Board Review - Classical hematology

Acute Myeloid Leukemia (AML)

5 year AML survival is ~30%

Risk factors: benzenes, pesticides, solvents, radiation, prior chemo (below) or RT, hereditary BMF (Fanconi DNA repair defect, Dyskeratosis Congenita telomere issue, Down, Li Fraumeni, Noonan, NF)

Alkylating agents —> chromosome 5 and 7 abnormalities; occurs 5-7 years after with MDs phase
Topoisomerase II inhibitors (anthracyclines, etoposide) in chromosome 11 lead to MLL/KMT2A rearrangement, occurs earlier in 3 years without MDS

DDX41 adult onset familial MDS/AML —> hypocellular marrow, most common inherited AML predisposition

Diagnosis of AML:

20% myeloid blasts (BM or PB) or AML defining genetic abnormality (below in pronostication)

-APL or APML: Blasts more mature and don’t have early lineage markers CD34 and HLA-DR are NEGATIVE

-Recommended to get initial genetic workup on diagnosis

Emergencies: Hyperleukocytosis/leukostatis, DIC, TLS, neutropenic fever

Prognostication in AML:

Consider age, PFS, cytogenetics, mutations. Now 2022 ELN risk stratification by genomics:

Favorable: T(8;21) RUNX1/RUNX1T1; inv(16) CBFB::MYH11; mutated NMP1 without FLT3-ITD; bZIP in frame mutated CEBPA
Intermediate: FLT3-ITD (regardless of allelic ratio) or t(9;11) MDS related
Adverse or bad: -5 or del(5q); -7; -17/abn(17p), complex or monosomal karyotype; mutated ASXL1, BCOR, EZH2, RUNX1, SFRB1, SRSF2, STAG2, U2AF1, ZRSR2, mutated TP53

*t(8;21) and inv(16) are the low risk core binding factor leukemias)

*MDS related mutations above are adverse

Treatment of AML

Treatment for FIT patients (young <65 yo, fit, not therapy related)

INITIAL THERAPY

Low risk AML

Likely core binding factor AML (inv 16 or t(8;21) or normal karyotype with MPN1 mutation

Standard induction: 7+3 —> 7 days of cytarabine (continuous) + 3 days of daunorubicin (100-200 mg/m2, 75 mg/m2 is INFERIOR – DON’T USE)) or idarubicin

Bone marrow after cycle 1 and then consolidate with HiDAC x3-4 cycles

High risk follows with alloSCT (intermediate also but with adequate donor)

*Add gemtuzumab ozogamicin if CD33 positive and favorable risk (anti CD33 which is 90%+) —> 3 mg/m2 (4.5 mg cap)

Intermediate risk AML (FLT3)

For both FLT-ITD or FLT-TKD = midostaurin (Ratify trial), improved OS 51.4 vs 40% against placebo

For FLT3-ITD only = Quizartinib (quiz only but “not good at fighting – no Tae Kwon Do or TKD”) Quantum first trial —> mOS 31.9 quizartinib vs 15.1 placebo. QTc prologngation with Quizartinib easy to remember hopefully

Consider alloSCT for most patients with intermediate risk AML

Secondary or Treatment-Related AML

CPX-351 (Vyxeos) = 5:1 molar ratio of 7+3 (liposomal form enhances uptake and accumulation in leukemia cells since they are “leaky”)

mOS 9.3 vs 5.9 months versus placebo, good numbers in CR

AFTER INITIAL THERAPY OR POST REMISSION

First, think transplant or not

alloSCT for adverse/unfavorable risk AML ASAP after probably 1-2 cycles of HiDAC
No transplant: low to intermediate risk, no transplant in first remission (CR1) but consider maintenance azacitidine (Quazar AML 001 trial; OS doubled 24 vs 14 mo)
Post transplant FLT3-ITD —> consider gilberitinib (Morpho trial) in MRD+ (benefit from 2 years of gilteritinib) but not in MRD-)

MRD use: Assess in patients achieving CR:

Flow cytometry up to 1 in 10,000 (0.01%) need expertise from lab
qPCR (1 in 100,000 or 0.001%) but need something to quantify such as CBFs or NMP1 (standard of care monitoring) —> if persistent MRD positive low risk could consider taking to alloSCT
NGS not ready yet

Treatment for UNFIT patients

Unfit = older, comorbidities, cardiac disease no anthracycline, especially those with complex cytogenetics or MDS related, TP53 mutations

Aza + venetoclax —> VIALE-A trial showed CR/CRi rate 66.4 vs 28.3%, mOS 15 vs 10 months —> careful with neutropenia and its complications, TLS not common
Decitabine + venetoclax
Low dose cytarabine (2o mg/m2)+ venetoclax —> mOS 8.4 vs 4.1 with placebo
Azacitidine + ivosidenib (in IDH1 mutation) —> Agile study aza 75 + ivosidenib —> 12 month EFS 37 vs 12% and mOS 29.3 vs 7.9 months
Ivosidenib alone

*Venetoclax interactions: CYP3A inhibitors interact with venetoclax:

High interaction: posaconazole, voriconazole
Intermediate interaction: ciprofloxacin and isovuconazole (Cresemba)

IDH mutaitons 1/2

IDH-1: 6-10% of patients, increases with age

Treatment for Relapsed/Refractory AML

Repeat genomic analysis at relapse ALWAYS since mutations and biology changes

Salvage chemotherapy: FLAG-IDA, MEC, CLAG, HiDAC

If patient did ok with chemotherapy in first time, repeat it and take to transplant

*FLT3 = Gilteritinib (ADMIRAL study) for both (ITD and TKD FLT3) only approved at R/R —> 12 mo OS 37 vs 17% and quizartinib for ITD only (No TKD quiz) —> watch lytes and QTc prolognation. Midostaurin not in relapsed setting.

*IDH inhibitors appproved in R/R —> Ivosidenib (also Tqc prolongation) and enasidenib (can cause increased bili) both CR 20% and mOS 9 months vs 5 mo. Olutasidenib also approved here only not 1L. IDH inhibitors take a very long time to response sometimes after 6 or more cycles. IDH inhibitors can cause differentiation syndorme, treat ASAP with dex 10 mg BID

Enasidenib —> IDH2
Ivosidenib —> IDH1 (remember I for 1)

*Oral menin inhibitors (Revumenib) in KMY2A (MLL1) mutated AML —> Approved in 2024, has risk of differentiation syndrome (Black box warning), CR/CRh ~21%, median duration ~6 months

Acute Promyelocytic Leukemia (APL)

CD33+ (say treat treat treat! Since it is so treatable, it sounds like 333), CD34-, and HLA-DR- makes i different than other AMLs

Auer rods and DIC risk

Has t(15:17) – PML/RARA fusion

Start ATRA, ATRA/ATO cure rate 95%

DIC + atypical promyelocytes with or without Auer rods + HLA-DR- —> ATRA**

Low intermediate risk ATRA + ATO, prednisone prophylaxis for differentiation syndrome, hydroxyurea if WBC above 10

High risk: ATRA + ATO + gemtuzumab ozogamicin if available or idarubicin —> Follow C9710

*Arsenic therapy can cause electrolyte issues and affect QTc

Early relapse (<6 months): Anthracycline based regimen for first relapse followed by ATO. Autologous HSCT considered after second relapse if PCR negative, clinical trial or AlloHSCT for PCR positive

CNS prophylaxis needed if complete response after second relapse

AML in pregnancy

Do not delay treatment

Ok 7 + 3 in 2/3 trimester

Induction of labor consideration

Dose chemo by actual body weight instead of ideal

CNS prophylaxis:

1-2 LBs with cytarabine in CR for FLT3, WBC >50, M4/M5 monocytic morphology

Myeloid sarcoma/extramedullary AML +- XRT (local therapy not effective for AML since it is a systemic disease)

Remission defininitions:

CR (morphologic): Blasts <5% + counts recovered + no extramedullary disease.
CRi: Same but no full count recovery.
MRD-negative CR: Morphologic CR + negative molecular/flow MRD.
Hypoplastic marrow at day 14–21: Wait for count recovery, then re-check marrow.

Differentiation Syndrome Causes:

Differentiation syndrome is a lot of inflamation = “An Abundant Inflamation” to remember the three most common causes: ATRA, ATO, IDH inhibitors

Chronic Myeloid Leukemia

Dx & Staging

Philadelphia chromosome t(9;22) → BCR-ABL1 TK fusion (quant PCR on IS for monitoring).

Phases:

Chronic (CP)
Accelerated (AP): blasts 10–19% (lab-dependent), basophils ≥20%, platelets <100k (not from therapy), new clonal cytogenetics.
Blast (BP): ≥20% blasts or extramedullary blasts

Baseline workup

CBC, CMP, bone marrow cytogenetics, BCR-ABL1 (IS), hepatitis B screen, EKG if QT risk, risk score (ELTS preferred; Sokal acceptable)

Treatment of Chronic Myeloid Leukemia

First line therapy for Chronic Phase (CP) CML

2nd-gen TKIs preferred:

Dasatinib 100 mg qd
Nilotinib 300 mg bid
Bosutinib 400–500 mg qd.
Imatinib 400 mg qd still reasonable low-risk.
Asciminib now an option front line in some guidelines; standard in later lines.

Response milestones (IS %)

3 mo: ≤10%
6 mo: <1%
12 mo: ≤0.1% (MMR)
Failure: miss milestones, 1-log rise with loss of MMR, loss of CHR/CCyR, or progression.

Monitoring

PCR q3 months until stable ≤0.1%, then q3–6 months.
Mutational analysis if failure/progression → guides TKI choice.

Key mutation

T315I: use Ponatinib (most potent; arterial risk) or Asciminib (STAMP; approved including T315I at higher dose).

When to stop (TFR)

On TKI ≥3 years, stable MR4–MR4.5 ≥2 years, reliable PCR access
After stop: PCR monthly ×6, q6–8 weeks to 12 mo, then q3 mo. Restart if loss of MMR.

Treatment of accelerated phase/blast phase (AP/BP) CML

Start 2nd/3rd-gen TKI (match to mutation) → evaluate for allo-HCT.
BP: TKI + ALL/AML-type chemo → HCT if eligible

TKI pearls & AEs

Imatinib: edema, cramps, GI upset, cytopenias.
Dasatinib: pleural effusions, pulm HTN; avoid with anticoagulation if possible.
Nilotinib: QT prolongation, hyperglycemia, hyperlipidemia; take fasting.
Bosutinib: diarrhea, LFT ↑.
Ponatinib: arterial/venous thrombosis, HTN; control CV risk, dose-reduce
Asciminib: lipase ↑, myalgia; fewer off-targets (STAMP = ABL myristoyl pocket).

Drug interactions

All TKIs: CYP3A4 substrates; avoid strong inhibitors/inducers; PPI/H2 issues (nilotinib needs fasting; dasatinib needs acid).

Special

Peri-op bleeding: hold ibrutinib? (for CLL). For CML TKIs: not platelet BTK—no mandatory holds, but many hold dasatinib if effusions risk
Pregnancy: avoid TKIs esp 1st trimester; consider interferon-α; no breastfeeding on TKIs
Vaccines: inactivated OK; avoid live

Quick management cues

CV disease → avoid ponatinib unless T315I/multi-resistant

Small PCR rise but still MMR → repeat in 1–3 mo

Pleural effusion on dasatinib → hold, diuretic/steroid, switch TKI if recurrent

QT risk or metabolic syndrome → prefer dasatinib/bosutinib over nilotinib

Atypical Chronic Myeloid Leukemia (aCML)

Rare type of MPN/MDS, negative BCR/ABL, poor prognosis (OS 12/21.8 months average) and high AML transformation rates (37-40%)
Differentials to consider here when BCR/ABL-:
- CMML
- Chronic neutrophilic leukemia (CNL)
- MDS/MPN overlap syndrome
aCML –> no basophilia (or minimal <2%) or monocytosis (usually <10%) in contrast with CML
Left shift seen in differential with abnormalities in segmentation of neutrophils or “hypogranular PMNs,” pseudo Pelger Huet anomaly (hypolobulated nuclei of granulocytes), and dysplasia with dyserythropoiesis and dysplastic megakaryocytes
Higher risk for AML transformation: females, WBC >40, increased immature precursors in peripheral blood, older age
Need karyotype and NGS to differentiate with others as above and find possible target therapies (none of them are pathognomonic):
- Higher frequency mutations (>20% of cases): SETBP1 (poor prognosis usually higher WBCs), ASXL1, N/KRAS, SRSF2, TET2
- Lower frequency (<10%): CBL, CSF3R (more common to indicate CNL if mostly neutrophilic), JAK2, ETNK1

WHO Diagnostic Criteria for Atypical CML (aCML):

Diagnostic Criteria:

-Peripheral blood leukocytosis (WBC ≥13 × 10^9/L) due to increased neutrophils & their precursors with dysgranulopoiesis

-Neutrophil precursors (promyelocytes, myelocytes, metamyelocytes) ≥10% of leukocytes

-No Ph chromosome or BCR-ABL1 fusion; does not meet criteria for PV, ET, or PMF

-No evidence of PDGFRA, PDGFRB, FGFR1 rearrangement, or PCM1-JAK2

-Minimal basophilia (<2% of leukocytes)

-No or minimal monocytosis (<10% of leukocytes)

-Hypercellular marrow with granulocytic proliferation & dysplasia ± erythroid/megakaryocytic dysplasia

-<20% blasts in blood and bone marrow (not meeting criteria for acute leukemia)

Diagnostic Evaluation of aCML:

Treatment of Atypical CML:

No standard of care –> bad prognosis and should consider ASCT first
HSCT:
- Mostly case reports and series, from 21 patients transplanted –> 17 alive at 5 years with mOS 47 months
- All got chronic GVHD and 63% had G2 or more acute GVHD.
- Consider alloSCT if SETBP1 or ASLX1 mutation present
If needing cytoreductive therapy or bridging –> consider HMAs or clinical trials
Targetable options:
- CSF3R (T618I) or JAK2 (V617F) mutations -> ruxolitinib
- RAS-mutated –> Trametinib (MEK inhibitor)
- Research ongoing: SETBP1 mutated –> fingolimod, SRSF2 –> spliceosome modulators,
Second line options to consider: PEG INF-alpha, hydroxyurea, ESAs

Acute Lymphoblastic Leukemia (ALL)

Heterogeneous disease, rare

Classified into precursor-B-ALL (CD19, CD20, CD79a, CD22; some with CD10, PAX5, TdT) or T-ALL (CD3, CD6, CD1A, CD4.

Precursor T cell has CD7 but negative CD8 and CD1A

ABL fusion = better response in general

If myeloid markers in ALL: no mixed lineage, same prognosis and does not change therapy in ALL (i.e. CD13+ and CD33+)

MLL (mixed lineage lymphoid leukemias): bad prognosis, KMT2A mutated, translocation t(4;11).

High yield topics:

Diagnosis of Burkitt ALL: morphology, translocations, treatment
Ph+ ALL: p190, Rx (TKI + chemoRx + allo SCT)
KTMT2A rearranged ALL: worse prognosis, needs allo in CR1
Precursor T-ALL: adverse, alloSCT in CR1
Ph-like ALL with ABL1 fusion: Rx Ph+ ALL

Poor risk cytogenetics/molecular groups in ALL:

Hypodiploidy (<44 chromosomes)

TP53 mutation

KMT2A rearranged (t[4;11])

IgH rearranged

HLF rearranged

ZNF384 rearranged

MEF2D rearranged

MYC rearranged

PAX5alt

t(9;22) with IKZF1 plus and/or antecedent CML

Complex karyotype (5 or more chromosomal abnormalities)

BCR-ABL1-like (JAK-STAT, ABL class, other etc)

Intrachromosomal amplification of chromosome 21

Alterations of IKZF1

If any of these present, most patients need consolidation alloSCT*

B-cell ALL (Ph-):

Diagnosis: B cell lymphoblasts –> CD19+, PAX5+, CD79a+, and cytoplasmic CD22+ (T cell markers could be present such as CD13+, CD33+. However, MPO MUST be negative. Otherwise, it is not B-ALL)

First Line Treatment of Adult ALL:

Therapy determined by ALL risk

Phases: Induction, maintenance and consolidation + CNS prophylaxis

Induction:
- VCR (vincristine), steroids, anthracyclines (=/-CTX, asparaginase)
  1. Maintenance:
    - Daily 6-MP, weekly MTX, VCR, steroids (POMP x 2-3 years)
      1. Consolidation:
        
        CTX, ara-C, asparaginase, VP-16, autoSCT or alloSCT

Check MRD after induction: If MRD- consider chemo + TKI, if MRD+ give inotuzumab +/- blinatumomab followed by alloSCT

Relapsed/Recurrent Disease:

Clinical trial, multiagent chemo + TKI, TKI +/- steroids, blinatumomab + TKI, inotuzumab + TKI, CAR-T therapy –> always consolidate with an alloSCT here

Third line and above:

Consider what has not been used, CAR-T here (tisagenlecleucel for AYA with >=2 lines of therapy and failure of TKIs

High risk features in ALL:

35 yo
Poor cytogenetics (TP53 mutation, etc),
Elevated WBC (>30 for B cells and >100 for T cells)

Ph-like ALL (negative Ph but CRLF2 in 80%, can have ABL1/2, PDGFR, JAK):

Genomically similar to Ph+ ALL, 25% of all adult ALL (>hispanics)

Prognosis poor historically but now better with TKI and CD19/20 therapy

2 main entities:
1. CRLF2 overexpression =/- JAK2 mutations (80%) –> responds better to chemo + blinatumumab or inotuzumab
2. ABL-translocations (true Ph-like, 20%) –> TKI added to treatment (similar to Ph+ ALL)

SoC still alloSCT in CR1

Philadelphia Positive (Ph+) ALL

About 20-30% of patients (both p190 and p210 transcripts)

Treatment of Ph+ ALL:

SoC fit:

Dose adjusted Hyper-CVAD + ponatinib or dasatinib + 12-15 IT chemotherapy cycles, and alloSCT in CR1
Alternative is Ph+ALL-p190: ponatinib + blinatumumab + IT x15

SoC unfit:

Dasatinib + blinatumomab
Add ponatinib, blinatumumab
Novel BCR::ABL1 TKIs (asciminib, olverembatinib)

Treatment of pre-B ALL:

Add anti CD19 antibodies (blinatumomab), CD20 (rituximab, CD20 biTES, CD22 (inotuzumab)

T-cell Acute Lymphoblastic Leukemia (T-ALL):

20% of all ALL
Marked leukocytosis, CNS and mediastinal involvement (arising from thymus)
TdT+, CD1a+, CD2+, CD3+, CD4+, CD5+, CD7+, CD8+
Subdivided into stages of intrathymic differentiation into pro-T, pre-T, cortical T, and medullary T cell

Treatment of T-ALL:

First line:

Induction: Multiagent chemo: HyperCVAD or CALGB +/- pegaspargase
Consolidation: HD-MTX + cytarabine +/- CTX
Maintenance: 6MCP + MTX +/- vincristine and prednisone pulses for 2 years

Check MRD: if positive or high risk, alloSCT in CR1 (can use nelarabine pre and post SCT)

Second line:

Nelarabine, CART, alloSCT if not done
Venetoclax
Bortezomib

Treatment of mature B-cell (Burkitt) ALL:

L3 morphology
Tdt is negative, Sig+, K or L restricted
CNS involvement in 50%, chin numbness 50%
t(8;2), t(8;14), t(8;22),
MYCC
If MYC + BCL2 and BCL6 = triple hit Burkitt ALL treated with R-DA-EPOCH
Dose intensive chemo without maintenance:

Fractionated high dose CTX, MTX, HD ara-C + rituximab

NO maintenance in Burkitt’s ALL
Consider consolidation with CAR-T in all cases
MRD tracking with clonoSEQ
Asparaginase side effects: allergies, hypofibrinogenemia, pancreatitis, increased LFT, thrombosis
All patients with ALL need CNS prophylaxis
Consider fertility preservation

Image

Inotuzumab has VOD risk

Hairy Cell Leukemia (HCL)

Type: Indolent B-cell leukemia
Key Mutation: BRAF V600E (≈100%)
Epidemiology: Middle-aged men (~5:1 M:F)
Clinical: Pancytopenia, splenomegaly, infections (esp. atypical mycobacteria), “dry tap” marrow
Peripheral smear: Cells with hair-like cytoplasmic projections
Immunophenotype: CD19+, CD20+, CD22+, CD11c+, CD25+, CD103+, Annexin A1+
Bone marrow: Fibrosis, TRAP-positive (tartrate-resistant acid phosphatase)
Treatment:
- 1st line: Purine analogs (Cladribine or Pentostatin) → long remissions
- Relapse or refractory: BRAF inhibitors (Vemurafenib ± Rituximab)
Prognosis: Excellent; median survival >20 years

Myelodysplastic Syndrome (MDS)

Ineffective hematopoiesis —> increases cellularity in marrow that cannot further advance
Diagnosis: 1 cytopenia + morphology (>10% dysplasia, increased blast, increased sideroblasts, MDS karyotype)
Karyotype includes mono 7, 5, 13,-7q, 17p del, 11q, -12p
Cytogenetics: SF3B1, bialelic TP53

Mutations in MDS:

High risk (adverse): TP53, RUNX1, EZH2, ASXL1, ETV6, NRAS/KRAS, NF1
- Associated with complex karyotype, therapy-related MDS, ↑AML transformation
Intermediate: U2AF1, SF3B1 (if no ring sideroblasts), BCOR, BCORL1, STAG2, ZRSR2
- Context-dependent; SF3B1 only favorable if RS present
Favorable: SF3B1 (with ring sideroblasts), TET2, DNMT3A, IDH1/2
- Often lower-risk disease and better response to HMA

Classifications: WHO 2022 and ICC (ICC includes MDs/AML category for blasts above 10%)

MDS with -5q = 5q syndrome

Hypoplastic erythroid lineage
Mild leukopenia and thrombocytopenia
Treat with lenalidomide

MDS/MPN:

CMML
MDS/MPN with neutrophilia
MDS/MPN with SF3B1 with thrombocytosis
MDS/MPN NOS

Suspect when dysplasia and at least one count increase instead of pure cytopenias

Prognosis: IPSS, IPPS-R, IPSS-M help estimate OS and AML risk of recurrence

Mutations:

CHIP —> mutations only “DAT” DNMT3A, ASLX1, TET2
ICUS —> Cytopenias only
CCUS —> Cytopenias + mutations but doesn’t meet MDS criteria

Predisposition to MDS —> remember 11q in topoisomerase therapy induced MDS (1-3 year latency); -5/-7 seen in alkylating agents (5-year latency)

Treatment of MDS:

Divide between low or intermediate vs high risk

Low risk: ESA, G-CSF, eltrombopag, luspatercept, imetelstat, 5-aza, decitabine
High risk: Hypomethylating agents
IDH 1/2 mutations = ivosidenib, enasidebib
HS-SCT with RIC

Diffuse Large B Cell Lymphoma (DLBCL)

First Line Treatment:

Fit patients or <80 years old:
- Pola-RCHP: Polatuzumab vedotin: Anti CD79b —> POLARIX trial (R CHOP vs pola RCHP) then 2 additional rituximab dosis —> improvement 6.5% PFS without significant side effects except for some neuropathy and neutropenia but no infection deaths —> ABC pola RCHP does well but GCB no difference
- R-CHOP
- DA-EPOCH
Cardiac dysfunction: RCDOP, RCEOP, DA-EPOCH, RGCVP, RCEPP
Frail patients or >80 yo: RCDOP, R-mini-CHOP, RGCVP, RCEPP

Relapsed Refractory (repeat biopsy considered):

Overall flow: Think of relapse timing: <12 months is worse than >12 months. Therefore, think CAR-T for <12 months and ASCT for >12 months. If doing CART or ASCT, need bridging chemo (more conventional stuff). However, if no CART or transplant planned, try newer treatments with bispecifics and so on.

Relapsed disease <12 months or primary refractory disease (highest risk):

CART eligible: Axi cell (ZUMA), tisacell (ELIANA/JULIET), lisocell (TRANSFORM)

Bridge with DHA + platinum +/- rituximab
GDP +/- rituximab
GemOx +/- rituximab
ICE +/- rituximab
Polatuzumab +/- rituximab +/- bendamustine
ISRT (monotherapy or sequencial with systemic therapy)

NOT CAR-T eligible:

Epcoritamab-bysp + GemOx
Glofitamab + GemOx
Polatuzumab +/- rituximab +/- bendamustine
Polatuzumab + mosunetuzumab
Tafasitamab + lenalidomide
Chemotherapy:
- CEOP
- DHA
- ESHAP
- GDP
- GemOx
- ICE
- MINE +/- R
- Brentuximab vedotin if CD30+
- Ibrutinib (nonGCB DLBCL)
- Lenalidomide +/- rituximab

Relapse >12 months (better than <12 months):

Transplant eligible (bridge with):

DHA + platinum +/- rituximab
GDP +/- rituximab
ICE +/- rituximab
Gem/Ox +/- rituximab

Transplant ineligible:

CAR-T (lisocell)
Epcoritamab-bysp + GemOx
Glofitamab + GemOx
Polatuzumab +/- rituximab +/- bendamustine
Polatuzumab + mosunetuzumab
Tafasitamab + lenalidomide

Third line and Subsequent:

T cell engager: CART or bispecifics
Brentuximab vedotin + lenalidomide + rituximab (CD30+ disease)
Loncastuximab tesirine
Selinexor
Polatuzumab vedotin antibody drug conjugate —> anti CD79b —> Monomethyl auristatin E (MMAE), a potent microtubule inhibitor

Tafasitamab + lenalidomide:

CR 43% of patients, ORR 48%
AEs: Neutropenia and other cytopenias

Selinexor

Oral selective inhibitor of nuclear export (SINE) that blocks XPO1 (a nuclear export protein) that shuttles tumor supressor proteins out of the nucleus (traps tumor supressor proteins inside the nucleus helping with their anti cancer functions
AEs: Cytopenias, GI side effects, constitutional

Bispecific antibodies (Mosunecutumab, glofitamab, epcoritamab, odronextamab)

Approved as monotherapies in third line setting

Glofitamab

CR 39%, ORR 52%
AEs: CRS, neutropenia and other cytopenias, sepsis, tumor flare, infection, iCANS (in 8% at any grade)

Epcoritamab

CR 68%, ORR 46%

Hodgkin Lymphoma (HL)

“Most complicated here is understanding the multiple treatment options for local disease”

IPS for advanced stage:

Male, albumin <4, Hb <10, age >45, stage IV, WBC >15, ALC <600 or 80% (each gives one point)

Deauville score (D): 1 no uptake to 5 markedly increased uptake à 4-5 is not good (PET/CT scan is negative if <3)

Treatment of Early-Stage Hodgkin Lymphoma

Risk adapted therapy

Image

Separate early-stage disease into 3 groups:

Favorable: ABVD x2 + 20 Gy radiation

Unfavorable: ABVD x4 + 30 Gy (20 Gy was inferior), alternative eBEACOPP x2 then AVBD x2 then 30 Gy (no OS benefit and not used in US)

Bulky: Similar than unfavorable

PET adapted therapy is also beneficial here:

RAPID study: ABVD x3 then PET:

D1-2 = No therapy or 30 Gy (97 vs 90% PFS)

D3-5 = ABVD x1 then RT

EORTC/LYSA/FIL Study: AVBD x2 then PET

AVBD x3 + RT vs AVBD better PFS but not OS

CALGB: AVBD x2 then PET

PET negative (D1-3): ABVD x2

PET positive (D4-5): escBEACOPP x2 then RT

ALLIANCE 50801 (bulky disease >=10 cm): ABVD x2 then PET

PET negative (D1-3): AVD x4

PET positive (D4-5): BEACOPP x3 then IFRT

Image

Treatment of Advanced Hodgkin Lymphoma

First line for stage III and IV: 

Nivo-AVD (Nivolumab + AVD) à replaces bleomycin in AVBD à reassess PET response after 6 cycles (better for >60 yo than BV-AVD)

BV-AVD (Brentuximab Vedotin + AVD) + G-CSF (ECHELON-1 study)à replaces bleomycin in AVBD à reassess PET response after 6 cycles

ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) – (RATHL trial); assess response after 2 cycles:

PET negative = continue 4 more cycles of AVD (drop bleomycin)

PET positive (Deauville 4 or 5) = BrECADD or eBEACOPP + GCSF x 3 cycles and repeat PET

PET negative = BrECADD  + G-CSF x1 +/- ISRT

PET positive (D4 or D5) = Repeat biopsy for primary refractory disease

BrECADD (Brentuximab, etoposide, cyclophosphamide, Adriamycin, dacarbazine, and dexamethasone) is superior and better tolerated than eBEACOPP à PET after 2 cycles but will decide 2 vs 4 additional chemo depending on results before a second restage to decide future plans.

eBEACOPP

PET adaptive strategies are not as used anymore with the newer treatments in advanced disease

Main adverse events to consider:

Bleomycin: pulmonary toxicity

Brentuximab vedotin: neutropenia and neuropathy

Nivolumab: ICI iRAEs 

Vinblastine: neutropathy

*Remember, nivo pembro and so on are only being used in advanced disease

Treatment of Relapsed/Refractory Disease

Second line therapy* (below) then evaluate PET:

PET negative (D1-3) = consolidate with HDT/ASCT à consider brentuximab maintenance for high risk patients (AETHERA study) if brentuximab naïve (can use in those who have received it as well)

PET positive (D4-5) = Additional salvage therapy or RT 

*Second line includes ICE à GVD, BVàaugICE, BVàICE, BV plus ICE, BV nivolumab, pembro + ICE or GVD and other options

Relapse after transplant: Repeat other second line options, clinical trial, alloSCT

Since HL is CD15, CD30 positive but usually not CD19 or CD20, CAR-T is not considered here!

Marginal Zone Lymphoma (MZL)

Marginal Zone Lymphomas

3 main types: Extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL)
EMZL: Associated to autoimmune and infectious causes
SMZL: related to HCV infection and may have MYD88+ (15% of cases)

Extranodal Marginal Zone Lymphomas (MALT)

Positive B cell markers: CD19,. CD20, CD79B, PAX5, Bcl-2
CD10-, cyclin D-
T(11;18), t(14:18) t(1;14), t(3;14)
Associated with autoimmune (Sjogren, Hashimoto), infection (H pillory gastric MALToma, Chlamydia psittaci, Borrelia, campylobacter)
Gastric MALT: H pillory+ treated with antibiotics and PPI can resolve, test 6 weeks after for eradication then EGD 3-6 months, if residual can repeat EGD and biopsy. If H Pylori negative consider RT or chemoimmunotherapy

Splenic Marginal Zone Lymphoma (SMZL)

Negative CD5, CD10, BCL6, positive sIgM
Involves spleen and marrow
20% have autoimmune cytopenias (ITP, AIHA, CAD) or angioedema
Ki67 is low
Check hepatitis C and can treat with antivirals with better OS
Treatment: Observe or if high tumor burden can consider rituximab (6x weekly) and splenectomy

Nodal Marginal Zone Lymphoma (NMZL)

Can have gain chromosome 3, FOXP1, NFKBIZ, BCL6) and 18p23
Plasma cell differentiation can occur (MYD88 positive and can associate with LPL/WM)
Also associated with hepatitis C
Treatment: Zanubrutinib (MAGNOLIA trial ORR 95% in all subtypes) for R/R disease

Multiple Myeloma

Multiple Myeloma

SPEP+ in 82% of patients, add IFE 93%+, and add light chains or UPEP/UIFE = 97-98% of patients (will only miss around 3% of patients with non-secretory myeloma when combining these tests)
Diagnosis: SLIM CRAB criteria

Cytogenetic Classification of Myeloma (primary cytogenetic abnormalities)

Standard risk:

Trisomies
t(11;14) CCND1
t(6;14) CCND3

High risk:

t(14;16) C-MAF
t(14;20) MAF-B
t(4;14) FGFR3/MMSET
del17p
1q gain

*All the ones with a 4 and multiple of 4s are high risk = 14:16, 14:20, 4:14. In contrast, 11:14, 6:14 (do not have a multiple of 4). The “4”s are for (four) the devil!

Risk stratification scales such as RISS are used mostly to counsel patients

First Line Therapy for Multiple Myeloma 

Treatment is divided into 3 phases: induction, consolidation, and maintenance

Induction Therapy (think of transplant candidacy and fitness and frailty):

Transplant candidate (offer quadruplet therapy):

Dara-VRd x4 cycles (Perseus trial in Europe) à PFS better at 4 years than VRd 48 months
Isa-VRd x4 cycles (IMROZ trial) à PFS 60 months

Not transplant candidate or frail patients (think triplets):

VRd (S0777 trial)
DRd (MAIA trial)
Can offer quadruplet to fit even if not pursuing transplant
1. Consolidation therapy:
Autologous SCT: Early use improves PFS but not OS
Deferred ASCT: collect but use at relapse
If not transplant candidate, complete 1 year of consolidation treatments
1. Maintenance:
Lenalidomide alone for standard risk 
If high risk disease: use doublet lenalidomide + bortezomib

Treatment of Relapsed Myeloma:

Triplet better than double in relapsed myeloma
Always consider transplant for eligible patients

Third line options:

Immunotherapy options such as CAR-T are considered here IsoCell, Ciltacell 
Bispecific antibodies: teclistamab BCMA, talquetamab GPRC5D

All medication options in myeloma:

Meds in blue above not approved yet

Supportive Care:

Bone resorptive agents: zolendronic acid, denosumab (better with renal failure)
AC on IMIDS
Cardiac monitoring on carfilzomib
Antibiotics and others on CART/bispecifics

Smoldering Multiple Myeloma

High risk myeloma important to recognize: 2-20-20 system (50% of patients progress to myeloma in 2 years)
- M spike >2
- BMPC >20%
- FLC ratio >20
Clinical trial or lenalidomide +/- dexamethasone use in high-risk patients can delay progression to MM

Cutaneous T-cell Lymphomas (CTCL)

Definitions:

Cutaneous T-cell Lymphomas (CTCL) = non Hodgkin lymphomas affecting the skin. Two main types:

Mycosis fungoides (MF): Indolent CTCL starting in skin (patch/plaques → tumors)
Sézary syndrome (SS): Leukemic variant of CTCL with diffuse erythroderma + circulating malignant T cells (>=1,000 mcL or clonal TCR by Sezary flow)

Classic Path/Immunohistochemistry:

Skin biopsy (MF): Epidermotropism of atypical CD3+ CD4+ T cells, loss of CD7 and/or CD26, Pautrier microabscesses
Blood (SS): CD4+ cells with CD7− and/or CD26−; TCR clonality matches skin

Sézary—Diagnostic Triad

Erythroderma (≥80% BSA)
Generalized lymphadenopathy
Circulating Sézary cells (see B2 below)

TNMB Staging (key cut points)

T1: Patches/plaques <10% BSA
T2: Patches/plaques ≥10% BSA
T3: Tumor(s) ≥1 cm
T4: Erythroderma ≥80% BSA
N0–N3: From none → involved nodes with/without clonal cells
M0/M1: No/Yes visceral disease
B (blood):
- B0: No significant blood involvement
- B1: Low-level abnormal cells
- B2 (SS): High tumor burden (e.g., ≥1000/µL CD4+CD7− or CD4+CD26−, or marked aberrant clone)

Work-up:

Multiple skin biopsies (include plaques/tumors).
Flow cytometry of blood, TCR clonality (skin ± blood).
CBC, CMP, LDH; imaging if ≥T3/N+ or symptoms.

Treatment (stage-driven)

Early MF (IA–IIA; T1–T2, N0–N1, B0): skin-directed

High-potency topical steroids, NB-UVB/PUVA, topical mechlorethamine, topical bexarotene, local RT.
Refractory: add systemic (low-dose MTX, bexarotene, interferon-α).

Advanced MF (IIB–IV) / Tumors / Erythroderma / N+ / B1–B2 (SS): combo skin-directed + systemic

Preferred in SS / erythrodermic disease:
- Mogamulizumab (anti-CCR4)
- Extracorporeal photopheresis (ECP) ± interferon-α or bexarotene
- HDAC inhibitors: Romidepsin (± Vorinostat)
If CD30+ lesions: Brentuximab vedotin
Other options: Pembrolizumab, Pralatrexate, Gemcitabine, Liposomal doxorubicin.
TSEBT for diffuse skin burden.
Allo-HCT in fit patients with advanced/refractory disease.

Prognosis—Bad Actors

Higher stage (T3/T4, N2–3, B2)
Large cell transformation
Folliculotropic MF
Elevated LDH, age, extensive tumors

Fast Pearls

SS = B2 blood involvement (think ≥1000/µL aberrant CD4+ cells + clone).
MF early = skin only → skin therapy. SS/erythroderma = systemic + skin therapy.
Mogamulizumab shines in Sezary (blood/skin responses).
Brentuximab if CD30+ MF.
ECP is a go-to in erythrodermic/SS, especially with pruritus/erythroderma.

NCCN guideline options:

Combination therapy options per NCCN include Skin-directed + Systemic therapy:

Skin directed therapies that are commonly used [For limited/localized skin involvement]:

Local radiation [ISRT]
Phototherapy [UVB]
Topical corticosteroids
Topical Imiquimod
Topical Nitrogen mustard
Topical retinoids

Skin directed therapies that are commonly used [For Generalized skin involvement]:

Phototherapy: UVB or NB-UVB, PUVA, UVA1
Topical corticosteroids
Topical Mechlorethamine
TSEBT (12-36 Gy)

For patients with Sezary syndrome with high disease burden (>5000 Sezary cells/mm3), the following are the preferred treatment options that are offered:

Mogamulizumab + Skin-directed therapy
Romidepsin + Skin-directed therapy
ECP + Interferon alfa or Retinoid + Skin-directed therapy
Retinoid + Interferon + Skin-directed therapy

Other systemic therapy options that can be given in combination with skin-directed therapy for these patients include:

Alemtuzumab
Bexarotene
Brentuximab vedotin
ECP
Gemcitabine
Interferon alfa
Doxil
MTX
Pembrolizumab
Pralatrexate
Vorinostat

Please note that: ECP=Extracorporeal photopheresis TSEBT=total skin electron beam therapy

Chronic Lymphocytic Leukemia (CLL)

Most prevalent leukemia in Western countries, small mature malignant cells
CLL = SLL (SLL is mostly referred to LN involvement but part of the same disease)

Staging of CLL

Rai and Binet Systems:

Combine physical exam findings and blood parameters (LN, liver, spleen, anemia and thrombocytopenia)
Low risk: Rai 0 –> 150 months OS
Intermediate risk: Rai 1-2 –> 71-101 months OS
High risk: Rai 3-4 –> 19 months OS

Note: Survival rates apply only to the era of chemoimmunotherapy.

Cytogenetic Abnormalities:

Del(13q) in 55% –> favorable
del(11q) in 18% –> extensive LAD intermediate risk
trisomy 12 (16%) –> intermediate risk
del(17p) in 7% –> poor risk (worse prognosis the higher the percentage of cells with del(17p))
del(6q) in 7% of patients

Prognostic Factors

Immunoglobulin heavy chain variable (IGHV) region gene mutations –-> Unmutated IGHV has lower response rates; chemoimmunotherapy especially is less effective. Prefer BTK inhibitors (BTKi) or BCL2 inhibitors (BCL2i).
Del(17p) and TP53 mutations: Poor prognosis, do not respond to chemoimmunotherapy, better with BTKi or venetoclax-based regimens.
Complex karyotype: ≥3 unrelated chromosomal abnormalities; worse prognosis. Better progression-free survival (PFS) with venetoclax regimens.
Mutations:
- High risk: TP53 and/or BIRC3
- Intermediate risk: NOTCH1 and/or SF3B1; and/or del[11q]
- Low risk: trisomy 12
- Very low risk: del[13q] only

*If TP53 mutation <10% VAF –> similar OS than not mutated if treated with targeted therapy

Prognostic Models

CLL-IPI Score:

Age >65 years
Clinical stage (Rai I–IV or Binet B/C)
Serum β2-microglobulin >3.5 mg/L
IGHV mutation status (unmutated = higher risk)
TP53 status (del(17p) and/or TP53 mutation = highest risk)

Scoring and Risk Groups:

Low risk (0–1 points): 5-year OS ~93%
Intermediate risk (2–3 points): 5-year OS ~79%
High risk (4–6 points): 5-year OS ~63%
Very high risk (7–10 points): 5-year OS ~23%

Diagnosis of CLL:

Monoclonal B cell lymphocytes above 5K (ALC >5K not enough but have to measure all the monoclonal ones)
Immunophenotype by flow cytometry –> CD19+, CD20 dim, CD200+, cyclin D-1, and IHC with LEF1 and SOX-11 helpful
Recommend cytogenetics, IGHV, FISH, and NGS
May need FNA or core biopsies of LN for SLL

Treatment of SLL/CLL

Evaluate if patient has symptomatic disease or other complications:

Localized forms of stage I SLL: Locoregional RT if symptomatic vs observation

Indications for Treatment in CLL:

Severe fatigue
Weight loss, night sweats, fevers without infection
Organ dysfunction
Progressive bulky disease (enlarged spleen and LN)
Progressive anemia or thrombocytopenia (except for AIHA and ITP that can be treated first)
Steroid-refractory autoimmune cytopenias

Treatment of Advanced CLL/SLL:

First line therapy (WITHOUT del(17p) or TP53 mutation):

Fixed Duration:
- BCL2i + cBTKi +/- antiCD20 MaB –> VenA +/- O (venetoclax + acalabrutinib) +/- obinutuzumab (fixed duration) – AMPLIFY study
- BCL2i + antiCD20 mAb –> VenO (venetoclax + obinutuzumab) – CLL14 study
- BCL2i + ibrutinib –> VenI (venetoclax + ibrutinib) – can be fixed duration or MRD based – CAPTIVATE study, FLAIR study (MRD based) and GLOW study (more toxicities seen with afib and deaths)
Continuous:
- cBTKi +/- antiCD20 mAb –> A+O (acalabrutinib +/- obinutuzumab) – ELEVATE study
- Zanubrutinib – SEQUOIA study
Others (less preferred):
- Venetoclax/zanubrutinib – SEQUOIA study (MRD guided, alternative to VenI)
- Ibrutinib +/- obinutuzumab
- BR
- FCR (chemoimmunotherapy)
- Obinutuzumab

First line therapy WITH del(17p) or TP53 mutation:

VenO (fixed duration)
VenA +/- O (MRD guided)
VenZ (MRD guided)
A +/- O (continuous)
Zanubrutinib (continuous)
VenI (fixed duration)

*Do not offer chemoimmunotherapy or conventional chemo in TP53 mutant

Second line therapy:

Use the option not previously considered:

VenO
Acalabrutinib
Zanubrutinib
Pirtobrutinib
Venetoclax + rituximab
Venetoclax
VenI
Ibrutinib

Relapsed/Refractory Disease

CAR-T anti CD19 lisocell
ncBTKi pirtobrutinib
PIKi-based regimens: Duvelisib, idelalisib +/- rituximab
FCR
R2 (rituximab + lenalidomide)
Obinutuzumab
Alemtuzumab + rituximab)
AlloSCT

Response Criteria in CLL (at least 2 months post treatment):

Complete response (CR): normal ALC, negative palpable LAD (<1.5 cm), no HSM, no constitutional or B symptoms, and normal blood counts without growth factors
Partial response (PR): >50% reduction of ALC, LAD, HSM, normalization of other blood counts
Partial response with lymphocytosis: Due to BTKi transient lymphocytosis, term used with BTKis when other sites of disease and counts are improving
Progressive disease: At least 50% increase from baseline in ALC, LAD, HSM, new lesions or cytopenias
Stable disease: Do not meet criteria for CR or PR and there is no progression
Relapse: Disease progression after a period of ?=6 months following initial CR or PR
Refractory disease: Lack of response to treatment or disease progression within 6 months of last treatment
Minimal residual disease (MRD): Detection of small amounts of CLL by blood or marrow testing with:
- NGS (uMRD) at the level of 10-6 (uMRD6) –> only one approved by FDA. Needs pre-treatment sample to compare
- Multicolor flow cytometry (MRD flow) = most widely used, detection at <10-4 CLL cells
- Allele-specific oligonucleotide PCR (ASO-PCR) – detects <10-5 CLL cells (expensive)

Summary of Study Findings:

Follicular Lymphoma (FL)

ICH: B cell markers + (CD19+, CD20+ CD22+, CD79a+); germinal center markers: BCL6, CD10+; High BCL2 expression
t(14;18) – not routinely done (85% of advanced and 50% of early stage)
Grade: 3b is treated as DLBCL and now is called follicular large B cell lymphoma
FL with uncommon features (blastoid type, diffuse growth pattern)
Prognosis: FLIPI, FLIPI-2, PRIMA-PI, FLEX. Divides into low, intermediate, or high risk

Maintenance treatment is approved for patinets who respond to induction therapy (PRIMA)

Gallium study no difference OS between rituximab vs obinutuzumab

Treatment of Relapsed/Refractory Follicular Lymphoma

ICH: B cell markers + (CD19+, CD20+ CD22+, CD79a+); germinal center markers: BCL6, CD10+; High BCL2 expression
t(14;18) – not routinely done (85% of advanced and 50% of early stage)
Grade: 3b is treated as DLBCL and now is called follicular large B cell lymphoma
FL with uncommon features (blastoid type, diffuse growth pattern)
Prognosis: FLIPI, FLIPI-2, PRIMA-PI, FLEX. Divides into low, intermediate, or high risk
Maintenance treatment is approved for patinets who respond to induction therapy (PRIMA)
Gallium study no difference OS between rituximab vs obinutuzumab
Treatment of Relapsed/Refractory Follicular Lymphoma

Important to biopsy at first recurrence
POD 24 = relapse in first 24 months is poor risk (some have transformed disease)
Obinutuzumab (GADOLIN): Obi Bendamustine better PFS and OS than benda alone
R2 = AUMENT Study better PFS and OS against rituximab alone
PI2K inhibitors: Idelalisib, duvelisib, copanlisib (after 2 lines of therapy) —> not used in the US anymore in FL
Tazemetostat (EZH2 mutation): oral ≥ 2 lines of therapy
CART (after 2 lines) axicell tisacell lisocell
Mosunetuzumab bispecific: oRR 80%, CR 60%, mPFS 17.9 months —> second line
Epcoritamab —> SC administration, ORR 80%, CR60%, ICANS and CRS
BTI inhibitors: zanu + obinutuzumab (ORR

Growth Factor Use in Hematology

Red Blood Cell Support

Physiology:

EPO = produced in peritubular cells of the kidneys in response to hypoxia –> bind to EPO receptors on erythroid progenitor cells in the marrow –> proliferation, differentiation, and increased survival or colony-forming unit-erythroid cells into mature RBCs

Mechanism of Action of Erythroid-Stimulating Agents (ESA)

ESA are recombinant forms of EPO and bind EPO receptors stimulating erythroid precursors to produce more RBCs
Key is to make sure there are enough substrates to produce an RBC (iron storages, folate, B12) –> “cannot build a Lego building without the Lego pieces”

Adverse Events of ESA

Increase in HB –> increase in blood viscosity and vascular resistance –> increased afterload causing BP and possibly heart failure
Direct vasoconstrictive effects by endothelin-1 production –> HTN
Increased viscosity has theoretical risk of increased VTE
CHOIR, CREATE, TREAT trials showed that aiming for a Hb >13 increased risk of stroke, MI, and death –> KDIGO recommends 10-11.5 g/dL as goal
Higher doses of ESA = higher risks even with no significant Hb increase

Indications for ESA use:

Anemia in CKD/ESRD
Chemotherapy-induced anemia
MDS and other hematologic disorders
Alternative to blood products

Main forms of ESA products

Short acting: Epoetin alfa (Epogen, Procrit)
Long acting: Darbepoetin alfa (Aranesp)

ESA use in CKD

CKD stage III (eGFR 30-59): Usually not necessary but considered sometimes when anemia <10 with no other clear causes
CKD stage IV-V (eGFR <30): Most patients develop decreased EPO production here
- Anemia can become symptomatic, treat with ESA if <10 with no other clear explanations
ESRD on dialysis:
- Usually administered to all patients in dialysis with anemia Hb <10

*Key to replenish iron storages before proceeding with the following goals:

CKD: Ferritin level above 100 or Tsat >20%
ESRD: Ferritin level above 500 and Tsat >30%

Dosing of ESA in CKD:

Epoetin alfa (Epogen/Procrit):
- Initial: 50–100 units/kg SC or IV 3 times/week (can increase to daily administration)
- Common outpatient regimen: 10,000–20,000 units SC weekly or every 2 weeks
Darbepoetin alfa (Aranesp):
- Initial: 0.45 mcg/kg SC or IV every 4 weeks (SC preferred)
- Common: 40–60 mcg SC every 2–4 weeks

*Adjustment: Every 4 weeks based on Hb response. Goal Hb: 10–11.5 g/dL (avoid >11.5).

Dosing of ESA in ESRD:

Epoetin alfa:
- Initial: 50–100 units/kg IV or SC 3 times/week (usually given during dialysis)
- Typical: 4,000–10,000 units per dose, 3 times/week (IV preferred)
Darbepoetin alfa:
- Initial: 0.45 mcg/kg IV or SC weekly
- Common: 200 mcg IV weekly (fixed dosing often used in HD units)

*There is no maximum dose but usually if >2 mcg/kg/week = ESA resistance and workup of other causes is recommended. KDIGO recommends IV iron in HD patients even if ferritin up to 500–700 ng/mL.

ESA Use in Chemotherapy-Induced Anemia:

Consider ESA if Hb <10 g/dL and patient receiving palliative chemo (ASCO/ASH guidelines).
Low-risk MDS with low EPO level (<500 IU/L).
?Avoid during curative intent chemo as it can cause cancer progression
Goal Hb: 10–11.5 g/dL (avoid >11 due to ↑ CV risk) – same as CKD
Monitor Hb every 2–4 weeks after initiation.
Iron status critical: TSAT >20%, ferritin >100

Clinical case:

ESRD patient with Hb 8.5 g/dL on HD, has a hemoglobin level of 9.2

What steps before ESA? (Iron, inflammation, dialysis adequacy).
Anemia → Check iron → Optimize iron → ESA → Monitor Hb → Adjust dose → Watch risks.
ESA ≠ iron replacement
Hb goal 10–11.5
Avoid high Hb targets (↑ CV risk)

White Blood Cell Support

Think of two main situations in which G-CSF is considered:

Expected profound neutropenia with risks (high dose chemo)
Patient at risk of neutropenia

Hemophilias

Type: X-linked recessive bleeding disorders (males >> females)

Types of Hemophilias:

Hemophilia A: ↓ Factor VIII
Hemophilia B: ↓ Factor IX
Hemophilia C (rare): ↓ Factor XI (AR, Ashkenazi Jews)

Labs:

↑ aPTT, normal PT, normal platelets, normal bleeding time

Symptoms:

Deep tissue bleeding: hemarthroses, muscle bleeds, delayed bleeding after trauma/surgery

Treatment:

Hemophilia A:
- Recombinant Factor VIII
- Desmopressin (DDAVP) → raises vWF + VIII (useful only in A, mild/moderate)
- Emicizumab (bispecific Ab mimicking VIII) for prophylaxis in A
Hemophilia B: Recombinant Factor IX

Board tips:

Normal PT + prolonged aPTT + deep bleeds = Hemophilia
Mixing study corrects → factor deficiency (not inhibitor)

Transfusion Medicine

Transfusion Reactions

General Management:
Stop the transfusion immediately, start IV fluids, treat symptoms, verify paperwork (unit, bag, patient ID), send the unit to the blood bank, and send a pink-top tube for post-transfusion Direct Antiglobulin Test (DAT).

Common Transfusion Reactions

Febrile Non-Hemolytic (FNHTR):

Timing: During or within 4 hours of transfusion
Mechanism: Cytokines from donor WBCs
Key Findings: Fever, chills, no hemolysis
Workup: DAT negative
Management: Stop transfusion, give antipyretics; use leukoreduced units in the future

Allergic (Urticarial):

Timing: During or within 4 hours
Mechanism: Plasma proteins trigger IgE
Key Findings: Urticaria, itching, no fever
Management: Stop transfusion, give antihistamines; may resume if mild

Anaphylactic:

Timing: Immediate
Mechanism: Anti-IgA antibodies in IgA-deficient recipient react against IgA in donor product
Key Findings: Hypotension, bronchospasm, shock
Management: Stop transfusion, epinephrine + airway support; use washed RBCs or IgA-deficient donors

Acute Hemolytic (AHTR):

Timing: Within minutes
Mechanism: ABO incompatibility → complement activation
Key Findings: Fever, flank pain, hemoglobinuria, DIC
Workup: Positive DAT, ↓ haptoglobin, ↑ bilirubin
Management: Stop transfusion, IV fluids, diuresis, supportive care. Work with blood blank for extended testing and determine feasibility of future transfusions.

Delayed Hemolytic (DHTR):

Timing: 3–14 days
Mechanism: Anamnestic alloantibody (e.g., anti-Kidd, Duffy). Think of the less frequent RBC antigens besides ABO groups.
Key Findings: Jaundice, mild anemia
Management: Supportive; avoid offending antigen by extended antibody testing by blood bank.

TRALI (Transfusion-Related Acute Lung Injury):

Timing: ≤6 hours
Mechanism: Donor anti-HLA or anti-neutrophil antibodies
Key Findings: Non-cardiogenic pulmonary edema, hypoxia
Workup: CXR: bilateral infiltrates without overload
Management: Stop transfusion, supportive O₂; avoid plasma from multiparous donors or individuals who have received multiple transfusions in the past (could develop anti-HLA and/or antineutrophil antibodies.

TACO (Transfusion-Associated Circulatory Overload):

Timing: ≤6 hours
Mechanism: Volume overload
Key Findings: Dyspnea, hypertension, JVD, pulmonary edema
Workup: BNP elevated, responds to diuretics
Management: Stop transfusion, diuretics, O₂; slow future transfusions or request fractioned blood products (divided units into smaller quantities to be administered at different times).

Septic Reaction (Bacterial contamination):

Timing: Immediate
Mechanism: Contaminated product (esp. platelets)
Key Findings: Fever, rigors, hypotension, shock
Workup: Gram stain, culture product
Management: Stop transfusion, broad-spectrum antibiotics, supportive care

Post-Transfusion Purpura (PTP):

Timing: 5–10 days
Mechanism: Anti–HPA-1a antibodies destroy donor and recipient platelets
Key Findings: Severe thrombocytopenia
Management: IVIG to neutralize antibodies

TA-GVHD (Transfusion-Associated GVHD):

Timing: 1–6 weeks
Mechanism: Donor T-cells engraft in immunocompromised or HLA-similar recipient
Key Findings: Fever, rash, diarrhea, pancytopenia
Management: Prevent with irradiated blood products (typically given to transplant recepients or immu

Key Preventative Measures to Prevent Transfusion Reactions

FNHTR → Leukoreduced products
Anaphylaxis (IgA deficiency) → Washed or IgA-deficient blood
TRALI → Avoid plasma from multiparous donors
TA-GVHD → Irradiated products
CMV infection → Leukoreduced or CMV-negative units

Thyroid Cancer

Types:

• Papillary (most common)

• Follicular

• Hürthle (oncocytic)

• Medullary (MTC)

• Anaplastic.

Key genetics:

• Papillary → BRAF V600E, RET/PTC

• Follicular → RAS, PAX8-PPARG

• Hürthle → mitochondrial/TERT

• MTC → RET (germline in MEN2)

• Anaplastic → TP53, TERT, ±BRAF

Workup:

• TSH, high-resolution neck US ± FNA; calcitonin/CEA if MTC suspected; baseline Tg/TgAb for PTC (not MTC)

Primary treatment:

Differentiated Thyroid Cancers (papillary/follicular/Hürthle):

Surgery:

<4 cm = lobectomy

>4 cm = total thyroidectomy

Multifocal, extrathyroidal, nodes = central neck dissection only if clinically involved nodes.

RAI ablation: intermediate/high-risk DTC or select >4 cm/ETE; not used in MTC or most Hürthle.

*TSH suppression goals: high-risk <0.1; intermediate 0.1–0.5; low-risk 0.5–2.

Medullary Thyroid Cancer (MTC):

• Total thyroidectomy + routine central neck dissection; no RAI.

• Screen RET/MEN2.

• Monitor calcitonin/CEA.

Anaplastic:

• Rapid airway assessment, urgent RT/systemic therapy;

• if BRAF V600E+ → dabrafenib + trametinib.

Advanced/RAI-refractory:

DTC:

• Lenvatinib (preferred) or sorafenib

• RET fusion → selpercatinib/pralsetinib

• NTRK fusion → larotrectinib/entrectinib

MTC:

• Vandetanib or cabozantinib

• RET-mut → selpercatinib/pralsetinib.

Follow-up:

Neck US, Tg/TgAb for DTC; calcitonin/CEA for MTC. Watch for hypocalcemia/RLN injury post-op.

Pearls: Papillary microcarcinoma can be surveilled in select patients; Hürthle less RAI-avid; RAI contraindicated in pregnancy.

Peripheral T-cell Lymphoma (pTCL)

Peripheral T-cell Lymphoma, NOS

Rare, heterogeneous group of predominant nodal T-cell lymphomas, can present with more lymph node and organ involvement.
pTCL, NOS is the most common type of peripheral T-cell lymphoma in Western countries (1/3 of cases), majority of cases in Asia.
Presentation: Lymphadenopathy with or without involvement of other organs. B and constitutional symptoms are common
Imaging: PET/CT recommended for most patients to assess extent of disease and identify biopsy targets (prefer excisional but core needle biopsy could be acceptable)
Pathology: Infiltration of mature T-cells with high mitotic rate (Ki 67 >70%) and flow cytometry (immunophenotype) showing at least one pan-T cell antigen (CD2, CD3, CD5 or CD6) confirming T-cell origin although loss of these markers is common. EBV negative. CD30 could be positive (allows use of brentuximab vedotin). Clonal T cell receptor (TCR) gene rearrangements noted. Not meeting criteria for AITL or ALCL (see below)
Staging: Use Ann Harbor staging depending on anatomic involvement and can consider IPI score for prognosis although it is extrapolated from B-cell non-Hodgkin lymphomas
Prognosis: Aggressive with poor prognosis, without treatment usually <6 months, with standard treatment (e.g. CHOP) ORR is 50-70%, CR 30-40%, mOS 2-3 years, 5-year OS 20-30%.

Treatment of pTCL, NOS

First line treatment:
- CD30+ disease (>1% of tumor cells): BV-CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone)
- CD30- disease:
  - Fit and younger patients (<65 yo): CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), CHOP, or dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) –> followed by autologous stem cell transplant (ASCT)
  - Older or less fit: CHOP (other regimens may be too toxic) –> followed by radiation therapy or observation depending on disease location

*Restage after 3 cycles of induction therapy and if complete or partial response, finish 6 cycles of therapy. If extensive residual disease or lack of response, treat as relapsed refractory disease

Relapsed/refractory disease:
- Fit and younger patients: salvage chemotherapy followed by SCT if not received vs allogeneic transplant. Can consider newer agents for refractory disease (relapse <6 months) seen below.
- Older or less fit: single agent treatment (newer agents or chemotherapy).

*Newer agents: Belinostat (histone deacetylase inhibitor or HDACi), duvelisib (PI3K inhibitor), romidepsin.(HDACi).

*Chemotherapy agents: Pralatrexate, brentuximab, bendamustine, lenalidomide, gemcitabine.

Bladder Cancer

cTa-T1 = treated with TURBT and post resection vesicle treatments, will need pembrolizumab only when BCG resistant/refractory (Keynote 057)

Neoadjuvant Chemotherapy:

Standard for muscle invasive disease
Cisplastin-based therapy (not carboplatin)
MVAC (preferred), DDMVAC acceptable, ifosfamide + doxorubicin + gemcitabine (for boards, think cisplatin)

*Adjuvant therapy given when neoadjuvant was not given

Need at least 13-15 nodes analyzed

Adverse prognostic factors:

LVI
Positive EUA
Tumor at ureteral orifice or hydronephrosis
Upper HG
Extension to local but resectable organs (prostate, some areas of vagina)

Adjuvant Therapy:

Nivolumab (CHECKMATE 274): Adjuvant nivo vs placebo –> DFS 20 vs 10.8 months, no OS benefit

Bladder Preservation:

When tumor is completely resected, no mass on EUA, solitary, not in CIS pathway, no complications
Radio sensitizing chemo recommended 5-FU with mitomycin, 5-FU + cisplatin, cisplatin/paclitaxel, etc.
TUR or partial cystectomy

Treatment of Metastatic Urothelial Cancer

Most common regional LN in pelvis, lung, liver, bone (skin and CNS late)
Without treatment patients live ~4 months

First Line Treatment of Bladder Cancer

Enfortumab vedotin + pembrolizumab (EV pembro – EV302/Keynote A39) –> EV targets Nectin-4; mOS 21 months
Cisplatin eligible:
- DDMVAC
- Gemcitabine/cisplatin + nivolumab –> RR 57 vs 43%, 37 months of duration
Cisplatin ineligible (renal, hearing issues)
- Gemcitabine carboplatin –> no survival difference but less toxicity
- Atezolizumab or pembrolizumab –> if cannot tolerate EV-Pembro or chemo

Maintenance: Avelumab –> after platinum front line, if CR or PR achieved, or stable disease (SD)

Second Line Treatment of Bladder Cancer

Pembrolizumab –> ORR 15-20%, improved OS over chemotherapy

Third Line or Post Immunotherapy

Erdafitinib –> for FGFR3 or FGFR2 genetic alterations (THOR Study) –> mOS 12.1 vs 7.8 (single agent chemo), ORR 45% vs 11%
Enfortumab vedotin –> if not previously used –> mOS 12.9 vs 9 months (vs single agent taxane)
Sacituzumab govitecan –> targets TROP2 –> phase 3 lots of drop outs due to toxicity myelosuppression and GI; likely need G-CSF use

Enfortumab vedotin adverse events: neuropathy, ocular, skin rash, SJS, liver disease (careful with Child B or C), hyperglycemia (expensive, every cycle of EV is 50K)

Kidney Cancer

Subtypes: Clear cell (75%, VHL), papillary low and high grade, chromophobe

VHL mutated cell produces VEGF and other agents causing carcinogenesis

Staging of Bladder Cancer

Stage I: <7 cm confined

Stage II: > 7 cm confined

Stage III: LN+

Stage IV: Invasion beyond Gerota’s fascia and metastatic disease

Prognostic Model IMDC (6 factors) – poor prognosis if >3

KPS <80
Diagnosis to treatment <1 year
Anemia
Hypercalcemia
Thrombocytosis
Leukocytosis

ASSURE normogram and other tools can help determining risk for treatment

Overview of the Treatment of Kidney Cancers

Stage 1,2,3:

Nephrectomy
Consider adjuvant pembrolizumab (KEYNOTE 564 vs placebo)

Stage 4:

Cytoreductive nephrectomy (CARMENA and SURTIME trials)
Systemic therapy

Systemic Therapy for Clear Cell Carcinoma

Cytoreductive Nephrectomy –> no OS benefit but consider in low metastatic burden, good performance status, readily resectable

First Line Systemic Therapy:

a) Favorable risk:

Axitinib + pembrolizumab –> KEYNOTE 426 vs sunitinib –> OS/PFS better in high risk patients
Cabozantinib + nivolumab –> CHECKMATE 9ER vs sunitinib –> mPFS 15 vs 7 months, better OS (good in all organ site mets)
Lenvatinib + pembrolizumab -> CLEAR study vs sunitinib vs lenvatinib/everolimus –> OS advantage in poor risk (good for all organ sites)
Ipilimumab/nivolumab –> CHECKMATE 214 vs sunitinib –> mOS 52 vs 37 months but ORR 39 vs 33% (not great for bone metastasis)

b) Poor risk (same as above plus):

Cabozantinib alone

No OS benefit in favorable risk patients in the combination studies above but benefit in intermediate and high risk populations

IO + TKI more probability of upfront response and better for bone mets

Subsequent Therapy:

IO naïve –> use IO combo
After IO: Do not continue PD1 blockage and use TKI cabozantinib, axitinib (CONTACT 03 trial was negative)
Tivozanib –> 2 or more prior lines of therapy
Belzutifan: small molecule inhibitor of HIF-2a (LITESPARK trial vs everolimus) –> ORR 25%, PFS 14.5 months (great here) –> hypoxia a major side effect

Systemic Therapy for Non-Clear Cell Carcinoma

Clinical trial
Cabozantinib
Cabozantinib + nivolumab
Lenvatinib + pembrolizumab

Testicular Cancer

Most important testicular cancers for the boards are germ cell tumors (GCT)s
Genetic fingerprint isochromosome 12p —> think this is a GCT
Main classification is seminoma and non seminoma (most non seminomas are mixed cell and even if they have some seminoma compontent, they are considered and treated non seminomas) —> “being seminoma is special”

Subtypes of Testicular Cancer

Germ cell tumors (GCT):
- Seminoma
- Embryonal carcinoma
- Choriocarcinoma
- Yolk sac tumor
- Teratoma
- Spermatocytic tumor (previously considered seminoma but now known to be benign)
Sex cord/gonadal stromal tumors:
- Leydig cell tumors
- Steroli tumors
- Granulosa cell tumors
Lymphoma

Serum Tumor Markers

AFP —> not produced in seminoma “seminoma no alpha”, ignore levels <20, drops every week by half with treatment (residual disease if not)
B-HCG —> Any type of GCT including seminoma (seminoma usually not >1K), half life 3 days (falls every 3 days instead of every week for AFP)
- IF very high, could be choriocarcinoma with high risk of brain mets
- Can increase with marijuana use
LDH (only for staging) in non seminomas: Use for D1C1 if elevated means bad outcome

Diagnosis:

Physical exam with mass
Transscrotal US (no CT or MRI, rarely used)
Serum bHCG, AFP, LDH should be checked prior to orchiectomy
Do not biopsy testis, do orchiectomy
Sperm banking, ok after orchiectomy
Brain MRI in select patients (significantly high bHCG concerning for chorio
CT C/A/P: Typically get it prior to surgery

Brain MRI indications:

Choriocarcinoma
Significant elevation of BHCG >5K, AFP >10K
Extensive lung mets
Mets to other solid organs

Staging:

Stage I: testis, spermatic cord, scrotum

Stage II: RP LN only

Stage III: Distant mets or RP nodes + highly elevated serum tumor markers STMS

T stage: risk factor to look for lymphovascular invasion —> high risk

Stage IS: any T but persistently elevated markers post orchiectomy —> treat as stage III

Mets to lungs better prognosis than other organs and mediastinal worse
LDH >2.5 also worse prognosis than <2.5

Treatment of Testicular Cancer

Treatment of Seminomas

Stage I (SoC is orchiectomy): Surveillance (preferred), single agent carboplatin (2 cycles, lowest relapse risk 2%), radiation to RP (less popular due to side effects)
Stage II (RP lymph node metastasis):
1. Nodes <3 cm (IIA/IIB): Radiation (30-36 Gy), chemotherapy (BEPx3 or EPx4), RPLND if <2 cm
2. Nodes >3 cm (IIB/C): chemotherapy preferred (BEPx3 or EPx4) from case series and expert recs
Stage III: Chemotherapy

Treatment of Non Seminomas:

Stage I: Surveillance (preferred), one cycle of BEP x1 (here 1 rather than 2, lowest relapse rate 2%), RPLND
Stage II:
1. IIA with normal markers: RPLND, BEP x3 or EPx4, if borderline adenopathy consider surveillance or RPNLD (as long as markers not elevated as they have higher risk and may need chemo) —> if malignant LN post RPLND = give 2 cycles of EP
2. IIB/IIC or IIA with S1: BEP x3 or EP x4 —> post chemo RPLND if residual masses
1. Stage III: Chemotherapy

In general, if pN+ post orchiectomy in stage II = if >5LN or >2 cm, recommend chemotherapy 2 cycles of BEP

Disseminated Disease (Stage III)

Good risk: SoC = BEP x3 or EP x4 (Bleomycin lung toxicity is increased in >50 yo, and renal dysfunction not the best candidates for BEP = drop the B and use EP)
Intermediate to poor risk: EP not strong enough. Therefore, SoC is BEP x4 or VIP x4 (use VIP when bleomycin is contraindicated)

Do not stop treatments for neutropenia, important to continue bleomycin (same for renal impairment)

How to differentiate good vs intermediate risk:

AFP >1K, BHCG >5K, LDH >2.5 ULN, mets to organs other than lungs, mediastinal NSGCT

Second Line Chemotherapy:

VeIP, TIP, high dose chemo (carbo + etoposide)

Growing teratoma syndrome

Teratoma doesn’t respond to chemotherapy and if tumor is mixed, the other part responds but teratoma will continue to grow

Residual masses

Seminomas: Most benign and PET could be helpful here (PET not used otherwise). Observe <3cm, PET>3cm, resect and sample if FDG+
Non seminoma: Multimodality therapy is SoC —> chemo then surgery unless they have a complete response (important to go to surgery if residual masses)

Late relapse:

Often can be cured, resection is key, risk of subsequent relapses

Prostate Cancer

Gleason scale (uniform way to describe pathology in prostate cancer):

Pathologist looks at sample and gives a score for the first and second most common pattern seen in sample. For example, if 3 and 4 are the most common patterns, if there are >3 the score is 3 + 4, but if there are more 4s the score is 4 + 3. Having more 4s than 3s is worse!

Mnemonic for risk assessment:

The = T disease

Prostate = PSA density and level

Cancer = Core biopsy %

Guide = Gleason

Risk category determines needed workup:

Bone scan and body imaging in symptomatic, elevated ALP, PSA 10-20, G7 or >50% socre positivity, locally advanced pT3 or pT4 or >10% risk of nodes

PSA recurrence: S/p local therapies

Post surgery: Failure to have undetectable PSA after RP, 2 or more increases or PSA >0.1 ng/mL
Post radiation: Increase PSA by 2 ng/mL or more above nadir

Doubling time <10 months is high risk

Treatment of Prostate Cancer

Adverse features post prostatectomy:

Positive margins
Seminal vesicle involvement
Extracapsular extension ECE (pT3a)
Persistently detectable PSA

Key Definitions

PSA persistence: never falls to undetectable after RP.
PSA recurrence (biochemical recurrence, BCR): PSA becomes detectable again after previously being undetectable, usually confirmed on ≥2 measurements.
Many guidelines use PSA ≥0.1–0.2 ng/mL as the threshold for defining recurrence and for considering salvage RT.

Pluvicto (lutetium 177 PSMA therapy) = Only for PSMA positive disease, use after ARPI and 1 taxane at least (not first line)

Difference between Local vs Biochemical recurrence:

Both have increased PSA but only local recurrence has imaging findings of recurrence or a positive biopsy
Local recurrence is treated with salvage RT. If no local recurrence, no RT need

Treatment of Biochemical Recurrence (has to be non-metastatic, otherwise treat as metastatic):

Think of doing imaging cause you may find mets

If negative imaging, repeat biopsy and confirm same pathology then

Castrate sensitive:

PSA doubling time >10 months (low risk) —> observation

PSA doubling time ≤9 months (high risk) —> treat with enzalutamide +- ADT (only enzalutamide is approved in castrate sensitive)

Castrate resistant:

Here is where one uses doubling time for castrate resistant:

10 months (lower risk) = ADT and observation
<10 months (higher risk) = ADT plus ARPI such as daro, apa, or enza

Treatment of Prostate Cancer

Treatment of Localized prostate cancer:

Very low/low risk prostate cancer: PSA ≤6, PSA <10, <3 prostate biopsy cancer within ≤ 50% of cancer in each core, PSA density <.15 mL/g:

<10 years of life expectancy: observation
10 years of life expectancy: active surveillance, prostatectomy or radiation

Intermediate risk:

T2b-T2c, Grade 2-3, PSA 10-20 (these 3 are called intermediate risk factors IRF)

–Intermediate favorable: 1 IRF, grade 1-2, percentage of positive biopsy cores is <50%

–Intermediate unfavorable: 2-3 IRFs, grade 3, ≥50% positive biopsy cores

10 years of life expectancy: Active surveillance, prostatectomy + PLND, radiation +- 4-6 months of ADT
<10 years of life expectancy: Observation or radiation

High risk/very high risk:

Surgery + PLND or radiation + ADT long term 2-3 years –> consider abiraterone for 2-3 years with ADT (ESTAMPEDE)

*Don’t get confused, abiraterone is used in the adjuvant setting with ADT in patients with localized high risk or very high risk (first line) VS ARPIs used in biochemical recurrence when PSA doubling time is <10 months

Treatment of Metastatic Prostate Cancer

Treatment of Metastatic Castrate-Sensitive Prostate Cancer

Low Volume Disease

ADT + ARPIs (enzalutamide, darolutamide, or apalutamide) +/- abiraterone

High Volume Disease (visceral mets or ≥4 bone lesions with at least one in axial skeleton)

ADT + ARPIs + docetaxel if needed

Treatment of Metastatic Castrate-Resistant Prostate Cancer

Need bone resorptive agents (zoledronic acid or denosumab)
ARPIs
Abiraterone/prednisone
Pluvicto (Lu-177) –> asymptomatic or minimally symptomatic PSMA positive
Radium-223 –> bone only
PARP if BRCA
Immunotherapy with pembrolizumab

Germline testing —> High risk, very high risk, node positive, or metastatic

Colon Cancer

Hereditary: HNPCC, Lynch
FAP, AFAP
Mixed polyposis
All patients should be tested for Lynch/HNPCC —> Check ICH MSI/MMR
Loss of MLH1 usually silencing is seen in sporadic dMMR (whereas in Lynch more are affected)
If MLH1 loss, check BRAF and if positive is sporadic. If BRAF negative, check for methylation of MLH1 —> if methylated is also sporadic. However, if not methylated, then it is hereditary and needs genetic testing
Lynch —> 12 polyps vs APC >100 polyps

Screening:

Start at age 45

Treatment of Localized Colorectal Cancer

Adjuvant treatment: 5 FU or cape

Treatment of Metastatic Colorectal Cancer

Can cure some patients
No difference between FOLFOX and FOLFIRI
Important to check biomarkers before therapy: RAS (Kras, NRAS), BRAF V600E, Her2, MSI-H, NRTK, and tumor sidedness (right vs left for EGFR use)
Bev cape combination is very active as well
CAIRO-3: Maintenance treatment better than holiday after first line, however no OS difference. Most use maintenance (dropping OX to avoid neurotoxicity) but resume OX if relapse
Right vs left sided = R is Rough —> worse prognosis than left
Right = more benefit from VEGF —> Bevacizumab benefit in R sided tumors
Left = better prognosis and response to EGFR (cetuximab) = Cetuximab for left
If BRAF V600E or RAS mutated = no benefit from EGFR

First Line Therapy

First line treatment (no mutations or all wild type RAS/BRAF)

Left sided tumor: FOLFOX or FOLRIFI +/- EGFR (cetuximab or panitumumab)
Right sided tumor: FOLFOX or FOLFIRI +/- bevacizumab

First line treatment (RAS mutated)

FOLFOX or FOLFIRI +/- bevacizumab (can be used in both sides but more benefit in R sided)

First line treatment (BRAF V600E mutated)

FOLFOXIRI + bevacizumab (if fit patient, higher risk needs more aggressive therapy)
Encorafenib + cetuximab +mFOFOX6 (BREAKWATER trial)

First line treatment (MSI-H/dMMR)

Pembrolizumab or ipilimumab/nivolumab

Second Line Therapy:

Depends of what was used, alternate with other first lines:
- FOLFOX ± bevacizumab —> FOLFIRI ± bevacizumab (or ramucirumab or aflibercept)
- FOLFIRI ± bevacizumab —> FOLFOX / CAPEOX ± bevacizumab
- Anti-EGFR used 1st —> Switch to VEGF-based regimen
- BRAF V600E mutant —> Encorafenib + cetuximab (this combination is not given in first line)
- MSI-H/dMMR not yet treated —> PD-1 inhibitor

Third Line Therapy:

Trifluridine/Tipiracil (TAS-102) ± bevacizumab
Regorafenib (multi-kinase inhibitor) —> ok to dose escalate from 80 mg daily (studies showed no difference with full dose)
Fruquitinib (VEGF TKI) —> OS benefit
HER2+ disease: Trastuzumab + pertuzumab or trastuzumab + tucatinib
NTRK fusion: Larotrectinib or entrectinib
RET fusion: Selpercatinib or pralsetinib
POLE mutations and TMB >10 sensitive to PD1

No BRAF MEK combination as in other tumors here

Liver Metastasis:

Solitary lesion resected has 71.5% survival in 5 years
40-50% in other resected lesions
Neoadjuvant therapy (usually 3 months at most): Has benefit and does not jeopardize surgery
Optimal timing of chemotherapy not established, biologic use still unclear

Rectal Cancer

Treatment of Localized Rectal Cancer

Need pretreatment staging with EUS or MRI, majority not metastatic (85%)
Never start with surgery unless small, well differentiated anal margin lesion
T1N0 = local transanal excision
T2N0 or high T3N0 = resection
T3 or more = need neoadjuvant therapy
Long course of radiation better than short course
Neoadjuvant more effective than adjuvant 5FU + RT (if rare PD1+ can use ICI)
Combination 5FU than radiation better than any of them alone
Neoadjuvant less toxic and more sphincter preservation
NO oxaliplatin in rectal cancer (only adds toxicity)
Adjuvant therapy is helpful as in colon cancer
Neoadjuvant therapies:
- 5FU or capecitabine + mitomycin + radiation (Nigro regimen)
- If mitomycin intolerant or contraindicated = use cisplatin
No role for adjuvant therapy

Treatment of Metastatic Rectal Cancer

First line:

Carboplatin + paclitaxel SoC (InterAACT trial)
Cisplatin + 5FU
FOLFOX

Second line:

MSI-H/dMMR = PD1 therapy
Palliative radiation + chemo

Treatment of Rectal Cancer

Very early disease:

cT1N0 (favorable: sm1–2, <3 cm, <30% circumference, well/mod diff, no LVI/PNI):
→ Local excision (transanal/TAMIS/TEMS) with full-thickness margins.
High-risk T1 or any T2N0:
→ Total mesorectal excision (TME) (LAR or APR).

Locally advanced (most common)

cT3–T4 or any N+ (mid/low rectum) OR threatened circumferential resection margin (CRM) on MRI:
→ Total Neoadjuvant Therapy (TNT) = give all neoadjuvant tx before surgery:
- Option A: Long-course chemoradiation (50–50.4 Gy with capecitabine) → systemic chemo (FOLFOX/CAPEOX) → TME
- Option B: Short-course RT (5×5 Gy) → systemic chemo (FOLFOX/CAPEOX) → TME
- Choose based on sphincter preservation goals, CRM, and center preference.

“Watch-and-Wait” (non-operative management)

For clinical complete response (cCR) after TNT (no residual tumor on DRE, endoscopy, MRI, and normalized CEA):

Active surveillance (q3–4 mo exams/MRI/endoscopy year 1), with salvage TME if regrowth. Great for low rectal tumors to avoid APR.

Surgery basics

TME is standard; aim for negative CRM.
LAR with coloanal anastomosis ± diverting ileostomy (very low anastomosis).
APR if sphincter involvement/poor function.
High rectum (>10–12 cm) often treated like colon: upfront surgery ± adjuvant chemo depending on pathologic stage.

Adjuvant therapy

If patient had TNT → usually no adjuvant.
If upfront surgery for pT3/4 or N+ and no preop therapy → adjuvant chemo (FOLFOX/CAPEOX) ± postop CRT if high-risk features/CRM+

Metastatic / oligometastatic

Potentially resectable liver/lung mets: Peri-op chemo (FOLFOX/CAPEOX) ± metastasectomy or ablation; integrate with rectal primary plan (TNT helpful).
Unresectable: FOLFOX/FOLFIRI/CAPEOX ± bevacizumab; if RAS/BRAF WT, left-sided, consider anti-EGFR.
dMMR/MSI-H: PD-1 inhibitor (pembro/nivo) frontline.

Palliative measures

RT for bleeding/pain/obstruction, stents/diversion as needed.

One-liners to remember

TNT is default for cT3/4 or N+, improves pCR, reduces distant mets, helps sphincter preservation.
Local excision is only for low-risk T1; anything riskier → TME.
cCR? You can watch-and-wait (esp. low tumors) with tight surveillance.
Threatened CRM on MRI → prefer long-course CRT as part of TNT
Upper/high rectum often surgery first

Anal Cancer

Histology

>90% = SCC (HPV 16, 18 related)
Anal canal adenocarcinoma → treat like rectal cancer (surgery-based)

Staging/workup

Pelvic MRI or CT, inguinal node exam, PET/CT.
Staging: by size (T1–T4) and inguinal/pelvic node involvement.

Treatment (SCC)

Stage I–III (localized/locally advanced):
→ Definitive chemoradiation (Nigro regimen):
- 5-FU (or capecitabine) + Mitomycin C + RT (45–59 Gy)
- No upfront surgery
Response: assess at 8–12 weeks; if residual → re-evaluate up to 6 months before declaring failure.
If persistent disease after CRT: APR (abdominoperineal resection)

Metastatic disease

First-line: Carboplatin + Paclitaxel (per InterAACT trial).
After progression: PD-1 inhibitors (Nivolumab, Pembrolizumab) if PD-L1+ or MSI-H.

Key pearls

Inguinal nodes = regional, not distant
No surgery upfront unless for salvage
HIV+ patients: treat the same (may need RT dose adjustment)
Follow-up: DRE and inguinal exam q3–6 mo x 5 yrs

Mnemonic: “FU + Mitomycin = No Knife.”

→ 5-FU + MMC + RT, avoid surgery unless salvage needed (goal is sphincter preservation)

Bone Cancers

Subtypes:

Osteosarcoma
Ewings sarcoma
Chondrosarcoma
Giant cell tumor (osteoclastoma)
Osteoid osteoma
Metastatic lesion (from another primary tumor)

Osteosarcoma

Site: metaphysis (around knee)
X-ray: sunburst, Codman triangle
Labs: ↑ALP
Risks: Paget, RB, Li-Fraumeni
Tx: surgery + chemo (MAP: high-dose MTX, doxo, cis)

Ewing sarcoma

Site: diaphysis (long bones, pelvis), young patients

X-ray: onion-skin periosteal reaction

Genetics: t(11;22) EWS-FLI1

Tx: chemo + RT + surgery

Chondrosarcoma

• Site: pelvis/shoulder; older adults

• Imaging: “popcorn” calcifications

• Tx: surgery (chemo/RT-resistant) = cartilage = no role of chemo

Giant cell tumor (osteoclastoma)

• Site: epiphysis; soap-bubble lytic lesion

• Tx: curettage ± denosumab

Osteoid osteoma

• Site: diaphysis, small (<2 cm)

• Pain: nocturnal, relieved by NSAIDs

• Tx: NSAIDs or ablation

One-liners for the boards:

• “OSteo = Sunburst, knee, young”

• “Ewing = onion rings, teens”

• Codman triangle → think osteosarcoma

Non-Small Cel Lung Cancer (NSCLC)

Differentiate by IHC:

Adenocarcinoma: TTF1+, CK7+
SCC: p40+, p63+

Staging of Lung Cancer

Stage 1: Small tumors only in one part of the lung, no LN or other involvement
Stage 2: Spread to N1 perihiliar or peribronchial LN (double digits usually 14,12)
Stage 3: Mediastinal involvement (usually single digit LNs for example 1, 2, 4, etc.)
Stage 4: Distant metastasis

Assess Resectability:

Stage I-III
Sublobar vs lobectomy are similar in efficacy
Hoarse voice or elevated hemidiaphragm contraindications
Cardiopulmonary reserve: Goal at least >40% post of predicated for FEV1 and DLCO
Tumors >2 cm usually need lobectomy

Adjuvant Treatment

Cisplatin-based therapy has evidence (not carboplatin unless combined with PD1)

IMPower010

Surgery —> chemo —> atezo or best supportive care (mDFS 36% vs 29%)
No benefit in PDL <1 (Pembro was beneficial in another study)

Treatment of Localized NSCLC (Stage I–III):

Stage I–II (Resectable)

Primary treatment: Surgical resection (lobectomy preferred)
Mediastinal node sampling required.
Adjuvant therapy:
- Stage IA: None
- Stage IB (>4 cm) or Stage II (peritracheal or peribronchial N1+ nodes): → Adjuvant platinum doublet (cisplatin + pemetrexed [non sq], or cisplatin + gemcitabine [sq])
- Stage II–IIIA, PD-L1 ≥1%, no EGFR/ALK mutation: → Adjuvant atezolizumab ×1 yr (atezo not for <1%)
- EGFR+ (exon 19/L858R): → Adjuvant osimertinib ×3 yr after chemo (ADAURA trial)
- ALK+: Alectinib adjuvant (ALINA trial)

Stage IIIA (Potentially Resectable)

Multimodality:
- Neoadjuvant chemo ± immunotherapy (nivolumab or pembrolizumab) → surgery → adjuvant therapy as above (CheckMate-816, KEYNOTE-671, and AEGEAN)
- If unresectable → treat as Stage IIIB

Stage IIIB–IIIC (Unresectable, Locally Advanced)

Concurrent chemoradiation (cisplatin/etoposide or carboplatin/paclitaxel) —> 60gy better than more 76Gy or more.
If no progression + PD-L1 ≥1%: → Durvalumab ×1 yr (PACIFIC trial) —> PDL1<1% may have higher risk of death may consider not using it
If EGFR mutated (exon 19 only)—> Osimertinib per Laura trial

Prophylactic cranial irradiation (PCI): if complete/partial response only for limited disease (no clear evidence in metastatic)

Adjuvant radiation: now not performed except for positive surgical margins

Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

Summary Flow:

Driver mutation?
→ Use targeted therapy
No driver mutation → Check PD-L1
- ≥50% → IO mono or chemo-IO
- <50% → Chemo-IO combo
Progression → Switch to next-line or trial

Initial Approach

Always test before treating unless urgent symptoms require empiric therapy

Key Biomarker Testing

Obtain comprehensive molecular and PD-L1 testing (ideally NGS panel):

EGFR (incl. exon 20 insertions)
ALK rearrangements
ROS1 rearrangements
BRAF V600E
MET exon 14 skipping
RET rearrangements
NTRK1/2/3 fusions
KRAS G12C
HER2 (ERBB2) mutations
PD-L1 expression (TPS %)

Treatment by Driver Mutation

Driver	Preferred 1st-line Targeted Therapy	Key Points / Notes	Adverse effects
EGFR activating mutation (exon 19 del, L858R)	Osimertinib	CNS active; standard of care
EGFR exon 20 insertion	Amivantamab + carboplatin/pemetrexed (or mobocertinib 2L)	NCCN 2025: amivantamab combo preferred
ALK rearranged	Alectinib, Brigatinib, Lorlatinib, crizotinib, ceritinib	Lorlatinib strongest CNS activity and approved in second line	Edema, hypercholesterolemia, weight gain (lorlatinib)
ROS1	Entrectinib or Crizotinib	Entrectinib covers CNS
BRAF V600E	Dabrafenib + Trametinib	Targeted combo
MET exon 14 skipping	Capmatinib or Tepotinib	Both CNS active
RET rearranged	Selpercatinib or Pralsetinib	Highly specific TKIs
NTRK fusion	Larotrectinib or Entrectinib	“Tumor-agnostic” indication
KRAS G12C	Adagrasib or Sotorasib (if no other target)	Typically after 1L chemo-IO
HER2 mutation	Trastuzumab deruxtecan (T-DXd)	After progression on chemo-IO

Exam tip: If a targetable mutation is present → start targeted therapy regardless of PD-L1

No Actionable Mutation (Wild-Type)

Treatment guided by PD-L1 expression and histology (nonsquamous vs squamous)

PD-L1 ≥50% (High expressor)

Pembrolizumab monotherapy (preferred)
Alternatives: Atezolizumab or Cemiplimab monotherapy
If high tumor burden → chemo-IO combo (e.g., pembro + carbo/pem)

PD-L1 1–49%

Chemo + IO (triplet):
- Nonsquamous: Carboplatin/cisplatin + pemetrexed + pembrolizumab
- Squamous: Carboplatin + (paclitaxel or nab-paclitaxel) + pembrolizumab
Atezolizumab-based regimens (IMpower150) or cemiplimab + chemo also valid

PD-L1 <1%

Chemo + IO (same as above)

Maintenance Therapy

After 4–6 cycles of induction chemo:

Nonsquamous: Continue pemetrexed ± pembrolizumab
Squamous: Continue pembrolizumab alone
If IO monotherapy given → continue IO up to 2 years if responding

Subsequent Therapy (After Progression)

If TKI failure (target therapy used): Use chemo ± IO (if not used before)
If IO + chemo failure: Consider targeted therapy (if new mutation) or clinical trial
Docetaxel + ramucirumab (REVEL trial) or docetaxel alone are standard 2L options
?Telisotuzumab (c-MET protein overexpression – not cMET mutation but protein increase)

Special Situations

Brain mets: CNS-active agents (osimertinib, lorlatinib, entrectinib) preferred; defer RT if asymptomatic
Oligometastatic disease: Consider local consolidative therapy after systemic control
Poor PS (≥3): Supportive care ± single-agent IO if PD-L1 ≥50%

Key Trial Associations (Board Clues)

Trial	Key Result
KEYNOTE-024	Pembro mono vs chemo, PD-L1 ≥50%
KEYNOTE-189	Chemo + pembro in nonsquamous
KEYNOTE-407	Chemo + pembro in squamous
IMpower150	Atezo + bev + chemo benefit esp. EGFR/ALK+ post-TKI
FLAURA	Osimertinib superior to 1st-gen EGFR TKIs
ALEX / ALTA-1L / CROWN	ALK TKIs 1L efficacy

Small Cell Lung Cancer (SCLC)

Definition

Limited-stage (LS-SCLC) = disease confined to one hemithorax and regional nodes that can be encompassed in a single tolerable radiation field.

(Usually T1–4, N0–3, M0 within one radiation port)

Goal: Curative intent (unlike extensive-stage).

Standard First-Line Treatment

Concurrent Chemoradiation

Preferred regimen: Platinum (cisplatin or carboplatin) + etoposide × 4 cycles + concurrent thoracic radiation therapy (TRT)
Druvalumab can be given as consolidation per ADRIATIC trial x24 months

Component	Preferred approach / notes
Chemotherapy	Cisplatin + etoposide (carboplatin acceptable if cisplatin intolerant)
RT timing	Start concurrently with cycle 1 or 2 of chemo (earlier = better OS)
RT schedule	Two main options:• 45 Gy BID × 3 weeks (standard, INT-0096)• 60–70 Gy once daily × 6–7 weeks (acceptable if BID not feasible)
Number of cycles	4 total cycles

Exam tip:

Concurrent (not sequential) chemoradiation → best survival (median OS ≈ 25–30 months, 5-yr ~25%).

Immunotherapy

Not standard yet for LS-SCLC outside clinical trials.
(Ongoing studies evaluating durvalumab/atezolizumab consolidation.)
NCCN: Clinical trial participation encouraged.

Post-Treatment Management

Prophylactic Cranial Irradiation (PCI)

Indication: For patients with CR or near-CR after chemoradiation.
Dose: 25 Gy in 10 fractions.
Purpose: ↓ brain metastases and improves OS (EORTC trial).
Alternative: MRI surveillance q3 months × 1 year if PCI declined.

Surveillance Imaging

CT chest ± abdomen every 3–6 mo × 2 yrs, then q6–12 mo.
Brain MRI every 3 mo if no PCI.

Relapse / Progression

Treated same as extensive-stage relapse algorithm:

Timing of relapse	Recommended therapy
≥6 mo after 1L	Re-challenge with platinum/etoposide
<6 mo	Lurbinectedin (preferred) or topotecan
After ≥2L	Clinical trial / palliative care

Key Trials to Remember

Trial	Finding
INT-0096 (Turrisi 1999)	BID RT (45 Gy/3 wk) ↑ OS vs QD 45 Gy
EORTC PCI study (Slotman 2007)	PCI ↓ brain mets & ↑ OS
CONVERT (2017)	BID vs QD RT → similar OS (BID still preferred)

Summary Flow (Board Format)

Limited-stage SCLC
→ Cisplatin + etoposide × 4 cycles + concurrent BID thoracic RT
If CR / near-CR → PCI (25 Gy/10 fx)
Surveillance: chest CT + brain MRI q3 mo
Relapse: follow ES-SCLC relapse pathways

Quick Mnemonic for LS-SCLC (Boards)

“4 + 45 + PCI”

→ 4 cycles chemo, 45 Gy BID, add PCI if response.

Treatment of Extensive Stage Small Cell Lung Cancer (ES-SCLC)

Standard of Care: Chemo-Immunotherapy

Platinum (cis/carboplatin) + etoposide + PD-L1 inhibitor

Regimen	Notes
Atezolizumab + carboplatin/cisplatin + etoposide → maintenance atezolizumab	IMpower133: OS benefit (~12.3 mo vs 10.3 mo)
Durvalumab + platinum/etoposide → maintenance durvalumab	CASPIAN: OS benefit, allows cisplatin or carboplatin
If immunotherapy contraindicated → platinum + etoposide alone

Duration:

4 cycles of platinum/etoposide
Continue PD-L1 inhibitor until progression or toxicity (up to 2 yrs)

Preferred platinum: carboplatin (better tolerated, equal efficacy)

Response Assessment / Consolidation

If limited metastatic burden (oligometastatic) → consider consolidative thoracic RT after systemic therapy
(per CREST trial, improved 2-yr OS).
If complete or partial response → offer prophylactic cranial irradiation (PCI) or MRI surveillance every 3 mo.
(PCI optional if good MRI access).

Second-Line / Relapsed Disease

Timing matters

Relapse Timing	Definition	Recommended Therapy
Sensitive	Relapse ≥ 6 mo after initial therapy	Repeat 1st-line platinum/etoposide ± IO (if not used)
Resistant / Refractory	Relapse < 6 mo or progression on 1L	Lurbinectedin (preferred) OR topotecan (IV or PO)
Other options	Paclitaxel, docetaxel, irinotecan, temozolomide, clinical trial

Lurbinectedin (ATLANTIS / PM1183): better tolerated than topotecan; FDA-approved for 2L after platinum.

Later-Line / Immunotherapy

If not used 1L: Nivolumab or Pembrolizumab may be considered (less favored now after PD-L1 combo standardization).
Clinical trials are strongly encouraged at any relapse.

Supportive / Special Considerations

Brain mets:
- Symptomatic → whole-brain RT
- Asymptomatic + IO ongoing → continue IO, add RT if progression
Leptomeningeal disease: palliative WBRT ± systemic therapy
Poor PS (≥3): consider single-agent chemo or best supportive care
SIADH / paraneoplastic syndromes: treat underlying tumor + supportive correction

Key Trials (for board associations)

Trial	Finding
IMpower133	Atezolizumab + Carbo/Eto → ↑ OS & PFS
CASPIAN	Durvalumab + Platinum/Eto → ↑ OS (adds choice of cis or carbo)
CREST	Consolidative thoracic RT → better 2-yr OS
Lurbinectedin (PM1183-B-005-14)	ORR ≈ 35%, FDA 2L approval

Summary Flow (Exam Format)

Extensive-stage SCLC
→ Platinum + etoposide + atezolizumab or durvalumab (4 cycles)
→ Maintenance PD-L1 inhibitor
Partial/Complete response
→ Consider thoracic RT ± PCI
Relapse ≥ 6 mo → Re-challenge platinum/etoposide
Relapse < 6 mo → Lurbinectedin > Topotecan
Progression after 2L → Tarlatamab (DLL3 BiTE) for relapsed, trial or palliative care

Trilaciclib aproved to reduce myelosupression in SCLC treatment (CDK4/6)

Mesothelioma

Diagnosis & Staging

Confirm with biopsy (thoracoscopy preferred)
Histology: epithelioid (best prognosis), biphasic, sarcomatoid
Stage with CT chest/abdomen ± PET; mediastinal staging if surgical candidate

Treatment of Mesothelioma

Localized (Potentially Resectable) Disease

Goal: macroscopic complete resection + adjuvant/trimodality therapy.
Candidates: early-stage, epithelioid histology, good performance status
Options:
- Extrapleural pneumonectomy or pleurectomy/decortication (P/D).
- Adjuvant chemo: cisplatin + pemetrexed (standard).
- Consider RT (hemithoracic) post-op in highly selected cases.
If not surgical candidate: definitive chemo ± RT.

Unresectable / Metastatic (Stage IV)

First-line options:

Preferred:
- Nivolumab + ipilimumab (CheckMate 743; OS benefit vs chemo, esp. non-epithelioid).
- Cisplatin + pemetrexed ± bevacizumab (MAPS trial; OS 18.8 vs 16.1 mo).
- Carboplatin may replace cisplatin if frail.
If contraindication to IO: use cis/pem ± bev.

Maintenance:

After chemo: observation (no standard maintenance)

Second Line Therapy:

After IO: if progression → switch to chemo (cis/pem ± bev).
Later-line: vinorelbine, gemcitabine (modest benefit).
TTFields (NovoTTF-100L): FDA-approved with chemo in unresectable disease (STELLAR trial).

Supportive / Key Concepts

Prognosis: median OS ~12 mo.
Asbestos exposure = key risk factor.
Palliative care early → improves QoL.
Avoid surgery in sarcomatoid (poor responders)

High-yield board takeaways:

Cis/pem ± bevacizumab = chemo backbone
IO (nivo + ipi) = new preferred 1L for most unresectable pts
Restrict surgery to epithelioid, localized, good PS
TTFields = niche but testable
No established targeted therapy yet; BAP1, NF2, CDKN2A often mutated (research)

Choriocarcinoma

Malignant gestational trophoblastic neoplasia (GTN) arising after molar pregnancy, miscarriage, or term pregnancy
Very high β-hCG levels → can cause hyperthyroidism or theca lutein cysts
Histology: cytotrophoblasts + syncytiotrophoblasts, no chorionic villi
Most common metastatic sites: lungs > vagina > brain > liver (avoid vaginal biopsy due to bleeding risk)

Diagnosis:

Persistently elevated β-hCG after pregnancy + imaging findings

Treatment based on FIGO score:

Low-risk (≤6): single-agent methotrexate or actinomycin-D
High-risk (≥7 –> disease >4 months from pregnancy, distant mets, B-HCG >100.000): multiagent EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine
Resistant/relapsed: EMA-EP or immune checkpoint inhibitor (rare)
Brain metastasis: add intrathecal methotrexate or whole-brain radiation

Surveillance and Follow-up:

Weekly β-hCG until normal ×3, then monthly for 12 months
Avoid pregnancy for 12 months (use contraception)
Pearl: Gestational choriocarcinoma (after pregnancy) has much better prognosis than non-gestational (ovarian germ cell type)

Hormone Receptor Positive Breast Cancer

Advanced Hormone Receptor (HR) Positive Breast Cancer

First line therapy: Early use of CDK4/6 + endocrine therapy if hormone sensitive.
Relapse/recurrent disease: Check for targetable therapy with NGS + germline testing.
Later lines increasingly depend on:
- Actionable mutations in NGS
- HER2 expression (low /ultra-low /0)

Definition of Endocrine sensitive:

De novo metastatic disease
OR relapse ≥12 months after completing adjuvant endocrine therapy
OR never received endocrine therapy

Endocrine resistant:

Progression on or within 12 months of adjuvant ET
OR progression on prior ET in metastatic setting

First-Line Therapy

CKD 4/6 inhibitor combined with endocrine therapy (ET)
- Ribociclib + aromatase inhibitor or fulvestrant (MONALEESA-2, 3, 7 → had OS benefit)
- Abemaciclib + ET (MONARCH-2, 3; no OS benefit)
- Palbociclib + ET (PALOMA-2, 3; no OS benefit)

Early ET Failure (progression on adjuvant ET or within 12 months)

If PIK3CA mutated: Palbociclib + fulvestrant + inavolisib (INAVO120 → OS benefit)
If PIK3CA wild-type: CDK4/6 + fulvestrant (if not previously used)

Treatment of Progressive Disease

Check for targeted therapy options with tumor NGS (PIK3CA, ESR1, AKT, PTEN) and germline testing: BRCA1/2

Targeted Therapy Available

PIK3CA/AKT/PTEN alterations: Capivasertib + ET (CAPItello-291)
ESR1 mutation: Elacestrant (EMERALD)
PIK3CA mutation (classic pathway):
- Alpelisib + ET (SOLAR-1, Bylieve post-CDK4/6 setting)
Germline BRCA1/2 mutation: PARP inhibitor
- Olaparib (OlympiAD)
- Talazoparib (EMBRACA)
Her2 expression (evaluate when endocrine resistant):
- HER2-Low (IHC 1+ or 2+/ISH-):
  - Trastuzumab deruxtecan – T-DXd (DESTINY-BREAST04)
  - Chemotherapy alternative
- HER2 ultra-low: Trastuzumab deruxtecan – T-DXd (DESTINY-BREAST04)
- HER2-0/HER2-Null:
  - Dato-DXd (TROPION-Breast01)
  - Sacituzumab govitecan (TROP-2)
  - Chemotherapy

Treatment of Progressive Disease Without Actionable Mutations

Everolimus + ET
Fulvestrant
Transition to chemotherapy as resistance develops

Malignant Hematology

Classical Hematology

Medical Oncology

Acute Myeloid Leukemia (AML)

Chronic Myeloid Leukemia

Atypical Chronic Myeloid Leukemia (aCML)

Acute Lymphoblastic Leukemia (ALL)

Hairy Cell Leukemia (HCL)

Myelodysplastic Syndrome (MDS)

Diffuse Large B Cell Lymphoma (DLBCL)

Hodgkin Lymphoma (HL)

Marginal Zone Lymphoma (MZL)

Multiple Myeloma

Cutaneous T-cell Lymphomas (CTCL)

Chronic Lymphocytic Leukemia (CLL)

Follicular Lymphoma (FL)

Treatment of Relapsed/Refractory Follicular Lymphoma

Growth Factor Use in Hematology

Red Blood Cell Support

White Blood Cell Support

Hemophilias

Transfusion Medicine

Transfusion Reactions

Common Transfusion Reactions

Key Preventative Measures to Prevent Transfusion Reactions

Thyroid Cancer

Peripheral T-cell Lymphoma (pTCL)

Peripheral T-cell Lymphoma, NOS

Treatment of pTCL, NOS

Bladder Cancer

Kidney Cancer

Testicular Cancer

Treatment of Testicular Cancer

Second Line Chemotherapy:

Prostate Cancer

Treatment of Metastatic Prostate Cancer

Treatment of Metastatic Castrate-Sensitive Prostate Cancer

Treatment of Metastatic Castrate-Resistant Prostate Cancer

Colon Cancer

First Line Therapy

Rectal Cancer

Anal Cancer

Bone Cancers

Non-Small Cel Lung Cancer (NSCLC)

Treatment of Localized NSCLC (Stage I–III):

Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

Small Cell Lung Cancer (SCLC)

Mesothelioma

Choriocarcinoma

Hormone Receptor Positive Breast Cancer

Advanced Hormone Receptor (HR) Positive Breast Cancer

First-Line Therapy

Treatment of Progressive Disease

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