Diffuse large B cell lymphoma natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2] Sowminya Arikapudi, M.B,B.S. [3]

Overview

The prognosis of diffuse large B cell lymphoma (DLBCL) depends on the stage of the disease. Diffuse large B cell lymphoma is associated with a 5 year survival rate ranging from 70% to more than 90% among children. There are several biologic factors a that are associated with the outcomes in patients with DLBCL

Prognosis

Several subtypes of diffuse large B cell lymphoma have been identified, each having a different clinical presentation and prognosis. However, the usual treatment for each of these is chemotherapy, often in combination with an antibody targeted at the tumor cells. The IPI (International Prognostic Index) score is used in prognosis in clinical practice.

INTERNATIONAL PROGNOSTIC INDEX (IPI)
Interantional Prognostic Index			Estimated 3 year Overall Survival (95% CI)
Risk Factors	Age >60 years
	Serum LDH >Normal
	Stage III-IV
	Performance Status 2-4
	Extranodal Sites >1
Risk categories	Low	0-1	91(89-94)
	Low Intermediate	2	81(73-86)
	High Intermediate	3	65(58-73)
	High	4-5	59(49-69)
AGE ADJUSTED INTERNATIONAL PROGNOSTIC INDEX (aaIPI) In Patients < or equal to 60 years
Risk Factors	Serum LDH >Normal
	Stage III-IV
	Performance Status 2-4
Risk Categories	Low	0	98(96-100)
	Low Intermediate	1	92(87-95)
	High Intermediate	2	75(66-82)
	High	3

• Through the treatments, more than half of patients with diffuse large B cell lymphoma can be cured and overall survival for older adults at five years is around 58%.
• For children with diffuse large B-cell lymphomas, most studies have found 5-year survival rates ranging from about 70% to more than 90%.
• The Germinal-center subtype has the best prognosis, with 66.6% of treated patients surviving more than five years.
• Lenalidomide has been recently shown to improve outcomes in the Non-germinal center subtype.

Biologic Factors Associated with Outcomes in Patients with DLBCL

Cell-of-origin molecular classification

• Various technologies (gene array, digital expression profiling, multiplex RT-PCR–based methods)

• ABC subtype is associated with poor prognosis

• ABC subtype may be associated with an increased risk of CNS relapse

Cell-of-origin IHC-based algorithms

• Various IHC-based algorithms to assign molecular subtype; most commonly the Hans algorithm

• Non-GCB subtype is associated with poor prognosis, although this is not confirmed in some studies

• Dichotomizes patients into GC and non-GCB subgroups and represents an approximation of molecular subtype as assessed by GEP

Double- or triple-hit rearrangement involving MYC and either BCL2 or BCL6 or both

• FISH is used primarily in clinical practice; the use of break-apart probes is recommended; GEP-based assays may identify additional cases with double-hit signature undetected by FISH with similar biologic features and outcome
• Double- or triple-hit cases are associated with poor prognosis; poor prognosis may be limited to cases in which the MYC translocation partner is an immunoglobulin gene locus
• Now classified by the WHO as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; majority of cases are GCB subtype; may benefit from more intensive therapies

MYC and BCL2 protein expression

• IHC measurement to estimate the percentage of cells expressing MYC or BCL2 protein or both; 40% cutoff threshold for MYC and 50% for BCL2
• Double expression of MYC and BCL2 or expression of BCL2 alone is associated with worse prognosis
• May have prognostic significance mainly in GCB-type DLBCL; MYC-BCL2 double expression may be associated with an increased risk of CNS relapse

Proliferation index

• IHC measurement of proliferation marker Ki67; no established cutoff threshold
• Higher proliferation may be associated with poorer prognosis, although it has not consistently been shown to be an independent prognostic marker
• High proliferation rate (>80%) may increase suspicion that patient has high-grade B-cell lymphoma (with or without double- or triple-hit rearrangements)

TP53

• PCR, NGS, or gene array for detection of mutation or deletion of TP53
• TP53 mutations in the DNA-binding domain are associated with poor prognosis
• May cluster with a genetic subset of DLBCL

CDKN2A

• Gene array, FISH, or PCR for detection of deletion of the CDKN2A locus or loss of the 9p21 region
• Deletion of the CDKN2A locus or loss of the 9p21 is associated with poor prognosis
• May cluster with some genetic subsets of DLBCL

MHC class II

• IHC measurement of partial or complete loss of MHC class II expression
• Loss of expression of MHC class II may be associated with a poor prognosis (more frequent in non-GCB subtype)
• Primarily observed in primary mediastinal B-cell lymphoma and in tumors with EZH2 mutations

Lymphocyte count and lymphocyte:monocyte ratio

• Measured in peripheral blood; low lymphocyte count (<1×109/liter) or low lymphocyte:monocyte ratio (various cutoff thresholds)
• Low lymphocyte count or low lymphocyte:monocyte ratio is associated with poor prognosis
• May have implications for immune-based therapies

Host genetics

• Single nucleotide variation in 5q23.2 or 6q21 (PCR or single nucleotide polymorphism array)
• Single nucleotide variation in 5q23.2 or 6q21 is associated with poor prognosis
• Further investigation is needed

Complications

Complications can be disease associated or treatment related. some of the complications included are:

• Infection (most commonly Pneumonia or Sepsis), that can lead to multiorgan failure
• Hepatic Failure (treatment Related)
• Gastrointestinal Bleeding (disease-related)
• Disease Progression leading to death

References

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