Advanced in management diffuse large B cell lymphoma
The current standards for diagnosing diffuse large B-cell lymphoma (DLBCL) including molecular subtypes, LymphGen classification, and frontline treatments. Learn about abbreviating chemotherapy, omitting radiotherapy, and emerging therapies like Polatuzumab, Monsutuzumab, and Axicaptagen Ciloleucil.
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Advanced in management diffuse large B cell lymphoma Boshra Alhoushi , MD Hematologist at Hematology Department in Tishreen University Hospital Oncology Conference Lattakia 17-18 March 2022
DLBCL what are the current standards for dignosis? what are the molecular subtypes ? What is LymphGen classification? What is the current frontline treatment ? Is it possible to abbreviate chemotherapy in the management limited stage or bulky disease ? Is it possible to omit radiotherapy in bulky disease? What are the emerging and novel therapies ? Polatuzumab? Monsutuzumab? Axicaptagen cilloleucil?
DLBCL 1- Introduction The most common subtype of NHL 25 30 % 150000 patients diagnosed annually worldwide Median age 66 years Male > female 1.5 : 1 Higher incidence in Caucasian -------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
DLBCL: 1-2 Current standards for diagnosis: Excisional or core biopsy Assessment of morphology Histologically Immunohistochemistry Immunophenotyping Fluorecence in situ hybridization: c MYC Molecular testing: Gene expression profile and LymphGen classification - ------------------------------------------------------------------------ Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
1-2 Current standards for diagnosis: 1-2-1 Molecular testing Gene expression profile using DNA microarrays initially identified 2 molecular subtype of DLBCL with differing cell of origin GCB type : Favorable prognosis ABC type Outcomes differ from patient with GCB vs. ABC with 5 years PFS 75% vs. 40% respectively after R-CHOP -------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
LymphGen classification Sehn L, Salles G. Diffuse large B- cell lymphoma. New England Journal of medicine, March 2021.
2- Current frontline treatment of DLBCL Treatment selection based on : Disease specific factors Patient specific factors Bulk Stage Double expressor of Current trials have attempt to improve R- CHOP by disease Treatment Intensifying therapy Adding maintenance Adding novel agents selection COO MYC gene rearrengment IPI , R-IPI
2- Current frontline treatment of DLBCL 2-1 Limited stage non bulky disease: 1 ICombined therpy 3 cycles of R- CHOP followed 30 GY IFRT has long been a standard approach for limited stage. This strategies is based on phase 2 SWOG trial with an exellant 4 years PFS 88% . Recent trials have also evaluated abbreviated chemotherapy without consolidative IFRT.
2-1 Limited stage non bulky disease: 2 The phase2 FLYER trial 592 patients : stage I-II non bulky , IPI 0 4 R- CHOP 6 R-CHOP 66 + 2 R Mon. PFS 3 years 93 % PFS 3 years 96 % Non inferiority of 4 vs. 6 cycles of R-CHOP --------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2-1 Limited stage non bulky disease DLBCL 3 Phase 3 LYSA LNH trial 650 patients, stage I II , non bulky, IPI 0 2 R- CHOP 2 R- CHOP PET scan PET scan 61 Mon. Regardless of PET scan + - 4 R- CHOP 3 years PFS 92% 3 years PFS 89 % 4 R- CHOP 2 R- CHOP Establishing the non inferiority of 4 versus 6 cycles of R CHOP in early responders ------------------------------------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2-1 Limited stage non bulky disease DLBCL 4 NCT S1001 128 patients, stage I II non bulky 3 R- CHOP Interim PET scan 59 Mon. - + Excellent 5 years PFS 89% Metabolic CR IFRT 36 GY 1 R- CHOP Ibritumomab Chemotherapy can be safely abbreviated and radiotherapy omitted in patient with limited stage non bulky disease who achieve an early MCR . ---------------------------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022 -
2 -Current frontline treatment of DLBCL 2-2 Bulky disease 1 Bulky disease is variably defined in different studies a MTD greater than 7- 10 cm. In the pre pet era EFS was inferior among patient with bulky disease who did not receive consolidative IFRT just 6 R- CHOP. Currently in the PET era trials have focused on omitting radiotherapy in patients who achieve a metabolic CR at the end of chemotherapy.
Bulky disease DLBCL 2 Historical controls OPTIMAL NCT RICOVER- 60 trial ,non bulky Bulky disease MTD 7.5 cm 6 R- CHOP 6 R- CHOP 14 PET scan PET scan - + - + Observed Observed 3 years PFS 82 % IFRT IFRT 3 years PFS 84 % There was no difference in 3 year PFS between patients with initial bulky compared with initial non bulky disease. ------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2-Current frontline treatment of DLBCL 2-2 Bulky disease 3 The results suggest that consolidative radiotherapy can be omitted with out compromising efficacy in patients who achieve a metabolic CR after 6 R- CHOP.
2-Current frontline treatment of DLBCL 2-3 Advanced stage disease 1 More than 60 % of patients DLBCL present with advanced stage disease. For the majority of these patients 6 cycles of R- CHOP remains the standard of care. No Added benefit with 8 vs. 6 cycles of R- CHOP. In high risk patients consolidative autologous stem cell transplant failed to improve outcomes
2-Current frontline treatment of DLBCL 2-3 Advanced stage disease 2 Trials have explored various maintenance strategies after 6 cycles of R- CHOP ( Rituximab, Everlimus, Lenaldomide). Phase 3 REMARC trial demonstrated a potential role for linaldomide maintenance in older adults with DLBCL. NCCN guidelines include lenaldomide maintenance as a category 2B recommendation for older adults with DLBCL achieving CR or PR after R- CHOP. ------------------------------------------------------------------ Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford, January 20, 2022
2-Current frontline treatment of DLBCL 2-3 Advanced stage disease 3 More intensive chemotherapy with DA- EPOCH- R ( high risk patients with IPI 3-5 , MYC rearrangement) 2 year PFS 71% ( Favorable out comes than R- CHOP) Obintuzumab - A glycoengineered anti CD20 antibody - Greater direct cell death. - More potent antibody- dependent cellular cytotoxicity. -More phagocytosis than rituximab. :
2-Current frontline treatment of DLBCL 2-3 Advanced stage disease 3 The phase 3 GOYA trials 1418 patients, advanced stage 6-8 6-8 29 Mon. R- CHOP G- CHOP PFS 67% PFS 70% There was no significant difference in PFS and higher incidence of serious events with G- CHOP ------------------------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2- Current frontline treatment of DLBCL 2-4DLBCL in the eldery and infirm: There is no standered of care approach for patients who are eldery. R- mini CHOP PFS 47% OS 59% R- mini CHOP + Azacitidin > 75 years old
2-Current frontline treatment of DLBCL 2-5 CNS prophylaxis CNS relapse of DLBCL is uncommon constituting 5% of patients treated with rituximab era Poor prognosis Median OS < 6 months High risk of CNS relapse: - Involvement of extra nodal sites -Biological factors ( non GCB type, MYC , MYD88) 2-4 cycles of HD MTX Or 4-8 doses of IT MTX or Ara
2-Current frontline treatment of DLBCL 2-6 Emerging and novel agents 1 IPI 3 High risk patients CAR t- cell therapy ciloleucel Axicabtagene Bcl2 overexpression ABC DLBCL Anti CD19 BiTEs Small molecules Emerging Mosunetuzumab (Bcl2 inhibitors) And Novel agents Anti- CD20\CD3 Ventoclax Antibodies drug conjugates Eldary Unfit patients Polatuzumab Pola -R- CHP Anti CD79b ---------------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2-6 Emerging and novel agents 2 Phase 3 POLARIX trial randomized Polatuzumab Anti CD 79b antibody 879 patients ,IPI 2 28 6 R CHOP 6 Pola- R-CHP Mon. PFS 57% PFS 73% PFS was superior in Pola arm with a favorable safely profile and may become a newer treatment options in eligible patients. --------------------------------------------------------------------------------------------------------------------- Spinner M, Advani R, et al. Current frontline treatment of diffuse large B cell lymphoma. Oncology journal vol 36,issu 1, page 50-58. Stanford,January 20, 2022
2-Current frontline treatment of DLBCL 2-6 Emerging and novel agents 3 Chimeric antigen T cell therapy: Target CD 19 Treatment relapse and refractory DLBCL Multistep process: -Leukapheresis of host T cells - Transfer of the gene encoding CAR into the T- cell genom- -Ex vivo expansion -Infusion of the CAR T cells after the treatment of patients with lymphodepleting chemotherapy. ------------------------------------------------------------------ Roschewski M, Wilson W, et al. CAR T-Cell Therapy for Large B Cell Lymphoma . New England Journal of Medicin, March 2022.
2-Current frontline treatment of DLBCL 2-6 Emerging and novel agents 3 Chimeric antigen T cell therapy: Axicabtagene ciloleucel, Tisagenlecleucel, and Lisocabtagene maralleucel are three different CD19- targeting CAR T cell products that have been approved for the third- line treatments of large B cell lymhoma on the bases of pivotal phase 2 studies. CRS and Neurotoxicities ------------------------------------------------------------------------ Roschewski M, Wilson W, et al. CAR T-Cell Therapy for Large B Cell Lymphoma . New England Journal of Medicin, March 2022.
Conclusion Shafey M, Savage k, et al. Canadian evidence-based guideline for the frontline treatment of diffuse large B cell lymphoma. 2022
