Mutations and CDs
Which translocation(s) are associated with Burkitt lymphoma
t(8;14) – most common
t(2;8)
t(8;22)
How do you differentiate between germinal vs non-germinal cell DLBCL?
Hans algorithm
--> Based on 3 markers--> CD10,BCl-6, MUM1
--> Remember that the CD10 and BCL6 are germinal center markers
--> Therefore CD10+ is GCB
--> BCl6 + (CD10 -ve and MUM-ve) is GCB
--> GCB is better!!!! 76% five year OS in GCB vs 34% in Non GC
Polarix Trial
--> In patients with previously untreated intermediate-risk or high-risk DLBCL [IPI score 2-5], the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.
--> PFS in Pola-R-CHP > RCHOP.
--> Subgroup analysis--> PFS in Pola-R-CHP > RCHOP only in ABC.
--> No difference in the PFS in GCB.
--> These subsets can be defined on Gene expression profiling.
--> It can also be done via IHC using Han's algorithm, but 20% of patients can be misclassified therefore, we should utilize GEP.
Polatuzumab Vedotin mechanism of action, adverse effects
Anti-CD79 b Antibody drug conjugate.
The most common adverse reactions (≥20%) included myelosuppression (neutropenia, thrombocytopenia, anemia), peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.
--> OTHER WARNINGS AND PRECAUTIONS
- Infections.
-Infusion-Related Reactions
- Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML
- Tumor Lysis Syndrome:
- Hepatotoxicity
FDA Approved CAR-T drugs approved in DLBCL?
Anti-CD19 CAR T-cell Constructs
--> Axicabtagene ciloleucel [Lets just call it Axi-cel]
--> Tisagenlecleucel [Tisa]
-->Lisocabtagene maraleucel [Liso]
* CAR-T therapies were initially approved for 3 rd and later line therapies. *****Even the patient's who have failed ASCT can be cured by CART!!!!!
* Now, it has also been approved in patients who relapsed within 12 months of Ritux-based therapy or were refractory. It is better than ASCT in such cases.
Recognise the tumor?
CD5+ CD10 - CD 20 dim, CD23 +, CD200+
Ans--> CLL
* CD5 is +ve in both CLL and Mantle cell but CD 20 dim, CD23 +, CD200+ is classic for CLL.
* Mantle cell is CD20+, CD23- and CD200 -
✅ CLL is "Cozy and Friendly" → Likes to invite CD23 over (positive) but likes to keep the lights Dim "CD20 dim"
What is a double or triple hit DLBCL?
Double hit--myc, BCl 2/or 6 rearrangenment--Bad!!!
drug resistant, very proliferative, poor prognosis.
Triple hit-- myc, BCL2 and 6 rearrangement--Bad!!!!!
*****Remember that the standard R-CHOP is suboptimal!
Management of Relapsed/Refractory DLBCL-- 1st line options
--> Evaluate if they are a candidate for an Autologous stem cell transplant?
--> Ineligible patients should go to 2nd and 3 rd line options.
--> Patients eligible for ASCT should receive platinum-based salvage therapy[RdHAP, RICE, RGDP]. Only 50% patients will respond to it and will get ASCT. The ones who did not respond (platinum refractory) should go to 3 rd line options.
--> CART has also been approved in patients who relapsed within 12 months of Ritux-based therapy or were refractory. It is better than ASCT in such cases.
CAR-T Toxicities? minimum 3
-> Cytokine release syndrome (CRS)--IL-6 mediated--IL-6 receptor antagonist, Tocilizumab --1st line.
--> Immune effector cell-associated neurotoxicity syndrome (ICANS)--> managed with steroids.
--> Prolonged cytopenias
--> B cell aplasia
--> Hypogammaglobinemia
Name any 3 aggressive B-cell lymphomas and 3 indolent B cell lymphomas?
-> DLBCL
Molecular subtypes--GCB, ABC
Pathologic subtypes--primary DLBCL of the CNS, primary cutaneous DLBCL-leg type, DLBCL associated with chronic inflammation, HHV-8 positive DLBCL, EBV positive DLBCL.
-> Other lymphomas of B cell eg primary mediastinal B cell lymphoma.
-> Burkitt lymphoma
--> Mantle cell lymphoma
Indolent B cell lymphoma
--> Follicylar Lymphoma
--> MALT
--> Marginal zone lymphoma
--> CLL
--> Hairy cell leukemia
--> Plasma cell neoplasms
--> Lymphoplasmocytic lymphoma
Which mutation is associated with the following lymphoma?
CD5+, CD10-,CD20+,CD23-
Mantle cell-----> t(11;14)
I could have given you Cyclin D1+, but I'm not that nice!" 😏💁♀️
Staging workup for DLBCL?
--> PET [if it doesn't show bone marrow disease, do a bone marrow biopsy to rule out stage IV disease]
--> TLS labs
--> Hep B testing
--> Echo
--> IPI score
Name 2nd and 3rd line regimens
-> CAR-T
-> Polatuzumab vedotin +BR
--> Tafasitamab-Lenalidomide [Tafasitamab is a CD19 monoclonal antibody]
--> Selinexor
--> Loncastuximab Teserine [Anti CD19 ADC]
--> Investigational trials
--> CD3/CD20 Bispecific Antibodies[Glofitamab, epcoritamab]
Drug tox with cyclophosphamide?
Cyclophosphamide- Hemorrhagic cystitis (↓ risk with mesna + hydration)
- SIADH
- Myelosuppression
True/false
CD3/20 bispecific antibodies can be used in DLBCL with prior ASCT or prior CART?
True!
What mutation is associated with follicular lymphoma
t (14;18)
Ann Arbor staging?
How do you treat non-bulky limited disease?
I: single LN group
II: Multiple LNs on one side of the diaphragm
III: Multiple LN's involving both sides of the diaphragm
IV: Involvement of extranodal sites
--> Non-bulky limited disease (i.e confined to one area and < 7.5 cm)-->can manage with 3 cycles of R-CHOP followed by restaging and if Complete or partial response, follow up with RT.
--> If bulky limited ds--RCHOP X6 cycles+RT
--> Extensive stage DLBCL--RCHOP X6 cycles, PET at 2-4 cycles/mini RCHOP for > 80 years old.
Name the drugs in R-EPOCH and which patient's with DLBCL need it?
Ritux, Etoposide, Prednisone, vincristine, cyclophosphamide and doxorubicin.
Double or triple hit, primary mediastinal, grey zone, HIV lymphomas.
Patient on R-CHOP has Red/orange urine. UA negative for RBC's.
Doxorubicin-->Red/orange color due to the drug’s pigment
True/false
1) CHOP-based therapy is not adequate for Burkitt Lymphoma.
2) In managing BL, to limit the severity of TLS, a pre-phase consisting of a week of glucocorticoid t/t and a dose of vincristine and cyclophosphamide before intensive chemotherapy has been incorporated into treatment regimens.
1) True!
Dose-intensive regimens needed (e.g. CODOX-M, DA-EPOCH, hyper-CVAD)
CODOX-M stands for:
C – Cyclophosphamide
O – Oncovin (Vincristine)
D – Doxorubicin (Adriamycin)
X – “X” as a placeholder (some say for high-dose Methotrexate)
M – Methotrexate (high-dose)
2) True!
Which mutation is present in nearly all cases of hairy cell leukemia?
When do you treat it? and how?
BRAF V600E mutations: nearly all cases of hairy cell leukemia
• Treatment (only if symptomatic or cytopenic like in CLL):
• Frontline: cladribine or pentostatin
--> IPI score
IPI score[ APLES--Age> 60, performance status aka ECOG>=2, LDH level >1× normal, Extranodal site(>1 site), Stage III-IV ]
--3-5 have poor prognosis
--3 is the High-intermediate risk group, 4 and 5 are the high risk groups.
Viruses associated with Burkitt Lymphoma?
EBV and HIV.
AML associated with Etoposide?
Timeline?
Mutation?
2-3 years
11q23 mutation
Summarize the entire DLBCL treatment algorithm!!!!!