Key takeaways from 6 major studies in Lymphoma presented at ASH 2018: Dr. Vishwanath & Dr. Vinayak
M3 India Newsdesk Dec 11, 2018
Noted Medical Oncologists, Dr. Vinayak Maka and Dr. Vishwanath Sathyanarayanan choose 6 major studies presented at this year's American Society of Hematology Annual Meeting, summarising them and providing their expert take on each.
The 60th Annual meeting of the American Society of Hematology (ASH) was held between December 1 and 4, 2018 at San Diego, USA. ASH is attended by more than twenty thousand haematologists globally. Groundbreaking research in haematology are presented and several of them are practice changing.
Here, we have critically analysed the oral and poster presentations made in Lymphoma and presented only the ones which may be important for practising oncologists in India.
Phase II KEYNOTE-170/KEYNOTE-013 Update: Pembrolizumab in Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma
Dr. Vishwanath: PMBCL is a disease of the younger individuals and though DA-EPOCH R gives a significant long-term survival, relapsed patients have a poor outcome and several newer therapies have been tried. Apart from CAR-T cell therapy, PD-1 blocker pembrolizumab seems promising. In this phase II study in R/R PMBCL patients, ORR was 43%, 12 months PFS and OS was 38% and 58%. Since CAR-T cell therapy is unavailable in India, this may be a reasonable option to consider in this subset of patients. However, larger phase III trial results are needed to further substantiate its usage.
Dr. Vinayak: Despite hematopoietic stem cell transplant option, chemo-refractory R/R PMBCL has unsatisfactory outcomes. We are slowly but surely finding targets to improve survival with manageable toxicity. Pembrolizumab may potentially be the answer with long-term data lacking.
Updated results of patients enrolled in KEYNOTE (KN)-013 study and first full analysis of phase 2 results from the KN170 was presented as an oral abstract at ASH 2018. The KN013 had 21 patients and KN170 had 53 patients enrolled. 10 patients from KN013 received 10 mg/kg Q2W and the remaining 11 plus all patients of KN170 received 200 mg Q3W for up to 2 years.
- Anti-tumour activity of pembrolizumab was assessed in both studies
- Primary endpoint was objective response rate (ORR)
- Secondary endpoints were duration of response (DOR), progression-free survival (PFS), and overall survival (OS)
Finding: Both trials confirmed pembrolizumab to show durable and excellent survival rates in R/R PMBCL (relapsed/refractory Primary Mediastinal Large B-Cell Lymphoma) patients.
AUGMENT study: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) Vs Rituximab/Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Dr. Vinayak: Indian patients have easy access to cheaper drugs in this combination which can give a meaningful benefit to patients who fear chemotherapy-related adverse effects.
Dr. Vishwanath: In R/R grade 1-3a FL and MZL, R2 significantly reduced risk of progression, improved PFS and OS, especially in FL. In MZL, the benefit was not so pronounced. This study highlights the importance of chemo-free regimen in R/R indolent lymphomas.
The AUGMENT trial compared the activity and safety of lenalidomide plus rituximab (R2) to rituximab plus placebo in patients with relapsed/refractory Follicular Lymphoma (FL) grade 1-3a and Marginal Zone Lymphoma (MZL). Patients were divided based on prior treatment of rituximab received and time spent since last therapy and randomized 1:1 to R2 or control for a period of 1 year.
- Primary endpoint was PFS as per 2007 IWG criteria without PET
- Secondary endpoint was fixed as ORR, complete response (CR), DOR, time to next anti-lymphoma treatment (TTNLT), OS, and safety
Finding: R2 performed better in terms of efficacy as compared to monotherapy (rituximab plus placebo). Fewer deaths were reported in the R2 group and despite haematological toxicity, patients in the R2 regimen could complete the therapy and the need for further treatment was also delayed.
FLYER: Phase III Trial of R-CHOP x 4 Followed by Rituximab x 2 vs R-CHOP x 6 in Younger Patients With Favorable-Prognosis DLBCL
Dr. Vishwanath: Interesting non- inferiority study which was primarily done to reduce toxicity. In stage I/II aggressive B cell lymphoma with favourable prognosis, first-line treatment with R-CHOP x 4 → R x 2 showed non-inferior PFS, EFS, and OS vs standard R-CHOP x 6. Moreover, toxicity was also reduced in the experimental arm.
This study may be relevant in the Indian context- toxicity, especially febrile neutropenia may be reduced. However, the biology of the disease also contributes to the outcome. A critical look at double expression, double hit, GCB/ non-GCB, Ki 67 should be done before deciding on going ahead with this regimen.
Dr. Vinayak: I would not change my standard practice based on this one study as DLBCL is an aggressive B-cell lymphoma and we know that 60-70% of patients are cured with current 6 cycles of R-CHOP. Biomarker identification for subgrouping is a welcome change.
The trial targeted 18 to 60-year-old patients who were randomised to receive 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) or 4 cycles CHOP-like chemotherapy plus 2x rituximab (R) in 21-day cycles.
- Primary endpoint was PFS with events of progressive disease, relapse, or death
Findings:
Of the 592 patients randomised for the FLYER trial between 2005 and 2016, 588 were available for evaluation and final analysis. 295 patients had been assigned 6x R-CHOP and 293 belonged to the 4x R-CHOP plus 2x R group.
- PFS was as good for the latter group patients as it was among patients in the 6x R-CHOP group.
- Three-year survival rate was 96% for 4x R-CHOP + 2x R group and 94% for 6x R-CHOP group.
- There was no significant difference in the relapse rates.
Phase III E1912: First-line Ibrutinib + Rituximab vs Standard-of-Care FCR in Younger Patients With Previously Untreated CLL
Dr. Vinayak: Clinicians in India, use FCR sparingly for CLL considering its significant haematological toxicities. This regimen seems promising, however, there can be increased atrial fibrillation risk with ibrutinib.
Dr. Vishwanath: In this phase III trial, first-line ibrutinib + rituximab followed by ibrutinib maintenance, significantly improves PFS and OS vs standard-of-care FCR in younger patients with previously untreated CLL. However, del 17 p patients were excluded from the study. This study again highlights the benefit obtained from a chemo-free regimen. As compared to the FCR, the haematological toxicity including the incidence of neutropenic fever was far lesser. Cost of ibrutinib remains a factor precluding its use in the Indian sub-continent.
A total 529 patients participated in the study and were randomly divided into groups (2 (354 patients):1 (175 patients)) and were set to receive either ibrutinib (420 mg/day until disease progression) plus rituximab (50 mg/m2- day 1 of cycle 2; 325 mg/m2- day 2 of cycle 2; 500 mg/m2- day 1 of cycles 3-7) or 6 sources of standard FCR (fludarabine- 25 mg/m2, cyclophosphamide- 250 mg/m2 on days 1-3 with rituximab- 50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6) every 28-days.
- Primary endpoint was PFS
- Secondary endpoint was OS
Findings: In both subgroup analysis for progression-free survival and current follow-up, the experimental therapy was found to be superior to standard FCR. Ibrutinib plus rituximab was found to be superior to FCR in patients (aged ≤70 years) with previously untreated CLL.
ECHELON 2 trial results: Results of a Randomized, Double-Blind, Active-Controlled Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas
Dr. Vishwanath: Finally some good news for adults with newly diagnosed CD30+ PTCL. Preliminary results showed an objective response rate (ORR) of 79% with 64% achieving a complete response (CR). The 3-year PFS and OS for all patients were 52.9% (95% CI: 47.7-57.7) and 73.1% (95% CI: 68.3-77.2). The regimen was well tolerated. Though BV is not currently available in India, it may be worthwhile importing this drug as the benefit is quite marked. However, etoposide was not used either of the arms.
Dr. Vinayak: T cell lymphomas have a rather poor outcome and based on this study, FDA has granted a breakthrough designation for newly diagnosed PTCL.
The ECHELON-2 trial sought to compare the efficacy and safety of brentuximab vedotin with CHP (CHOP without vincristine to eliminate additive neurotoxicity) versus standard CHOP treatment in patients with Peripheral T-cell Lymphomas (PTCL). Patients received 21-day cycles of either CHOP or A+CHP for 6 to 8 cycles. Primary endpoint was PFS.
Finding: Pooled data showed that the therapy was well tolerated with good 3-year PFS and OS.
A Global, Randomized, Placebo-Controlled, Phase 3 Study of Ibrutinib Plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (RCHOP) in Patients with Previously Untreated Non-Germinal Center B-Cell-like (GCB) Diffuse Large B-Cell Lymphoma (DLBCL)
Dr. Vinayak: Non-Germinal cell DLBCL have inferior outcomes when compared to GCB DLBCL so there was need of augmentation of existing regimes to improve outcome without treatment-related toxicities. This abstract address this unmet need.
Dr. Vishwanath: This study was in Non-GCB newly diagnosed DLBCL patients. Though the results showed EFS, PFS and OS benefit in patients <65 years of age, it would be rather premature to adopt this regimen, considering the cost of ibrutinib. Results of the biological characteristics including DEL, DHL may throw further light into the usage of this regimen in a specific subset of patients.
The study analysed the efficacy of adding ibrutinib to RCHOP as compared to standard RCHOP in previously untreated patients with non-GCB DLBCL. Patients either received 560 mg/d ibrutinib with RCHOP or placebo with RCHOP in 21-day cycles for 6 to 8 cycles.
- Primary endpoint was event-free survival (EFS; time from randomisation to progression), relapse from complete response (CR), tx initiation for PET-positive or biopsy-proven residual disease after more than 6 or more cycles of RCHOP, or death in intent-to-treat (ITT) or activated B-cell (ABC) population
- Secondary endpoint was PFS, CR rate, OS, and safety
Findings:
- Efficacy was seen in the <65 years old patients treated with ibrutinib plus RCHOP with significant reductions noted in PFS, EFS, and OS. Similar results were noted in the ABC group as well.
- Patients 65 and over in age experienced increased toxicity associated with the addition of ibrutinib to RCHOP.
- Patients in the ITT group did not show much improvement with ibrutinib plus RCHOP.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.
Dr. Vinayak Maka is a Senior Medical Oncologist who teaches and practice at the MS Ramaiah Medical College and the HCG MSR Cancer Centre, Bangalore.
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