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Diffuse Large B Cell Lymphoma

Accounts for 35% of cases of B-cell non-Hodgkin’s lymphoma and is the most common lymphoma.

Defined by large neoplastic cells with clinically aggressive behavior.

Accounts for 80% of aggressive lymphomas.

Accounts for 50% of cases of NHL in elderly patients.

The single most common hematologic malignancy of all.

DLCBL accounts for approximately 28,000 new cases and nearly 10,000 deaths per year in the US.

Accounts for an estimated 150,000 new cases annually worldwide.

Almost one third of newly diagnosed patients are over the age of 75 years.

Median age of newly diagnosed DLBCL patients is mid 60s.

Patients typically present with progressive lymphadenopathy, extranodal disease or both and require treatment.
Diagnosis relies on detailed examination of a tumor tissue, best achieved with an excisional biopsy and evaluation by a haematopathologist.
Biopsy evaluation includes morphologic characteristics, accurate classification with immunohistochemistry, flow cytometry, florescence in situ hybridization (FISH), and molecular testing.
Fine needle aspiration biopsy specimens are in padequate for pathological assessment.

Core biopsy should be performed only if excisional biopsy is not feasible.

More than 50% of cases are cured with present treatment, and the majority of patients who fail to respond will succumb to the disease.

10 to 15% of patients have a primary refractory disease within three months after treatment initiation, and another 20-35% have a relapse.

With patients unable to proceed to high-dose chemo therapy and hematopoetic stem cell transplantation as second line therapy, the prognosis is poor, with the median overall survival of 4.4 months and one year and two year overall survival of 23% and 16%, respectively.

A clinically and biologically diverse disease.

Can be divided into at least 3 molecular subtypes, that corresponds to distinct stages of B-cell differentiation.

Gene expression profiling subdivides DLCBL in 2 groups: Germinal Center B-cell-like (GCB) and activated B-cell-like (ABC) subgroups.

Genes associated with GCB subtype include CD10 and BCL6, EZH2 gene markers of germinal center differentiation.

GCB is the more prevalent subtype in about 56% of a cohort of study population, with 32% ABC and 11% type three.

In the ABC type nuclear factor kappa B (NF-kB) pathway is active with high expression of NF-kB target genes.

The ABC subtype is associated with a worse outcome.
With standard chemotherapy, the ABC same time as inferior outcomes compared to the germinal  center B cell (GCB) subtype.
in the pre-rituximab era five year overall survival was 60 to 70% with GCB, and 16 to 35% with ABC subtype: post rituximab era these figures have improved to 78% and 56%, respectively.
Germinal centers of lymph nodes give rise to heterogeneity of DLBCL.
Germinal centers are transient structures that develop upon antigen challenge.
In the germinal centers B lymphocytes undergo maturation to become plasma B cells, which secrete high affinity antibodies, or memory B cells primed against future infection.
The germinal center facilitates  T-cell dependent humoral immunity and adaptive immunity.
As B cells transit the germinal center, class switch recombination confers risk of unintended mutations leading to lymphomagenesis.

Both GCB and ABC subtypes express B-cell lymphoma 2 (BCL2).BCL2 is induced greater than 30 fold during peripheral B cell activation and expression greater than 4 fold higher in most ABC DLCBLs compared with GCB DLCBLs.

Because there is a distinct genetic characteristic of the GCB and a CBC subtypes the derivation of the malignancy from different stages of B-cell differentiation is suspected: with the GCB subtype arising from germinal center B cells and the ABC subtype from post-germinal center B cells that are blocked during plasmacytic differentiation.

Prognosis for patients treated with CHOP-R is significantly worse for ABC subtype than for those with GCB subtype.

Patients with activated B-like disease have about a 40% average survival rate, while those with germminal B-celllike have about a 75% average survival rate.

The most common molecular subtype of DLCBL is GCB.

GCB subtype typically occurs in children in young adults has a much better prognosis than ABC subtype DLCBL.

10-15% of cases are unclassifiable.
Subtypes arise from different stages of lymphoid differentiation, with separate oncogenic mechanisms, with ABC subtype having inferior outcome of three-year progression free survival of approximately 40-50% versus 75% with the GCB sub group.

Approximately 30% of patients with GCB DLCBL are not cured with R-CHOP.

In GCB DLCBL subtype BCL6 is highly expressed, while it is rarely expressed in ABC DLCBL subtype.

BCL6 transcription factor re-presses target genes involved in lymphocyte activation, apoptosis, and DNA damage response.

BCL6 deregulation may occur with chromosomal translocation, or it may be altered by somatic mutations and may result in enhanced inhibitory effects on the apoptotic stress response, leading to tumor proliferation and treatment failure.

A third molecular subtype of DLCBL is a primary mediastinal B-cell lymphoma arising from a thymic B cell.

The primary mediastinal B-cell lymphoma subtype is seen for dominant the girls of young women and has many features clinically similar to classic Hodgkin lymphoma nodular sclerosing type.

5-10% of cases have t(8;14) translocation typical of Burkitt’s lymphoma.

International Prognostic Index (IPI) incorporates 5 clinical parameters: age, stage, performance status, serum LDH, and number of extranodal sites.

The International Prognostic Index (IPI) subdivides patients with DLBCL into low, low-intermediate, high-intermediate and high risk disease with predicted 5-year overall survival rate of 73%, 51%, 43% and 26%, respectively.

Staging is in accordance with the Ann Arbor staging.

PT/CT scanning has replaced CT in staging.

total metabolic tumor volume at diagnosis may be prognostic.

Staging bone marrow biopsy is positive in 15 to 20% of cases and when concordant large B cells are present, it is associated with a poor prognosis.

Bone marrow biopsy is no longer required for patients who have undergone PET/CT staging..

Despite and advanced stage a presentation the majority of patients, more than 60% can be cured with R-CHOP chemotherapy.

Patients who fail R-CHOP often have a poor outcome, particularly in those with disease that is refractory to front line or subsequent therapies.

Approximately 40-60% of patients with relapsed or refractory DLBCL have a response to a second line chemotherapy and 50% of these patients proceed to autologous hematopoetic transplantation, and of these approximately 30 to 40% remain progression free three years after transportation.

Treatment with high-dose chemotherapy and autologous stem cell transplantation offers the best chance of curing patients with chemotherapy sensitive relapsed or refractory disease.

Patient survival within same groups have significant variation due to high degree of clinical, morphological and molecular heterogeneity.

ctDNA pre-treatment levels predicting 24 month event free survival, as well as overall survival.

ctDNA changes during treatment or prognostic for outcomes as early as 21 days into therapy.

ctDNA is detected im 98% of patients.

While a potentially controllable process, evidence suggests elderly patients do worse than their younger counterparts.

Originates from germinal center B cells.

Elderly patients may be biologically and molecularly different from younger patients, and are more frequently diagnosed with an immunoblastic variant than are younger patients.

The immunoblastic variant of DLBCL Is often a marker of the ABC genotype, which carries a poor prognosis.

The activated B cell type DLBCL and the Epstein-Barr virus related lymphomas are more common in elderly patients and both portend a worst outcome.

Histone deacetylase involved in the pathogenesis of some lymphomas, particularly diffuse large B cell lymphoma, via regulation of the BCL6 gene

Gene expression profiles have identified at least 3 molecular subtypes: GCB (germinal center B cells), ABC (activated peripheral blood B cells) and PMBCL ( primary mediastinal large B cell lymphoma).

The germinal center B cell like diffuse large B cell lymphoma subtype probably arises from normal germinal center B cells, whereas the activated B cell subtype may arise from a post-germinal center B cell that is blocked during plasmacytic differentiation.

Patients with ABC DLBCL are more likely to respond to targeted therapy

with ibrutinib than patients with GCB DLBCL.

A small number of cases are unclassifiable by gene profiling.

12% of patients harbor a MYC gene rearrangement, which is associated with a worse outcome.

 MYC rearrangements concurrent with BCL2, BCL6 or both occur in 4-8% of cases of DLBCL-The majority of which are the GC be subtype, in which BCL 2 rearrangements occur exclusively.
Classification of lymphoma with MYC and BCL2 and/or BCL6 rearrangements are referred to as high-grade B cell lymphoma: double or triple hit lymphoma:Having a poor outcome after R-CHOP.
Double or triple hit high grade B cell lymphoma is relatively rare, but the overall expression of MYC proteins occurs in approximately 45% of cases and over expression of BCL2 protein occurs in approximately 65% of cases.
The overexpression of MYC and BCL2 occurs in approximate 30% of cases of DLBCL: double espressor lymphoma is associated with a worse prognosis than single or no overepexpression of either MYC or BCL2.
Double espressor lymphoma can occur with both GCB and ABC subtypes, but it’s more common in the ABC subtype.

10-25% have bone marrow involvement at time of diagnosis.

Bone marrow involvement associated with a poor outcome.

Many patients have concordant involvement with bone marrow infiltrates of small B-cell lymphoma cells reported in 40-72% of patients with bone marrow involvement at the time of staging (Chung R et al).

Concordant bone marrow involvement may be associated with a poorer outcome.

20 times more common than Burkitt’s lymphoma.

Bcl-2 expression confers resistance in chemotherapy treatment, but when rituximab is added to CHOP the resistance is overcome.

Historically radiation therapy was the primary treatment for localized disease.

The addition of chemotherapy to radiation significantly decreases the risk of relapse for patients with stage I and II disease.

The addition of radiation to bulky disease, regardless stage, is a consideration especially in older patients where long-term consequences are not a major consideration.

Presently, Rituxan-cyclophosphamide, Adriamycin, Vincristine and prednisone (R-CHOP) is the therapy of choice for both localized and advanced disease.

Among patients 65-75 years 50% achieve complete remission with conventional chemotherapy, with a 5-year survival of about 33%.

Patients have a low risk of recurrence once they reach two years in remission, with the subsequent risk of relapse of 8%, and then overall survival equivalent to age and sex match controls.

No clear benefit for surveillance scans in lymphomas have been shown.

In refractory patients there is an overall response rate of 26%, a complete response rate of 7% and a median overall survival of 6.3 months after treatment with salvage therapy (Crump M).

In patients over the age of 75 years complete response rate falls to 40%, with a 16 month median response duration.

Rituximab as a single agent has a 37% response rate in relapsed or refractory diffuse large B cell lymphoma, with a median time to progression in responders of approximately 8 months.

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy associated with long-term remission in 40% of patients.

The International Prognostic Factors Project pooled data from phase II/III doxorubicin based combination treatments and found a 66% complete remission rate with a 41% relapse rate by 5 years.

Attempts to improve survival with chemotherapy treatments more aggressive than CHOP have failed to show benefits.

Rituximab-CHOP superior to CHOP alone with improvement in relapse free survival.

The addition of rituximab immunotherapy to CHOP chemotherapy has improved overall survival by 10-15%.(Coiffler).

The use of rituximab with chemotherapy in first-line treatment improved five-year event free survival from 29% to 47% among patients between age 60 and 80 years, and improved 3 year event free survival from 59% to79% in patients age 18-60 years (Philip T et al).

Phase II trial for second line treatment with Rituximab and bendamustine (Rituximab 375 mg/m2 q 28 days and bendamustine 120 mg/m2 days 1 and 2 q 28 days): overall response rate of 58% and complete response rate of 19% (Varcirca JL).

British Columbia Cancer Agency (BCCA) recommends that patients with limited stage DLBCL undergo PET scan after three cycles of CHOP-R to identify patients that are chemosensitive: if patients have a negative PET scan they are offered one additional cycle of CHOP-R and if PET is positive they receive involved field radiation-2 year estimated progression free survival 93% for the entire group with 97% and 83% for PET negative and PET positive patients, respectively.

BCCA findings for their studies is that 4 cycles of CHOP-R are sufficient for patients with limited disease who are PET can negative after three cycles of treatment and can be spared radiation treatment.

CHOP-R standard of care but only 50% of patients have durable complete response rate.

Group d’Etude des Lymphomes deaths l’Adulte (GELA) found that newly diagnosed patients older than 60 year treated with CHOP-R improved complete remission rate but also the 2-year survival from 57% with CHOP to 70% with CHOP-R and at 5-years demonstrate an overall survival of 58% for those treated with Rituxan compared to 45% for those that did not.

CHOP followed by rituximab maintenance can yield similar relapse free and overall survival similar to rituximab-CHOP.

Ifosfamide, carboplatin and etoposide effective second-line chemotherapy in relapsed refractory disease.

High dose therapy and stem cell transplantation offers best opportunity for long term survival in patients with relapsed or refractory disease.

PARMA study randomized relapsed but chemotherapy sensitive patients to salvage therapy with several cycles of cis-platinum/cytarabine/dexamethasone (DHAP) with or without dose intense chemotherapy with autologous bone marrow transplantation: Five-year event free survival of 46% for patients randomized to transplantation compared with 12% for patients who received DHAP alone.

Variant disease includes mediastinal large B cell lymphoma which is believed to arise from thymic medullary B cells.

Mediastinal large B cell lymphoma accounts for 2% of NHL, with a higher incidence in young adults.

May be 2 distinct genetic subtypes-germinal center B cell (GCB) expressing CD10 and Bcl-6 and not MUM-1, and non-germinal center B cell type lacking CD10, Bcl ± and MUM-1+.

The GCB subtype associated with improved event-free survival following first line chemotherapy.

Germinal center type, activated B-like and type 3 DLCBL have a 60%, 35% and 39% 5-year survival, respectively.

A small proportion of cases are indolent lymphomas diagnosed at the time of transformation, and these lesions have an aggressive clinical presentation and survival similar to de novo DLBCL with a higher risk of indolent relapses.

Autologous hematopoietic cell transplants, as initial therapy for DLCBL has not shown clear benefit overall R-CHOP.

Axicabtagene ciloleucel is an autologous anti-CD19 CAR T-cell therapy for treatment of adults with relapsed or refractory DLBCL after 2 or more lines of systemic therapy.

Tisagenlecleucel, a CAR T-cell therapy in relapsed/refractory diffuse large B cell lymphoma in adults has high rates of durable responses.

ZUMA-1 suggests that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma,

With CAR-T therapy for DLBCL refractory and recurrent disease objective response rates are 74% with a complete response rate of 54%, and ongoing response of 36% and median duration has not been reached in the ZUMA-1 trial (Acicabtagene).

Circulating tumor DNA (ctDNA) levels before and during treatment can predict how a patient with diffuse large B cell lymphoma responds to standard therapy.

Long-term outcomes can be predicted as early as three weeks after iniation of drug therapy.

FDA Approves Polatuzumab Vedotin for DLBCL for use in combination with bendamustine and rituximab (BR) for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received at least 2 prior therapies.

The FDA has approved selinexor as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma, who have received ≥2 prior therapies.

The phase 2b SADAL trial, in which Selinexor demonstrated a 28.3% overall response rate (ORR), including an 11.8% complete response (CR) rate and a median duration of response of over 9 months.

Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export protein for tumor suppressor proteins and eIF4E-bound oncoprotein RNAs. 

XPO1 inhibition via selinexor promotes nuclear localization of eIF4E and activation of tumor suppressor proteins relevant to non-Hodgkin lymphoma including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes.

SADAL findings of 127 evaluable patients who had received a median of 2 prior treatment regimens: 28.3% ORR comprised 36 responses, with a disease control rate was 37%.

Deep and durable responses occurred in patients, regardless of DLBCL subtype. 

Common nonhematologic AEs: mostly nausea (52.8%), fatigue (37.8%), and anorexia (34.6%). 

Grade 3/4 AEs include: thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%).

FDA Approves Tafasitamab Plus Lenalidomide in Relapsed/Refractory DLBCL

It is a humanized Fc-modified cytolytic CD19-targeting monoclonal antibody.

The FDA has approved ((tafasitamab))-cxix in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant.

Trade name Monjuvi.

Approved tafasitamab-cxix (Monjuvi) in combination with lenalidomide (Revlimid) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ,including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant.

Phase 2 L-MIND trial, demonstrated that tafasitamab in combination the lenalidomide elicited an ORR of 55%, which was comprised of a complete response (CR) rate of 37% and a partial response (PR) rate of 18%. 

The median duration of response  in the study was 21.7 months.

The overall response rate 

was 58% with a CR rate of 33% and a PR rate of 25%. 

The 12-month duration of rrsponse in this population was 70.1%; it was even higher in those who achieved a CR, at 87.0%.

Tafasitamab side facts: infusion-related reactions (6%), serious or severe myelosuppression, including neutropenia (50%), thrombocytopenia (18%), anemia (7%), infections (73%), and embryo-fetal toxicity. 

Analysis demonstrated a statistically significant superior best overall response rate with the combination compared with lenalidomide alone, at 67.1% versus 34.2%, respectively.

The CR rates were 39.5% and 11.8% with the combination and the monotherapy, respectively. 

The median OS had not yet been reached in the combination arm versus 9.3 months in the single-agent arm.

Lisocabtagene maraleucel approved for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

CNS relapse in diffuse large B cell lymphoma historically occurs early in the disease course and carries an estimated survival of 3 to 7 months, and has no clearly defined standard of care.
Methotrexate-based prophylaxis doing  frontline therapies are commonly use to prevent CNS relapse in high-risk patients without randomized trials showing efficacy. 
CNS relapse affects roughly 5% of DLBCL patients with a disproportionate risk among patients with involvement of extranodal sites (testes, bone marrow, kidneys, adrenals) and has been associated with high risk molecular features such as double hit lesions and activated B cell origin.
Patient should be clinically monitored every three months to two years after treatment, then every 6 to 12 months: patients who remain event free for two years can expect the overall survival to be almost similar to the general age matched  population.

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