NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-19-008-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/85881; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: June 10, 2019; Expiration date: June 10, 2020
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for B-Cell Lymphomas
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for B-Cell Lymphomas
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Andrew D. Zelenetz, MD, PhD, Panel Chair, has disclosed that he receives consulting fees/honoraria from Amgen Inc.; Celgene Corporation; Gilead Sciences, Inc.; Janssen Pharmaceutica Products, LP; Novartis Pharmaceuticals Corporation; Adaptive Biotechnologies Corporation; Genentech/Roche; AbbVie, Inc.; AstraZeneca Pharmaceuticals LP; Pharmacyclics; and MorphoSys AG. He also receives grant/research support from BeiGene, Gilead Sciences, Inc., MEI Pharma Inc., and Roche Laboratories; receives an other financial benefit from BeiGene; and is a scientific advisor for AbbVie Inc., and AstraZeneca Pharmaceuticals LP.
Leo I. Gordon, MD, Vice Chair, has disclosed that he is a scientific advisor for Juno Therapeutics/Celgene Corporation, Gilead Sciences, Inc., and Bayer HealthCare; receives grant/research support from Juno Therapeutics/Celgene Corporation; and has ownership/partnership/principal in Zylem.
Jeremy S. Abramson, MD, Panel Member, has disclosed that he receives consulting fees/honoraria from AbbVie Inc., Bayer, EMD Serono, Genentech, Inc., Janssen Pharmaceutica Products, LP, Karyopharm Therapeutics Inc., and Kite Pharma, Inc.
Thomas M. Habermann, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Stephen D. Smith, MD, Panel Member, has disclosed that he receives grant/research support from Acerta Pharma, AstraZeneca Pharmaceuticals LP, Denovo Biopharm, Genentech, Inc., Incyte Corporation, Merchk Sharp Dohme Corporation, and Portola Pharmaceuticals, Inc.; he is a consultant for AstraZeneca Pharmaceuticals LP; and his spouse receives grant/research support from Ayala Pharmaceuticals, Bristol-Myers Squibb Company, and Ignyta Inc.
Mary A. Dwyer, MS, CGC, Senior Manager, Guidelines, NCCN, has disclosed that she has no relevant financial relationships.
Hema Sundar, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Clovis Oncology, Eisai, Genentech, Genomic Health, Inc., Novartis, Taiho Oncology, Inc., and TESARO. This activity is supported by an independent educational grant from AbbVie. This activity is supported by educational funding provided by Amgen. This activity is supported by an unrestricted educational grant from Gilead Sciences, Medical Affairs.
Overview
Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas (NHLs) in adults, accounting for approximately 30% and 22%, respectively, of all newly diagnosed NHLs annually.1 Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients, with an estimated annual rate of 2% to 3%, and is generally associated with a poor clinical outcome.2–4 In a pooled analysis of French and US cohorts of patients with newly diagnosed FL, TFL after diagnosis was the leading cause of death (77 of 140 deaths).5 Recent studies evaluating outcomes of patients with TFL in the rituximab era have reported improved survival in a subset of patients (eg, those with histologic transformation after early-stage FL, those with no previous exposure to chemotherapy or rituximab before histologic transformation).4,6,7
Recently, small molecule inhibitors targeting a variety of kinases involved in the B-cell receptor pathway have demonstrated promising activity for the treatment of relapsed/refractory FL. CAR T-cell therapy has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL.
These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for B-Cell Lymphomas regarding the treatment of FL (relapsed/refractory disease and TFL) and DLBCL (relapsed/refractory disease).
Follicular Lymphoma
Anti–CD20 antibody–based chemoimmunotherapy is the standard initial treatment for newly diagnosed and relapsed/refractory FL. Frequently, patients with relapsed or progressive disease after first-line therapy will benefit from a second period of observation. Considerations and indications for treatment of relapsed/refractory or progressive disease include, among other factors, the modified GELF criteria, which include symptoms attributable to FL (not limited to B symptoms); threatened end-organ function; significant cytopenia secondary to lymphoma; bulky disease; splenomegaly; and steady progression over at least 6 months.
Progression of disease (POD) within ≤24 months of diagnosis and failure to achieve event-free survival at 12 months after initial treatment with chemoimmunotherapy have been identified as a prognostic indicators of poor survival.8–10 In the National LymphoCare Study, the 5-year overall survival (OS) rate was 50% for patients with POD ≤2 years after first-line therapy with R-CHOP (rituximab + cyclophosphamide/doxorubicin/vincristine/prednisone) compared with 90% for those without POD within ≤2 years.8 In a population-based analysis of relative survival of patients with FL compared with age- and sex-matched controls (from US and French datasets), patients who remained event-free 12 months after initial disease management had similar OS outcomes to the control group, whereas patients who experienced an event within 12 months had poor subsequent OS.9 Duration of response to first-line therapy is an important factor in the selection of second-line therapy. Options for treatment at first relapse include alternate non–cross-resistant chemoimmunotherapy regimens or combination lenalidomide + rituximab. Rituximab monotherapy may be appropriate for patients with late relapse as well, particularly if disease burden is low.
PI3K inhibitors (idelalisib, copanlisib, and duvelisib) have shown promising results in the treatment of relapsed/refractory disease after 2 prior therapies.11–15 Idelalisib and copanlisib have also been shown to be effective in high-risk patients with disease relapse ≤2 years after first-line therapy.14,16
Based on the recent FDA approvals, idelalisib, copanlisib, and duvelisib are included as options for relapsed/refractory disease after 2 prior therapies. Evidence from clinical trials supporting this recommendation is discussed as follows.
Idelalisib
In a phase II multicenter single-arm study of 125 patients with rituximab- and alkylating agent–refractory indolent NHL (72 patients with FL), idelalisib resulted in tumor reductions in 90%, with an overall response rate (ORR) of 57% (6% complete response [CR]).11 Median duration of response and median progression-free survival (PFS) were 13 and 11 months, respectively. In a post hoc subgroup analysis of 72 patients with FL, the ORR was 56% (14% CR and 42% partial response [PR]) and the overall disease control rate was 87%.12 PFS rate at 12 months and estimated OS rate at 24 months were 43% and 70%, respectively. Grade ≥3 toxicities included neutropenia (27%), elevated alanine aminotransferase level (13%), diarrhea (13%), and pneumonia (7%), and thrombocytopenia (6%). In a post hoc analysis, median PFS was 8 months for patients with POD within 12 months compared with 14 months for those with POD between 12 and 24 months.16 The ORR, however, was not significantly different between the 2 groups (71% and 45%, respectively; P=.18).
Copanlisib
In a phase II study (CHRONOS-1) of 142 patients with relapsed/refractory indolent NHL after ≥2 prior lines of therapy, copanlisib resulted in an ORR of 59% in the subgroup of 104 patients with FL (14% CR and 44% PR) and median duration of response of 12 months. Median PFS and OS were 11 months and not reached, respectively.13 The 2-year follow-up data confirmed these results: ORR was 61% (20% CR and 39% PR) and median PFS and OS were was 13 and 43 months, respectively.14 Among the 98 patients with FL and POD within 24 months, the ORR was 60% (22% CR and 38% PR), which was not significantly different from the ORR of 59% for patients with POD after 24 months; however, the CR rate was higher in the group that experienced POD in <24 months (22%) compared with 18% in the group with POD after >24 months.14 Grade ≥3 toxicities included hyperglycemia (41%), neutropenia (24%), hypertension (24%), pneumonia (15%), thrombocytopenia (7%), and diarrhea (5%).
Duvelisib
In the phase II DYNAMO study evaluating the safety and efficacy of duvelisib in 129 patients with indolent NHL refractory to both rituximab and chemotherapy or radioimmunotherapy (RIT), duvelisib resulted in an ORR of 47% (42% for the subgroup with FL).15 Estimated median duration of response and median PFS were 10 and 9.5 months, respectively. Grade ≥3 toxicities included neutropenia (25%), anemia (15%), diarrhea (15%), and thrombocytopenia (12%).
Special Considerations for Use of PI3K Inhibitors
Diarrhea/colitis, hepatotoxicity, hyperglycemia, and transient cytopenias are the most common adverse events associated with PI3K inhibitors, and there are some differences in toxicities among the 3 available agents (Table 1).11,13,15 Recommendations for the monitoring and management of specific adverse events are outlined on pages 658 and 659 (NHODG-E).
Adverse Events of PI3K Inhibitors
Diffuse Large B-Cell Lymphoma
Second-line therapy followed by high-dose therapy with autologous stem cell rescue (HDT/ASCR) is appropriate treatment for relapsed/refractory DLBCL that is chemotherapy-sensitive at relapse in patients who are candidates for transplant.17–20 Outcomes of relapsed/refractory DLBCL differ based on the response to initial therapy, timing of relapse, and opportunity to undergo HDT/ASCR. In a population-based study of 1,039 patients treated with anthracycline-based chemoimmunotherapy, 244 (23%) had relapsed disease that was subsequently re-treated.21 Across all therapies, the 4-year OS rate from relapse was 28%, and was 51% among those who underwent HDT/ASCR. The 4-year OS rate was 47% for patients with disease relapse after 12 months from initial diagnosis, whereas it was 13% for those with a transient or no response to initial therapy. The efficacy of second-line therapy is predicted by the second-line age-adjusted International Prognostic Index (IPI).22,23 Pretransplantation PET scans have been identified as predictive factors in patients undergoing HDT/ASCR, with positive PET results following second-line therapy predicting poor outcomes with transplantation.24–26
Second-line combination chemotherapy is recommended for patients with an intention to proceed to transplant (see BCEL-7, page 656). Rituximab should be included if disease relapse occurs after a reasonable remission period (>6 months) and biopsy demonstrates continued CD20 expression; however; rituximab may be omitted in patients with primary refractory disease. Consolidation therapy with HDT/ASCR (category 1 for patients with CR) ± radiotherapy (RT) is recommended for patients with CR or PR to second-line therapy, if they are candidates for transplant.17,20 Involved-site RT (ISRT) before HDT/ASCR has been shown to result in good local disease control and improved outcome.27 Additional RT can be administered to limited sites with prior positive disease before or after HDT/ASCR. Allogeneic hematopoietic cell transplant (alloHCT) should be considered in select patients with mobilization failures and persistent bone marrow involvement or lack of adequate response to second-line therapy, although they should be in CR or near-CR at the time of transplant.
Patients who are not candidates for transplant should ideally be treated in the context of a clinical trial. Standard options include gemcitabine-based regimens ± rituximab,28 bendamustine ± rituximab,29,30 or brentuximab vedotin for CD30-positive disease.31 Lenalidomide ± rituximab32,33 and ibrutinib34 are appropriate options at relapse, particularly for patients with non–germinal center B-cell–like (GCB) DLBCL.
Patients who are not candidates for transplant and experience a PR to second-line therapy, those with POD or refractory disease during second-line therapy (regardless of transplant eligibility), and those who experience disease relapse following HDT/ASCR or alloHCT should be managed with third-line systemic therapy, palliative ISRT, or best supportive care (see BCEL-8, page 657). Repeat biopsy should be strongly considered before additional therapy in patients who are noncandidates for transplant achieving PET-positive PR to second-line therapy, because PET positivity may represent posttreatment inflammation.
However, patients experiencing POD after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from currently available systemic therapy options. The results of a recent multicenter, retrospective study (SCHOLAR-1) showed that outcomes are consistently poor among patients with refractory DLBCL.35 In this study evaluating the outcome of 636 patients with refractory DLBCL (defined as progressive or stable disease as best response at any point during chemotherapy [>4 cycles of first-line or 2 cycles of later-line therapy] or disease relapse at ≤12 months from HDT/ASCR), the pooled ORR was 26% (7% CR) to the next line of therapy, and median OS was 6 months.35 Response rates were much lower for patients with primary refractory disease or refractory disease after second-line or subsequent therapy (20% and 26%, respectively) compared with those with disease relapse ≤12 months from HDT/ASCR. Data from recent clinical trials (discussed in the following section) suggest that CAR T-cell therapy represents an improved treatment option for this group of patients.
CAR T-Cell Therapy
Axicabtagene ciloleucel and tisagenlecleucel are anti-CD19 CAR T-cell therapies FDA-approved for the treatment of adult patients with relapsed/refractory DLBCL, high-grade B-cell lymphomas (HGBL), and TFL (after ≥2 prior systemic therapy regimens).36–38 Axicabtagene ciloleucel is also approved for relapsed/refractory primary mediastinal B-cell lymphoma (PMBL; after ≥2 prior systemic therapy regimens).
A multicenter phase II study (ZUMA-1) evaluated axicabtagene ciloleucel in patients with refractory DLBCL (n=81), TFL (n=30), or PMBL (n=8).36 Eligible patients had an absolute neutrophil count >1,000 cells/mcL, an absolute lymphocyte count >100 cells/mcL, a platelet count >75,000 cells/mcL, adequate organ function, no central nervous system (CNS) involvement, and no active infection. In the primary analysis that included 101 patients (78 with disease refractory to ≥2 lines of prior therapy and 21 with disease relapse after HDT/ASCR) who were evaluated 6 months after the infusion of axicabtagene ciloleucel, the ORR was 82% (54% CR and 28% PR). With a median follow-up of 15 months, the estimated PFS rate at 15 months and the OS rate at 18 months were 41% and 52%, respectively. The ORR was 81% (49% CR and 32% PR) and 83% (71% CR and 12% PR), respectively, for the subgroup of patients with DLBCL and TFL or PMBL. The 2-year follow-up data also confirmed these initial findings.37 After a median follow-up of 27 months, 39% of patients remained in ongoing remission and 51% remained alive. Median duration of response was 11 months and median PFS was 6 months.
The global multicenter phase II study (JULIET) evaluated tisagenlecleucel in patients with relapsed/refractory DLBCL (after ≥2 lines of therapy, including rituximab and an anthracycline) and TFL.38 Patients who were previously treated with anti-CD19 CAR T-cell therapy, received an alloHCT, had PMBL, or had active CNS involvement were excluded. In this study, 11 patients received an infusion with tisagenlecleucel. Among the 93 patients included in the efficacy analysis with ≥3 months of follow-up or had discontinued participation in the study before 3 months, the best ORR was 52% (40% CR and 12% PR). The estimated PFS rate at 12 months was 83% for patients who had a CR or PR at 3 months. The estimated OS rate at 12 months was 49% for all patients and 90% for those with a CR.
Axicabtagene ciloleucel and tisagenlecleucel result in responses across all subgroups, including double-hit/triple-hit lymphomas, GCB and non-GCB subtypes, and patients with either relapsed or primary refractory disease.36–38 CD19 expression levels did not correlate with response. The NCCN Guidelines recommend CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) for patients achieving PR after second-line therapy (regardless of their eligibility for transplant) and for those with disease relapse after achieving CR to second-line therapy or with progressive disease (see BCEL-7, opposite page, and BCEL-8, above).
Guidance for Treatment With CAR T-Cell Therapy
Axicabtagene ciloleucel and tisagenlecleucel should only be dispensed and administered in healthcare facilities that are enrolled in and comply with the Risk Evaluation and Mitigation Strategies (REMS) requirements.
Cytokine-release syndrome (CRS) and neurologic toxicity (also known as CAR T-cell–related encephalopathy syndrome [CRES]) are the most frequent life- threatening toxicities associated with CAR T-cell therapy. In the ZUMA-1 trial, CRS and neurologic toxicity of any grade were reported in 93% and 64% of patients, respectively.36,37 Median time from infusion to onset of symptoms was 2 and 5 days, respectively, with a median duration of 8 and 17 days, respectively. Grade ≥3 CRS and neurologic events occurred in 13% and 28% of the patients, respectively. Pyrexia (11%), hypoxia (9%), and hypotension (9%) were the most common symptoms of grade ≥3 CRS. Median time to onset of CRS was 2 days after infusion, and median time to resolution was 8 days. Encephalopathy (21%), confusion (9%), aphasia (7%), and somnolence (7%) were the most common grade ≥3 neurologic events. The incidence of grade ≥3 CRS and neurologic events decreased over the course of the study (occurring in 12% and 31% of patients, respectively, after a median follow-up of 15 months). In the JULIET trial, CRS and neurologic toxicity of any grade were reported in 58% and 21% of patients, respectively,38 and in 22% and 12%, respectively, for grade ≥3. Median time from infusion to onset of symptoms was 2 and 6 days, respectively, with a median duration of 7 and 14 days, respectively. Notably, different toxicity scales were used for grading CRS in the ZUMA-1 and JULIET trials (grade 3 CRS in JULIET was similar to grade 2 in ZUMA-1); therefore, although rates of any CRS can be compared, the rates of severe (grade 3/4) CRS specifically cannot be directly compared with accuracy.
The anti–interleukin-6 (IL-6) receptor monoclonal antibody tocilizumab is highly effective for the management of CRS, inducing rapid reversal of symptoms in most patients.39 Tocilizumab is approved for the treatment of CRS occurring after CAR T-cell therapy, and its use has not been shown to have any impact on the efficacy of CAR T-cell therapy in terms of response rates or duration of response. Corticosteroids are also an important adjunctive treatment of CRS, in concert with tocilizumab. Corticosteroids are preferred for the management of neurologic toxicity if not associated with CRS, whereas tocilizumab in combination with corticosteroids is recommended for management of CRS occurring in tandem with neurologic toxicity.39 Use of corticosteroids for the management of toxicities associated with CAR T-cell therapy did not impact the efficacy of CAR T-cell therapy, although it has been to shown to impair T-cell function. CRS and neurologic toxicity should be managed based on the toxicity grade as outlined in the CAR T-cell therapy–related toxicities section of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
Histologically Transformed FL
Risk Factors
Advanced-stage FL at diagnosis, high-risk Follicular Lymphoma IPI and IPI scores at diagnosis, elevated lactate dehydrogenase level, and B symptoms at diagnosis have been reported to be risk factors for TFL.2–4,6,40,41
Retrospective analyses have suggested that early initiation of treatment at diagnosis relative to observation may decrease the risk of transformation in some studies.4,6,40 However, in the randomized phase III Intergroup trial that evaluated the role of immediate treatment with rituximab versus observation in patients with advanced-stage, asymptomatic, low-tumor-burden FL, and that also addressed whether early intensive rituximab therapy would change the risk of histologic transformation, no difference in time to transformation or incidence of histologic transformation was detected among the 3 groups after a median follow-up of almost 4 years.42
Treatment Options
No data from randomized studies support the optimal treatment of patients with TFL, because clinical trials have often excluded this group of patients. Results from retrospective cohort studies suggest that rituximab monotherapy or in combination with anthracycline-based chemotherapy is associated with improved OS.4,6,41 RIT has also been shown to induce high response rates and durable remissions in patients with TFL.43,44
In a series that reported the outcomes of 60 patients with biopsy-proven TFL, R-CHOP was the most commonly used treatment (n=35; 59%), associated with a median OS of 50 months.4 At a median follow-up of 60 months, the 5-year OS rate was 66% for patients with TFL treated with R-CHOP, which was similar to the outcome of patients with de novo DLBCL treated with R-CHOP in the validation cohort (5-year OS rate of 73%). In the National LymphoCare Study that included 147 pathologically confirmed and 232 clinically suspected cases of TFL, most patients were treated with rituximab-based therapy (26% of patients received rituximab monotherapy and 35% received chemotherapy with rituximab).6 At a median follow-up of 7 years, median PFS and OS were 12 and 60 months, respectively, for patients with biopsy-proven TFL. In another study (PRIMA) that evaluated the outcomes of patients with FL who experienced histologic transformation after response to first-line chemoimmunotherapy, most with TFL received chemoimmunotherapy regimens recommended for DLBCL, with a 5-year OS rate of 48% to 50%.41
HDT/ASCR as consolidation therapy has been evaluated only in retrospective studies,45–52 with some series reporting a survival benefit for patients who proceeded to transplant.48,50,52 AlloHCT has been shown to benefit select patients with disease relapse after HDT/ASCR, but it is also associated with significant transplant-related mortality.48,49,51,53 However, it should be noted that the efficacy HDT/ASCR or alloHCT in patients with TFL has not been confirmed in prospective controlled studies.
Histologic Transformation After Minimal or No Prior Chemotherapy
Anthracycline-based chemoimmunotherapy (with regimens recommended for first-line therapy for DLBCL, unless contraindicated) ± ISRT is recommended for TFL without double-hit cytogenetics (see FOLL-6 and FOLL-7, pages 652 and 653).4,6 Histologic transformation to HGBL with translocations of MYC with either BCL2 or BCL6, also called double- or triple-hit lymphoma, occurs in approximately 24% of patients and has been associated with inferior survival compared with TFL without double-hit cytogenetics.54,55 TFL with double-hit cytogenetics should be managed with more aggressive chemoimmunotherapy regimens, as recommended for HGBL with translocations of MYC and BCL2 and/or BCL6.
Consolidation therapy with HDT/ASCR ± ISRT (if not previously given) or observation are included as treatment options for patients achieving CR or PR to initial treatment.48,50,52 If transformation is coexisting with extensive FL, rituximab maintenance should be considered for patients achieving CR. Additional systemic therapy ± ISRT to induce CR should be considered for patients achieving PR, if proceeding to transplant. Repeat biopsy should be strongly considered before additional therapy in patients with PET-positive PR, because PET positivity may represent posttreatment inflammation. AlloHCT may be considered in selected patients.
RIT with ibritumomab tiuxetan or ISRT (for localized residual disease and/or residual FDG-avid disease not previously irradiated) are included are alternative treatment options for patients achieving PR.43,44 RIT with ibritumomab tiuxetan or best supportive care are recommended for patients with nonresponsive or progressive disease.43,44 Based on the FDA approval, CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) is included as an option (only after ≥2 prior chemoimmunotherapy regimens for indolent or transformed disease) for patients achieving PR or those with nonresponsive or progressive disease.36–38
Histologic Transformation After Multiple Lines of Prior Therapies
Enrollment in an appropriate clinical trial is the preferred option. In the absence of a suitable clinical trial, treatment options include chemoimmunotherapy (with regimens recommended for second-line therapy for DLBCL) ± ISRT, RIT with ibritumomab tiuxetan, ISRT, or best supportive care (FOLL-8, page 654).41,43,44 Based on the FDA approval, CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel) is included as an option for patients who have received ≥2 prior chemoimmunotherapy regimens for transformed disease.36–38
Consolidation therapy with HDT/ASCR ± ISRT (if not previously given) or observation are included as treatment options for patients who achieve CR.48,50,52 AlloHCT may be considered in selected patients. For patients experiencing PR to initial therapy of TFL, treatment options include second-line regimens for DLBCL, alloHCT ± ISRT in selected patients, CAR T-cell therapy (axicabtagene ciloleucel or tisagenlecleucel for patients who have received ≥2 prior chemoimmunotherapy regimens for transformed disease) if not previously given, or ISRT for localized residual disease and/or residual FDG-avid disease not previously irradiated. However, it should be noted that data on the efficacy of transplant in patients who have received CAR T-cell therapy are not available. HDT/ASCR is not recommended after CAR T-cell therapy; alloHCT could be considered but remains investigational.
Patients with nonresponsive or progressive disease can be treated with any of the treatment options (not received previously) if they are candidates for additional therapy.
References
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2019. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
