Case study 52.1
You are requested to see a 61-year-old very successful hedge fund manager with diffuse large B-cell lymphoma (DLBCL). He comes to you for a third medical oncology opinion with recently diagnosed stage IIIB disease. He has excellent performance status. At the time of diagnosis, the LDH was above the upper limit of normal. His lymphoma does not have c-myc translocation or overexpress bcl-2 protein. The Hans criteria points toward the activated B-cell (ABC) subtype. The gene expression profiling (GEP) analysis confirms the ABC subtype. Approximately 8 weeks ago, he completed six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy with positron emission tomography (PET) negativity. The cycles were given every 3 weeks. His assistant made an internet search and told him that he has a “high-risk” lymphoma. He informs you, “I’m a fixer and I want to be sure that my lymphoma does not come back ever.”
• How would you explain to him the therapeutic and prognostic implications, especially of molecularly defined “ABC high-risk” lymphoma?
Numerous prognostic markers and indices are under investigation since the initial publication of the International Prognostic Index (IPI) model in 1993. The rationale behind such investigations stems from the inability of currently applied clinical prognostic model(s) to precisely capture the heterogeneity in outcomes experienced with delivery of category 1 NCCN recommended therapy. Obviously, this is due to the fact that DLBCL is not a single disease but encompasses various clinical and biologic subgroups. In the era of R-CHOP, the most applicable and widely acceptable prognostic models are the IPI and Revised IPI (R-IPI). Based on the age-adjusted (age >60) IPI model, this patient would be categorized into high-intermediate (HI) risk with a 5-year overall survival (OS) rate of 37%. And according to the R-IPI model, which appears to be a superior model in the rituximab era, the 4-year progression-free survival (PFS) and OS would be 53% and 55%, respectively. Using R-IPI, the best outcomes are achieved in patients categorized as very good risk with a remarkable 4-year PFS and OS of 94%. Notably, within these well-defined prognostic categories, layers of prognostic complexity remain. Indeed, utilizing the GEP method has the potential to refine the prognostic algorithm; however, not all genes within cell-of-origin (COO) classification have a strong prognostic significance. Importantly, as opposed to the highly curative strategies employed in acute promyelocytic leukemia (APL) following seminal discovery of the PML–RARα gene, the obstacle of isolating and targeting a disease-driving single gene in DLBCL remains a formidable challenge.
Intriguing retrospective data do exist in front-line settings, showing inferior PFS and OS in patients with GEP-defined ABC- versus germinal B-cell (GBC) DLBCL in the context of currently available therapies. A French group (the LNH98.5 trial) reported outcomes of 67 older adults with inferior OS rates in ABC (n = 42) versus GBC DLBCLs (n = 25) with a hazard ratio of 0.18 (0.04–0.76) in the context of R-CHOP therapy. The COO distinction remained statistically significant in a multivariate analysis for OS. Similarly, a study from the US National Institutes of Health (NIH) demonstrated PFS of 40% versus 75% (P < .001) with ABC and GBC DLBCL, respectively, in patients treated with R-CHOP. Gutiérrez-García and colleagues (2010) from the University of Barcelona showed, in 52 patients, a 5-year PFS of 31% versus 76% (P = .005) in patients with ABC and GBC DLBCL, respectively. In Europe, a phase III molecularly guided randomized control trial (RCT), ReMoDL-B (ISRCTN 51837425), is ongoing. This is the first study with prospective GEP analysis as a means of stratifying randomization of DLBCL subgroups between treatment with R-CHOP or R-CHOP plus bortezomib. The goal of the trial is to determine if there is a subset of DLBCL in which bortezomib improves outcome. Altogether, despite unsatisfactory statistics procured with any of the aforementioned prognostic models, the recommended treatment, outside of a clinical trial, remains remarkably uniform within all risk categories in patients with stages III and IV DLBCL.
1. After hearing your explanation, he says, “So tell me, should I get ready for more chemotherapy and/or transplant, Doc, or should I get another opinion trans-Atlantic?” What do you recommend?
- Front-line consolidation high-dose chemotherapy (HDT) and autologous hematopoietic cell transplant (auto-HCT)
- Rituximab maintenance for 2 years.
- Surveillance
This question highlights two important clinical issues in the management of DLBCL: (i) what are the optimal number of treatment (R-CHOP) cycles (e.g., 6 versus >6, especially in HI/HR risk category or ABC DLBCL)? And (ii) what is the highly debated role of frontline HDT and auto-HCT in DLBCL? The answers to these questions are not straightforward.
(i) The RICOVER-60 trial compared six and eight cycles with and without rituximab in 1222 patients ages 61 to 80 years with aggressive non-Hodgkin’s lymphoma (NHL), but the cycles were every 2 weeks (R-CHOP14) instead of every 3 weeks (R-CHOP21). The authors concluded that six cycles should be the standard using R-CHOP-14. In our opinion, extrapolation of these data with R-CHOP21 in older adults with high-risk disease is an unsettled issue. The trial incorporated histologies other than DLBCL (20% of the patients did not have DLBCL) and <50% of the patients with aggressive lymphoma (all histologies included) had IPI >3. In our practice, we prefer R-CHOP21 ×6 cycles in the majority of adults with de novo (c-myc translocation negative and not transformed) DLBCL. However, European Society of Medical Oncology (ESMO) guidelines for DLBCL recommend R-CHOP21 ×8 in healthy older (age >60 to 80 years) adults with high IPI scores and R-CHOP21 ×6 in patients with low IPI scores or, alternatively, R-CHOP14 ×6 with an additional two doses of rituximab (total doses of rituximab ×8) for all healthy older (>60 years) patients up to age 80 years.
(ii) The majority of randomized clinical trials (RCTs) failed to demonstrate OS benefit with frontline auto-HCT in DLBCL. In addition, two meta-analyses (in 2003 and 2007) were unable to show OS benefit. On the contrary, detrimental effects with transplant were observed in low-risk IPI patients. The evidence for or against frontline auto-HCT in patients with high IPI scores continues to be debated especially following the SWOG 9704 study presentation during the American Society of Clinical Oncology (ASCO) meeting in 2011. This North American Intergroup was designed and approved prior to rituximab; however, the drug was incorporated into the CHOP regimen upon its availability. In this large RCT, patient with high-intermediate-risk (HI) and high-risk (HR) IPI received CHOP +/− rituximab ×5 and then were randomized to either three additional cycles of CHOP +/− rituximab (n = 128) or one additional cycle of CHOP +/− rituximab followed by auto-HCT (n = 125). Obviously, the randomization was performed only in patients who achieved greater than or equal to a PR (“chemosensitive disease”). The study was unable to demonstrate an OS benefit with front-line auto-HCT, not even in patients who received rituximab (n = 72). Rigorous subset analysis showed that only patients with HR IPI had OS benefit with auto-HCT, and a 2-year OS of 82% versus 64%; however, this was analyzed only in 44 and 40 patients in the auto-HCT and CHOP +/− R arms, respectively. Thus, these positive results beg caution to conclude that frontline auto-HCT comprise the best therapeutic strategy for HR IPI patients. For example, not all patients analyzed had DLBCL (78% of all patients in the study had DLBCL), only 32% of patients had HR IPI, rituximab was administered in approximately 48% of patients with B-cell lymphomas (not just DLBCL), and, finally, the analysis was exploratory. The final results of this study were recently published in NEJM. A separate French (GOELAMS 075) study did not demonstrate OS benefit with auto-HCT compared to R-CHOP. In fact, the 3-year EFS was superior with R-CHOP compared to auto-HCT (56% vs. 36%, respectively), with no impact of IPI risk categories on outcomes. The Italian Lymphoma Foundation (DLCL04) reported a 2 × 2 trial comparing R-CHOP14 with R-MegaCHOP in the first randomization, and auto-HCT versus continuation of the original induction regimen in the second randomization, in high-risk patients with DLBCL. The CR/unconfirmed CR (CR/CRu) rates were 70% for R-CHOP14 and 77% for R-MegaCHOP. With second randomization, there was a 2-year PFS in favor of the auto-HCT arm compared with the continuation-of-induction-chemotherapy arm. It was 72% for auto-HCT versus 59% for chemotherapy (P = .008), with no difference seen in OS. The therapeutic implications of interim PET scan is important and are discussed in Chapter 61. Presently, ABMTR guidelines (updated 2011) do not support frontline auto-HCT in patients with either HI or HR IPI or R-IPI scores or GEP-defined ABC DLBCL. However, this discussion remains open for debate and investigation. In view of the benefit of auto-HCT in the salvage setting, it is likely that certain subgroups of newly diagnosed DLBCL patients may benefit from this strategy in the frontline setting. The ability to identify such patients based on clinical or biologic markers continues to evolve and is under intensive investigation.
2. Unfortunately, approximately 9 months following front-line immunochemotherapy, he develops severe B-symptoms; a PET–computed tomography (CT) scan reveals extensive fluoro-deoxyglucose (FDG)-avid lymphadenopathy at original sites. Repeat biopsy confirmed a relapse of ABC DLBCL. Bone marrow exam remains negative. What do you recommend?
- R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin)
- R-ICE (rituximab, ifosfamide, etoposide, and carboplatin)
- R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin)
- R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin)
- R-MINE (rituximab, mesna, ifosfamide, mitoxantrone, and etoposide)
- R-GemOx (rituximab, gemcitabine, and oxaliplatin)
- R-DA-EPOCH (rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)
- Any of the above regimens is a reasonable option.
Salvage chemotherapy followed by auto-HCT is considered standard treatment for relapsed and refractory DLBCL. The choice of a specific salvage regimen prior to auto-HCT should take into consideration patient’s comorbidities, physician comfort level with a particular regimen, and the regimen’s ability to reduce disease burden without hampering the mobilization process. Achievement of complete response (CR2) is always preferred over partial response, but it is not a prerequisite to proceed with auto-HCT. Patients refractory to salvage regimens are not candidates for auto-HCT. These patients have a grim outlook with survival not more than a few months. In responding patients, PET scan negativity portends favorable outcomes for patients compared to a positive scan prior to auto-HCT (discussed in Chapters 40 and 61). Multiple salvage regimens have been developed, and there remains no standard of care. As such, there is no single best regimen; thus, patients should be encouraged to participate in clinical trials. It must be stated that outcomes are suboptimal even for patients responding and proceeding to auto-HCT. In the rituximab era, the landmark Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) intergroup study is a RCT that compared the two most commonly utilized salvage regimens, R-ICE and R-DHAP. In the CORAL trial, patients received either R-ICE or R-DHAP, and responding patents had BEAM (carmustine, etoposide, high-dose cytarabine, and melphalan) and auto-HCT, and then had second randomization between observation and rituximab maintenance for 1 year. Several important questions related to relapsed and refractory DLBCL were elegantly addressed in this phase III trial (reviewed in Table 52.1). Noteworthy, only half of the patients were able receive the intended auto-HCT. This was mainly secondary to progressive disease and highlights the key limitations of currently available salvage regimens. A larger RCT study (NCIC CTG LY12) with similar design under National Cancer Information Center (NCIC) sponsorship has been completed. In this study, R-GDP (gemcitabine, dexamethasone, and platinum) was compared with the R-DHAP regimen in patients with aggressive NHL (71% of the patients had DLBCL). The R-GDP was non-inferior to R-DHAP with less toxicity. Altogether, it is prudent to effectively incorporate novel agents, preferably early during the course of disease to improve on the inefficient outcomes demonstrated in the majority of patients with relapsed and refractory disease. Numerous experimental agents (Table 52.2) are in different evaluation phases, and it is hoped that they will be integrated into the treatment algorithm of DLBCL in the near future.
Table 52.1 Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) (data from CORAL study).
Treatment algorithm: R-ICE vs. R-DHAP → BEAM and Auto-HCT → rituximab versus observation |
|---|
Question |
Answera |
Comments |
RICE and R-DHAP are comparable salvage regimens. |
Yes |
EFS: 26% vs. 35% (P = .6) at 3 years
OS: 47% vs. 51% (P = .5) at 3 years |
Did prior (front-line) rituximab-based regimen affect outcomes differently? |
Yes |
Probability of survival was 34% vs. 66% with and without rituximab, respectively. |
Did relapse greater or less than 12 months affect outcomes differently? |
Yes |
3 year EFS was 20% vs. 45% for relapse >12 or <12 months, respectively. |
Did prior (front-line) rituximab-based regimen affect outcomes differently if relapse was within 12 months of initial therapy? |
Yes |
3 year EFS was 21% (<12 months) vs. 41% (>12 months). |
Did prior (front-line) rituximab-based regimen affect outcomes differently if relapse was >12 months following initial therapy? |
No |
No difference in EFS or OS between the two subgroups with or without rituximab exposure |
Did secondary aaIPI had any bearing on prognosis? |
Yes |
3-year EFS with secondary aaIPI 2–3 was 18% vs. 40% for secondary aaIPI 0–1 (P = .0001). |
Did patients with GBC DLBCL respond better to a salvage regimen compared to ABC DLBCL (COO defined by the Hans criteria)? |
Yes |
Retrospective analysis of the CORAL study showed PFS 70% and OS 74% for GBC DLBCL versus PFS 28%, and OS 40% for ABC DLBCL. |
Did patients with GBC DLBCL fare better in outcomes with R-DHAP compared to R-ICE (COO defined by the Hans criteria)? |
Yes |
Retrospective analysis of CORAL study showed PFS at 3 years of 100% with R-DHAP and 27% with R-ICE. This needs confirmation by a prospective study. |
Did patients with ABC DLBCL fare better in outcomes with R-ICE compared R-DHAP (COO defined by the Hans criteria)? |
No |
Retrospective analysis of the CORAL study showed equally poor outcomes in ABC DLBCL (via the Hans criteria) with either regimen. |
Was incidence of c-myc greater in GBC DLBCL compared to ABC DLBCL by the Hans criteria? |
Yes |
Retrospective analysis showed that c-myc by FISH was positive in 17 patients with GBC DLBCL versus 10 patients with ABC DLBCL. |
Was incidence of c-myc greater in GBC DLBCL compared to ABC DLBCL by GEP analysis? |
Yes |
Retrospective analysis showed that c-myc was more common in GBC DLBCL (n = 3), whereas no cases were associated with ABC DLBCL. |
Does R-DHAP show OS improvement when compared to R-ICE in patients with c-myc (genetically defined) positive relapsed or refractory DLBCL? |
No |
Retrospective analysis showed that the type of salvage regimen, R-DHAP or R-ICE, had no impact on survival, with 4-year PFS rates of 17% vs. 19% and 4-year OS rates of 26% vs. 31%, respectively. |
Were the majority of biological characteristics similar between diagnosis and relapse in the 45 matched-pair biopsies studied? |
Yes |
Retrospective analysis showed this to be true in 87% of the cases. |
Did maintenance rituximab therapy following auto-HCT improve PFS? |
No |
The 4-year postautologous transplant EFS rates were 52% and 53% for the 122 patients with rituximab and the 120 patients in the observation group, respectively (P = .7). |
Table 52.2 Experimental agents under investigation in diffuse large B-cell lymphoma (DLBCL).
Ofatumumab (anti-CD20 antibody) |
Obinutuzumab (GA101) (anti-CD20 antibody) |
Veltuzumab (anti-CD20 antibody) |
Dacetuzumab (SGN-40) (anti-CD40 antibody) |
Blinatumomab (MT 103) (bispecific anti-CD19 and CD3 antibody) |
Epratuzumab (anti-CD22 antibody) |
Inotuzumab ozogamicin (CMC-544) (anti-CD22 antibody conjugate with calicheamicin) |
Pidilizumab (CT-011) (immune modulation via binding to PD-1) |
Ipilimumab (MDX-010) (anti–CTLA-4 antibody) |
Deacetylase inhibitors |
Lenalidomide (immune modulation) |
Fostamatinib disodium (splenic tyrosine kinase inhibitor) |
PCI-32765 (Burton’s tyrosine kinase inhibitor) |
Bortezomib (nuclear factor kappa B (NF-κB) inhibitor) |
3. The patient received two cycles of R-DHAP and achieved CR2 by PET–CT criteria. What do you now recommend?
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17: Management of Therapy-Related Myeloid Neoplasms
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
