Current Treatment of Burkitt Lymphoma and High-Grade B-Cell Lymphomas

Oncology, ONCOLOGY Vol 36, Issue 8, Volume 36, Issue 8
Pages: 499-505

P. Connor Johnson, MD, and Jeremy S. Abramson MD, MMSc, discuss available treatments for patients with Burkitt lymphoma and high-grade B-cell lymphoma.


Purpose of Review: This article reviews the current data and future directions in the management of Burkitt lymphoma (BL) and high-grade B-cell lymphoma (HGBL).

Recent Findings: BL is a rare, mature B-cell lymphoma molecularly defined by translocation of the proto-oncogene MYC. Multiple intensive combination chemoimmunotherapy regimens have demonstrated excellent efficacy in this disease, although treatment toxicity remains a challenge in many patients. Double-hit lymphoma (DHL) represents HGBL with translocations of the oncogene MYC along with either BCL2 or BCL6, or both. In 2016, the World Health Organization update of this classification was revised to a new entity defined by cytogenetics: HGBL with MYC and BCL2 and/or BCL6 rearrangements. Recent prospective data using dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab has demonstrated encouraging treatment efficacy in these patients. HGBL, not otherwise specified (NOS) is a heterogeneous, aggressive, mature B-cell lymphoma that does not meet criteria for BL, DHL, or diffuse large B-cell lymphoma NOS. Therapy for this entity is not well established.

Summary: The aggressive B-cell lymphomas BL, DHL, and HGBL, NOS are unique diseases with specific pathogenesis and biology. Insights into the molecular biology of these diseases have enabled new classifications and personalization of therapy.

Key Words: non-Hodgkin lymphoma; diffuse large B-cell lymphoma; high- grade B-cell lymphoma; Burkitt lymphoma; double-hit lymphoma


Non-Hodgkin lymphoma (NHL) is the seventh most common cancer in the United States, with approximately 77,000 new cases and 20,000 deaths in 2020.1 A significant minority of these cases were the especially aggressive B-cell lymphomas Burkitt lymphoma (BL) and high-grade B-cell lymphoma (HGBL), the latter of which includes the histologic subtypes HGBL with MYC and BCL2 and/or BCL6 translocations (conventionally referred to as double-hit lymphoma [DHL]) and HGBL, not otherwise specified (NOS).2 The understanding of the molecular pathogenesis of these diseases continues to expand, which has permitted changes in classification and further personalization of therapy in these diseases.2 In this article, we review the pathogenesis and management of BL and HGBL.

Burkitt Lymphoma

Histology and molecular biology

BL is an uncommon mature B-cell NHL, accounting for approximately 1% of all cases of NHL. It is one of the most aggressive malignancies in existence, with a rapid growth pattern, and it is uniformly fatal if untreated.3,4 BL is classified into 3 variant forms: the “endemic” variant, which is associated with Epstein-Barr virus (EBV) and has a geographic pattern of incidence; an “immunodeficiency-associated” variant, which is typically associated with HIV; and a “sporadic” variant, which most frequently occurs in young adults.5-7 Morphologically, BL involves monomorphic medium-sized B cells with basophilic cytoplasm, numerous mitotic figures, rounded nuclei with finely clumped chromatin, myriad apoptosis, and tingible body macrophages, which result in a classic “starry sky” pattern. Immunophenotypically, the cells express membrane IgM with light chain restriction, CD19, CD20, CD22, CD79a, PAX5 (B-cell antigens), the germinal center markers CD10 and BCL6, and strong MYC expression with a Ki-67 of nearly 100%. The molecular hallmark of the disease is the translocation of the proto-oncogene MYC at band 8q24 to the IGH region on chromosome 14q32, t(8;14)(q24;q32) or, less frequently, to the IGK locus on 2p12, t(2;8), or the IGL locus on 22q11, t(8;22). In a minority of cases, no MYC rearrangement can be identified, but gene-expression profiling has identified identical signatures to the typical MYC translocated cases.8 Additionally, the 2016 revision of the World Health Organization (WHO) Classification of Lymphoid Tumors added a provisional entity called Burkitt-like lymphoma with 11q aberration, which lacks a MYC rearrangement but instead has a chromosome 11q alteration with interstitial gains in 11q23.2-23.3 and losses of 11q24.1-qter.8

Clinical presentation and prognostic factors

Each variant of BL has distinct clinical features. The endemic variant typically occurs in children aged 4 to 7 years, with a male predominance and a predilection for jaw involvement, although other extranodal sites can be involved; it is uniformly associated with EBV.3,9 Endemic BL classically occurs in equatorial Africa and Papua New Guinea. The immunodeficiency variant typically occurs in patients with HIV infection, usually with preserved CD4 counts, and often presents with abdominal disease and extranodal involvement, and is associated with EBV in 25% to 40% of cases.7,8 Sporadic BL has a median age at diagnosis of 30 years and also frequently presents with abdominal involvement, most classically the ileocecal valve; 20% to 30% of cases are associated with EBV.8,10,11 Recently, a large multicenter study created an adult BL prognostic model, identifying age greater than or equal to 40 years, an ECOG performance status greater than or equal to 2, a lactate dehydrogenase (LDH) level exceeding 3 times the institutional upper limit of normal (ULN), and central nervous system (CNS) involvement as independent prognostic factors. The BL International Prognostic Index (IPI) comprises these 4 risk factors and places patients into categories of low risk (0 risk factors; 3-year progression-free survival [PFS] rate, 92%), intermediate risk (1 risk factor; 3-year PFS rate, 72%), and high risk (≥ 2 risk factors; 3-year PFS rate, 53%).12


BL is a highly curable disease, with a recent real-world study demonstrating a 3-year overall survival (OS) rate of approximately 70%.13 Historically, commonly used regimens included intensive therapies such as CODOX-M/IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate, etoposide, ifosfamide, cytarabine, intrathecal methotrexate, and cytarabine) or Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine), although more recent data have emerged with DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab).14-16 The backbone of many active regimens in this disease includes cyclophosphamide, doxorubicin, and vincristine, as well as CNS-penetrating agents.17,18 Commonly used contemporary regimens include modified R-CODOX-M/R-IVAC,16,19-21 R-Hyper-CVAD,14,22 the CALGB-10002 trial (NCT00039130) regimen,23,24 DA-EPOCH-R,15,25 and European LMBA02 (NCT00180882)26,27 and GMALL05 (NCT00199082) trial regimens.28 No randomized clinical trials have been conducted to identify a single preferred regimen. Maintaining treatment intensity is challenging, and treatment-related mortality is a critical problem, most notably in older or frail adults and immunocompromised individuals.

Magrath and colleagues initially published data using CODOX-M/IVAC with intrathecal methotrexate and cytarabine. Patients with low-risk disease, defined as a single site less than 10 cm with a normal LDH (or completely resected abdominal disease), received 3 cycles of CODOX-M; all others received 4 courses of alternating therapy with CODOX-M and IVAC. In a patient population with a median age of 25 years, the 2-year event-free survival (EFS) rate was 92%.16 Because of the high rates of toxicity with this regimen, investigators established a modified-Magrath regimen with reduced doses of methotrexate and cytarabine, demonstrating a 2-year PFS rate of 64%, including a 2-year PFS rate of 49% in high-risk patients.19 The addition of rituximab to CODOX-M/IVAC is associated with enhanced PFS and OS,29 and a phase 2 study including mostly high-risk patients that included rituximab with CODOX-M/IVAC reported a 2-year PFS rate of 80% and 2-year OS rate of 80%.30 Hyper-CVAD demonstrated a 3-year OS rate of 49%,14 and the addition of rituximab was associated with improved outcomes, including a 3-year EFS rate of 80% and 3-year OS rate of 89%.14 A regimen developed by the Cancer and Leukemia Group B incorporating prephase therapy of cyclophosphamide and prednisone followed by 3 cycles of ifosfamide, methotrexate, vincristine, cytarabine, etoposide, and dexamethasone alternating with cyclophosphamide, methotrexate, vincristine, doxorubicin, and dexamethasone, as well as intrathecal chemotherapy, demonstrated a 5-year OS rate of 52% (of note, a portion of these patients also received cranial irradiation).23 As with other regimens, the inclusion of rituximab was associated with improved outcomes, with a prospective study noting a 4-year EFS rate of 74% and 4-year OS rate of 78%.24 The French Lymphomes Malins B (LMB) regimen administered cyclophosphamide, doxorubicin, vincristine, and prednisone (COPAD) to low-risk patients (resected stage I and abdominal stage II disease). For high-risk patients (bone marrow and/or CNS involvement) and intermediate-risk patients (all others), prephase therapy included cyclophosphamide, vincristine, and low-dose steroids. The intermediate group received 5 additional cycles of COPADM/CYM, which also included high-dose methotrexate, cytarabine, and intrathecal methotrexate, and high-risk patients received 8 cycles with augmented doses of methotrexate, cytarabine, etoposide, and intrathecal methotrexate and cytarabine, or COPADM, CYVE. Those with CNS involvement also received cranial radiotherapy to 24 Gy. The 2-year EFS rate with this regimen was 65% in a cohort with a median age of 33 years.26 The addition of rituximab was evaluated in a phase 3 randomized controlled trial, with its incorporation resulting in improved 3-year EFS (75% vs 62%) and no difference in adverse events.27

More recently, prospective data using the less intensive DA-EPOCH-R regimen have emerged. Investigators at the National Cancer Institute treated 30 patients, including a cohort of HIV-negative patients receiving DA-EPOCH-R and a cohort of HIV-positive patients treated with short course (SC)-EPOCH-RR (2 rituximab doses per cycle). The median age was 33 years in this study, with a median follow-up of 86 months and 73 months in the respective groups; the freedom from progression was 95%.25 A multicenter follow-up study enrolled 113 patients, with a median age of 49 years. Low-risk patients, defined as having stage I or II disease with normal LDH, no mass greater than or equal to 7 cm, and an ECOG performance status of 0 or 1, received 3 cycles of DA-EPOCH-RR without CNS prophylaxis, and high-risk patients received 6 cycles of DA-EPOCH-R with intrathecal CNS prophylaxis on days 1 and 5 of cycles 3 through 6 (or with extended intrathecal treatment twice weekly for at least 4 weeks, weekly for 6 weeks, and then monthly for 6 months if active CNS involvement). At a median follow-up of 58.7 months, the EFS rate was 84.5% and OS rate was 87.0%, including EFS rates of 100% and 82% in low- and high-risk patients, respectively. Among 11 patients with cerebrospinal fluid involvement at presentation, 6 experienced disease progression or died, with a 4-year EFS rate of 45.5% compared with 89.9% in those with high-risk disease but no CNS involvement, suggesting that intensive regimens with augmented CNS penetration may be preferable in this subset of patients. Inferior outcomes were also seen in those with blood and/or marrow involvement, for whom more intensive strategies can be considered in young, fit patients.15

Relapsed BL, although uncommon, remains an unmet medical need, as the prognosis remains extremely poor, with a median survival of approximately 2.8 months.31-33 Salvage regimens using hyper-CVAD reinduction, high-dose cytarabine, R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), and R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin) have all been used with limited data for long-term efficacy, and patients who do achieve remission should be considered for transplant.33 Given the unmet need for rationally designed therapies, a phase 2 study investigating CPI-613, an analogue of lipoic acid and inhibitor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, in relapsed BL is currently ongoing (NCT03793140), and other effective agents in chemotherapy-refractory aggressive B-cell lymphomas such as chimeric antigen receptor (CAR) T-cell therapy warrant further evaluation.34

Double-Hit Lymphomas

Histology and molecular biology

DHL is the conventional terminology for an HGBL with translocations of the oncogene MYC along with either BCL2 or BCL6, or both. The 2008 WHO classification previously classified this entity morphologically as either diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLu). However, in the 2016 WHO update, this entity was revised to a new entity defined by cytogenetics, called HGBL with MYC and BCL2 and/or BCL6 rearrangements.8 DHLs usually have germinal center B-cell–like (GCB) cell of origin, particularly DHL with rearrangements of MYC and BCL2, which is the most common variation of DHL, although a minor fraction of cases can be non-GCB (usually MYC and BCL6 DHL). Most cases have high Ki-67 proliferation fractions and immunohistochemical coexpression of MYC and BCL2 and/or BCL6.35-40

Clinical presentation and prognostic factors

The clinical presentation of DHL is often in older adults; it typically presents at an advanced stage of disease with frequent extranodal involvement and elevated LDH.41 Bone marrow and peripheral blood involvement is more common with DHL than with DLBCL, and the risk of CNS involvement is high at initial diagnosis or relapse. Historically, the prognosis of DHLs has been poor, with a median OS of less than 1 year,42-45 but these data have been affected by selection bias, in which only the most aggressive-appearing cases (either clinically or histologically) were evaluated via fluorescence in situ hybridization for the presence of MYC translocations.46 A prospective series of DHLs that were morphologically classified as DLBCL and uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP–like chemoimmunotherapy demonstrated a 5-year PFS of approximately 60%, suggesting that the prognosis is indeed more favorable than initially reported in retrospective studies and highlighting that good clinical outcomes can be achieved in a significant proportion of patients with morphologic DLBCL with MYC and BCL2 and/or BCL6 translocation utilizing standard R-CHOP.47 With respect to prognostic factors, the IPI is associated with outcome,37,48 and in a large retrospective analysis, advanced stage, LDH level greater than 3 times the institutional ULN, leukocytosis, and CNS involvement were all adverse factors with respect to OS.48


Management of DHL remains relatively controversial in the absence of randomized trials, but historically poor outcomes with R-CHOP have prompted investigations of more intensive treatment strategies. Retrospective data demonstrated a 2-year PFS rate of less than 20% with R-CHOP compared with approximately 50% with more intensive treatment regimens, such as DA-EPOCH-R, R-Hyper-CVAD, or R-CODOX-M/R-IVAC.48 However, multiple recent studies, including a cohort of patients from prospective clinical trials and population registries with morphologic DLBCL and the presence of MYC and BCL2 and/or BCL6 rearrangements, have shown better outcomes with R-CHOP than previously reported, with a 2-year PFS rate of approximately 60%.47,49 These findings underscore that initial retrospective data were likely affected by significant selection bias and that some patients, particularly those with morphologic DLBCL, may have superior clinical outcomes with R-CHOP than was previously thought. A multicenter study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphomas given for 6 cycles and administered with prophylactic intrathecal methotrexate demonstrated an overall response rate (ORR) of 87%, a 48-month EFS rate of 71%, and a 48-month OS rate of 77%; 45% of patients had DHL, with a 4-year EFS rate of 73%.50 A recent multicenter Alliance for Clinical Trials in Oncology randomized clinical trial investigated DA-EPOCH-R with or without the BCL2 inhibitor venetoclax in DHLs. Although the addition of venetoclax resulted in excess toxicity and death, the control arm of DA-EPOCH-R demonstrated an ORR of 73%, a complete response rate (CRR) of 67%, and a 15-month PFS rate of approximately 65%. This prospective clinical trial is the largest conducted to date in DHL and provides prospective clinical trial data for the use of DA-EPOCH-R in this disease with favorable outcomes compared with historical studies.51 Consolidation with high-dose chemotherapy has been utilized at some centers, but retrospective analyses have not demonstrated a survival advantage.37,48,52 Limited-stage disease is uncommon but is associated with a much more favorable prognosis, with a 2-year PFS rate approaching 75% and 2-year OS rate of approximately 80% with R-CHOP or DA-EPOCH-R.48,53,54 R-CHOP may be sufficient systemic therapy in patients with limited-stage disease, although many practitioners still prefer DA-EPOCH-R in the absence of a contraindication. In the absence of definitive data, our preference is to include consolidative radiation therapy for localized disease, given that this disease has exhibited an increased risk of chemoresistance.53

In the relapsed setting, salvage chemoimmunotherapy regimens have been associated with dismal outcomes,37,48 and the most effective therapy to date in the relapsed setting is anti-CD19 CAR T-cell therapy, with response rates of approximately 80% and durable PFS in approximately 40% of patients.55-58 Notably, outcomes with CAR T-cell therapy appear to mirror that of other non-DHL disease subtypes, in stark contrast to chemotherapy.

Additional novel therapies have been developed primarily in DLBCL but have included a small number of HGBL cases in pivotal trials. Loncastuximab tesirine-lpyl, an antibody-drug conjugate containing a humanized CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin, SG3199, was evaluated in relapsed/refractory DLBCL, including 15 cases of DHL. The ORR for the entire study was 48%, with a 24% CRR, median duration of response (DOR) of 10.3 months, and manageable safety profile. Among DHL cases, the ORR was 33%, with a CRR of 33% and median DOR of 13 months.59 Polatuzumab vedotin-piiq, a CD79B-targeting antibody-drug conjugate with monomethyl auristatin E, a microtubule inhibitor, was evaluated in combination with rituximab and bendamustine in a cohort of patients with DLBCL that included 5 with HGBL. The ORR for the entire study was 62.5%, with a CRR of 52.5% and DOR of 10.9 months.60 Tafasitamab-cxix, an anti-CD19 monoclonal antibody, was evaluated in combination with lenalidomide in the L-MIND trial (NCT02399085), a phase 2 trial of adults with relapsed/refractory DLBCL. The regimen demonstrated durable remissions in a subset of patients and an encouraging safety profile, but patients with DHL were excluded from this study.61 Selinexor, a novel oral selective inhibitor of nuclear export, was examined in patients with relapsed/refractory DLBCL, including 5 patients with DHL. Among all 127 patients evaluated in the study, the ORR was 28%, with a CRR of 12% and median DOR of 9 months.62 Finally, multiple bispecific antibodies with binding to CD20 on B cells and CD3 on T cells have emerged as promising therapeutics in relapsed/refractory aggressive B-cell NHLs, including DHL. Mosunetuzumab in aggressive B-cell NHLs demonstrated an ORR of 35%, CRR of 19%, and median DOR of 23 months in patients with a complete response.63 Glofitamab in aggressive B-cell NHLs demonstrated an ORR of 48%, CRR of 33%, and overall median DOR of 5.5 months.64 Epcoritamab in patients with relapsed/refractory DLBCL showed an ORR of 68% and a CRR of 45%,65 and odronextamab administered to patients with relapsed/refractory DLBCL demonstrated an ORR and CRR of 60%, with a median DOR of 10 months in those without prior CAR T-cell therapy versus an ORR of 33%, CRR of 24%, and median DOR of 3 months in those with prior CAR T-cell therapy.66

CNS prophylaxis has historically been routinely incorporated into up-front therapy, given the increased risk of CNS involvement; however, multiple recent large retrospective studies have called into question the utility of CNS prophylaxis in DLBCL, demonstrating similar CNS relapse rates as a series without prophylaxis incorporated.48,67-69 Whether CNS prophylaxis is effective at reducing CNS events specifically in DHL is unknown, but it has been associated with improved outcomes in a multicenter retrospective analysis and is routinely included by many practitioners. Novel targets continue to be explored in this disease, including venetoclax in combination with R-CHOP, and inhibition of PLK1, which promotes MYC protein stability.70,71

High-Grade B-Cell Lymphoma, NOS

Histology and molecular biology

HGBL, NOS is a biologically heterogeneous aggressive mature B-cell lymphoma that does not meet criteria for DHL, DLBCL, NOS, or BL.8 In the previous 2008 WHO classification, HGBL, NOS cases were included alongside DHL in the category of B-cell lymphoma, unclassifiable, with features intermediate between those of DLBCL and BL. Given the separation of DHL into its own classification, HGBL, NOS encompasses the remaining cases of this prior classification category, such as blastoid-appearing mature B-cell neoplasms that do not meet a diagnosis of mantle cell lymphoma. The morphologic appearance of HGBL, NOS mimics BL, with a diffuse proliferation of medium to large cells with no stromal reaction or fibrosis. Starry-sky macrophages, mitotic figures, and apoptosis are common. There can be greater morphologic heterogeneity than in a typical BL. The immunophenotype is not distinctive, given the heterogeneity of the category, but is typically CD20 positive, BCL6 positive, IFR4/MUM1 negative, and variable with respect to CD10 expression, Ki-67 positivity, and MYC expression. The molecular and cytogenetic profile includes a MYC rearrangement in 20% to 35% of cases, and by definition, a MYC rearrangement must not be present with either a BCL2 and/or BCL6 rearrangement.8 Recent work using gene expression profiling of a set of centrally confirmed cases showed a high rate of reclassification as DLBCL and did not identify any shared molecular features among cases, suggesting that this entity does not necessarily denote a truly distinct disease and may be changed in future classification updates.72

Clinical presentation and prognostic factors

HGBL, NOS is poorly characterized given its recent reclassification, but it is commonly a disease of older adults, with a median age at presentation of
70 years. Adverse IPI risk factors are also frequently observed, as a prior series of B-cell lymphoma, unclassifiable/HGBL demonstrated that most cases had advanced-stage disease, elevated LDH, and IPI greater than or equal to 3, and one-third of cases involved more than 1 extranodal site. Two-year PFS rates range from 23% to 69% in published series, with 2-year OS rates ranging from 30% to 77%.73-78


Therapy for HGBL, NOS is not well established, as prior clinical trials mostly included these lymphomas with other aggressive B-cell lymphomas. A retrospective study that included a portion of HGBL, NOS cases as well as DHL cases reported a CR rate of 43% and a 5-year EFS rate of 23%, with most patients receiving R-CHOP.74 Moreover, a series of 52 patients with the former entity B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, found that the PFS of patients treated with R-CHOP was significantly inferior to those receiving the more intensive R-Hyper-CVAD regimen, highlighting concern that more intensive regimens are needed, at least for patients with high-risk features.75 A small number of HGBL, NOS cases were included in the FLYER trial (NCT00278421) of low-risk aggressive B-cell lymphomas (IPI of 0 and no tumor size ≥ 7.5 cm); the 3-year PFS rate for the overall study cohort was 96% with 4 cycles of R-CHOP with 2 additional rituximab doses.79 Similarly, the S1001 trial (NCT01359592) included 17% HGBL, NOS cases and reported a 5-year PFS rate of 87% for the overall study cohort. In the S1001 trial, patients with nonbulky (< 10 cm) stage I/II disease received 4 cycles of R-CHOP if an interim PET/CT after 3 cycles was negative vs 3 cycles plus involved-field radiation therapy and ibritumomab tiuxetan.80 Collectively, these studies highlight the possibility that R-CHOP can be associated with good clinical outcomes in patients with early-stage, nonbulky disease and an IPI of 0.

The more intensive BL regimen R-CODOX-M/IVAC demonstrated a 2-year PFS rate of 68% in a phase 2 clinical trial that also enrolled patients with CNS involvement at presentation.81 The aforementioned multicenter study of DA-EPOCH-R in aggressive B-cell lymphomas enrolled 10 patients (19% of the cohort) with HGBL, NOS; overall, the 4-year EFS of the cohort was 71.0%.50 Notably, patients up to 80 years of age could enroll in this trial, emphasizing that DA-EPOCH-R is feasible in older adults despite its dose intensity. The role of CNS prophylaxis in HGBL, NOS is unclear, given a paucity of data, although notably R-CODOX-M/IVAC includes multiple agents with CNS activity, and DA-EPOCH-R was given with intrathecal methotrexate prophylaxis in the multicenter trial. Given that DA-EPOCH-R is as effective as R-CHOP in DLBCL,82 our preference in the absence of more definitive data is to treat these patients with DA-EPOCH-R, as this appears more effective than R-CHOP in the high-grade histologies of DHL and BL and not inferior to R-CHOP in DLBCL. We still consider use of R-CHOP in select low-risk and older patients.

Salvage therapy for relapsed/refractory HGBL, NOS is extrapolated from DLBCL treatment paradigms, given that little data exist specifically for HGBL, NOS.83,84 Anti-CD19 CAR T-cell therapy represents a promising treatment strategy for relapsed/refractory disease, given its excellent outcomes in other aggressive B-cell NHLs, including DHL. ZUMA-1 (NCT02348216) did include 2 patients with HGBL, NOS, and a real-world study included 17 patients with HGBL, NOS who received CAR T-cell therapy with axicabtagene ciloleucel, with a response rate of 88%.55,85 We hope that future work will evaluate other novel agents such as tafasitamab, polatuzumab vedotin, loncastuximab tesirine, and bispecific antibodies, as well as expand the role of CAR T-cell therapy in this disease.


The aggressive B-cell lymphomas BL, DHL, and HGBL, NOS are unique diseases, each with specific pathogenesis and biology (Table). Insights into the molecular biology of these disease have enabled new classifications and personalization of therapy. Prospective multicenter studies have established multiple intensive regimens as viable therapeutic options for BL as well as DA-EPOCH-R for DHL. HGBL, NOS remains a disease with limited data to guide treatment selection, but at this juncture, more intensive regimens are often favored (Figure). Additional studies are warranted to optimize therapy in these aggressive diseases, especially for older adults and in the relapsed setting.

Disclosures: JSA reports consulting for AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Century, Epizyme, Genentech, Genmab, Incyte, Kite Pharma, Kymera, Lilly, MorphoSys, Mustang Bio, Ono Pharma, and Regeneron; PCJ reports consulting for AstraZeneca.

Author affiliations:

P. Connor Johnson, MD1,2; and Jeremy S. Abramson MD, MMSc1,2
1Massachusetts General Hospital, Boston, MA.

2Harvard Medical School, Boston, MA

Corresponding Author:
P. Connor Johnson, MD

Massachusetts General Hospital

55 Fruit Street, Boston, MA 02114

Phone: 617-724-4000

Fax: 617-724-0220



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