Confirmation of Diagnosis

No consensus exists for which DLBCL patients should be tested using immunohistochemistry analysis to confirm DHL diagnosis. Given that lymphoma subtypes require different treatments, the review authors recommended that all patients with DLBCL and transformed follicular lymphoma be tested for MYC and BCL-2/BLC-6 mutations.1

Traditional Treatment Options

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Currently, no standard therapy exists for the treatment of DHL. Due to the rarity of the disease, most studies on treatment options for DHL have been conducted retrospectively, and few prospective trials exist. Therefore, the authors recommended that whenever possible, patients with DHL be enrolled in clinical trials.1

Many patients with DLBCL are recognized to have DHL after an intensive induction regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) proves to be insufficient.5 Thus, R-CHOP is not considered suitable as intensive induction for DHL treatment.1 However, results from retrospective studies indicate that dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) therapy may be appropriate for patients with DHL, but validation through randomized, prospective trials is still needed.1,6

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Although autologous stem cell transplant (ASCT) is an important therapy for patients with aggressive lymphomas, retrospective studies have concluded that patients with DHL do not benefit from ASCT.1 However, at least 1 study has shown that patients with non-DHL and DHL experienced no significant difference in outcome after allogeneic stem cell transplant (alloSCT).7 The review authors suggested that alloSCT be further explored for patients with DHL in first remission and encouraged patients who did not achieve complete remission or who have progressive disease after intensive induction to seek enrollment in clinical trials.1

Despite the uncertainty in the comprehensive treatment strategy for patients with DHL, one certainty is the need for central nervous system (CNS) prophylaxis. Patients with DHL are known to have increased risk of CNS involvement (21%-45%).1,8 Therefore, the review authors recommended a baseline evaluation of CNS involvement at the time of diagnosis and intravenous administration of methotrexate as part of the intensive induction.1

Novel Treatment Options

Novel approaches for treatment of DHL consist primarily of immunotherapy, BCL-2 inhibitors, and MYC inhibitors.1 Most of these treatments are still in the preclinical phase, and the review authors highlighted promising results.

Cluster of differentiation (CD) 19-directed chimeric antigen receptor T-cell (CAR-T) therapy in 2 multicenter studies, the phase 2 Juliet trial ( Identifier: NCT02445248) and TRANSCEND study ( Identifier: NCT03241459), showed overall response rates of 59% and 84%, respectively, with each study population consisting of 27% patients with DHL.9,10 Additionally, in the phase 2 HOVON study, the standard R-CHOP regimen plus lenalidomide resulted in a 1-year overall survival rate of 79% in patients with newly diagnosed DLBCL (54% of patients were confirmed to have DHL).11

Though BCL-2 and MYC inhibitors were demonstrated to be active in preclinical studies, their efficacy and safety have yet to be demonstrated in patients with DHL through clinical trials.1 Promising BCL-2 inhibitors include ABT-199 (venetoclax), a selective BCL-2 antagonist; PNT2258, a DNA inhibitor that blocks BCL-2 transcription; CPI203, an inhibitor of a BCL-2-like compensatory protein BFL-1; and dinaciclib, an inhibitor of another BCL-2-family compensatory protein MCL-1. The review authors provided a detailed list of select targeted therapies for more information.1

Drug development with a focus on MYC includes MYC inhibitors as well as inhibitors of upstream regulators of MYC and downstream signaling targets. These targets include members of the ubiquitin-proteasome system, mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 (GSK-3-beta), histone deacetylase (HDAC), phosphoinositide 3 kinase (PI3K), and polo-like kinase-1 (PLK-1).1

Importantly, BCL-2 and MYC inhibitor combinations are being tested against DHL cell lines and are showing promising results.1 For example, the PLK-1 inhibitor volasertib was efficacious in killing DHL cells alone or when combined with the BCL-2 inhibitor venetoclax or with HDAC inhibitors belinostat and vorinostat.12 Similarly, GSK-3-beta inhibitor 9-ING-41 demonstrated antineoplastic effects alone or when combined with venetoclax, the PLK-1 inhibitor idelalisib, and the CDK-9 inhibitor BAY-1143572.13

DNA Sequencing for DHL

Lastly, given the critical role of accurate diagnosis based upon known genetic variants associated with DHL, the review authors highlighted the growing application of high-throughput DNA sequencing for patients with DHL.

“[In addition to MYC and BCL-2,] high-throughput sequencing technology has described rearrangements within several cancer-associated genes, such as PRKCA, ANO3, PCDH9, NKAIN3, and TSPAN8 in the double-hit cell line U-2973,” said Dr Wang.

“Nonsynonymous mutations of ID3, CCND3, C-MYC, BCL-2, EZH2, CREBBP, and MEF2B were also recognized, implying divergent genetic mechanisms with different clinical responses amongst subgroups of the DHL population. Remarkably, the frequency of TP53 mutations in MYC+/BCL-2+ DHL was found between that of DLBCL and Burkitt lymphoma but found [to be] scarce in MYC+/BCL-6+ DHL. Future attempts to demonstrate the role of these mutations in predicting both outcomes and potential novel combination therapies for patients with DHL are expected.”


1. Li L-R, Wang L, He Y-Z, Young KH. Current perspectives on the treatment of double hit lymphoma [published online April 19, 2019]. Expert Rev Hematol. doi:10.1080/17474086.2019.1623020

2. Lynch RC, Gratzinger D, Advani RH. Clinical impact of the 2016 update to the WHO lymphoma classification [published online July 3, 2017]. Curr Treat Options Oncol. doi:10.1007/s11864-017-0483-z

3. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma [published online April 12, 2018]. N Engl J Med. doi:10.1056/NEJMoa1801445

4. Scott DW, King RL, Staiger AM, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology [published online February 23, 2018]. Blood. doi:10.1182/blood-2017-12-820605

5. Staton AD, Cohen JB. A clinician’s approach to double-hit lymphoma: identification, evaluation, and management [published online September 21, 2016] . J Oncol Pract. doi:10.1200/JOP.2015.009647

6. Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study [published online December 1, 2018]. Lancet Haematol. doi:10.1016/S2352-3026(18)30177-7

7. Herrera AF, Rodig SJ, Song JY, et al. Outcomes after allogeneic stem cell transplantation in patients with double-hit and double-expressor lymphoma [published online November 28, 2017]. Biol Blood Marrow Transplant. doi:10.1016/j.bbmt.2017.11.023

8. Qualls D, Abramson JS. Advances in risk assessment and prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma [published online December 20, 2018]. Haematologica. doi:10.3324/haematol.2018.195834

9. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130(Suppl 1).

10. Abramson JS, Palomba ML, Gordon LI, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): Defined composition allows for dose-finding and definition of pivotal cohort. Blood. 2017;130(Suppl 1). Accessed June 21, 2019.

11. Chamuleau MED, Nijland M, Zijlstra JM, et al. Successful treatment of MYC rearrangement positive large B cell lymphoma patients with R-CHOP21 plus lenalidomide: results of a multicenter phase II HOVON trial. Blood. 2018;132(Suppl 1):786-786. doi:10.1182/BLOOD-2018-99-110240

12. Hassan QN, Alinari L, Byrd JC. PLK1: a promising and previously unexplored target in double-hit lymphoma [published online November 5, 2018]. J Clin Invest. doi:10.1172/JCI124919

13. Karmali R, Chukkapalli V, Gordon LI, et al. GSK-3-beta inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents. Oncotarget. doi:10.18632/oncotarget.22414