Guidelines released by the Society for Immunotherapy of Cancer are intended to provide clinicians with the most current thinking on how experts can integrate immunotherapy into the treatment of patients with lymphoma.
As treatment options continue to expand across numerous disease settings, new practice guidelines were released by the Society for Immunotherapy of Cancer (SITC) on the use of immunotherapy in the treatment of lymphoma.1 The guidelines, published in the Journal for ImmunoTherapy of Cancer, are intended to provide clinicians with the most current thinking on how experts can integrate immunotherapy into lymphoma treatment.
“Practicing clinicians have to take care of so many types of cancer, whereas in the old days there were common therapies across the board,” Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai, explained in an interview with CancerNetwork®. “Now, the therapies are so much better individualized that [it can be] difficult for practicing community oncologists to stay abreast of every update.”
“Advances in lymphoma are more rapid than any other type of cancer, and a piece of evidence for that is there are more FDA approved medicines for lymphoma [than any other cancer type], with 43 approved medicines for lymphoma,” added Brody.
The SITC Lymphoma Immunotherapy Guideline Expert Panel included a total of 12 stakeholders, consisting of 9 medical oncologists, 1 pediatric oncologist, 1 nurse practitioner, and 1 patient advocate. Each of the panelists reported having experience in administering or advocating for cancer immunotherapies including monoclonal antibodies (mAbs), immune checkpoint inhibitors (ICIs), adoptive cellular therapies, and vaccines.
For the development of the guidelines, the Institute of Medicine’s (IOM) Standards for Developing Trustworthy Clinical Practice Guidelines were used as a model. Following the IOM Standards, the current recommendations are based on evidence found in literature, where possible, and clinical experience, when appropriate. For these SITC guidelines, the MEDLINE database was used to search the scientific literature for current therapies related to Hodgkin and non-Hodgkin lymphoma (NHL) as well as immunotherapy; the search was limited to clinical trials, meta-analyses, practice guidelines, and research in humans.
Importantly, the panel focused solely on drugs already approved by the FDA for the treatment of patients in the United States.
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General Recommendations and Clinical Trials
Overall, the panel generally recommended that clinical trial participation be a consideration for any patient with lymphoma. To support this ideal, a systematic review of patient outcomes established that participation in a clinical trial typically does not result in worse outcomes for patients. Given this finding, the panel indicated that participation in clinical trials may be recommended routinely, especially in cases where approved treatment options may be limited.
There was also consensus amongst the panel that all individuals with newly diagnosed lymphoma should receive initial imaging via fluorodeoxyglucose PET/CT. It was recommended that patients should routinely be administered complete blood count (CBC) and serum IgG tests. In patients with decreased neutrophil and absolute lymphocyte counts from CBC tests as well as those with low levels of serum IgG, the panel concluded that infection precautions may be considered.
In addition, there was consensus that all patients with newly diagnosed lymphoma should receive assessment of their cardiovascular history and risk factors before receiving potentially cardiotoxic therapies. Based on risk assessment, it was recommended that these patients be examined and routinely monitored with transthoracic echocardiogram and ECG, among others.
Recommendations for Patients With Classical Hodgkin Lymphoma
First-Line Treatment, Stage I/II
For the first-line treatment of patients with stage I/II classical Hodgkin lymphoma (cHL), there was consensus within the panel that patients should receive a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). This regimen has been the established standard of care for the first-line treatment of all stages of cHL for almost 3 decades.
This recommendation was based on results from a prospective, randomized Cancer and Leukemia Group B trial in patients with newly diagnosed, advanced-stage Hodgkin's disease.2 The study, published in 1992, compared 3 regimens, including mechlorethamine, vincristine, procarbazine, and prednisone (MOPP; the standard treatment at that time) for 6 to 8 months, ABVD for 6 to 8 months, and MOPP alternating with ABVD for 12 months.
Ultimately, the study revealed that ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both therapies were superior to MOPP alone. Additionally, ABVD was revealed to be less myelotoxic than either of the alternatively studied regimens.
First-Line Treatment, Stage III/IV
Consensus was not reached regarding a single preferred regimen for the first-line treatment of patients with stage III/IV cHL. Two options for treatment were presented by the panel, including ABVD and the combination of brentuximab vedotin (Adcetris; BV), doxorubicin, vinblastine, and dacarbazine (A-AVD).
As previously reported, ABVD has been long established as the standard of care for all stages of cHL. However, in the randomized phase 3 ECHELON-1 trial (NCT01712490) in which 1334 patients with previously untreated stage III or IV cHL were administered either ABVD or A-AVD, patients who received A-AVD were revealed to have a significantly higher progression-free survival (PFS) rate after a median follow-up of almost 2 years.3 Patients in the A-AVD arm also showed higher overall survival (OS) than those in the ABVD group at 24-months of follow-up, though this difference was not found to be significant.
For the second-line treatment of cHL, there was consensus within the panel that patients should receive either salvage chemotherapy or immunotherapy, and, if eligible, should also receive autologous stem cell transplant (ASCT). According to the panel, treatment options for pre-ASCT chemotherapy or immunotherapy include BV plus bendamustine, ifosfamide plus carboplatin and etoposide (ICE), BV plus nivolumab, or BV monotherapy.
This recommendation was based on findings from the AETHERA trial (NCT01100502), which enrolled BV-naïve patients who had received ASCT and were considered to be at high risk for relapse to receive either the antibody-drug conjugate or placebo.4 Based on the results of this trial, the FDA approved BV in 2015 as consolidation therapy for patients with cHL who have received ASCT and are at high risk of relapse. However, given that the AETHERA trial only examined patients who were BV-naïve, BV consolidation in patients who have previously received BV remains investigational.
The panel did not reach consensus on a single preferred regimen for the third-line treatment of cHL. Options for treatment discussed by the panel were dependent on prior therapies received as well as patient status and included salvage chemotherapy or immunotherapy plus ASCT, if they were transplant-eligible; PD-1 inhibitor therapy; or BV.
Recommendations for Patients With non-Hodgkin Lymphoma
Diffuse Large B-Cell Lymphoma
For the first-line treatment of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL), there was consensus within the panel that the regimen used should be rituximab (Rituxan) plus a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This recommendation was based on findings from the NHL Studies 7 (ECOG-4494, NCT00003150), 8 (GELA LNH-98.5), and 9 (MInT, NCT00064116) of patients with previously untreated DLBCL.5 Within each of the studies, R-CHOP provided patients with extended PFS when compared with CHOP alone.
Moreover, for pediatric patients with newly diagnosed DLBCL, there was consensus that first-line treatment should consist of combination treatment with rituximab and French-American-British (FAB) backbone chemotherapy.
For the second-line therapy of DLBCL, there was consensus that transplant-eligible patients should receive a chemoimmunotherapy regimen that includes rituximab (such as rituximab plus ICE, or R-ICE; or with dexamethasone, cytarabine, and cisplatin, or R-DHAP), followed by ASCT consolidation if complete response (CR) is achieved. For those who are transplant-ineligible, the panel did not reach consensus on a salvage chemotherapy or immunotherapy regimen. Treatment options presented by the panel included lenalidomide (Revlimid), lenalidomide plus tafasitamab-cxix (Monjuvi), polatuzumab vedotin-piiq (Polivy) combined with bendamustine and rituximab (BR) or an appropriate salvage chemoimmunotherapy regimen (including rituximab, gemcitabine, and oxaliplatin or rituximab, gemcitabine, cisplatin, and dexamethasone).
Lenalidomide has resulted in similar efficacy to investigator’s choice therapies, and when a clear OS advantage is not demonstrated over other agents, it is sometimes used as alternative treatment for DLBCL with a different toxicity profile.
Study GO29365 (NCT02257567) supported the recommendation of polatuzumab vedotin-piiq plus BR, demonstrating that in patients with DLBCL, the combination resulted in a significantly higher median PFS and increased objective response rate (ORR) compared with BR alone.6
For the third-line treatment of DLBCL, there was consensus that in fit patients, treatment should consist of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with either axicabtagene ciloleucel (Yescarta) or tisagenlecleucel (Kymriah). This recommendation was supported by results from the single-arm ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel in patients with large B-cell lymphomas and the phase 2 JULIET trial (NCT02445248) of tisagenlecleucel in relapsed/refractory DLBCL.7,8 However, for those who are ineligible for third-line anti-CD19 CAR T-cell therapy, it was recommended that polatuzumab vedotin-piiq plus BR be administered instead.
Mantle Cell Lymphoma
Consensus was not reached regarding the first-line treatment of patients with mantle cell lymphoma (MCL) who are eligible for transplant. Options presented by the panel included chemoimmunotherapy with ASCT or chemoimmunotherapy alone. Of note, an anti-CD20 mAb is included in the standard of care for first-line MCL treatment as part of the chemoimmunotherapy regimen. Further, according to the panel, patients who receive ASCT for MCL should also receive rituximab maintenance. However, for those with MCL who are transplant-ineligible, there was consensus that first-line treatment should consist of an appropriate chemoimmunotherapy regimen with rituximab as maintenance therapy.
The panel again did not reach consensus on second-line or later lines of treatment for patients with MCL. Treatment options discussed included brexucabtagene autoleucel (Tecartus), proteasome inhibitors, Bruton tyrosine kinase (BTK) inhibitors, BTK inhibitors plus rituximab, or lenalidomide plus rituximab. Brexucabtagene autoleucel was approved by the FDA in July 2020 based on results from the open-label, phase 2 ZUMA-2 trial (NCT02601313), in which the agent demonstrated promising ORRs and rates of OS and PFS.9
For patients with low tumor burden follicular lymphoma (FL), the panel did not reach consensus on a preferred treatment. Treatment options presented included rituximab monotherapy, lenalidomide plus rituximab, or chemoimmunotherapy. Rituximab was evaluated for the first-line treatment of FL in combination with cyclophosphamide, vincristine, and prednisone (CVP) in NHL Study 4, resulting in an increased PFS compared to patients who were treated with only CVP.10 Moreover, in the AUGMENT trial (NCT01938001), lenalidomide plus rituximab resulted in a significantly increased median PFS and ORR among patients with FL compared with those who were given rituximab plus placebo.11 However, among patients with high tumor burden FL, there was consensus that first-line treatment should consist of an appropriate chemoimmunotherapy regimen.
For the second-line treatment of patients with FL, there was consensus that treatment regimens will vary and should be decided on a case-by-case basis by looking at factors that include prior therapies, time of relapse, tumor bulk, age, and comorbidity status. If deemed appropriate, the expert panel suggested ibritumomab tiuxetan (Zevalin) may be used in this context. This recommendation was based on the findings of a phase 3 trial (NCT00185393), which found that among patients with FL who achieved a partial response (PR) or CR following first-line chemotherapy and were administered either ibritumomab tiuxetan or no consolidation therapy, there was significantly higher PFS noted in the active therapy arm.12
Further, when anti-CD20 antibody therapy is indicated, there was consensus that rituximab should be used over obinutuzumab (Gazyva) when possible, given that obinutuzumab did not demonstrate an OS benefit in comparison to rituximab in the GALLIUM trial (NCT01332968).13 In the trial, obinutuzumab was investigated for the first-line treatment of FL in comparison to rituximab and revealed a PFS advantage at 3 years maintenance. However, the results did not demonstrate statistically significant differences in OS.
Moreover, among patients who have been treated with rituximab, the panel came to a consensus that if relapse occurs less than 6 months after the last dose of rituximab, obinutuzumab should instead be used. However, should relapse occur more than 6 months after the last dose of rituximab, there was consensus that rituximab should be administered again.
Marginal Zone Lymphoma
For patients with advanced-stage, low tumor burden marginal zone lymphoma (MZL), there was consensus within the panel that first-line treatment should consist of rituximab monotherapy. For those with advanced-stage, high tumor burden MZL, there was consensus that first-line treatment should consist of an appropriate chemoimmunotherapy regimen.
Regarding the second- or later-line treatment of patients with MZL, there was consensus that regimens will vary and should be determined on a case-by-case basis using factors including prior therapies, time of relapse, tumor bulk, age, and comorbidity status.
Primary Mediastinal B-Cell Lymphoma
For the first-line treatment of primary mediastinal B-cell lymphoma (PMBCL), a subtype of DLBCL, there was consensus within the panel that treatment should consist of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-R-EPOCH). This recommendation was based on the results of a phase 2 clinical trial (NCT00001337), which found that patients treated with DA-R-EPOCH experienced high OS and event-free survival (EFS) rates.14 Moreover, a retrospective analysis also identified similar rates of OS and EFS.15
Regarding the second-line treatment of PMBCL, there was consensus that treatment should be identical to the recommendations listed for DLBCL.
For the first-line treatment of Burkitt’s lymphoma (BL) in children, adolescents, and young adults (AYAs), there was consensus that treatment should consist of a rituximab-containing chemoimmunotherapy regimen, such as the rituximab-plus-FAB chemotherapy backbone or rituximab plus Berlin-Frankfurt-Münster (BFM) chemotherapy backbone. For the second-line treatment of BL in children and AYAs, there was consensus that treatment should consist of a rituximab-containing chemoimmunotherapy regimen such as R-ICE or a combination of rituximab, cytarabine, and etoposide (R-CYVE).
Among adults with BL, there was consensus that first-line treatment should consist of a rituximab-containing chemoimmunotherapy backbone. Moreover, for the second-line treatment of adults with BL, there was consensus treatment should consist of rituximab-containing chemoimmunotherapy regimens similar to those recommended for the first-line treatment of BL.
The expert panel did not reach consensus regarding a single recommended regimen for the first-line treatment of patients with CD30-positive, peripheral T-cell lymphoma (PTCL). Treatment options presented included BV with cyclophosphamide, doxorubicin, and prednisone (CHP), chemotherapy alone, or chemotherapy plus ASCT if patients are eligible. This recommendation was partially based on results from the ECHELON-2 trial (NCT01777152), in which patients with CD30-positive, PTCL received CHOP chemotherapy or BV with CHP (A+CHP) as first-line therapy.16 In this study, patients treated with A+CHP experienced a significantly increased median PFS.
However, for the first-line treatment of CD30-negative PTCL, there was consensus that treatment should consist of an appropriate chemotherapy regimen plus ASCT.
The panel again did not reach consensus on a single recommended regimen for the second-line treatment of PTCL in patients eligible for stem cell transplant. Treatment options presented included chemotherapy plus ASCT, chemotherapy plus allogeneic stem cell transplant (alloSCT), or histone deacetylase (HDAC) inhibitors.
For the second-line treatment of patients with CD30-positive PTCL who are ineligible for stem cell transplant, there was consensus that treatment should consist of BV with a total of up to 16 doses. This recommendation was based on a systematic review of pooled outcomes from patients with CD30-positive post-transplant lymphoproliferative disorder (PTLD) who were treated with BV across clinical trials and case studies.17 The review ultimately found that results were mostly positive, with over half of patients experiencing complete remission.
For CD30-negative PTCL, there was consensus that second-line treatment should consist of HDAC inhibitors.
For the first-line treatment of cutaneous T-cell lymphoma, the panel did not reach consensus on a single recommended regimen. Treatment options recommended included BV, HDAC inhibitors, and an appropriate chemotherapy regimen. Further, the panel again did not reach consensus on a single recommended regimen for the second-line treatment of cutaneous T-cell lymphoma. Treatment options discussed included HDAC inhibitors, an appropriate chemotherapy regimen, such as pralatrexate, and BV.
1. Neelapu SS, Adkins S, Ansell SM, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma. Journal of ImmunoTherapy of Cancer. 2020;8:e001235. doi: 10.1136/jitc-2020-001235
2. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327:1478-1484. doi: 10.1056/NEJM199211193272102
3. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331-344. doi: 10.1056/NEJMoa1708984
4. Moskowitz CH, Walewski J, Nademanee A, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. 2018;132(25):2639-2642. doi: 10.1182/blood-2018-07-861641
5. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med. 2002;346:235-242. doi: 10.1056/NEJMoa011795
6. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. Published online November 6, 2019. doi: 10.1200/JCO.19.00172
7. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet Oncol. Published online December 2, 2028. doi: 10.1016/S1470-2045(18)30864-7
8. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
9. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347
10. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105(4):1417-1423. doi:10.1182/blood-2004-08-3175
11. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. Published online March 21, 2019. doi: 10.1200/JCO.19.00010
12. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90—ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. Published online September 22, 2016. doi: 10.1200/JCO.2008.17.2015
13. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377:1331-1344. doi: 10.1056/NEJMoa1614598
14. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368:1408-1416. doi: 10.1056/NEJMoa1214561
15. Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Brit Jour of Haem. 2017;179:739-747. doi: 10.1111/bjh.14951
16. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. The Lancet. Published online June 6, 2017. doi: 10.1016/S0140-6736(17)31266-7
17. Berger GK, McBride A, Lawson S, et al. Brentuximab vedotin for treatment of non-Hodgkin lymphomas: A systematic review. Critical Review in Oncology/Hematology. 2017;109:42-50. doi: 10.1016/j.critrevonc.2016.11.009