypy'.)

BCR stereotypy suggests a role for antigens in the pathogenesis and evolution of CLL/SLL. Some but not all studies have implicated the Epstein-Barr Virus (EBV) in the pathogenesis of RT [13,67,68]. Although the pathogenic role of the virus is unclear, evidence for its involvement is probably greatest in the Hodgkin lymphoma variant of RT, in which EBV can be found in the malignant Hodgkin/Reed-Sternberg cells in a majority of the limited reported cases [1,13].

TREATMENT AND PROGNOSTIC FEATURES

Prognosis — Historically, Richter transformation (RT) has been associated with a dismal prognosis, with median survivals of five to eight months [1,69,70]. In a series of 148 patients with biopsy-proven RT, of whom 135 received therapy and 130 were assessable, the overall response rate to a variety of regimens was 39 percent, with 12 percent complete responses (CR) [13]. Although not statistically significant, there appeared to be an improvement in response rate with the addition of rituximab, from 34 percent to 47 percent. The median failure-free and overall survivals were seven and eight months, respectively.

On multivariate analysis, factors that independently correlated with shorter survival included [13]:

Platelet count <100,000/microL

Eastern Cooperative Oncology Group (ECOG; Zubrod) performance status >1 (table 1)

Tumor size >5 cm

More than one prior treatment

Lactate dehydrogenase (LDH) level >1.5 times the upper limit of normal

Median survivals for those with zero to one, two, three, or four to five of these adverse factors were 1.12, 0.90, 0.33, and 0.14 years, respectively.

Another series of 86 patients with biopsy-proven RT reported a median survival from the time of RT diagnosis of 19 months [20]. On multivariate analysis, the following factors were independent predictors of shorter survival:

ECOG (Zubrod) performance status >1 (table 1)

Failure to achieve a CR after induction therapy for RT

TP53 disruption on molecular analysis

Patients with an ECOG performance status >1 had a poor outcome, irrespective of the other two factors, with a median survival of 7.8 months. Patients with an ECOG performance status <1 who did not have evidence of TP53 disruption and achieved a CR with induction therapy had the best outcomes with a five-year survival rate of 70 percent. All other patients had an intermediate prognosis and a median survival of 24.6 months.

Of importance, the clonal relationship between the RT and the original chronic lymphocytic leukemia (CLL) was determined in 63 patients, 79 percent of which were clonally related. Patients with clonally unrelated diffuse large B cell lymphoma (DLBCL) had a significantly longer median survival (63 versus 14 months) that resembled that of de novo DLBCL. These results suggest a subset of patients with clonally unrelated DLBCL may be cured of their DLBCL. Prospective studies are needed to confirm whether clonally unrelated DLBCL occurring in the context of CLL has similar outcome to de novo DLBCL.

One additional large series of 204 biopsy-proven cases of RT reported a median overall survival (OS) of 12 months [11]. Key predictors of improved survival included treatment-naïve CLL (median OS 46.3 versus 7.8 months), normal LDH, and intact TP53. IGHV, cell of origin, and double or triple hit status had no impact on survival, underscoring the distinct biology of RT.

Treatment — The preferred treatment depends on the histology and treatment context (algorithm 1). Our approach is generally consistent with guidelines from the National Comprehensive Cancer Network [71], The European Society of Medical Oncology [72], and the British Society for Haematology [73].

DLBCL variant — Most patients with the DLBCL variant of RT are treated with combination chemotherapy regimens used for patients with de novo DLBCL with the goals of symptom relief and minimizing disease burden (algorithm 1). In patients with clonally related RT, CRs after chemotherapy are short-lived, and treatment with chemotherapy alone is palliative; allogeneic hematopoietic cell transplantation (HCT) may offer long-term survival. Patients who develop RT while on a Bruton tyrosine kinase (BTK) inhibitor may have particularly poor outcomes [34,36], and these patients should be referred for clinical trials or considered for novel agent therapy rather than standard chemotherapy [35]. In contrast, patients who develop RT while on venetoclax may achieve long-term survival with standard chemotherapy with or without autologous HCT [74].

Long-term survivors have been reported following allogeneic HCT; as such, we offer nonmyeloablative allogeneic HCT to most eligible patients in remission, although the number of patients eligible for allogeneic HCT who also attain a stable remission is small. While initial studies have demonstrated responses with targeted therapies, further research is needed to determine the best way to use these agents for patients with RT.

Evidence regarding the treatment of RT comes from small, single-arm prospective trials and extrapolation of data from other aggressive B cell malignancies. There have been no randomized clinical trials evaluating treatments in RT. Given the suboptimal results with available regimens, patients should be encouraged to participate in clinical trials, when available.

The role of radiation therapy is generally limited to palliation, since RT is rarely a localized disease. Adjuvant radiation therapy, analogous to the approach used for limited stage DLBCL, may also be considered for the rare case in which RT is localized. (See "Initial treatment of limited stage diffuse large B cell lymphoma".)

Combination chemotherapy — For most patients with the DLBCL variant of RT, we suggest combination chemotherapy with anthracycline-based regimens such as that used for de novo DLBCL rather than more aggressive or less aggressive regimens (algorithm 1). We usually offer R-CHOP-21 (ie, cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab, given every 21 days) in this setting, but dose-adjusted (da)-EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab) is also reasonable.

Small studies that have evaluated combination chemotherapy regimens used for aggressive non-Hodgkin lymphomas or acute lymphoblastic leukemias reported overall response rates ranging from 5 to 40 percent [1,13,75-78]. In three reports from MD Anderson, median survival duration was 8 to 10 months despite intensive multiagent chemotherapy (eg, hyper-CVXD, CHOP, ESHAP, MINE, FCR), with or without the addition of rituximab, with complete and overall response rates of 14 and 39 percent, respectively [13], and a rate of early death as high as 20 percent [75,76]. The overall response rate was higher when rituximab was added to the chemotherapy regimen (47 versus 34 percent), although this difference did not attain statistical significance.

A retrospective study of 46 RT patients receiving EPOCH-R suggested a possible plateau on the progression free survival (PFS) curve which has not been seen with other chemotherapy regimens, although the median PFS was only 3.6 months and the regimen was toxic [78]. In multivariable analysis, the primary predictor of poor survival was a complex CLL karyotype.

A combination chemotherapy regimen containing oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) has been developed for RT and fludarabine-refractory CLL [79]. Twenty patients with RT were treated, with a 50 percent response rate and a median response duration of 10 months. Unfortunately however the six-month overall survival rate of this group was still only 59 percent. Yttrium-90 ibritumomab tiuxetan has been tested in seven patients with no clinical responses and significant hematologic toxicity [77]. Improved therapeutic options are clearly needed.

Hematopoietic cell transplantation (HCT) — Since CRs after chemotherapy are short-lived, and long-term survivors have been reported following HCT, we and others suggest the use of nonmyeloablative allogeneic HCT when first remission has been achieved in patients who are transplant candidates (algorithm 1) [80].

Observation until progression is an acceptable alternative to consolidation with transplant for those who achieve a CR after initial anthracycline-based combination chemotherapy if the DLBCL variant RT is clonally unrelated to the prior CLL, or if they are diagnosed simultaneously. If clonal relationship cannot be determined (as is common in clinical practice), patients with DLBCL variant who have not received therapy for CLL prior to RT and achieve CR after initial anthracycline-based combination chemotherapy can do well without transplant consolidation [11,20,35].

Data regarding HCT in this setting are limited to retrospective case series [13,80-84]. Studies of allogeneic HCT using modern transplant techniques in RT have reported approximately 40 percent of patients alive and free of disease progression at four to five years [84-86].

While older, the following data compare HCT versus no HCT and allogeneic HCT versus autologous HCT.

A potential benefit from consolidative HCT was demonstrated in a single-center case series of 20 patients with RT treated with chemotherapy or chemoimmunotherapy with or without HCT (3 autologous, 17 allogeneic of which 15 were nonmyeloablative) [13]. Estimated three-year overall survival rates were:

75 percent for patients who underwent allogeneic HCT following an objective response to prior chemotherapy (ie, attainment of CR, CRu, or partial response [PR]). Four of the 17 patients undergoing allogeneic HCT in this report remained in CR, with progression-free survivals between one and six years.

27 percent for patients with an objective response to chemotherapy who did not have a consolidative HCT.

21 percent for patients with relapsed or refractory RT who underwent allogeneic HCT as salvage therapy.

A potential benefit from HCT was further supported by a retrospective, multicenter analysis of 59 patients with RT who underwent HCT [82].

Autologous HCT was performed in 34 patients, 28 of whom had documented chemotherapy-sensitive disease. Estimated three-year overall survival and relapse-free survival and the cumulative incidences of relapse and nonrelapse mortality were 59, 45, 43, and 12 percent, respectively.

Allogeneic HCT was performed in 25 patients, 16 of whom had documented chemotherapy-sensitive disease. Reduced intensity conditioning was used in 18 cases. Estimated three-year overall survival, relapse-free survival, and the cumulative incidences of relapse and nonrelapse mortality were 36, 27, 47, and 26 percent, respectively. When compared with younger adults, those over 60 years at the time of HCT had inferior estimated survival (17 versus 47 percent) and relapse-free survival (0 versus 42 percent) at three years.

Activity of targeted therapies — Therapies targeted at the B cell signaling pathway, immune checkpoint regulation, and other pathways are being studied in RT. Interest in these targeted therapies has been driven by the poor response rates and durability of combination chemotherapy in patients with the DLBCL histologic pattern of RT, as well as the advent of targeted therapies for CLL. While initial studies have demonstrated responses with targeted therapies, further study is needed to determine the best way to use these agents for patients with RT. Many experts turn to these options first in patients with aggressive progression on a BTK inhibitor. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

The following studies illustrate the published experience with some of these agents:

Venetoclax (BCL2 inhibitor) – PRs were seen in three of seven patients with RT treated with venetoclax [87]. In a phase 2 study of venetoclax plus R-EPOCH in RT, CR was obtained in 13 of 26 patients (50 percent), median PFS was 10.1 months, and median OS was 19.6 months [88]. Of the 18 patients who were candidates for cellular therapy at the time of enrollment, eight proceeded to allogeneic HCT and one underwent chimeric antigen receptor T cell therapy.

BTK inhibitors – In a case series of four ibrutinib-naïve patients with RT, ibrutinib resulted in one CR and two PRs, with median duration of ibrutinib therapy of six months [89]. In a single-arm trial of acalabrutinib in RT, responses were seen in 10 of 25 patients (2 complete) with a median duration of response of 6.2 months [90]. Median PFS was 3.2 months.

Pembrolizumab (PD-1 inhibitor) – In a phase 2 study of pembrolizumab, objective responses were seen in four of nine patients with RT who had received prior ibrutinib (no activity was seen in the 16 patients with CLL) [91]. There was one CR. At a median follow-up of 10.4 months, three patients with RT had progressed and four had died. In another phase 2 study of pembrolizumab, a partial response was seen in 1 of 21 patients with DLBCL variant RT [92]. Both patients with Hodgkin lymphoma variant RT had an objective response, one of which was complete.

Nivolumab (PD-1 inhibitor) – An ongoing study at MD Anderson has also suggested activity of nivolumab in RT [93]. Patient numbers remain quite small, however, so additional studies will be needed.

CAR-T cells — Chimeric antigen receptor T (CAR-T) cells are a treatment option for patients with DLBCL relapsed after two or more lines of systemic therapy. While regulatory approval includes patients with transformation from follicular lymphoma, CAR-T remains investigational (off-label) for patients with RT.

CAR-T cells are a form of genetically modified autologous immunotherapy. This customized treatment uses the patient's own T lymphocytes, which are genetically modified (transduced) 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.

The largest published cohort was a single center report of axicabtagene ciloleucel (axi-cel) in nine patients with RT [94]. One patient died after a complicated hospital course following infusion. Of the other eight, all had an at least partial response, including three complete responses. After a median follow-up of six months, one patient had disease progression and seven remained in remission, one of which had undergone allogeneic HCT. Another study using a locally produced CAR-T cell in eight patients with transformed CLL included six patients with RT and reported that five of eight achieved complete response at one month [95].

Further study, with longer follow-up, is needed before incorporating CAR-T cells into the routine management of patients with RT. Use of CAR-T in CLL is discussed in more detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Chimeric antigen receptor T cells'.)

Hodgkin lymphoma variant — For the Hodgkin lymphoma (HL) variant of RT, data on therapy are limited; we suggest the use of combination chemotherapy regimens employed in patients with advanced stage HL (eg, doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]) (algorithm 1).

Those that achieve a CR are observed until progression. Those who do not achieve a CR are offered serial regimens used for refractory HL with a plan to perform nonmyeloablative allogeneic HCT in first CR, if feasible. The majority of patients have high-risk features if prognostic models for de novo HL are applied [12,45,96]. Disease response and clinical outcomes are worse than in de novo HL but better than in DLBCL RT [9,12,44,69]. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

The majority of patients reported in the literature have received combination chemotherapy targeted at HL, including ABVD, MOPP, or CVPP, with a 44 percent response rate in the largest series and some long-term survivors [12]. In one study, the CR rate following ABVD was 68 percent overall [96]. The CR rate was influenced by the International Prognostic Score and time from last CLL treatment. Achieving CR with ABVD was the only significant predictor of survival.

Regimens used for aggressive non-Hodgkin lymphoma such as those used for DLBCL RT have also been tried, with fewer reported successes [12].

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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic lymphocytic leukemia/small lymphocytic lymphoma".)

SUMMARY AND RECOMMENDATIONS

When to suspect – Richter transformation (RT) should be suspected in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who develop rapidly progressive lymphadenopathy or extranodal sites of disease, systemic symptoms, or elevated levels of serum lactate dehydrogenase. (See 'Incidence and clinical features' above.)

Diagnosis – Biopsy is required to confirm the diagnosis. Biopsy should aim to sample a lymph node with the highest avidity on positron emission tomography (PET) imaging. Histology usually shows a pattern consistent with diffuse large B cell lymphoma (DLBCL). Occasional patients may have a histologic picture consistent with Hodgkin lymphoma (HL). The diagnosis of RT can be challenging, and review by an experienced hematopathologist is important. (See 'Making the diagnosis' above.)

Prognosis – The prognosis and outcome are historically poor for RT, and the disease is invariably fatal if left untreated. (See 'Prognosis' above.)

Treatment – The preferred treatment depends on the histology and treatment context (algorithm 1) (see 'Treatment' above):

For most patients with the DLBCL histologic pattern of RT, we suggest the use of combination chemotherapy plus rituximab as employed for aggressive lymphoma rather than more or less aggressive therapies (table 2) (Grade 2C). We usually offer R-CHOP-21 (ie, cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab, given every 21 days) in this setting, but dose-adjusted (da)-EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab) is also reasonable.

An important exception is that patients who develop RT on a Bruton tyrosine kinase (BTK) inhibitor should be referred for a clinical trial or considered for novel agent therapy rather than standard chemotherapy, since these patients often have an aggressive course.

Since complete remissions after chemotherapy are short-lived, and long-term survivors have been reported following hematopoietic stem cell transplantation (HCT), we suggest nonmyeloablative allogeneic HCT when first remission has been achieved in most patients who are transplant candidates (Grade 2B). Observation until progression is an acceptable alternative to consolidation with transplant for those in first remission after initial anthracycline-based combination chemotherapy if the DLBCL variant RT is clonally unrelated to the prior CLL, or if they are diagnosed simultaneously. (See 'Hematopoietic cell transplantation (HCT)' above.)

For patients with the HL variant of RT, data are very limited; we suggest the use of combination chemotherapy regimens employed in patients with advanced stage HL (eg, ABVD) (Grade 2C). (See 'Hodgkin lymphoma variant' above and "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

Given the limited data on treatment outcomes for RT, all patients with RT are best advised to enroll in an appropriately designed clinical trial, particularly those whose RT developed while on a BTK inhibitor.

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References