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State of the science: High-priority transplant trials for lymphoma
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In the June 10 issue of HemOnc Today, we launched a series of columns to discuss high-priority proposals that emerged from the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium.
The State of the Science Symposium (SOSS), which began in 2001 and is held every 7 years, highlights the challenges associated with hematopoietic cell transplantation (HCT) and establishes research priorities for the field. Ten topic-specific committees composed of scientific and clinical leaders were formed to identify the most compelling opportunities for clinical research, and to frame the scientific agenda going forward for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) during the next several years. From this process, 12 study concepts emerged.
Each of our columns begins with a clinical case scenario that highlights one or more high-priority concept areas discussed at the 2014 BMT CTN SOSS in a way that is intended to be applicable to the nontransplant clinician. The scenario is followed by scientific background in that area and a discussion of the specific high-priority strategies proposed by the SOSS committee in this area. We conclude with some thoughts about the potential effect these strategies may have for the nontransplant provider.
This column focuses on lymphoma.
Clinical scenario
William Wood
A 51-year-old male presents to your office with fevers, night sweats, progressive fatigue and profound weight loss. PET imaging showed supraclavicular, hilar, para-aortic and inguinal lymphadenopathy.
Biopsy of one of his lymph nodes confirmed a diagnosis of diffuse large B-cell lymphoma (DLBCL) with activated B-cell subtype (ABC). A bone marrow biopsy did not reveal any detectable disease, and he had an International Prognostic Index (IPI) score of 3.
He was subsequently treated with six cycles of R-CHOP and achieved a complete response. After 6 months, he developed night sweats, fevers and weight loss, and PET imaging suggested relapsed disease. Bone marrow biopsy confirmed involvement by DLBCL, ABC subtype.
Current guidelines
Relapsed/refractory DLBCL remains the second most common indication for autologous hematopoietic cell transplantation (HSCT), and it offers a curative modality for treatment.
In 2013, the National Marrow Donor Program/Be The Match (bethematchclinical.org) and the American Society for Blood and Marrow Transplantation jointly developed the following transplant referral guidelines for high-dose therapy with autologous stem-cell rescue for DLBCL:
- At first or subsequent relapse;
- CR1 for patients with high- or high-intermediate IPI risk;
- Primary refractory disease/no complete remission with initial treatment; and
- Second or subsequent remission.
National Comprehensive Cancer Network guidelines also recommend evaluation for autologous HSCT for relapsed/refractory DLBCL, with consideration for autologous HSCT for DLBCL in first remission only in selected high-risk circumstances or in the context of a clinical trial.
Aggressive B-cell lymphomas and autologous HSCT
Alizadeh and colleagues at the NCI described the ABC subtype of DLBCL.
ABC-like DLBCL is characterized by activation of NF-kappaB, mostly through chronic activation of the B-cell receptor (BCR) pathway. This is postulated to be a mechanism for the perceived chemoresistant nature of ABC-like DLBCL.
The NCI study demonstrated the poor prognostic value of ABC-like DLBCL compared with the germinal center subtype (GCB) of DLBCL. This was confirmed in the post-rituximab (Rituxan; Genentech, Biogen Idec) era by Lenz and colleagues, who showed that — following initial treatment with CHOP or R-CHOP — cell of origin was prognostic, as ABC-like DLBCL was associated with shorter OS and PFS than GCB-subtype DLBCL.
A study by Nowakowski and colleagues, published in August in Journal of Clinical Oncology, evaluated the addition of the immunomodulatory drug lenalidomide (Revlimid, Celgene) to R-CHOP (R2-CHOP) for ABC-like DLBCL in the front-line setting. Based on these data, it is possible that — as an initial regimen — R2-CHOP may mitigate the poor prognosis of ABC-like DLBCL, as the reported PFS and OS were similar to historic controls of DLBCL patients treated at the same institution during a 6-year period.
Thieblemont and colleagues evaluated the significance of DLBCL cell of origin in the context of autologous HSCT in the relapsed/refractory setting.
Researchers reviewed histologic samples from patients who were previously enrolled in the CORAL study, which showed that R-ICE and R-DHAP followed by high-dose therapy and autologous HSCT were equally efficacious as salvage therapy; that maintenance rituximab did not provide benefit; and that rituximab resistance conferred less response to autologous HSCT.
These samples were then, by Hans criteria, defined as GCB subtype or ABC subtype. GCB-like DLBCLs were associated with better survival outcomes than ABC-like DLBCLs. Three-year OS rates were 74% for GCB and 40% for ABC-like DLBCL, and 3-year PFS rates were 70% for GCB and 28% for ABC-like DLBCL. These data demonstrate the guarded prognosis of ABC-like DLBCL after autologous transplantation.
High-priority strategies
In recognition of the risk for relapse of DLBCL after autologous HSCT, particularly in those with high-risk features, the BMT CTN SOSS committee focused on lymphoma established a high-priority strategy.
The strategy calls for a randomized trial of ibrutinib (Imbruvica; Pharmacyclics, Janssen) during and after autologous HSCT in patients with relapsed and refractory DLBCL of ABC subtype.
Ibrutinib is a selective covalent inhibitor of Bruton’s tyrosine kinase (BTK) that is approved for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma.
BTK is a critical component of the BCR signaling cascade, which leads to the activation of downstream pathways that contribute to survival and proliferation of B-cell malignancies. Advani and colleagues studied ibrutinib in refractory/relapsed B-cell non-Hodgkin’s lymphoma and CLL. The drug was well tolerated and was associated with significant responses in all histologies, including DLBCL, CLL, mantle cell lymphoma, Waldenström’s macroglobulinemia and marginal zone lymphoma.
Given the chronic activation of the B-cell signaling pathway seen in ABC subtype DLBCL, ibrutinib would appear to be an attractive strategy in this setting. Wilson and colleagues presented phase 2 data at the 2012 ASH Annual Meeting and Exposition that showed a significant improvement in response to ibrutinib monotherapy (41% vs. 5%) and OS (9.76 months vs. 3.35 months) among ABC subtype DLBCL compared with GCB subtype.
Younes and colleagues published data from a phase 1b/2 study of ibrutinib combined with R-CHOP. Five (71%) of seven patients with GCB subtype and two (100%) patients with ABC subtype demonstrated complete response.
Based on the encouraging early data for ibrutinib in patients with ABC-subtype DLBCL, ibrutinib in the post-autologous HSCT setting is an interesting strategy that may provide benefit for this high-risk group. However, the benefit in this setting is as yet undefined and — with a well-designed study — lack of efficacy or unexpected toxicities associated with post-autologous HSCT ibrutinib may emerge. Thus, a prospective clinical trial to address this question clearly is needed.
This strategy is proposed as a large randomized phase 3 study, designed to determine whether the addition of ibrutinib post-autologous HSCT will improve PFS in ABC subtype DLBCL. Provided that sufficient response to salvage therapy has been demonstrated, participants will be randomly assigned before autologous HSCT to either ibrutinib or placebo. Ibrutinib at a dose of 560 mg daily will be started at day 8 in the intervention group and will continue for 12 months post-autologous HSCT. Crossover from placebo to ibrutinib will be allowed if post-autologous HSCT progression occurs while on placebo.
Targeted enrollment is approximately 300 patients. It will take about 36 months to complete accrual, and an additional 24 months will be needed for follow-up. If the intervention is found to be associated with clinical benefit, this study could lead to improved outcomes in a high-risk, poor-prognosis group of patients undergoing autologous HSCT. This strategy also could lead to additional studies designed to investigate the role of post-transplantation ibrutinib in other lymphoid malignancies.
Conclusion
High-risk lymphomas such as ABC-subtype DLBCL remain difficult to treat, with a high relapse risk after autologous HSCT. Post-transplant relapse prevention remains a high priority in high-risk lymphoid malignancies, with potential strategies including earlier transplant referral, as well as trials of post-transplantation maintenance therapies such as ibrutinib.
As a transplant community, we are eager to work with referring providers to help formulate plans tailored for each patient, regardless of whether the management plan ultimately includes earlier, later or no transplantation.
For the patient in our initial vignette, enrollment on a study of autologous transplantation followed by post-transplantation maintenance ibrutinib could be a reasonable strategy. This is an interesting approach with a newer drug in a patient who clearly is at high risk for relapse. Because equipoise currently exists regarding the potential benefit of this strategy, enrollment on a clinical trial designed to address this question would be appropriate.
As always, we welcome further conversation or questions about these topics. Readers are encouraged to email us or visit Healio.com/HemOnc so we can continue this dialogue.
References:
Advani RH. J Clin Oncol. 2013;31:88-94.
Alizadeh AA. Nature. 2000;403;503-511.
Lenz G. N Engl J Med. 2008;359:2313-2323.
Lenz G. Proc Natl Acad Sci USA. 2008;105:13520-13525.
Matthews Griner LA. Proc Natl Acad Sci USA. 2014;111:2349-2354.
National Marrow Donor Program/Be the Match. Transplant referral timing guidelines. 2013. Available at: bethematchclinical.org/transplant-indications-and-outcomes/referral-timing-guidelines. Accessed on Nov. 5, 2014.
Nowakowski G. J Clin Oncol. 2014;Published online ahead of print Aug. 18.
Thieblemont C. J Clin Oncol. 2011;29:4079-4087.
Wilson WH. Abstract #686. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.
Younes A. Lancet Oncol. 2014;15:1019-1026.
For more information:
Hemant Murthy, MD, is a hematology-oncology fellow at East Carolina University — Brody School of Medicine.
William Wood, MD, is an assistant professor of medicine in the division of hematology/oncology at the University of North Carolina in Chapel Hill. He also is a HemOnc Today Editorial Board member. He can be reached at UNC Health Care System, Division of Hematology and Oncology, 101 Manning Drive, Chapel Hill, NC 27514; email: wawood@med.unc.edu. You also may follow him on Twitter (@WoodBD).
Disclosure: Murthy and Wood report no relevant financial disclosures.