Targeted Treatments, Cell Therapies Are Explored in Double-Hit Lymphoma

The most recent updated World Health Organization (WHO) classification of lymphoid neoplasms included a new category of mature B-cell neoplasms, high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations. These lymphomas are referred to as double-hit lymphomas (DHL, with MYC and 1 other translocation) or triple-hit lymphomas (THL with MYC and 2 other translocations).1 The high-grade DHL/THL classification includes B-cell lymphomas that would be classified morphologically as diffuse large B-cell lymphomas (DLBCL) or Burkitt lymphoma, and excludes those that meet the definitions of follicular or lymphoblastic lymphoma.¹

Accurate determination of the subtype is necessary to inform treatment decisions. Diagnostic tests for lymphoma subtype include immunohistochemistry (IHC), flow cytometry, karyotype, cytogenetic or molecular analyses, and fluorescence in situ hybridization (FISH). FISH or standard cytogenetics can be used to identify the MYC and BCL2 and/or BCL6 gene translocations that characterize DHL/THL.²

A study in a large series of lymphomas showed that the only way to detect all cases of DH/TH-HGBL among patients with DLBCL morphology is to test all for MYC rearrangements by FISH, and to follow this by testing for BCL2 and BCL6 rearrangements in those patients who are MYC-rearrangement–positive.³

Accurate identification is important because DHL and THL often have poor prognostic factors, including elevated lactate dehydrogenase (LDH), involvement of the bone marrow and/or central nervous system (CNS), and a high International Prognostic Index (IPI) score.²

Current State of Treatment and Unmet Needs

The National Comprehensive Cancer Network (NCCN) recommends enrollment on a clinical trial as the best option for the treatment of patients with DHL/THL, noting that there is no established standard of care for this type of lymphoma.²

Laurie H. Sehn, MD, MPH, a clinical assistant professor in the Division of Medical Oncology at The University of British Columbia in Canada, and the chair of the Lymphoma Tumour Group at BC Cancer, attributes the absence of a standard of care to the lack of clinical trials that have assessed different treatment approaches in this group. “Everything we know is from [a] retrospective analysis,” said Sehn, who explored DHL during her session at the eighth annual meeting of the Society of Hematologic Oncology (SOHO).

This is due in part to the low frequency of DHL and, therefore, relatively small numbers of patients, as well as the rapid course of the disease, which make prospective clinical studies challenging.4,5 Several induction regimens have been implemented (TABLE 12).

Because of the potential for toxicities, clinicians should consider patient performance status and comorbidities for the use of either R-HyperCVAD or R-CODOX-M/R-IVAC. The role of high-dose therapy and ASCT has not been established,2,5 and high-dose therapies have resulted in few long-term responses. ASCT may prolong progression-free survival (PFS) in those receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction rather than high-dose therapy.^5,6

R-CHOP has also been used, generally resulting in poorer responses than more intense regimens.² Sehn said during an interview prior to the meeting that although about half of patients could be cured with R-CHOP, retrospective data suggest more intensive chemotherapy should yield better responses. Her center, like others, uses DA-EPOCH as a more intensive regimen compared with R-CHOP. She said that everyone has different criteria for choosing a more versus less intensive approach.

“I would say that there is no absolute age cut-off or guideline on that, it really is clinical judgment based on age and the weight of comorbidities and overall fitness,” she added. However, R-CHOP could be an option for patients who could not tolerate a dose-intensive approach.

According to Sehn, the use of DA-EPOCH-R has an advantage in that it includes intrathecal methotrexate that addresses the higher risk of CNS recurrence in DHL. For those with DHL who are at very high risk, such as the presence of a high bone marrow burden, numerous extranodal involved sites, or high renal or adrenal involvement, Sehn said there are no data to indicate whether systemic high-dose methotrexate after completion of DA-EPOCH-R would have an impact.

When DHL/THL progresses or relapses, standard treatment is salvage chemotherapy then consolidation with ASCT in patients who have chemotherapy-sensitive disease and are eligible for transplant. However, outcomes are poor compared with those without DHL.⁵

Patients with DHL/THL have an unmet medical need as there is no established standard of care for those with either newly diagnosed or relapsed/ refractory disease.^2,4 The prognosis is particularly bleak for those patients who are not eligible for ASCT, experience relapse after ASCT, or have primary progressive disease.^4,5

Emerging Therapies

Targeted Therapy Combinations

A phase 1, multicenter trial (V+DA-EPOCH-R; NCT03036904) investigated the dose, safety, and efficacy of adding venetoclax, a BCL-2 inhibitor, to DA-EPOCH-R to treat aggressive B-cell lymphomas, including high-grade B-cell lymphomas.^7,8 Of 30 patients enrolled, there were 15 with DHL or THL. Of these, 13 experienced a complete response (CR), 1 had a partial response, and 1 was not evaluable. Among the patients with CR, 10 remained in CR at a median follow-up of 11 months, 2 had progressive disease, and 1 died. Rutherford said that cytopenias, fatigue, and nausea were the most common adverse events (AEs). Serious gastrointestinal AEs mostly resolved, and require close monitoring in future trials. The results of this trial have informed the initiation of the randomized, multicenter, phase 2/3 Alliance A051701 trial (NCT03984448) of venetoclax plus usual chemotherapy in high-grade lymphomas, with DA-EPOCH-R for patients with DHL. The primary end point is PFS.^8,9 A multicenter, phase 1, open-label, dose-escalation study (NCT01742988) is designed to assess the safety and pharmacokinetics of fimepinostat, a dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) in patients with lymphoma.¹⁰ The phase 2 dose-expansion cohort will include patients with relapsed/refractory DHL or THL.¹¹

A lead-in and phase 2 open-label trial (NCT03136146) of combination therapy with clofarabine, etoposide, cyclophosphamide, liposomal vincristine, dexamethasone, and bortezomib for patients with relapsed/refractory hematologic malignancies, including DHL, is recruiting participants. This study, with an anticipated enrollment of 42 patients, will assess safety and initial efficacy of the combination. The estimated completion date is 2026.¹² The REMoDL-B study (NCT01324596) was a phase 3 trial comparing R-CHOP with and without the proteasome inhibitor bortezomib in patients with previously untreated DLBCL (n = 459 in both treatment groups).^13,14 Gene-expression analysis was used to determine the cell of origin. In this trial, the addition of bortezomib to R-CHOP did not improve PFS.

Nearly half of the DHL did not appear to have progressed at 30 months of follow-up, and the PFS in the bortezomib plus R-CHOP group was 58.8% versus 38.9% in the R-CHOP group.

The R2-GDP-GOTEL trial looked at the addition of lenalidomide to rituximab, cisplatin, gemcitabine, and dexamethasone, followed by lenalidomide maintenance, in patients ineligible for ASCT who had relapsed/refractory lymphoma. In patients with DHL (n = 16) after a median follow-up of 13 months, the overall response rate was 37.5%, with a 25% CR rate.¹⁵ A phase 2 trial (NCT02213913) is investigating the addition of lenalidomide to DA-EPOCH-R in patients with MYC-associated B-cell lymphomas, including DHL.¹⁶

There have been mixed results with the addition of ibrutinib to chemotherapy. In a phase 1 trial (NCT02219737) in 21 patients, ibrutinib plus ifosfamide, carboplatin, and etoposide in relapsed/refractory DLBCL was tolerable, with an overall response rate of 90%.¹⁷ In a randomized phase 3 trial (NCT01855750) of ibrutinib or placebo added to R-CHOP, the primary end point of event-free survival was not met. Patients younger than 60 years seemed to benefit from the ibrutinib combination, whereas patients 60 years and older experienced increased toxicities that compromised their R-CHOP dosing and resulted in a poorer outcome. These findings suggest further investigation is warranted.¹⁸

A phase 2b study (NCT02227251) treated patients with relapsed/refractory DLBCL (n = 127), including 5 patients with DHL, with single-agent selinexor, an oral selective inhibitor of nuclear transport. Given the small number of patients with DHL, it is difficult to draw any conclusions; however, selinexor was associated with durable responses with a manageable toxicity profile, warranting further investigation.¹⁹

Cell-Based Therapies

Chimeric antigen receptor (CAR) T-cell–based therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel, Kymriah), have been approved for the treatment of DLBCL and other aggressive lymphomas. These treatments have yielded impressive results, although they are associated with potentially severe AEs, and require patients to wait several weeks for cell manufacture. Real-world studies outside clinical trials suggest these therapies are feasible, although bridging therapy, AE management, development of markers for efficacy, and drug combinations are required.²⁰

Several trials of CAR T-cell–based therapies that include patients with relapsed/refractory high grade lymphomas have been planned or initiated, including the following (TABLE 2):

• Phase 1/2 study of the Bruton tyrosine kinase inhibitor acalabrutinib plus the anti-CD19 CAR T-cell axicabtagene ciloleucel (NCT04257578)²¹
• Phase 1 study of anti-CD19 (CAR)-4-1BB-CD3zeta-EGFRt–expressing (huJCAR014) CAR T cells (NCT03103971)²²
• Safety and efficacy phase 1/2 multicenter trial of KTE-C19 (ZUMA-1) and the anti-CD19 CAR T-cell axicabtagene ciloleucel (NCT02348216)23
• Phase 2 multicenter, efficacy and safety study (JULIET; NCT02445248) of tisagenlecleucel-T (CTL019)²⁴
• TRANSCEND-NHL-001 (NCT02631044), a phase 1 study of a second-generation CAR T-cell therapy, JCAR017 (lisocabtagene maraleucel). The trial is still recruiting participants, although the DLBCL cohort that included DHL/THL is no longer enrolling. Investigators have not yet reported results.²⁵

Looking Ahead

Improved therapies to address the unmet needs of patients with DHL/THL is required. These patients represent a heterogeneous group.

“I think understanding more about the molecular differences between these patients would be highly relevant,” Sehn said. Gene expression profiling, which is not conducted in routine practice, may identify unique signatures associated with prognosis and response to treatment, and warrants further development, along with more detailed molecular testing.

“I think we are gradually improving our biological understanding of this group, and I think that should provide more clarity [regarding] who might benefit from more intensive therapy and who might be being overtreated with today’s more rudimentary understanding,” Sehn said. A better understanding of the underlying biology of patients with DHL/THL could lead to more tailored, risk-adjusted, personalized therapy.

_References:

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_{7. Phase I study of venetoclax plus DA-EPOCH-R for the treatment of aggressive B-cell lymphomas. Updated April 10, 2020. Accessed August 7, 2020. https://bit.ly/30DiH3i}

_{8. Rutherford SC, Abramson JS, Bartlett NL, et al. Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas. J Clin Oncol. 2020;38(suppl 15):8003. doi:10.1200/JCO.2020.38.15_suppl.8003}

_{9. Randomized phase II/III study of venetoclax (ABT199) plus chemoimmunotherapy for MYC/BCL2 double-hit and double expressing lymphomas. Updated August 7, 2020. Accessed August 7, 2020. https://bit.ly/3gGlPAP}

_{10. Phase 1 open label, multi-center, dose-escalation study to assess the safety, tolerability and pharmacokinetics of orally administered fimepinostat (CUDC-907), a PI3K and HDAC inhibitor, in subjects with refractory or relapsed lymphoma. Updated March 23, 2020. Accessed August 7, 2020. https://bit.ly/33Ep1cy}

_{11. Younes A, Batlevi CL, Cohen JB, et al. A multi-center dose-finding study to assess safety, tolerability, pharmacokinetics and preliminary efficacy of fimepinostat (CUDC-907) in combination with venetoclax in patients with relapsed/refractory (R/R) lymphoma. Blood. 2019;134 (suppl 1):4104. doi:10.1182/blood-2019-128857}

_{12. Lead-in and phase II study of clofarabine, etoposide, cyclophosphamide [CEC], liposomal vincristine (VCR), dexamethasone and bortezomib in relapsed/refractory acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Updated June 22, 2020. Accessed August 7, 2020. https://bit.ly/3fGHKGG}

_{13. A randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib. Updated April 15, 2016. Accessed August 7, 2020. https://bit.ly/3fAVsL9}

_{14. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(5):649-662. doi:10.1016/S1470-2045(18)30935-5}

_{15. de la Cruz Merino L, Martin A, Fernández EN, et al. Lenalidomide plus R-GDP (R2-GDP) in relapsed/refractory diffuse large B-cell lymphoma: final results of the R2-GDP-GOTEL trial. J Clin Oncol. 2020;38(suppl 15):8019. doi:10.1200/JCO.2020.38.15_suppl.8019}

_{16. Godfrey JK, Nabhan C, Karrison T, et al. Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2. Cancer. 2019;125(11):1830-1836. doi:10.1002/cncr.31877}

_{17. Sauter CS, Matasar MJ, Schoder H, et al. A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL. Blood. 2018;131(16):1805-1808. doi:10.1182/blood-2017-08-802561}

_{18. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large b-cell lymphoma. J Clin Oncol. 2019;37(15):1285-1295. doi:10.1200/JCO.18.02403}

_{19. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4}

_{20. Ghesquieres H, Salles G. Early off-study experience of chimeric antigen receptor t cells in aggressive lymphoma: closer to a real-world setting. J Clin Oncol. Published online July 15, 2020. doi:10.1200/JCO.20.01134}

_{21. Acalabrutinib in combination with anti-CD19 chimeric antigen receptor T-cells (CART) in B-cell lymphoma. Updated August 10, 2020. Accessed August 10, 2020. https://bit.ly/3a2R6eS}

_{22. A two-stage phase 1 open-label study of huJCAR014, CD19-targeted chimeric antigen receptor (CAR)-modified T cells bearing a human binding domain, in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma and acute lymphocytic leukemia. Updated July 27, 2020. Accessed August 7, 2020. https://bit.ly/30ArItC}

_{23. A phase 1/2 multicenter study evaluating the safety and efficacy of KTE-C19 in adults with refractory aggressive non-Hodgkin lymphoma. Updated March 31, 2020. Accessed August 7, 2020. https://bit.ly/2PwpN2T}

_{24. A phase II, single arm, multicenter trial to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Updated May 20, 2020. Accessed August 7, 2020. https://bit.ly/31yIXLr}

_{25. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134 (suppl 1):241. doi:10.1182/blood-2019-127508}