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Lymphoma diffuse large cells.docx
1. DIFFUSE LARGE B-CELL NON-HODGKIN’S LYMPHOMA (DLBCL)
Aspect Summary
Prevalence
- Diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) is the most
common aggressive B-cell lymphoma, accounting for ∼
30% of all
lymphomas.
Age at Diagnosis - Median age at first diagnosis is approximately 70 years.
First-line Cure Rate
- Between 50% and 60% of all patients are cured with rituximab-
based chemoimmunotherapy in the first-line setting.
Treatment-Related Morbidity
and Mortality
- Treatment leads to substantial morbidity due to acute and long-
term toxicity.
- Treatment-related mortality ranges from 2% to 8%.
Relapse and Refractory Disease
- Relapsed or refractory disease typically occurs within the first 2
years after diagnosis.
Treatment Options for Relapsed
Disease
- More intensive treatment with high-dose chemotherapy, CD-19-
directed CAR-T-cell therapy, or experimental therapy in eligible
patients.
Term Definition
Single MYC
Rearrangement
A genetic alteration in which the MYC gene, which plays a role in cell
growth and division, undergoes rearrangement or translocation involving
its genetic material. In DLBCL, it often leads to overexpression of the MYC
protein and can be associated with aggressive disease behavior.
Double-Expressor DLBCL
A subtype of DLBCL characterized by the concurrent overexpression of both
MYC and BCL2 proteins. This phenotype is associated with inferior
outcomes following standard therapies and may require alternative
treatment strategies.
Double-Hit or Triple-Hit
DLBCL with MYC and BCL2 and/or BCL6 genomic rearrangements, referred
to as "double-hit" or "triple-hit" lymphomas. These are high-risk subtypes
associated with a worse prognosis following standard
chemoimmunotherapy, often requiring more intensive treatments such as
dose-intense regimens or stem cell transplantation.
2. Parameter General Index Age Adjusted Index
Age > 60 years 1 n.a.
PS (Performance Status) 1 1
Stage 3-4 1 1
LDH elevated 1 1
Extra nodal >1 site non considered 5
No. of Risk Factors IPI Group
0 - 1 1 = low
2 2 = low intermediate
3 3 = high intermediate
4 - 5 4 = high
Treatment Drugs Included Response
Rate
Progression-
Free Survival
Overall
Survival
First Line
R-CHOP Rituximab, Cyclophosphamide,
Doxorubicin, Vincristine,
Prednisone
~70% ~3 years ~60% at 5
years
DA-EPOCH-R Rituximab, Etoposide, Prednisone,
Vincristine, Cyclophosphamide,
Doxorubicin
~80% ~3 years ~60% at 5
years
3. Polatuzumab
vedotin + R-CHP
Rituximab, Cyclophosphamide,
Doxorubicin, Vincristine,
Prednisone, Polatuzumab vedotin
~85% Not yet
established
Not yet
established
Acalabrutinib +
R-CHOP or R-
DHAP
Rituximab, Cyclophosphamide,
Doxorubicin, Vincristine,
Prednisone (or High-Dose
Cytarabine) + Acalabrutinib
Not yet
established
Not yet
established
Not yet
established
Tafasitamab +
Lenalidomide +
R-CHP
Rituximab, Cyclophosphamide,
Doxorubicin, Vincristine,
Prednisone, Tafasitamab,
Lenalidomide
Not yet
established
Not yet
established
Not yet
established
Second Line
ICE Ifosfamide, Carboplatin,
Etoposide
~60% ~2 years ~25-30% at
5 years
R-ICE Rituximab, Ifosfamide,
Carboplatin, Etoposide
~70% ~2 years ~30-40% at
5 years
GEMOX Gemcitabine, Oxaliplatin ~50% ~1.5 years ~35-40% at
5 years
Third Line
4. DHAP or ESHAP Cytarabine, Cisplatin,
Dexamethasone (or Etoposide,
Methylprednisolone, Cisplatin)
~50% ~1 year ~25-30% at
5 years
R-DHAP or R-
ESHAP
Rituximab, Cytarabine, Cisplatin,
Dexamethasone (or Etoposide,
Methylprednisolone, Cisplatin)
~60% ~1.5 years ~30-40% at
5 years
GDP Gemcitabine, Dexamethasone,
Cisplatin
~50% ~1 year ~25-30% at
5 years
Stage of Disease Treatment
Limited stage (stage I or II) Combined modality therapy consisting of 3-4 cycles of R-
CHOP chemotherapy followed by involved-field radiation
therapy (IFRT)
Advanced stage (stage III or IV) R-CHOP chemotherapy for 6-8 cycles
Advanced stage (stage III or IV) with high
tumor burden or poor prognostic factors
R-CHOP chemotherapy followed by high-dose
chemotherapy and autologous stem cell transplant (ASCT)
Relapsed or refractory disease Salvage chemotherapy followed by high-dose
chemotherapy and autologous stem cell transplant
(ASCT), or CAR T-cell therapy
5. Second-line treatment for patients
ineligible for ASCT
Polatuzumab vedotin in combination with bendamustine
and rituximab (BRP)
Maintenance therapy Lenalidomide or rituximab for up to 2 years after initial
therapy
Pharmaceutical
Name
Commercial
Name
Manufacturer Dose and Route of Administration
Polatuzumab
vedotin
Polivy Genentech/Roche 1.8 mg/kg intravenous
Acalabrutinib Calquence AstraZeneca 100 mg twice daily oral
Tafasitamab Monjuvi MorphoSys/Incyte 12 mg/kg intravenous over
approximately 30 minutes on days 1, 8,
15, and 22 of each cycle in combination
with lenalidomide
Lisocabtagene
maraleucel
Breyanzi Bristol Myers
Squibb/Juno
Therapeutics
A single infusion of 0.6 to 6.0 × 10^8
CAR-positive viable T cells in 68 to 92
mL via intravenous infusion
Umbralisib Ukoniq TG Therapeutics 800 mg orally once daily
Drugs Indications Year of
Approval
FDA
Approval
EMA
Approval
Clinical Trials Results
6. Polatuzumab
vedotin
In combination
with
chemotherapy
2019 Yes Yes GO29365
(NCT02257567)
Improved median
OS vs R-CHOP
(12.4 vs 4.7
months)
Acalabrutinib In combination
with
chemotherapy or
alone
2020 Yes Yes ACE-LY-308
(NCT02953814)
Improved ORR
and PFS vs
placebo
Tafasitamab In combination
with lenalidomide
2020 Yes Yes L-MIND
(NCT02399085)
Improved ORR
and CR vs
lenalidomide
alone
Lisocabtagene
maraleucel
(Liso-cel)
Relapsed or
refractory DLBCL
2021 Yes Pending TRANSCEND
(NCT02631044)
ORR of 73% and
CR of 53%
Umbralisib In combination
with ublituximab
2021 Yes Pending UNITY-NHL
(NCT02793583)
Improved ORR
and CR vs
ublituximab alone
Zanubrutinib In combination
with rituximab
2021 Yes Pending SEQUOIA
(NCT03332017)
Improved PFS and
ORR vs R-CHOP
Drugs Advantages Disadvantages Adverse Events (percentage)
Polatuzumab
vedotin
Improved
progression-free
survival and overall
survival when added
to chemotherapy
compared to
chemotherapy alone
Increased risk of
infection, liver
damage, and nerve
damage; infusion
reactions (31% had
grade 3 or higher)
Infections (48%), neutropenia (46%),
anemia (32%), thrombocytopenia
(21%), peripheral neuropathy (16%)
8. survival when added
to ublituximab
compared to
ublituximab alone
bleeding and skin
cancers
infection (23%), pneumonia (22%),
headache (21%), rash (21%),
abdominal pain (20%), decreased
appetite (19%), vomiting (19%),
peripheral edema (19%),
thrombocytopenia
Polatuzumab vedotin: Polatuzumab vedotin was approved by the FDA in 2019 for the treatment of
relapsed or refractory DLBCL in combination with bendamustine and rituximab (BRP), following at
least two prior therapies. In the updated table, polatuzumab vedotin is listed as a second-line
treatment option for patients who are ineligible for ASCT.
Acalabrutinib: Acalabrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was approved by the FDA
in 2020 for the treatment of adult patients with relapsed or refractory DLBCL who have received at
least two prior lines of systemic therapy. However, it should be noted that acalabrutinib is currently
not listed in the NCCN guidelines as a standard treatment option for DLBCL.
Tafasitamab: Tafasitamab is a CD19-directed antibody that was approved by the FDA in 2020 for the
treatment of relapsed or refractory DLBCL in combination with lenalidomide. In the updated table,
tafasitamab is not listed as a standard treatment option, but could be considered in certain cases as
salvage therapy.
Lisocabtagene maraleucel: Lisocabtagene maraleucel (liso-cel) is a chimeric antigen receptor (CAR) T-
cell therapy that targets CD19. It was approved by the FDA in 2021 for the treatment of relapsed or
refractory DLBCL after at least two prior therapies. In the updated table, liso-cel is listed as a potential
option for patients with relapsed or refractory disease.
Umbralisib: Umbralisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor that was granted
accelerated FDA approval in 2021 for the treatment of relapsed or refractory marginal zone lymphoma
and follicular lymphoma. It has not yet been approved for the treatment of DLBCL.
9.
10.
11.
12.
13. Table 1: Diagnosis, Staging, and Initial Work-up
Aspect Summary
Initial Work-up
- Includes complete physical examination, blood count, renal and liver
function, and more.
- Contrast-enhanced CT scan of neck, thorax, and abdomen is often
performed at first presentation.
- Bone-marrow biopsy with t(14;18) analysis is conducted in all patients to
exclude lymphoma infiltration.
14. Aspect Summary
Risk Stratification
- IPI (International Prognostic Index) used for risk assessment at initial
diagnosis.
- CNS-IPI for estimating individual prognosis and CNS involvement risk.
- Consider cerebral MRI and cerebrospinal fluid analysis for high CNS-IPI or
neurological symptoms.
- Additional risk factors discussed but not conclusive for CNS involvement.
Comorbidity
Assessment
- Echocardiography, electrocardiogram, brain natriuretic peptide for
anthracycline-based chemotherapy.
- HIV, hepatitis B and C serology checked before treatment.
Psychological Support - Psychological support offered to patients and families at initial diagnosis.
Table 2: Histological Assessment at First Diagnosis
Aspect Summary
Histological
Assessment
- Histological assessment is the cornerstone of first diagnosis.
- Standard immunohistochemistry panel used for B- and T-cell markers and
cell of origin analysis.
- MYC, BCL2, and BCL6 FISH analysis conducted as per WHO classification.
- Assessment of human herpesvirus-8 status in relevant pleural or peritoneal
effusion cases.
Table 3: First-line Treatment of Low-risk Patients
Aspect Summary
Low-risk Patients- Rituximab-based chemoimmunotherapy for patients with an IPI below 2.
- Equivalence of four vs. six cycles of R-CHOP chemotherapy in limited disease.
- Abbreviated treatment and interim PET for selected patients with low-risk and
limited-stage disease.
- Consider consolidation radiotherapy or prolonging R-CHOP for positive interim
PET cases.
15. Aspect Summary
- Repeated biopsy for patients with progressive disease based on CT and PET after
three cycles of R-CHOP.
Table 4: First-line Treatment of Higher-risk Patients
Aspect Summary
Higher-risk Patients - Polatuzumab vedotin preferred in patients with IPI >2.
- Use of anti-nausea medications and filgrastim to manage chemotherapy side
effects.
- Liposomal anthracyclines in patients with cardiovascular risk factors and
age >60 years.
- Clinical examination and CT/PET scans during treatment to assess response.
- Consider early PET scans for patients with signs of early progression.
Table 5: Survivorship and Follow-up After First-line Treatment
Aspect Summary
Survivorship and Follow-
up
- Psychological support and psychotropic drugs offered for anxiety.
- Symptomatic treatment for polyneuropathy, dose reductions, and
rehabilitation clinics recommended.
- Avoid regular CT scans in asymptomatic patients due to lack of efficacy.
- Recommended follow-up includes blood count, renal and liver function,
LDH, and clinical examination.
- Use chest X-ray and ultrasonography for selected cases.
Table 6: Relapsed or Refractory Disease
Aspect Summary
Relapsed or Refractory
Disease
- Conduct a new biopsy to confirm malignancy and the former diagnosis.
- CAR-T-cell therapy preferred in the second-line setting for eligible
patients.
16. Aspect Summary
- Alternative therapeutic antibodies, such as polatuzumab vedotin and
tafasitamab with lenalidomide, used.
- Epcoritamab and glofitamab considered for heavily pretreated patients.
- Individualized treatment decisions for patients not recruitable to clinical
trials.
Table: Evolving Treatment Approaches for Diffuse Large B-cell Lymphoma (DLBCL)
Aspect Summary
CAR T-Cell Therapy
- Three FDA-approved options for relapsed/refractory DLBCL patients who had
at least two prior lines of therapy.
- Recent approvals for second-line therapy (axicabtagene ciloleucel and
lisocabtagene maraleucel) based on ZUMA-7 and TRANSFORM studies.
TRANSFORM Study
- TRANSFORM study compared liso-cel to standard-of-care (high-dose
chemotherapy and autologous stem cell transplantation).
- Liso-cel group showed significantly improved median event-free survival,
progression-free survival, and complete response rate.
- Low rates of grade 3 cytokine release syndrome (1%) and neurologic events
(4%).
Glofitamab
- A promising CD20/CD3 bispecific monoclonal antibody for relapsed/refractory
DLBCL patients.
- Phase 2 trial results showed significant complete and objective response rates,
with low-grade cytokine release syndrome.
Bispecific
Antibodies
- Advantages include off-the-shelf access and favorable toxicity profiles.
- Longer follow-up needed to determine response durability beyond 1 year.
Future Directions
- Questions about sequencing with CAR T-cell therapy and combining bispecific
antibodies with other regimens.
- Ongoing studies of bispecific antibodies in combination with
chemoimmunotherapy and other treatments.
17. Table: Axi-Cel Therapy for Relapsed/Refractory Large B-cell Lymphoma
Aspect Summary
Response Rates
- In a multicenter phase 2 trial, 82% of patients with refractory
large B-cell lymphoma had an objective response, and 54% had a
complete response with axi-cel therapy.
Comparison to Existing
Therapies
- Axi-cel response rates compare favorably to SCHOLAR-1 study
results for existing therapies (objective response rate of 26% and
complete response rate of 7%).
Duration of Response
- Responses were ongoing in 42% of patients, including 40% with a
complete response, with the emergence of a plateau in response
duration at 6 months.
Monitoring for Improved
Response
- Consider monitoring patients without a complete response at the
first assessment for an opportunity for improvement, as
consolidation with allogeneic stem-cell transplantation has high
treatment-related mortality.
Overall Survival
- Median overall survival not reached; 18-month overall survival
rate of 52%. Ongoing durable remissions observed at 24 months.
Consistency Across Covariates
- Responses consistent across key covariates, including CD19 status
and T-cell phenotypes.
Need for Prospective Data
- Prospective data needed to understand the influence of disease
biology (e.g., double- and triple-hit lymphomas) on CAR T-cell
therapy outcomes.
Centralized Manufacturing and
Coordination
- Confirmed feasibility and reliability of centralized manufacturing
and coordination of leukapheresis procedures.
Feasibility in Medical Facilities
- Axi-cel safely administered even in centers with no prior CAR T-
cell therapy experience.
Management of Cytokine
Release Syndrome
- Effective implementation of algorithms for cytokine release
syndrome management; incidence decreased over time.
Safety Compared to Allogeneic
Stem-Cell Transplant
- Favorable 3% rate of death during treatment compared to
allogeneic stem-cell transplantation rates.
Correlation of CAR T-Cell Levels
with Response
- CAR T-cell levels during the first 28 days correlated with objective
response, supporting the potential for higher levels to augment
efficacy.
18. Aspect Summary
Biomarker Analysis
- Serum biomarker analysis confirmed associations with the
cytokine release syndrome and neurologic events, aiding in
understanding adverse events.
Use of Immunosuppressive
Agents
- Use of tocilizumab or glucocorticoids did not appear to affect
overall response.
Future Optimization and
Combinations
- Ongoing exploration of CAR construct and manufacturing
optimization and combination strategies with immunomodulatory
agents.
Table 1: Current First-Line Treatment of DLBCL
Treatment Patient Population Key Findings
R-CHOP
Elderly patients
(60-80 years)
Improved complete response rates (76% vs 63%) compared to
CHOP. Improved EFS and OS without increased toxicity. 10-year
PFS: 36.5% with R-CHOP vs 20% with CHOP alone. 10-year OS:
43.5% with R-CHOP vs 27.6% with CHOP alone. [16,17]
R-CHOP
Young patients (18-
60 years)
Increased complete response rates, improved EFS, and OS. 6-
year EFS: 74.3% with R-CHOP+rituximab vs 55.8% without. 6-
year OS: 90.1% with R-CHOP+rituximab vs 80.0% without.
[18,19]
R-CHOP
Elderly patients
(≥60 years)
No significant difference in outcomes between six and eight
cycles of R-CHOP. [20]
R-CHOP
Standard First-Line
Therapy
Six cycles of R-CHOP established as standard first-line therapy
for DLBCL.
Table 2: Beyond Standard R-CHOP Therapy
Treatment Patient Population Key Findings
R-ACVBP
Young patients (18-59
years)
Significantly improved EFS and OS but logistically
complex and with high risk of hematological
toxicities. Limited to patients with aa-IPI scores of
1. [21]
DA-EPOCH-R Not specified
No demonstrated significant benefit over R-CHOP.
[22]
High-dose
chemotherapy (HDC)
Not specified
No demonstrated significant benefit over R-CHOP.
[23,24,25]
19. Treatment Patient Population Key Findings
Novel agents with R-
CHOP
Not specified
None showed significant success despite promising
early signals of efficacy. [26-31]
Lenalidomide
Elderly patients
responding to R-CHOP
Maintenance therapy with lenalidomide prolonged
PFS but no OS benefit. Controversial due to
toxicities. [32]
Polatuzumab vedotin
(pola-R-CHP)
Intermediate to high-risk
DLBCL (IPI score ≥ 2)
Improved PFS over R-CHOP. No significant OS
difference. [37,38]
Polatuzumab vedotin
(pola-R-CHP)
Intermediate to high-risk
DLBCL (IPI score ≥ 2)
Less subsequent treatment required with pola-R-
CHP. [37,38]
Table 3: Low Risk Patients with Limited-Stage Disease
Treatment Patient Population Key Findings
R-CHOP
Limited stage (I or II) with aa-IPI of
0 and non-bulky disease (< 7.5 cm)
Highly favorable outcomes with 6-
year PFS approximating 90% and OS
at 95%. [18,19]
CHOP + Radiation Limited stage disease
Non-inferior to eight cycles of CHOP
alone but inadequate by modern
standards. [43,44]
Four cycles of R-CHOP + Two
additional rituximab doses
Young patients (18-60 years) with
limited stage and non-bulky
disease (< 7.5 cm), good ECOG
performance status (0-1), and
normal serum LDH levels
Non-inferior to standard six cycles
of R-CHOP. [46]
PET Response-Adapted
Approach
Limited stage (non-bulky < 10 cm)
and aa-IPI of 0
Four cycles of R-CHOP in case of
negative interim PET resulted in
excellent survival. [47]
PET Response-Adapted
Approach
Limited stage (aa-IPI scores of 0)
A negative interim PET allowed
patients to receive four cycles,
while a positive interim PET led to
six cycles. Non-inferiority
demonstrated. [48]
Table 1: Current First-Line Treatment of DLBCL
20. Treatment Category Treatment Regimen Patient Criteria Outcomes
Standard-Risk DLBCL
R-CHOP
chemoimmunotherapy
All standard-risk
DLBCL patients
6 cycles, 21-day cycle
Intermediate/High-
Risk
Pola-R-CHP
IPI score of 2–5, cost
not a limiting factor
6 cycles, 21-day cycle
Low Risk (Limited-
Stage)
Abbreviated R-CHOP
Limited stage (I or II)
with aa-IPI of 0, non-
bulky
4 cycles, 21-day cycle
Abbreviated R-CHOP (FLYER
Criteria)
Limited stage, non-
bulky, good ECOG,
normal LDH
4 cycles R-CHOP followed
by 2 cycles rituximab
PET-Guided Approach
For selected "low-
risk" DLBCL cases
3-4 cycles R-CHOP followed
by consideration of
consolidation radiation
therapy, guided by PET
imaging
Table 2: High-Risk Genetics in DLBCL
High-Risk Genetics Treatment Regimen Patient Criteria Notes
Single MYC
Rearrangement
R-CHOP
chemoimmunotherapy
All patients with single
MYC rearrangements
6 cycles, 21-day cycle
Double-Expressor
DLBCL
R-CHOP
chemoimmunotherapy
All patients with double-
expressor DLBCL
6 cycles, 21-day cycle
Double-Hit or Triple-Hit DA-EPOCH-R or R-CHOP
Patients with double-hit
or triple-hit genetics
6 cycles, 21-day cycle
for both DA-EPOCH-R
and R-CHOP
Consideration of
consolidation
therapies
Table 3: Special Considerations
Patient Group Treatment Regimen Patient Criteria Notes
Elderly and Frail
R-miniCHOP or other
regimens
Patients aged over 80
years or frail patients
Consideration of alternative
regimens
Disease Site-
Specific
Various
Based on primary site of
the disease
Tailored treatment approaches
for specific disease sites
21. Patient Group Treatment Regimen Patient Criteria Notes
DLBCL in HIV/AIDS
DA-EPOCH-R or
Abbreviated EPOCH-
RR
Patients with HIV-
associated DLBCL
Consideration of response-
adapted strategies
Table 4: Role of CNS Prophylaxis in DLBCL
CNS Prophylaxis
Strategy
Patient Criteria Preferred Method Notes
HD-MTX
High CNS-IPI scores, high-
risk sites
Over IT prophylaxis
Intercalated or at the end of
induction
Intrathecal (IT) MTX
Variable based on
guidelines
Less preferred
May not significantly reduce
CNS relapse
Table 1: Treatment Options for Relapsed or Refractory DLBCL
Patient Eligibility Treatment Regimen Notes
Transplant Eligible R-ICE, R-DHAP, R-GDP, Pola-R-ICE
High-dose chemotherapy followed by
ASCT is a curative option
Transplant
Ineligible
R-GDP, R-GEMOX, Pola-BR, Pola-R-ICE
Options for patients ineligible for ASCT or
CAR-T therapy
CAR-T Therapy
Eligible
CD19-directed CAR-T therapies
Axicabtagene ciloleucel, tisagenlecleucel,
lisocabtagene maraleucel for eligible
patients
CAR-T Therapy
Ineligible
Pola-BR, Tafasitamab + Lenalidomide,
Loncastuximab tesirine, Selinexor
Options for patients not eligible for ASCT
or CAR-T therapy
Table 2: Use of Next-Generation Sequencing in DLBCL
Molecular Classification
System
Clinical Implications Current Clinical Practice
Molecular Classification
Systems
Identification of unique
genomic subtypes
Subtyping DLBCL based on molecular
classification systems is not yet a standard
practice in current clinical treatment
decisions.
C1 to C5, BN2, A53, EZB,
ST2, MCD, N1
Genetic clusters with
distinct signatures
These classifications are based on whole
exome and deep targeted sequencing and
may guide future clinical trials.
22. Molecular Classification
System
Clinical Implications Current Clinical Practice
LymphGen Probabilistic
Classifier
Assign patients to genetic
subtypes
Currently, routine genomic profiling's value in
frontline or relapsed treatment selection is
unclear.
Heterogeneity of DLBCL
Potential rational
explanation for targeted
therapy failures
Challenges, costs, and implications on
treatment selection need further study.
