B CELL LYMPHOMA

Question 1

Typical immunophenotype FL:

Answer 1

CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+, BCL6+

Rare cases of FL may be CD10- or BCL2-.

Question 2

Anti-CD20 mAbs for FL include:

Answer 2

Rituximab or obinutuzumab

Obinutuzumab is not indicated as single-agent therapy.

Question 3

Consider possibility of histologic transformation in patients with:

Answer 3

• Progressive disease, especially if LDH levels are rising
• Single site is growing disproportionately
• Extranodal disease develops
• There are new B symptoms

Question 4

Preferred treatment for: Stage I or Contiguous stage II FL

Answer 4

ISRT

Question 5

Type of FL

Morphology: expansile follicles, effacement of architecture, absence of diffuse area

Presents as localized disease (stage I, II)

Male sex predominant

Younger age than typical FL (though can occur in adults >60 years)

Answer 5

Pediatric type Follicular Lymphoma

If the patient has disease >stage II, it is by definition not PTFL.

Question 6

Immunophenotype of Pediatric FL:

Answer 6

Expresses: BCL6, CD10, ± IRF4/ MUM1 (~20%)

Proliferation index (Ki-67/MIB-1) >30%

No rearrangement of BCL2, BCL6, IRF4/MUM1

Question 7

Preferred treatment for Pediatric FL:

Answer 7

Excision

RCHOP for patients with extensive local disease who are not candidates for excision or ISRT

Question 8

Guide for initiation of treatment in FL

GELF CRITERIA

Answer 8

• Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm
• Any nodal or extranodal tumor mass with a diameter of ≥7 cm
• B symptoms
• Splenomegaly
• Pleural effusions or peritoneal ascites
• Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L)
• Leukemia (>5.0 x 109/L malignant cells)

Question 9

Prognostic Index for FL

FLIPI - 1 CRITERIA

Answer 9

• Age ≥60 y
• Ann Arbor Stage III-IV
• Hemoglobin level <12 g/dL
• Serum LDH level >ULN (upper limit of normal)
• Number of nodal sites ≥5

Low 0-1
Intermediate 2
High ≥3

Question 10

Preferred regimens high tumor burden FL

Answer 10

• Bendamustine + obinutuzumab or rituximab
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
  + obinutuzumab or rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumabe or rituximab
• Lenalidomide + rituximab

Question 11

Preferred regimens low tumor burden FL

Answer 11

Rituximab (375 mg/m2 weekly for 4 doses)

Question 12

Preferred regimens older patients with FL

Answer 12

Rituximab (375 mg/m2 weekly for 4 doses)

Other recommended regimens
* Chlorambucil ± rituximab
* Cyclophosphamide ± rituximab

Question 13

Preferred regimens extended therapy or maintainance

Answer 13

• Rituximab maintenance 375 mg/m2 one dose every 8–12 weeks for 2 years for patients initially presenting with high tumor burden (category 1)
• Obinutuzumab maintenance (1 g every 8 weeks for 12 doses)

If initially treated with single-agent rituximab, rituximab maintenance 375 mg/m2 one dose every 8 weeks for 4 doses

Question 14

Preferred regimens third line and subsequent therapy

Answer 14

T-cell engager therapy
Bispecific antibody therapy
- Epcoritamab-bysp
- Mosunetuzumab-axgb

Chimeric antigen receptor (CAR) T-cell therapy
- Axicabtagene ciloleucel (CD19-directed)
- Lisocabtagene maraleucel (CD19-directed)
- Tisagenlecleucel (CD19-directed)

Question 15

A EZH2 inhibitor for FL

Answer 15

Tazemetostat

Question 16

BTK inhibitor (BTKi) for FL

Answer 16

Zanubrutinib

Question 17

TRUE OR FALSE

Diagnosis of EMZL of the stomach requires an endoscopic biopsy.

Answer 17

TRUE

Diagnosis of EMZL of the stomach requires an endoscopic biopsy.

Question 18

Typical immunophenotype of Extranodal Marginal Zone B-Cell Lymphoma/Gastric :

Answer 18

CD10-, CD5-, CD20+, cyclin D1-, BCL2- follicles

Question 19

Treatment for Stage I/III EMZL

H.pylori positive, t(11;18) negative, or t(11;18) unknown

Answer 19

Antibiotic therapy for H. pylori

Question 20

Treatment for Stage I/III EMZL

H.pylori positive, t(11;18) positive

Answer 20

Antibiotic therapy for H. pylori + ISRT

Antibiotic therapy for H. pylori + Rituximab (if ISRT is contraindicated)

Question 21

Treatment for Stage I/III EMZL

H. pylori negative

Answer 21

ISRT

Rituximab (if ISRT is contraindicated)

Question 22

Preferred treatment for Stage III/IV EMZL

Answer 22

• Bendamustine + rituximab
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + rituximab

Other recommended regimens
* Lenalidomide + rituximab (category 2B)
* Rituximab (375 mg/m2 weekly for 4 doses) for EMZL and nodal MZL

Question 23

Karyotype that has locally advanced disease and is a predictor for lack of tumor response (<5%) to antibiotics

Answer 23

t(11;18)

Question 24

Molecular analysis that help differentiate Waldenström macroglobulinemia (WM) (90%) versus MZL (10%) if plasmacytic differentiation present

Answer 24

MYD88 mutation status

Question 25

Indications for treatment in EMZL

Answer 25

* Symptoms * Gastrointestinal (GI) bleeding * Threatened end-organ function * Clinically significant bulky disease * Steady or rapid progression ## Footnote **Surgical resection** is generally limited to specific clinical situations (ie, life-threatening hemorrhage).

Question 26

Restaging with endoscopy/biopsy for H. pylori/lymphoma after antibiotics is done after

Answer 26

6 months

Question 27

Restaging with endoscopy/biopsy for H. pylori/lymphoma after ISRT or rituximab is done after

Answer 27

6 months

Question 28

Typical nongastric sites of EMZL include the following:

Answer 28

Bowel (small and large), breast, head and neck, lung, dural, ocular adnexa, ovary, parotid, prostate, and salivary gland

Question 29

Based on anecdotal responses to antibiotics in **ocular and cutaneous marginal zone lymphomas**, some physicians will give an empiric course of ____________ prior to initiating other therapy.

Answer 29

Doxycycline

Question 30

# TRUE OR FALSE MZL is rare and occurs most commonly as spread from extranodal sites

Answer 30

TRUE ' MZL is rare and occurs most commonly as spread from extranodal sites

Question 31

**SMZL** is most definitively diagnosed at _________________

Answer 31

Splenectomy ## Footnote Since the immunophenotype is nonspecific and morphologic features on the bone marrow may not be diagnostic However, the diagnosis of SMZL may be made on the basis of bone marrow ± peripheral blood involvement by small lymphoid cells with Ig light chain restriction that lack characteristic features of other small B-cell neoplasms (ie, CD5, CD10, cyclin D1)

Question 32

Typical immunophenotype of SMZL:

Answer 32

CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and cyclin D1-, BCL2- follicles, annexin A1, and CD103- (distinction from hairy cell leukemia [HCL]) with expression of both IgM and IgD

Question 33

May be helpful to differentiate SMZL from other B-cell lymphoma subtypes.

Answer 33

NOTCH2 and KLF2 mutation

Question 34

Prefrred treatment for SMZL with splenomegaly, HCV negative, with symptoms and cytopenias

Answer 34

Rituximab

Question 35

Typical immunophenotype of MCL:

Answer 35

CD5+, CD20+, CD43+, CD23-/+, cyclin D1+, CD10-/+. ## Footnote Note: Some cases of MCL may be CD5- or CD23+. If the diagnosis is suspected, **cyclin D1 staining or FISH for t(11;14)** should be done. There are rare cases of **CCND1- MCL (< 5%)** with an otherwise typical immunophenotype.

Question 36

Most common biomarker for indolent disease:

Answer 36

SOX11- [IGHV mutated]

Question 37

Features of indolent MCL:

Answer 37

* Leukemic non-nodal CLL-like with splenomegaly * GI or blood/ bone marrow involvement only * Low tumor burden * Ki-67 proliferation fraction <10%

Question 38

Preferred Aggressive induction therapy for MCL:

Answer 38

* **LyMA regimen**: RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) x 4 cycles followed by RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for non-PET CR * **NORDIC regimen**: Dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP) alternating with rituximab + high-dose cytarabine * Rituximab, bendamustine followed by rituximab, high-dose cytarabine * **TRIANGLE regimen**: Alternating RCHOP + covalent BTKi/RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) (category 2A for ibrutinib; category 2B for acalabrutinibj or zanubrutinib) ## Footnote Other recommended regimen * HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) + rituximab * RBAC500 (rituximab, bendamustine,c cytarabine)

Question 39

Preferred **Less aggressive** induction therapy for MCL

Answer 39

* Bendamustine + rituximab * VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) * RCHOP * Lenalidomide (continuous) + rituximab

Question 40

Induction Therapy (STAGE II BULKY OR NONCONTIGUOUS, III, OR IV MCL; CLASSICAL TP53 MUTATED)

Answer 40

Zanubrutinib/obinutuzumab/venetoclax

Question 41

MAINTENANCE AFTER HDT/ASCR OR AGGRESSIVE INDUCTION THERAPY

Answer 41

Covalent **BTKi** x 2 yearsh (category 2A for ibrutinib; category 2B for acalabrutinib or zanubrutinib) + **rituximab** every 8 weeks x 3 years

Question 42

MAINTENANCE AFTER LESS AGGRESSIVE INDUCTION THERAPY

Answer 42

* **Rituximab** every 8 weeks for 2–3 years following RCHOP (category 1) or * **Bendamustine + rituximab**

Question 43

Typical immunophenotype DLBCL:

Answer 43

CD20+, CD45+, CD3-

Question 44

Definition of bulky in DLBCL

Answer 44

≥7.5 cm ## Footnote Some studies have used 10 cm as the cutoff for bulky disease.

Question 45

# TRUE OR FALSE In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given.

Answer 45

TRUE In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT should be given.

Question 46

The optimum timing of end-of-treatment PET/CT is unknown; however, waiting a minimum of ______________ weeks after RT to repeat PET/CT scan is suggested.

Answer 46

8 weeks

Question 47

INTERNATIONAL PROGNOSTIC INDEX

Answer 47

* Age >60 years * Serum LDH > normal * Performance status 2–4 * Stage III or IV * Extranodal involvement >1 site ## Footnote * Low 0 or 1 * Low-intermediate 2 * High-intermediate 3 * High 4 or 5

Question 48

AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEX ≤60 YEARS

Answer 48

* Serum LDH > normall * Stage III or IV * Extranodal involvement >1 site ## Footnote * Low 0 * Low-intermediate 1 * High-intermediate 2 * High 3

Question 49

STAGE-MODIFIED INTERNATIONAL PROGNOSTIC INDEX (smIPI)

Answer 49

* Age >60 years * Serum LDH > normal * Performance status 2–4 * Stage II or IIE ## Footnote * Low 0 or 1 * High 2–4

Question 50

NCCN-IPI

Answer 50

**Age, years** * >40 to ≤60 1 * >60 to <75 2 * ≥75 3 **LDH, normalized** * >1 to ≤3 1 * >3 2 **Ann Arbor stage III–IV 1** **Extranodal disease 1** **Performance status ≥2 1** ## Footnote Extranodal: Disease in bone marrow, CNS, liver/GI tract, or lung.

Question 51

PROGNOSTIC MODEL TO ASSESS THE RISK OF CNS DISEASE CNS IPI

Answer 51

* Age >60 years * Serum LDH > normal * Performance status >1 * Stage III or IV * Extranodal involvement >1 site *** Kidney or adrenal gland involvement** ## Footnote * Low risk 0–1 * Intermediate-risk 2–3 * High-risk 4–6 or kidney or adrenal gland involvement

Question 52

Additional indications for CNS prophylaxis independent of CNS risk score

Answer 52

* Testicular lymphoma * Primary cutaneous DLBCL, leg type * Stage IE DLBCL of the breast * Kidney or adrenal gland involvement

Question 53

If CNS prophylaxis is used, options include:

Answer 53

* Systemic high-dose methotrexate (3–3.5 g/m2 for 2–4 cycles) during or after the course of treatment and/or * IT methotrexate and/or cytarabine (4–8 doses) during or after the course of treatment

Question 54

A mature aggressive B-cell lymphoma characterized by large cells with **plasmablastic** differentiation and cytoplasmic expression of **ALK**, and **lacking CD20** expression

Answer 54

ALK-positive DLBCL ## Footnote EBV and HHV8 are negative in ALK-positive LBCL, and there is no association with immune deficiency. t(2;17)(p23;q23), denoting the CLTC (clathrin heavy chain)/ ALK fusion The median age at diagnosis is approximately 40 years and there is a strong male predominance. Most patients present with rapidly progressive disease at advanced stage, and both nodal and extranodal involvement are common.

Question 55

* Present with large anterior mediastinal mass with or without supraclavicular lymph nodes. * More common in males, presenting between 20–40 y * Typically larger and more pleomorphic than in PMBL, sometimes resembling lacunar or Hodgkin-like cells. * A worse prognosis than either CHL or PMBL has been suggested.

Answer 55

MEDIASTINAL GRAY ZONE LYMPHOMA (MGZL)

Question 56

Typical immunophenotype of MGZL:

Answer 56

CD45+, PAX5+, BOB.1+, OCT-2+, CD15+, CD20+, CD30+, and CD79a+; CD10- and ALK- BCL6 is variably expressed and EBV is usually negative

Question 57

Preferred for DLBCL * Stage I–II * Stage II (with extensive mesenteric disease) or Stage III–IV

Answer 57

* RCHOP * Pola-R-CHP

Question 58

Regimens for DLBCL Patients with **Poor Left Ventricular Function**

Answer 58

* DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab * RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) * RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) * RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisone) * RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine) (category 2B)

Question 59

Regimens for DLBCL Very Frail Patients and Patients >80 Years of Age with Comorbidities

Answer 59

* RCDOP * R-mini-CHOP * RGCVP * RCEPP (category 2B)

Question 60

Regimen for concurrent presentation with CNS Disease

Answer 60

* **Parenchymal**: systemic high-dose methotrexate (≥3 g/m2 given with RCHOP cycle that has been supported by growth factors). * **Leptomeningeal:** IT methotrexate/cytarabine, consider Ommaya reservoir placement. OR Systemic high-dose methotrexate (3–3.5 g/m2) can be given in combination with RCHOP or as consolidation after RCHOP + IT methotrexate/cytarabine ## Footnote Different schedules have been used for the integration of high-dose methotrexate with RCHOP (early- or mid-cycle or day 15 of a 21-day cycle)

Question 61

Preferred therapy for DLBCL Secondline therapy (intention to proceed to transplant):

Answer 61

* DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) ± rituximab * GDP (gemcitabine, dexamethasone, cisplatin) ± rituximab or (gemcitabine, dexamethasone, carboplatin) ± rituximab * ICE (ifosfamide, carboplatin, etoposide) ± rituximab

Question 62

Preferred therapy for DLBCL Secondline therapy (no intention to proceed to transplant):

Answer 62

* CAR T-cell therapy (CD19-directed)k (if eligible) Lisocabtagene maraleucel * Polatuzumab vedotin-piiq ± bendamustinel ± rituximab * Tafasitamab-cxixl + lenalidomide

Question 63

Preferred therapy for DLBCL Secondline therapy (relapsed disease <12 mo or primary refractory disease):

Answer 63

CAR T-cell therapy * Axicabtagene ciloleucel (CD19-directed) (category 1) * Lisocabtagene maraleucel (CD19-directed) (category 1)

Question 64

Can be defined as a clinical entity presenting with primary site of disease in the anterior mediastinum with or without other sites and has histology of DLBCL

Answer 64

Primary Mediastinal Large B-Cell Lymphoma

Question 65

First line therapy for Primary Mediastinal Large B-Cell Lymphoma

Answer 65

* Dose-adjusted EPOCH-rituximab * RCHOP-21 x 6 cycles * RCHOP-14 followed by ICE

Question 66

Therapy for R/R Primary Mediastinal Large B-Cell Lymphoma

Answer 66

* Pembrolizumab * Nivolumab ± brentuximab vedotin * Manage as relapsed/refractory DLBCL

Question 67

LBCL with **MYC** and **BCL2** or **BCL6** rearrangements as detected by FISH or standard cytogenetics are known as.

Answer 67

"double-hit" lymphomas ## Footnote If all three rearrangements present, they are referred to as **"triple-hit" lymphomas.** The vast majority are **germinal center B-cell (GCB)–like lymphomas**. Patients often present with poor prognostic variables, such as **elevated LDH, bone marrow and CNS involvement, and a high IPI score**.

Question 68

Typical immunophenotype of BL:

Answer 68

sIg+, CD10+, CD20+, TdT-, Ki-67+ (≥95%), BCL2-, BCL6+

Question 69

Most common karyotype is _______ rearrangement as a sole abnormality.

Answer 69

MYC rearrangement

Question 70

There is an uncommon variant of BL without MYC rearrangement but with 11q aberration

Answer 70

LBCL with 11q aberration [ICC] HGBL with 11q aberrations [WHO5] ## Footnote Optimum management of this rare subtype is undefined, though it is most often treated like typical BL.

Question 71

Low Risk BL

Answer 71

* Normal LDH * Stage I and Completely resected abdominal lesion * Single extraabdominal mass <10 cm

Question 72

High Risk BL

Answer 72

* Stage I and Abdominal mass * Single extraabdominal mass >10 cm * Stage II–IV

Question 73

# TRUE OF FALSE CHOP is an adequate therapy for BL.

Answer 73

FALSE CHOP is an adequate therapy for BL.

Question 74

Preferred regimens for BL

Answer 74

* **CODOX-M** (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal [IT] methotrexate and cytarabine followed by high-dose systemic methotrexate) + rituximab * **Dose-adjusted EPOCH** (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab * **HyperCVAD** (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes IT therapy) ## Footnote For High Risk: Started with the portion of the systemic therapy that contains CNS-penetrating drugs: * CODOX-M alternating **with IVAC** * HyperCVAD * **Dose-adjusted EPOCH intrathecal methotrexate**- for patients with high-risk BL and with baseline CNS disease not able to tolerate aggressive treatments **Prophylaxis for tumor lysis syndrome is mandatory**

Question 75

Preferred regimen for BL ≥60 y Low and High Risk

Answer 75

Dose-adjusted EPOCH

Question 76

# HIV-Related B-Cell Lymphomas In general, avoidance of the ff ARV __________________ is strongly recommended.

Answer 76

Zidovudine, cobicistat, and ritonavir ## Footnote Antiretroviral therapy (ART) can be administered safely with chemotherapy

Question 77

Preferred Regimens for **HIV-BL**

Answer 77

* Modified CODOX-M/IVAC/rituximab * Dose-adjusted EPOCH/rituximab ## Footnote * If CD4 < 50, maximize supportive care and monitor closely for cytopenias and infections while administering lymphoma therapy * Granulocyte colony-stimulating factor (G-CSF) for all patients

Question 78

Preferred regimens for HIV-**DLBCL**, **HHV8 POSITIVE DLBCL, NOS, PEL**

Answer 78

* EPOCH/rituximab ## Footnote * RCHOP

Question 79

Initial treatment for **HIV-DLBCL R/R**

Answer 79

* Bortezomib/ICE * Bortezomib/ICE/rituximab

Question 80

Preferred regimens for **HIV-Plasmablastic Lymphoma**

Answer 80

* EPOCH ## Footnote * Modified CODOX-M/IVAC * HyperCVAD

Question 81

RECOMMENDATIONS FOR EPOCH ± RITUXIMAB DOSE ADJUSTMENTS FOR NON-BURKITT LYMPHOMAS

Answer 81

Day 5 cyclophosphamide dosing * If baseline CD4 count is **> 200**cells/mm3, start cyclophosphamide at **750** mg/m2 * If baseline CD4 count is **50–200** cells/mm3, start cyclophosphamide at **375** mg/m2 * For baseline CD4 counts **< 50** cells/mm3, cycle 1 doses of cyclophosphamide above 187.5 mg/m2 have not been published ## Footnote * Rituximab (if CD20-positive) 375 mg/m2 IV on Day 1 * Etoposide 50 mg/m2/day continuous IV infusion for 4 days (96 hours) * Doxorubicin 10 mg/m2/day continuous IV infusion for 4 days (96 hours) * Vincristine 0.4 mg/m2/day continuous IV infusion for 4 days (96 hours) * Prednisone 60 mg/m2/day for 5 days

Question 82

Typical immunophenotype: B-LL:

Answer 82

sIg-, CD10+/-, CD19+, CD20-/+, TdT+, CD34+, CD79a+

Question 83

Typical immunophenotype T-LL:

Answer 83

sIg-, CD10-, CD19/20-, CD3-/+, CD4/8+/+, CD1a+/-, TdT+, CD2+, CD7+ cytoplasmic CD3+, sCD3-/+

Question 84

B Cell Neoplasm: Small cells

Answer 84

* Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) * Mantle cell lymphoma (MCL) * Splenic marginal zone lymphoma (SMZL) * Hairy cell leukemia (HCL) * Lymphoplasmacytic lymphoma (LPL) * Extranodal marginal zone lymphoma (EMZL) * Nodal marginal zone lymphoma (NMZL) * Follicular lymphoma (FL) * Pediatric-type follicular lymphoma (PTFL)

Question 85

B Cell Neoplasm: Medium cells

Answer 85

* Burkitt lymphoma (BL) * MCL, blastoid variant * High-grade B-cell lymphoma (HGBL), NOS * HGBL with MYC and BCL2 rearrangements (ICC and WHO-5 * HGBL with MYC and BCL6 rearrangements (ICC) * LBCL with 11q aberration [ICC]; HGBL with 11q aberrations [WHO]

Question 86

B Cell Neoplasm: Large cells:

Answer 86

* Diffuse large B-cell lymphoma (DLBCL), NOS * DLBCL associated with chronic inflammation * Lymphomatoid granulomatosis * Primary mediastinal large B-cell lymphoma (PMBL) * Intravascular LBCL * ALK-positive LBCL * Plasmablastic lymphoma * HHV8+ LBCL, NOS * LBCL with IRF4 rearrangement * Primary effusion lymphoma (PEL) * Mediastinal gray zone lymphoma (MGZL) * MCL, pleomorphic variant

Question 87

Viral condition that can arise from use of anti-CD20 mAb Therapy and Brentuximab Vedotin

Answer 87

Progressive multifocal leukoencephalopathy (PML):