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Lymphoproliferative

Disorder

frequency

Lymphoblastic
85% of childhood acute
Leukemia/ Lymphoma B leukemias; peak in incidence at
age 4
cell

Lymphoblastic
Leukemia/ Lymphoma T
cell

15% of adolescent acute


leukemias; 40% of childhood
lymphomas; most commin in
male patients b/w 15-20 yrs

Small Lymphocytic
Lymphoma/Chronic
Lympocytic Leukemia

3-4% of adult lymphomas; 30%


of all leukemias

Lymphoplasmacytic
Lymphoma

B-cell neoplasm of older adults;


presents in 6th or 7th decades

most common lymphoid


Plasma Cell Lymphoma
neoplasm in adults > 40-50 yrs
(Multiple Myeloma)
old

Solitary Myeloma
(Plasmacytoma)

3-5% of all plasma cell


neoplasms

Smoldering Myeloma
Monoclonal
Gammopathy of
Uncertain Significance
(MGUS)

most common plasma cell


dyscrasia

Mantle Cell Lymphoma

3-4% of adult lymphomas;


occurs mainly in men > 50 yrs

Follicular Lymphoma

40% of adult lymphomas

Burkitt Lymphoma

<1% of lymphomas in the U.S.

Marginal Zone
Lymphoma

5% of adult lymphomas

Diffuse Large B cell


Lymphoma

40-50% of adult lymphomas;


15% of childhood lymphomas

Hodgkin Lymphoma

most common cancer of


adolecents and young adults

Mixed-cellularity
Hodgkin Lymphoma

most common form in patients


> 50 yrs; male predominance

LymphocytePredominance Hodgkin
Lymphoma
Lymphocyte-Depletion
least common form of HL (< %)
Hodgkin Lymphoma

Peripheral T cell
Lymphoma

most common adult T cell


lymphoma

Hairy Cell Leukemia

rare B-cell neoplasm (2%


leukemias); age 55 y, 5:1 M:F

Anaplastic Large Cell


Lymphoma

occurs in young adults/children

Adult T-cell
Leukemia/Lymphoma

CD+ T-cell lymphoma in adults


infected by HTLV-1

Large Granular
rare neoplasm of T cell and NK
cell; occurs in adults
Lymphocytic Leukemia
Extranodal NK/T cell
Lymphoma

2-3% NHL in Asia

Mycosis
Fungiodes/Sezary
Syndrom

CD4+ T helper cell neoplasm


involving skin

ABVD

Doxorubin, Bleomycin,
Vinblastine, Dacarbazine

BEACOPP

bleomycin, etoposide,
doxorubicin,
cyclophasphamide, vincristine,
procarbazine, prednisone

R-CHOP

Rituximab, cyclophosphamide,
doxoroubin, vincristine,
prednisone

ICE

Ifosfamide, carpoplatin,
etoposide

pathogenesis

genetic features

acquired mutations in specific


BCR-ABL fusion (9;22
transcription faotrs that reg the
translation i.e. Philadelphia
differentiation of immature
chromosome) for adult;
lymphoid or myeloid
childhood pre-B cell are
progenitors; blasts
hyperdiploidy, (12;21)
accumulating in marrow
translocation involving TEL1 an
suppress growth of normal
AML1 genes in 25%
hematopoetic cells

frequent translocation incolving


T cell receptor loci and TFs
genes as TAL1

tumor cells contain high levels


trisomy 12 and deletions of
of BLC2, protein that inhibits
chromosomes 11, 13, 17;
apoptosis; suppress normal B
activating mutations in NOTCH1
cell function often resulting in
receptor
hypogammaglobulinemia

similar to CLL/SLL, but


neoplastic cells undergo
terminal diff to plasma cells

acquired mutation in MYD88


(activates NK-kB)

frequently arise in bone


marrow; rearrangement of IgH
locus and various protooncogenes, proliferation and
survival dependent on IL-6

solitary lesion of bone or soft


tissue

overexpresison of cyclin D1
promotes S phase progression
during cell cycle

(11;14) translocation that


fuses cyclin D1 gene to the
IgH locus

inappropriate
"overexpression" of BCL2
protein in the tumor cells and
contributes to tumor cell
survival

85% of tumors have


characteristic (14;18)
translocation that fuses BCL2
to IgH

transcriptional regulator that


increases expression of genes highly assoc w/ translocation
requires for aerobic glycolysis, involving MYC gene on chrom
allowing cells to biosyn all
8 w/ igH on chrom 14; may be
building blocks for cell growth
t(2;8) or (8;22)
and division (Warburg effect)

(11;18) translocation involving


MALT1 and IAP2 genes ->
highly predictive of failure of
gastric tumors to respond to
antibiotic treatment
1/3 have rearrangements of
aberrations in MYC (5%) or
BCL6 gene, located on 3q27,
t(14;18) translocation;
and an even higher fraction
mutations in genes encoding have activated point mutations
acetyl transferases (alteration in BCL6 promoter; another 30%
of chromatin structure)
have (14;18) translocation
involving BCL2 gene

neoplasm arising from germinal


center B cells; EBV present in
RS cells in up to 70% of cases
of mixed-cellularity substype;
non-neoplastic inflammatory
cell infiltrtae generated by
cytokines (IL-5, TFGB, IL-13)
due to NF-kB activation

70% EBV+ in RS cells

reactive lymphocytes =
majority of celluraity

EBV infected RS cells > 90% of


cases

point mutation in serine


threonine kinase: BRAF (valine
to glutamate substitution at
residue 600)
activate tyrosine kinase trigger rearrangements in ALK gene on
RAS and JAK/STAT signaling
chr 2p23-> chimeric genes
pathways
encoding ALK fusion proteins

30-40% mutations in
transcription factor STAT3

salient morphology

immunophenotype

lymphoblasts w/ irregular nuclear


contours, condensed chromatin, small
nucleoli, and scant agranlar cytoplasm;
found in hypercellular bone
marrow/peripheral blood

TdT+ immature B cells


(CD19+, CD22), variable
expression of other B cell
markers)

identical to precursor B cell lymphoblastic


leukemia/lymphoma; masses in thymus TdT+ immature T cells (CD2+,
w/ "starry-sky" appearance
CD7+, variable expression of
(macrophages ingesting apoptotic tumor
other T cell markers)
cells)

small resting lymphocytes (dark, round


nuclei, scanty cytoplasm) mixed w/
CD5+ B cell expressing surface
variable numbers of large activated cells Ig (CD19, CD20, CD23)
"proliferation centers"; lymph nodes
diffusely effaced; "smudge cells"

small lymhpod cells exhibiting various


degress of plasma cell differentiation

B cell (CD20) expressing IgM;


plasma cell CD20-

plasma cells in sheets, sometimes


prominent nucleoli or inclusions
containing Ig

terminally differentiated plasma


cells containing cytoplasmic
Igs, CD138, CD56

plasma cells represent 10-30% of bone


marrow

small to intermediate sized irregular


CD5+ mature B (CD19 and
lymphocytes growing in a diffuse pattern; CD20) that express cyclin D1
bone marrow involved in most cases
and have surface IgM and IgD

frequent small "cleaved" cells


(prominent indendations and linear
infoldings) mixed w/ large cells; growth
parttern usually is nodular (follicular)

CD10+, BCL2+ mature B cells


(CD19 and CD20) that express
surface Ig

intermediate-sized round lymphoid cells


w/ several nucleoli (2-5); diffuse growth
mature CD10+ B cells
pattern assoc w/ apoptosis produces a
expressing surface Ig and IgM;
"starry sky" apperance; very high rates
germinal center B cell CD10
of proliferation and apoptosis are
and BCL6
characteristic

malignant B cells home to epithelium,


creating "lymphoepithelial lesions"

CD5-, CD10-, mature B cells w/


surface Ig

variable; most resemble large germinal


center B cells; diffuse growth pattern

mature B cells w/ variable


expression of CD10 and surface
Ig and IgM

reactive lymphocytes, macrophages,


stromal cells; malignant Reed-Sternberg
cells (two mirror-image nuclei or nuclear
lobes, each containing large acidophilic
nucleolus surrounded by clear zone, "owleye") make up a minor part of the tumor
mass; lacunar cell (single multi-lobate
nucleus, multiple small nucleoli and
abundant, pale-staining cytoplasm)

RS cells express CD15 and


CD30, CD45-

classic RS w/in heterogenous


inflammatory infiltrate containing small
lymphocytes, eosinophils, plasma cells,
macrophages
lymphohistiocytic (L&H) variant RS cells
that have delicate multilobed, puffy
nucleus resembling popped corn
("popcorn cell") found w/in large nodules
containing small resting B cells mixed w/
macrophages

L&H variants express B cell


markers (e.g. CD20); CD15-,
CD30-

relative paucity of lymphocytes and


plasma cells, abundance of RS cells or
pleomorphic variants

classic HL

variable; usually a spectrum of small to


large lymphoid cells

mature T cell phenotype


(CD3+, CD2+, CD5+_

cells have filamentous, hair like


projections

B-cell (CD19, CD20, CD22),


kappa or lambda, CD103,
CD11c, CD25, Annexin 1

large lymphocytes w/ abundant pale ot


blue cytoplasm; few coarse azurophilic
granules in peripheral blood

T cell (CD3), NK cells (CD3-,


CD56+)

CD3-, express NK cell markers


upper epidermis and dermis infiltrated by
tumor cells w/ cerebriform nuclear
CLA, CCR4/CCR10 (chemokine
contours; later spreads to bone marrow
receptors)
and lymph node

clinical features

diagnosis

abrupt stormy onset (w/in 3


mo), fatigue, fever
(neutropenia), bleeding
(petechiae, ecchymoses,
epistaxis), bone pain and
tenderness, generalized
lymphadenopathy,
splenomegaly,
hepatosplenomegaly), CNS
manifestations

identification of blasts (25% of


marrow cellularity), white cell
count may be > 100,000
cells/uL (increased
lymphoblasts); anemia is
almost always present, platelet
count < 100,000/ulL

initially asymptomatic, easy


fatigability, weight loss,
anorexia, lymphadenopathy,
hepatosplenomegaly (50-60%),
hypergammaglobulinemia,
autoimmune hemolytic
if peripheral blood lymphocyte
anemia/thrombocytopenia (less
count exceeds 4000-5000
common)
cells/uL; if not, diagnosis of SLL
made; 15% of patients have
autoAb against their own RBCs
weakness, fatigue,
or platelets
lymphadenopathy,
splenomegaly, hepatomegaly
(50%), hyperviscosity
syndrome (Waldenstrom
macroglobulinemia) -> visual
impairment, neuro problems,
bleeding, cyroglobulinemia

detection of monoclonal protein


bone pain, hypercalcemia
in serum or urine
(neuro manifestations),
(electrophoresis - M spike,
recurrent bacterial infections, immunofixation); radiographic
renal failure due to secretion of
findings (punched-out lytic
only light chain in urine
bone lesions on XR) + lab
(Bence-Jones proteins),
studies (Rouleaux formation amyloidosis
RBC stacked like poker chips)+
bone marrow examination
modest elevation of M protein
in blood or urine in some
patients
M protein > 3 gm/dL

M component < 3 gm/dL

fatigue, painless
lymphadenopathy, generalized
disease involving bone marrow,
spleen, liver, and GI

adults > 50 yrs, generalized,


painless lymphadenopathy, not
curable; "waxing and waning"

arises in extranodal sites;


endemic tumors often manifest
as maxillary or mandibular
masses, sporadic BL in
ileoceum and peritoneum

rapidly enlarging often


symtomatic mass at one or
several sites; extranodal
presentations are common (GI,
brain); Waldyer ring

histological diagnosis rests on


lower cervival, supraclavicular,
definitive indentification of RS
mediastinal lymph nodes
cells or variants in appropriate
(nodular sclerosis)
backgorund of reactive cells

adults older than nodular


sclerosis HL; disseminated,
assoc w/ systemic
manifestations (night sweats,
weight loss, advanced tumor
stage)

cervical or axillary
lymphadenopathy

older adults, HIV+, non-indus


countries

lymphadenopathy, sometimes
eosinophilia, pruritis, fever,
weight loss
infiltration of bone marrow,
liver, spleen -> splenomegaly,
pancytopenia, hepatomegaly
(some cases), infection

skin lesions,
lymphadenopathy,
hepatosplenomegaly,
peripheral blood lymphocytosis,
hypercalcemia
mild to moderate
lymphocytosis, anemia, Felty's
syndrome (RA, splenomegaly,
neutropnia)
destructive nasopharyngeal
mass, less often presents w/
involvement of skin and testis
skin lesions (premycotic phase,
plague phase, tumor phase)

causes marrow fibrosis -> dry


tap on aspiration, stains TRAP
positive

prognosis

treatment

children 2-10 yrs have best


prog w/ intesive chemo up to
80% cured; "good prognosis" hyperdiploidy, trisomy 4, 7, 10,
presence of (12;21); poor
prognosis - BCR-ABL fusion

variable and depends on


clinical stage; medial survival
4-6 yrs; worse prognosis deletion of 11q and 17p, lack of
somatic hypermutation,
expression of ZAP-70, presence
of NOTCH1 mutations, Richter's
transformation

incurable and progressive; 4


year medial survival

plasmapheresis; low dose


chemo and anti-CD20

not "curable"; can use


bortezomib and
dexamethasone PLUS
(cyclophosphamide/doxorubicin
or lenalidomide) thalidomide,
prednisone; maintenance Bortezomib, lenalidomide

median survival 3-4 yrs, poor


prognostic factors - blastoid
varient, "proliferative"
expression profile

not curable w/ conventional


chemo

watch and wait, involvedpfield


median survival 7-9 yrs; in radiotherapy (Stage I/II), chemo
40% of patients, progresses to (bendamustine/rituximab, anti
diffuse large B cell lymphoma
CD 20, R-CHOP, RCVP),
immunotherapy

urgent initation of treatment,


regimens (dose adjusted REPOCH, hyper CVAD, CALGB
10002 regimen), incorp therapy
to cross BBB

often cured by local excision or


radiotherapy

aggressive/fatal, but w/
urgent initation of treatment,
intensive combo chemo and
dose-adjusted R-EPOCH, RCHOP
anti-CD20 immunotherapy,
+/- radiation; RCHOP then ICE
complete remissions and
+/- radiation
achieved in 60-80% of patients

5-yr survival rate for patients ABVD (Doxorubicin, Bleomycin,


w/ stage I-A/II-A close to 100%; vinblastine, dacarbazine) 4-6
advanced disease overall 5 yr
cycles +/- involved site
disease free survival rate is
radiation therapy (ISRT);
around 50%
advanced stage - BEOCOPP

very good prognosis

excellent

least favorable prognosis of HL


subtypes

aggressive (worse than diffuse


large B cell lymphoma)
sensitive to "gentle" chemo
regimens - cladribine,
pentostain
good prognosis; cure rate 7580%, ALK negative worse
prognosis
rapidly progressive (death one
month - year w/ aggressive
therapy)

respond to radiation therapy,


but are resistent to chemo
indolen, median survival 8-9
yrs, may transform to
aggressive T celle lymphoma
late in course

comments

usually manifests as acute


leukemia; less common in
adults; prognosis is predicted
by karyotype; most spread to
CNS and testes

most common in adolescent


males; often manifests as
mediastinal mass assoc w/
NOTCH1 mutation; assoc w/
Down syndrome

occurs in older adults; usually


involves nodes, marrow, and
spleen; most patients have
peripheral blood involvement;
indolent

autoimmune hemolysis caused


by cold agglutinins (10%)

myeloma manifests as
disseminated bone disease,
often w/ destructive lytic
lesions; "CRAB" hypercalcemia, renal
involvement, anemia, bone
lytic lesions/back pain

may lead to multiple myeloma,


no "CRAB" findings
occurs mainly in occur males;
usually involves nodes, marrow,
spleen, and GI tract; t(11;14) is
characteristic; moderately
aggressive
occurs in older adults; usually
involves nodes, marrow, and
spleen; assoc w/ t(14;18);
indolent

endemic in Africa, sporadic


elsewhere; assoc w/
immunosuppression and EBV
(subset of cases);
predominantly affects children;
often manifests w/ visceral
involvement; highly aggressive

frequently occurs at extranodal


sites involved by chronic
inflammation (i.e. Sjogren
syndrome, H. pylori gastritis);
very indolent;
occurs in all age groups, but
most common in adults; often
arise at extranodal sites;
aggressive; EBV-assoc, Kaposi
sarcoma herpesvirus (HHV-8),
primary effusion lymphoma,
mediastinal large B cell
lymphoma
arise in single lymph node or
chain of lymph nodes and
typically spread in a stepwise
fashion to anatomically cont
nodes; five subtypes - nodular
sclerosis, mixed cellularity,
lymphocyte rich, lymphocyte
depletion, lymphocyte
predominance

transform to diffuse large B cell


lymphoma in 5% of cases; no
assoc w. EBV

probably spans a diverse


collection of rare tumors; often
disseimnated, generally
aggressive

frequently involve soft tissue

Southern Japan, West Africa,


Caribbean basin; occasionally
causes demyelinating disease
of CNS and spinal cord

highly assoc w/ EBV


Sezary syndrome - variant of
mycosis fungoides causes
generalized exfoliative
erthyroderma

Drug

Daunorubicin

Subclass

anthracyclines

Idarubicin
Doxorubicin

cytarabine

methotrexate

antimetabolites (Sphase specific; inhibits


DNA synthesis by either
incorporating into DNA
as a purine/pyrimidine
or interfeing w/ folate
synthesis)

mercaptopurine
fludarabine
Leucocovorin

MTX rescue

Glucarpidase

MTX rescue

cyclophosphamide
ifosfamide
carmustine

alkylating agents

melphalan
bendamustine
decarbazine
procarbazine
vincristine

Vinca Alkaloids

Vinblastine
Vinorelbine
Etoposide

topoisomerase II
inhibitors

Thalidomide

Lenalinomide

antiangiogenic agents

Pomalidomide
Carboplatin
Cisplatin

platinum analogs

platinum analogs

Oxaliplatin
Imatinib
Dasatinib
Ponatinib

tyroskine kinase
inhibitors

Nilotinib
Busotinib
Bortezomib
Carfizomib
Ixazomib

proteosome inhibitors

Rituximab

monoclonal antibodies

Brentuximab

Vedotin
Elotuzumab

Bleomycin

ATRA

Omacetaxine
Panobinostat

MOA

Indications

Contraindications

inhibits DNA/RNA syn by


interacalating base pairs and
all hematological
steric obstruction; generates
cancers, breast cancer,
ROS, interferes w/ topoisomerase
metastatic cancers
II

pyrimidine analog -> inhibition of


DNA pol

competitively inhibits DHFR ->


decrease DNA syn

decrease de novo purine


synthesis; activated by HGPRT
actively competes w/ MTX for
transport sites; restores active
folate stores
recombinant enzyme rapidly
hydrolyzes MTX to inactive
metabolites; rapidly decrease
MTX levels (w/in 1 hr)

multiple uses in
malignancy; CNS
prophylaxis/treatment
(able to cross BBB);
AML, lymphomas

cancers: leukemias
(ALL), lymphomas,
choriocarcinoma,
sarcoma; non-neoplastic sulfa, NSAIDS, PPI
- ectopic pregnancy, RA, (e.g. omeprazole),
psoriasis, IBD, vasculitis penicillins, ascorbic
acid, acidic
beverages,
aspirin
prevent organ rejection,
RA, IBD, SLE

MTX rescue therapy


(>= 500 mg/m^2)
leucovorin is
substrate for
lucarpidase

alkylating DNA, causing crosssolid tumors, leukemia,


liking, inducing strand breakage;
lymphomas
require bioactivation by liver

requires bioactivation, cross BBB


SCT prepartive
-> CNS; cross link DNA
regimens; heme cancers

M and S phase-speficic; bind to solid tumors, leukemias,


tubulin and inhibit polymerization; Hodgkin (vinblastine)
arresting mitotic spindle
and non-Hodgkin
formation
(vincristine) lymphomas

blocks topoisomerase II,


preventing re-ligation of DNA
strand

solid tumors
(particularly testicular
and small cell lung
cancer), leukemias,
lymphomas

selectively inhibits seretion of


proinflammatory cytokines;
enhances cell mediated immunity

myeloma,
myelodysplastic
syndrome

inhibits DNA crosslinking and


promotes strand breakage

testicular, bladder,
ovary, and lung
carcinomas

inhibits DNA crosslinking and


promotes strand breakage

testicular, bladder,
ovary, and lung
carcinomas

CML, GI stromal tumors


avoid PPI
BCR-BL tyrosine kinase inhibitor
avoid PPI

second line treatment


reversible inhibit of 26S
proteasome in mammalian cells

relapsed or refractory
low grade or follicular
chimeric monoclonal Ab directed
CD20+, B cell NHL; first
against CD20 antigen
line alone or w/ chemo
in all CD2-+ lymphomas

antibody drug conjugate


(brentoximab vedotin)

Refractory Hodgkin
Lymphoma, systemic
anaplastic large cell
lymphoma

binds to DNA -> ds and ss breaks

Hodgkin's Lymphoma,
testicular cancer

induces differentiation

APL

bleomycin (increased
risk of pulmonary
toxicity)

protein synthesis inhibitor

CML (chronic or
accelerated phase)

histone deacetylase (HDAC)


inhibitor; induces apoptosis

attenuates activity of
proteosome inhibitors in
multiple myeloma

Toxicity/Drug Interactions

Route of
Adminstration

Other Notes

cardiotoxicity, bone marrow


suppression, hand-foot
syndrome (mucositis);
vesicant, extravasation

monitor ejection fraction


(MUGA or ECHO at
baseline); extravasation
relieved by COLD,
cumulative dose caps due to
risk of cardiotoxicity;
antidote is Dexrazorane
(catalytic inhibition of
topoisomerase II)

myelosuppression
(panCYTopenia), cytarabine
syndrome (fever, myalgia, bone
pain, malaise 6-12 hrs after
admin), moderate emetic
potential/diarrhea, anal
inflammation, ocular toxicity hemorrhagic
conjunctivitis/neuro toxicity
(higher doses)

manage cytarabine
syndrome w/ corticosteroid;
risk factors: underlying renal
impairment, > 50 yr,
increase alkaline
phosphatase, pre-existing
CNS lesion, neuro checks
every day

nephrotoxicity,bone marrow
suppression, mucositis,
diarrhea, skin desquamation,
nausea/vomiting, pulmonary
fibrosis
myelosupression, GI, liver;
increased toxicity w/ allopurinol
or febuxostat
bone marrow suppression

risk factors: failure to


alkanalize urine, 3rd space
fluids, baseline renal
impairment (CrCl should be
> 60 ml/min) , baseline
hepatic impairment

HOLD leucovorin 2-4 hrs


before to 2-4 after

BMS (dosing limiting),


secondary malignancies,
hemorrhagic cystitis
(metabolite acrolein)

Mesna for high dose


cyclophosphamide and any
dose of ifosfamide; monitor
urinalysis while receiving
infusion

ocular and pulmonary toxicities

fatal at high doses if not


followed by stem cell
rescue; monitor vital signs
every 15 min

Gi, mucositis, diarhea, N/V,


infection risk after SCT

oral

oral
chemotherapy induced
peripheral neuropathy,
autonomic, neuropathy
(conspitation), vesciant (warm),
bone marrow suppression
(vinblastine)

fatal if given intrathecally,


give prophylactic bowel
region (due to possibility of
paralytic ileus)

BMS, hypotension during


infusion, hypersensitivity rxn, GI
upset, alopecia

HL (escalated BEACOPP,
BEAM), NHL (R-EPOCH)

edema, VTE risk, fatigue,


thrombocytopenia, teratogenic,
neuropathy

oral

edema, VTE risk, fatigue,


thrombocytopenia, teratogenic,
myelosuppression
edema, VTE risk, fatigue,
thrombocytopenia, teratogenic,
myelosuppression
highly ematogenic

nephrotoxicity (cisplatin)

prevent nephrotoxiity w/
amifostine (free radical
scavenger) and chloride
(saline) diuresis

CIPIN (cold-induced (oxaliplatin)


fluid retention, rash, N/V
QT prolongation, fluid retention,
rash N/V
heart failture, hepatotoxic,
vascular occlusion, fluid
retention, rash, N/V
pancreatitis, QT prolongation

peripheral neuropathy, BMS

subQ

fatal if given intrathecally

oral
infusion reactions, possible
reactivation of hepatitis B, risk
of PML

peripheral neuropathy,
neutropenia, anemia
thrombocytopenia, skin rash,
fever/infusion related rxn, risk of
PML, infusion reactions, possible
reactivation of hepatitis B
infusion reactions, possible
reactivation of hepatitis B
infusion reactions, possible
reactivation of hepatitis B
pulmonary toxicity
(pneumonitis), risk of
anaphylaxis, skin
hyperpigmentation, mucositis,
minimal myelosuppression
differentiation syndrome, rash,
HA, bone pain,
hypertriglyceridemia,
hyperluekocytosis, teratogenic

check PFTs at baseline

SubQ