6.7 NHL (ONLY T2K)

NHL is the _____ cancer with highest incidence in men and ______ in women. For both, is the ____ cancer with more deaths.

7th

6th

9th

Which infectious agents could cause NHL?

EBV, HTLV-1, HHV-8, HCV, H. pylori (MALT Lymphoma associated)

Germinal center B-cell: ______ mutation causes Burkitt's Lymphoma

C-myc oncogene (chromosome 8) translocations

Germinal center B-cell: ______ mutation causes DLBCL

BCL-6 expression

Germinal center B-cell: ______ mutation causes FL

t(14;18)(q32;q21)

Germinal center B-cell: ______ mutation causes MZL

BCL-10 overexpression

Germinal center B-cell: ______ mutation causes mantel cell lymphoma

t(11;14)(q24;q32)

Lymph nodes: cancer nodes that appear above the DIAPHRAGM are generally stages ______, and below are stages _____

1-2

3-4

Which system is used for NHL staging?

Ann Arbor Staging System

A single nodal region or single extranodal site

Stage IA or IB

Two or more nodal regions or an extranodal site on same side of diaphragm

Stage IIA or IIB

Lymph node involvement on both sides of the diaphragm

Stage IIIA or IIIB

Lymph node and extensive involvement of liver, lung, or bone marrow

Stage IVA or IVB

B symptoms

symptoms including:

- unexplained weight loss (10% in 6 months prior to diagnosis)

- unexplained fever and

- drenching night sweats

Stage "X" characteristic

bulky disease

Stage "E" characteristic

means contiguous extranodal involvement

For example, what does "Stage IIBX" mean?

involvement of two or more nodal regions on one side of the diaphragm with B symptoms and a bulky mass

Which are intrathecal drugs used for NHL?

Methotrexate and cytarabine, often given with hydrocortisone as "triple IT" for CNS prophylaxis or leptomeningeal disease

What is ESSENTIAL in the workup of a newly diagnosed NHL patient?

1. Hepatitis B testing

2. ECHO or MUGA

3. Pregnancy testing if childbearing age

4. Discussion of fertility issues and sperm banking

5. HIV testing

"Indolent/follicular lymphoma" is a ______ B‑cell non‑Hodgkin lymphoma that often develops gradually over months to years, so people typically present with a long history of ________

slow‑growing

painless, waxing‑and‑waning lymph node enlargement and few or no systemic symptoms.

"Indolent/follicular lymphoma" can ____, but in about 15-30% of patients it eventually "transforms" into ________

temporarily shrink without treatment ("spontaneous" remission)

an aggressive lymphoma (most often diffuse large B‑cell lymphoma)

NHLs are a heterogeneous group of lymphoproliferative disorders, derived from monoclonal proliferation of _________ and their precursors

malignant B or T lymphocytes or NK cells

Lymphomas can be classified by their _______ and ______

cell growth/size & by type (AIDS, CNS, Cutaneous, PTLD)

Type of Lymphomas with B-cell origins, _________ is characterized as INDOLENT, _______ as AGGRESSIVE, and ________ as HIGHLY AGGRESSIVE

Follicular < Diffuse large B-cell (DLBCL) < Burkitt's Lymphoma

For early/low grade lymphomas what is the treatment?

watch and wait

For advanced lymphomas what are the treatment options?

- Chemotherapy

- Targeted (oral-PI3K inhibitors, BTK inhibitors)

- Radiation

- Radioimmunotherapy

The International Prognostic Index (IPI) gives ______ a percent of 5-year overall survival rate based on patient characteristics, each characteristic counts as 1 PROGNOSTIC VARIABLE which are then added.

Aggressive lymphomas

Which are the patient characteristics that are considered PROGNOSTIC VARIABLES for IPI?

1. Age >60 yrs

2. Stage III, IV

3. Extranodal involvement ≥ 2 sites

4. Performance status ≥ 2

5. LDH > 1 x ULN (above the upper limit of normal)

IPI Low Risk indicates: ______ (# prognostic variables), _____ (Complete response rate), ______ (5-year overall survival)

0-1

87%

73%

IPI Low/Int Risk indicates: ______ (# prognostic variables), _____ (Complete response rate), ______ (5-year overall survival)

2

67%

51%

IPI High/Int Risk indicates: ______ (# prognostic variables), _____ (Complete response rate), ______ (5-year overall survival)

3

55%

43%

IPI High Risk indicates: ______ (# prognostic variables), _____ (Complete response rate), ______ (5-year overall survival)

>4

44%

26%

Example: a 70‑year‑old with stage IV DLBCL, ECOG 2, high LDH, and liver plus marrow involvement has_____ and is ________ by IPI

all five factors and is high‑risk

Which is the PREFERRED 1st Line Tx for Diffuse Large B-Cell Lymphoma?

R-CHOP x 4-6 cycles + locoregional RT

1 cycle = every 3 weeks (21 days)

R-CHOP stands for

Rituximab

Cyclophosphamide

Doxorubicin (Hydroxydaunorubicin)

Vincristine (Oncovin)

Prednisone

Which is ANOTHER 1st Line Tx for Diffuse Large B-Cell Lymphoma?

R-EPOCH

(E: etoposide)

For DLBCL 2nd line treatment are used if 1st line FAILS, and these include:

1. DHAP (dexamethasone, cisplatin, cytarabine) +/- rituximab

2. ICE (ifosfamide, carboplatin, etoposide) +/- rituximab

3. Others regimens

4. Autologous or allogeneic BMT

_____ receptor on B cells is the most commonly targeted for Lymphomas

CD19

When targeting B lymphomas, there are various receptors for drug targets:

a. Blinatumomab & CART:

b. Rituximab, ofatumumab, obintuzumab:

c. Inotuzumab ozogamicin:

d. Polatuzumab vedotin:

a. CD19

b. CD20

c. CD22

d. CD79b

Rituximab addition to CHOP showed an increase in probability of survival. It is an antibody that targets _________ B-cells and causes ________ , ________, and _________

CD20+

Antibody-dependent cell mediated Cytotoxicity (ADCC)

Complement-dependent cytotoxicity (CDC)

Apoptosis

Rituximab has BLACK BOX WARNINGS and we should be on the lookout for __________, specially on patients with very bulky tumors

Tumor lysis Syndrome

Rituximab BLACK BOX WARNINGS include (x4):

• Infusion related reactions (Premeds - antihistamine, diphenhydramine, APAP)

• Hepatitis B reactivation

• Severe mucutaneous reactions

• Progressive multifocal leukoencephalopathy (PML)

Which is the R-CHOP regimen?

Rituximab 375 mg/m2 Day 1

Cyclophosphamide 750 mg/m2 day 1

Doxorubicin 50 mg/m2 day 1

Vincristine 1.4 mg/m2 day 1

Prednisone 100 mg PO days 1-5

What are the TOXICITIES related to Cyclophosphamide?

- Severe nausea/vomiting

- Hemorrhagic cystitis (Blood in urine)

- Alopecia

- Nail/pigmentation changes

- Impairment of fertility

- Secondary malignancies

What are the TOXICITIES related to Doxorubicin?

- Cardiotoxicity

- Extravasation

- Myelosuppression

- Alopecia

- Nausea/vomiting

- Mucositis

- Hyperpigmentation

- Urine discoloration

What are the TOXICITIES related to Vincristine?

DO NOT GIVE INTRATHECALLY (Neuro probl) !!

- Constipation, paralytic ileus

- Neurotoxicity (Paresthesia, Neuropathic pain, Loss of reflexes)

- Myalgias

- Extravasation

What are the TOXICITIES related to Rituximab?

-Transient infusion reactions (fevers, chills, myalgias, dyspnea, hypotension)

- Rapid depletion of circulating B-cells lasting 3-6 months

- Normal immunoglobulin levels remain unchanged, no excess risk of infection

______ also has a SQ inj which can be administered over 5-7 minutes, can be given if the pt already received at least 1 full dose IV, but has to be premedicated before each dose (antihist + APAP)

Rituximab (Rituximab Hycela)

______ is an initial treatment phase used to rapidly achieve significant improvement or remission

Induction therapy

Which are Induction therapies mentioned for Burkitt's Lymphoma?

1. Hyper-CVAD

2. CODOX-M (cyclophosphamide, doxorubicin, vincristine with IT methotrexate (MTX) and cytarabine followed by high dose systemic MTX + rituximab

3. Dose adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab

_______ is an intensive chemotherapy regimen for aggressive B‑cell lymphomas (e.g., Burkitt's, mantle cell) and adult ALL; it stands for hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (doxorubicin), and Dexamethasone.

Hyper-CVAD

Hyper-CVAD Treatment alternates two courses

A = the CVAD drugs (with mesna and growth‑factor support)

B = high‑dose methotrexate with leucovorin rescue plus cytarabine

*for CD20‑positive disease rituximab is added (R‑Hyper‑CVAD), and intrathecal methotrexate/cytarabine is commonly given for CNS prophylaxis.

For Burkitt's Lymphoma the Course B Treatment is

- Methotrexate 1 g/m2 IV over 24 hours with leucovorin rescue Day 1

- Cytarabine 3 g/m2 IV over 2 hours Q12hr x 4 doses Days 2-3

- Filgrastim 10 mcg/kg SQ beginning 24 hrs p

Which are the TOXICITIES for Methotrexate?

Myelosuppression*, mucositis*, hepatotoxicity, nephrotoxicity, neurotoxicity*

Part of Pharm. D. job is TDM with ______ , which is monitored and "rescued" to prevent toxicity. MTX levels are checked after the infusion starts and to ensure toxicity DOES NOT occur, _________ is administered Q4-6 H

High‑dose methotrexate (HD‑MTX)

Leucovorin

Which are some Risk Factors for Delayed MTX Excretion?

1. Drug interactions [NSAIDs, PPIs, PCNs, prior renal toxicity agents (platinums)]

2. Third spaces [Drug slowly leaks out, causes prolonged increase in drug exposure]

3. POOR hydration/alkalinization -> sodium bicarbonate (100-150 mEq) IV fluids

4. Direct nephrotoxicity by MTX

______ refers to a treatment regimen administered after initial therapies have failed to control or cure a disease

Salvage therapy

Which are Salvage therapy options for Aggressive lymphomas?

1. Autologous transplant (Gold standard for patients relapsing after conventional chemotherapy, this is changing)

2. Allogeneic transplant

3. Salvage chemotherapy [DHAP; ESHAP; (R)- ICE (ifosfamide, carboplatin, etoposide)]

Anti‑CD19 CAR‑T therapy uses a patient's T cells engineered to attack CD19; the FDA‑approved products are_________ and ______

tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta)

_________ is for adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma

Kymriah

_______ is for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Yescarta

In summary, new therapies for Lymphomas are ________

salvage/refractory