97 Diffuse Large B-Cell Lymphoma and Related Diseases Flashcards
Histological description of DLBCL
Proliferation of sheets of large, transformed B lymphocytes (“centroblasts”) that replace and efface normal lymph node architecture
Diffuse large-cell lymphomas is an aggressive lymphoma, recognizing its potential to cause death within ___ months of diagnosis if left untreated.
3 months
Most common DLBCL subtype
DLBCL not otherwise specified (NOS)
Most common non-Hodgkin lymphoma (NHL) diagnosis globally
DLBCL
There is a slight ____________predominance, and incidence varies by ethnicity, with persons of European descent being more likely to develop the disease than people of African or Asian descent
Male
The median age of diagnosis
65 years
Gene translocation found in 40% of cases of DLBCL
B-cell lymphoma 6 gene (BCL6)
One-third of patients with DLBCL has this mutation and are usually associated with DLBCL arising from follicular lymphoma
t(14;18) involving the Ig heavy chain and BCL2
** coexistent mutations of p53 are often present
Approximately 10% of cases of DLBCL has this mutation and is associated with increased cell survival and a poorer clinical outcome
c-MYC
3 subtypes of DLBCL based on gene expression
- Germinal center B-cell-like (GCB)
- Activated B-cell like (ABC)
- Unclassifiable group
Mutated genes in ABC DLBCL
CD78B, PIM1, MYD88, and TNFA1P3
Other frequently mutated gene, such as CARD11, MLL2, and CREBP commonly exist in both ABC and GCB lymphomas.
Mutated genes in GCB DLBCL
MYC, BCL2, and EZXH2
Other frequently mutated gene, such as CARD11, MLL2, and CREBP commonly exist in both ABC and GCB lymphomas.
Which has inferior survival (ABC or GCB)
ABC lymphomas
Six molecular clusters of DLBCL
MCD
N1
A53
BN2
ST2
EZB
(EZB) was divided into two by the presence or absence of MYC expression
Poor prognosis: MCD, N1
Good prognosis: A53, BN2, EZB
Very Good prognosis: ST2
Molecular group identifier present in more than 90% of GCB type lymphomas
EZB
Molecular group identifier present in more than 90% of ABC type lymphomas
MCD
The A53 group was also ABC type in the majority of cases, yet this category had a good prognosis.
The typical presentation of DLBCL
Lymph node swelling
The classic “B symptoms” is present in approximately ___________of cases
One-third
The use of the B symptoms suffix is no longer used in the description of stage in the NHLs
Approximately _____of patients present with stage III or IV disease.
60%
The most common extranodal sites of involvement
Gastrointestinal tract or marrow
TRUE OR FALSE
Extranodal disease involvement is a marker of overall prognosis with the number of extranodal sites predicting both long-term survival and risk of CNS involvement at baseline or of CNS relapse.
TRUE
Extranodal disease involvement is a marker of overall prognosis with the number of extranodal sites predicting both long-term survival and risk of CNS involvement at baseline or of CNS relapse.
TRUE OR FALSE
Patients at high risk of CNS involvement should additionally undergo an examination of the cerebrospinal fluid by flow cytometry and cytology.
TRUE
Patients at high risk of CNS involvement should additionally undergo an examination of the cerebrospinal fluid by flow cytometry and cytology.
A marker of disease burden and is an important and universally available element of prognostic scoring systems
Elevation of the lactate dehydrogenase (LDH)
TRUE OR FALSE
Flow cytometry is sufficient alone to secure a diagnosis of DLBCL because the immunophenotypic features are unique to DLBCL and different from follicular lymphoma and Burkitt lymphoma.
FALSE
Flow cytometry is insufficient alone to secure a diagnosis of DLBCL because the immunophenotypic features are not unique to DLBCL and may be shared with follicular lymphoma and Burkitt lymphoma.
Immunophenotype of DLBCL
POSITIVE
pan B-cell antigens CD19, CD 20, CD 22, pax-5, and CD79a
pan-hematopoietic marker CD45
LESS COMMON
CD10 and CD5
CD5 coexpressing DLBCL, which must be differentiated from mantle cell lymphoma, may be associated with more clinically advanced presentations and a poorer outcome
CD10-positive disease must be differentiated from Burkitt lymphoma or follicular lymphoma based on histologic and molecular features.
Three cytologic patterns of DLBCL
Centroblastic, immunoblastic, and anaplastic
The diagnostic hallmark of most cases of DLBCL
Presence of sheets of large cells
Rearrangements in high-grade B-cell lymphoma (HGBL)
MYC and BCL2/and or BCL6
A full workup of DLBCL should typically include an IHC panel that allows the pathologist to determine the COO and to assess protein expression of BCL-2 and MYC
Fluorescence in situ hybridization (FISH) may determine the presence or absence of rearrangements of MYC.
Optimal imaging for staging of DLBCL
PET imaging with coregistered computerized tomography (CT) imaging
Magnetic resonance imaging (MRI) of the brain and spinal cord may be indicated in patients at the highest risk of CNS disease because PET imaging is useful but has reduced sensitivity in staging the CNS
How to differentiate viral infection syndromes should be differentiated from clonal disorders (large activated lymphocytes)
Absence of light-chain restriction by flow cytometry
Appropriate viral testing
The objective of the treatment of DLBCL
Cure
Clinical risk scores for DLBCL
International Prognostic Index (IPI)
NCCN-IPI
The risk of CNS involvement at baseline may be evaluated by use of the CNS-IPI.
The backbone of therapy for DLBCL
Cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (R-CHOP), delivered on a 21-day cycle for six cycles
Adjustments and modifications may be made depending on the clinical stage of presentation and patient-related factors
In Dose-adjusted R-EPOCH, doses of etoposide, doxorubicin, and cyclophosphamide are increased ______ over the dose in the previous cycle if the nadir of the absolute neutrophil count in the previous cycle was _________.
20%
≥0.5 × 109/L
International Prognostic Factor Index
- Age older than 60 years
- Serum lactic dehydrogenase greater than twice normal
- Performance status ≥2
- Stage III or IV
- Extranodal involvement at more than one site
PALSE
Most commonly used for CNS prophylaxis
Methotrexate
High-dose IV methotrexate : at least two cycles of at least 3 g/m2 intravenously before, during, or after R-CHOP treatment
Central Nervous System International Prognostic Factor Index
- Age older than 60 years
- Serum lactic dehydrogenase greater than normal
- Performance status ≥2
- Stage III or IV
- Extranodal involvement at more than one site
- Kidney and/or adrenal glands involved
>10% or a CNS IPI score of ≥4 and in cases of extranodal involvement of the testes, ovaries, renal, adrenal gland, or breast)
The presence of rearrangements of MYC with BCL2 or BCL6 or potentially high protein expression may be risk factors for CNS relapse.
All patients should have an assessment of viral serologic status:
** risk of reactivation
Hepatitis B (HBV), hepatitis C (HCV), and HIV
If a carrier for hepatitis B, acceptable practice is to offer antiviral prophylaxis against hepatitis reactivation for at least ___________ after completion of rituximab-containing combination chemotherapy
12 months
Special Considerations in Older Patients
Short course of glucocorticoid monotherapy (steroid prephase)
Dose-attenuated regimens such as R-mini-CHOP
Limited-stage disease refers to stages
Stages I and II
Trial that primarily explored the question of whether the addition of rituximab to biweekly CHOP, given for either six or eight cycles, would improve overall outcome in patients with DLBCL older than the age of 60 years.
RICOVER-60 trial
The nonrandomized comparison of those who did and did not receive radiation demonstrated an inferior OS in those with bulky disease for whom radiotherapy was not delivered.
Trial that included patients to receive either six cycles of CHOP plus six cycles of rituximab or four cycles of CHOP plus six cycles of rituximab
No significant OS difference was seen; therefore, abbreviated R-CHOP has become the accepted standard for this small subset of the best prognosis patients.
FLYER trial
Standard chemotherapy regimen for advanced-stage DLBCL
R-CHOP
Rituximab 375 mg/m2
Cyclophosphamide 750 mg/m2 IV
Doxorubicin 50 mg/m2 IV
Vincristine 1.4 mg/m2 IV (sometimes capped at 2-mg flat dose)
Prednisolone 100 mg PO daily for 5 days,
21-day cycle for six to eight cycles
Trial that showed that reduction in treatment interval to every 2 weeks appeared to improve 5- year EFS and OS in both age groups.
“NHL-B1” trial: age of 18 and 60 years
“NHL B2” trial: age of 61 and 75 years
Reduction in treatment interval to every 2 weeks appeared to improve 5- year EFS and OS in both age groups.
This came at the cost of the need for routine granulocyte colony-stimulating factor support and more myelotoxicity in the 14-day treatment arms.
The addition of etoposide improved the survival outcomes of younger patients with good prognosis disease as defined by a normal LDH level.
Trials for the monoclonal anti–CD-20 antibody rituximab
GELA LNH98-5 clinical trial
MInT trial (Mabthera International trial)
RICOVER-60 trial
TRUE OR FALSE
There is no role for routine autologous transplantation as part of initial therapy for DLBCL.
TRUE
There is no role for routine autologous transplantation as part of initial therapy for DLBCL.
The DA-EPOCH-R regimen was also successfully used in what subtypes of DLBCL
Primary mediastinal B-cell lymphoma (PMBCL)
DEL and DHL
Trial on R-CHOP plus ibrutinib (n = 419) versus R-CHOP alone (n = 419) as the initial treatment of non-GCB subtype DLBCL (determined by immunohistochemistry)
Phoenix trial
Approximately one-third of patients with DLBCL manifest disease relapse, predominantly within the first __ years of primary therapy.
2 years
Salvage Chemotherapy for relapsed or refractory DLBCL
- R-DHAP (rituximab, dexamethasone, high-dose Ara-C, and cisplatin)
- R-ICE (rituximab with ifosfamide, carboplatin and etoposide)
- GDP (gemcitabine dexamethasone cisplatin)
Platinum-containing chemotherapeutic agent
There is no gold standard salvage regimen in relapsed and refractory DLBCL. No difference in survival outcomes
The advantages of GDP are its outpatient deliverability and improved toxicity profile compared with DHAP.
Randomized trial of a modified DHAP salvage regimen with and without rituximab demonstrated a significant improvement in response rate in the rituximab-treated arm (75%) versus the standard arm (54%, P < .001) and failure free-survival.
Very few patients in this trial had received prior rituximab.
HOVON (Hemato-Oncologie voor Wolwassenen Nederland)
There are no prospective randomized data exploring the role of rituximab added to chemotherapy after failure of a frontline rituximab-containing treatment.
Trial that established high-dose therapy and autologous stem cell transplantation as the standard of care with curative potential in the setting of chemosensitive relapsed DLBCL
PARMA prospective randomized clinical trial
Chimeric Antigen-Receptor T Cells used for second or subsequent disease relapse of DLBCL
Directed against CD-19
Tisagenlecleucel
Axicabtagene ciloleucel
Key toxicity of CART which manifests as fever and in some cases progresses to severe symptoms of multiorgan dysfunction and a sepsis-like syndrome
This typically occurs between 24 hours and 7 days after the infusion.
Cytokine release syndrome
The major benefit of this treatment is the potential for a single infusion to deliver a sustained remission in patients with chemoresistant lymphoma.
Management of cytokine release syndrome
Glucocorticoids
IL-6 antagonist tocilizumab
The most sensitive clinical sign of neurologic complications are peculiar to T cell–activating therapies
Alterations in handwriting
Others: Nominal aphasia and deterioration in the Mini-Mental Status Examination
A novel antibody-drug conjugate that targets CD79b
Effective as monotherapy for relapsed or refractory DLBCL
Approved in the United States for use in combination with BR as a third-line therapy for DLBCL
Polatuzumab vedotin (Pola)
The use of bendamustine-containing combinations is probably best avoided when future autologous CAR-T therapy is planned because of the potential detrimental effect of bendamustine on lymphocyte function.
The standard curative pathway for patients who have responsive DLBCL and who are fit to tolerate the potential toxicities of the conditioning regimen
Autologous stem cell transplantation
Standard approach for patients who relapse after second-line therapy
CAR-T cell therapy
Calculated by the integration of tumor volume determined by CT and the PET SUV, and this parameter is a significant prognostic indicator for outcome independent of the IPI.
Total metabolic volume (TMV)
This parameter is a significant prognostic indicator for outcome independent of the IPI.
A commonly used algorithm which defines CD10-positive DLBCL as GCB subtype
Hans classifier
The absence of BCL-6 or CD10 defines these tumors as non- GCB.
The diagnosis of DEL does not impact treatment choices at this time.
COO by immunohistochemistry is less consistently predictive of prognosis and inconsistencies with the gene expression profiling classifier creates uncertainty as to its application
FISH!!!
Also a marker of non-GCB phenotype when CD10 expression is absent and BCL6 expression is present.
MUM1
Characterized by a lymphohistiocytic infiltrate with a diffuse or nodular growth pattern
Similarities to nodular lymphocyte-predominant HL
T-cell/histiocyte-rich large B-cell lymphoma
Advanced-stage disease and B symptoms, splenic infiltration, and widespread extranodal disease.
This EBV-associated rare B-cell lymphoproliferative disorderthat is angiocentric and angiodestructive, and there is a prominent reactive cytotoxic T-cell infiltrate within the disease lesions.
CD20 positive, and Epstein-Barr encoding region in situ hybridization (EBER-ISH)
Lymphomatoid granulomatosis
Most common site of involvement of Lymphomatoid granulomatosis
Pulmonary
Lymph node and marrow disease are rare.
The lesions in the lungs are typically bilateral, are more common in the lower lobes, and may cavitate.
Median survival of Lymphomatoid granulomatosis
2 years
Medication active in early grade disease of Lymphomatoid granulomatosis
Interferon-α
Precursor of PMBCL
Thymic B-cell precursor
Most commonly seen in young and middle-aged adults with a female preponderance
Typically with an anterior mediastinal mass with locoregional nodal involvement.
PMBCL
CART used in patients with PMBCL
Axicabtagene ciloleucel
Immunophenotype of PMBCL
Weak CD 30, lack CD15
CD20, CD19, and CD79a
TRUE OR FALSE
Expression of PDL1 in PMBCL was associated with improved PFS.
TRUE
Expression of PDL1 in PMBCL was associated with improved PFS.
Pembrolizumab has received approval in several countries for the treatment of patients with PMBCL.
A rare extranodal lymphoma that presents in the lumina of blood vessels, typically adhering to the endothelial wall
CNS involvement is common.
Intravascular large B-cell lymphoma (IVLBCL)
Classical variant
Cutaneous variant
Hemophagocytic syndrome–associated variant
Treatment of patients with IVLBCL
R-CHOP
Most experts include high-dose methotrexate as prophylaxis against CNS relapse.
Lymphomas that are often virally associated with
EBV
Human herpes virus 8 (HHV8)
EBV: PCNSL, Plasmablastic lymphoma
HHV8: Primary effusion lymphoma
Acquired immunodeficiency states associated with Lymphoma, the two most frequent are
- HIV
- Posttransplant situation when there is continuous use of immunosuppressive agents
Most common morphology of HIV-associated lymphoma
DLBCL with immunoblastic morphology
PCNSL typically develops in the most immunosuppressed patients (CD4 counts <________) and is almost always EBV positive
CD4 counts <50/μL
TRUE OR FALSE
The management of HIV-associated DLBCL is the same as in patients with DLBCL who do not have HIV infection,
TRUE
The management of HIV-associated DLBCL is the same as in patients with DLBCL who do not have HIV infection,
HIV infection should be simultaneously suppressed with highly active antiretroviral therapy (HAART), and attention should be paid to the increased possibility of opportunistic infections.
Posttransplantation lymphoproliferative disorders (PTLDs): highest risk in what type of transplantation
The incidence is approximately 1% to 2% in solid-organ transplant recipients
Heart, lung, and intestinal transplantation
Particularly during the first year after transplantation.
The incidence of PTLD after blood or marrow transplantation is lower than after solid-organ transplantation and ranges from 0.5% to 1.0% in reported series.
The major risk factors that have been identified for the development of PTLD
- Type of organ transplanted
- EBV-positive serology pretransplantation
- Intensity of immunosuppressive regimen used
Management of PTLD is not uniform. Many cases of polyclonal PTLD resolve completely with a reduction in immunosuppressive therapy, but patients with more aggressive monoclonal PTLD are less likely to respond
