BMT Drugs Flashcards
Abatacept (orencia)
Selective T-cell costimulation blocker- binds CD80 and CD86
-10 mg/kg IV day before transplant, then on days 5, 14, and 28
-to prevent GVHD in combo with CNI and MTX in mismatched unrelated donor
Antithymocyte globulin equine (Atgam)
Immunosuppressant
-can be given for steroid refractory acute GVHD tx
-can do test ID dose to assess for anaphylaxis
Antithymocyte globulin rabbit (Thymoglobulin)
Immunosuppressant
-can be given as part of conditioning regimen for GVHD prevention
Belumosudil (Rezurock)
Rock2 inhibitor
-steroid refractory chronic GVHD after 2 prior lines of therapy
-DDI with PPIs- increase dose to BID
-skin, GI, joint, **eyes, oral, liver, lungs **
Busulfan (Busulfex, Myleran)
Alkylating agent
-daily or Q6h
-used in myeloablative and reduced intensity regimens
-IV most common but can use PO (inter patient variability with PO)
-can use TDM
-seizure ppx with keppra
-DLTs: pulmonary fibrosis, hepatotoxicity, mucositis
-caution in pulmonary dysfunction
-sinusoidal obstruction syndrome -ursodiol ppx
-pharmacokinetic monitoring
-Q6h IV: AUC goal 3.9-6.2
-daily iv: AUC goal 14.8-24.6
-DDI- azoles, APAP, metronidazole (all increase busulfan)- avoid APAP/met 72h before and after, also phenytoin
-hepatic metabolism via enzymatic conjugation with glutothione
Carmustine (BiCNU)
Alkylating agent
-in BEAM regimen (often used in autologous for lymphoma)
-can cause infusion rxn, HA, perioral paradthesia, flushing d/t etoh in formulation- doses >150 mg/m2 (give APAP, HM, or BZD to mitigate)
-pulmonary toxicity >450 mg/m2- give steroids pred 1mg/kg/d
-renal elimination
-avoid drugs that can cause disulfiram like rxn d/t etoh content
Cyclophosphamide (Cytoxan)
Alkylating agent
-used in mx drug regimens
-hemorrhagic cystitis if high doses
-cardio toxicity >150 mg/kg (at ~10days)- monitor w/ ECG
-also used in GVHD ppx
-hepatotoxicity
DI: Give before busulfan and thiotepa
Busulfan and phenytoin increase cyclo metabolism to toxic metabolites
Cyclosporine (Gengraf, Neoral)
Calcineurin inhibitor
-commonly used for pts with aplastic anemia
-used to prevent and tx GVHD
-renal toxicity, hypomagnesemia, hyperkalemia, and HTN
-rarely causes PRES (posterior reversible encephalopathic syndrome)
-many DDIs including letermovir and 3A4 substrates
-200-300 ng/mL
-IV:PO 1:4 (sandimmune), 1:2-3 (modified)
Hirtuism (unlike tacrolimus)
Cytarabine
Pyramidine analog
-used in BEAM conditioning regimen
-DLT: neurotoxicity (but most transplant regimens are no high dose- they are usually <1g/m2/dose)
Etoposide (toposar)
Topo-II inhibitor
-commonly used in mx drug regimens
-if undiluted it can cause hypotension and precipitation so give with high volume of fluid
-metabolic acidosis- large amount of etoh
-DLT: mucositis
-3A4 substrate- interactions!
-metabolized in liver then renally excreted, 1/3 renally excreted unchanged
-renal elimination increases with hepatic impairment
Fludarabine (Fludara)
Purine analog
-common drug used in mx regimens
-watch for renal impairment and potential CNS toxicity- esp 40-100 mg/m2/d or total 200 mg/m2 with accumulation (happens ~2 months later)
-immunosuppressive (like cyclophos) so it’s good for NMA regimens
Ibrutinib (imbruvica)
BTK inhibitor
-CLL
-used to tx steroid refractory chronic GVHD (less evidence than ruxolitinib and belumosudil)
-DDI with azoles that are dose adjusted specifically based on indication
ADRs: cardiac toxicity (afib, HTN), bleeding (hold for surgery), arthralgia/myalgia, transient lymphocytosis)
cGVHD: skin, oral, GI
Letermovir (Prevymis)
Antiviral
-prevents clinically significant CMV in allogenic recipients who are CMV positive (R+)
-Started after HCT and continued through day 100
-dose adjust if given with cyclosporin
Maribavir (Livtencity)
Antiviral
-post transplant refractory CMV infection- refractory to IV ganciclovir
-given for 8 weeks
Melphalan (Alkeran, Evomela)
Alkylating agent
-most commonly used in autologous regimens for myeloma
-short stability
-given with cryotherapy (ice chips chewed) to prevent mucositis
-VOD
-renal elimination
Methotrexate
Antimetabolite
-used to prevent GVHD
-typically 4 doses beginning day +1 in mini-doses (can omit 4th dose if hemorrhagic mucositis)
-no dose adjustment for DDI and no leucovorin since mini-doses
-mucositis
-delayed engraftment
Decrease by 50% for scr >2x BL, LFT>200, or bili >5
Motixaforide (Aphexda)
CXCR4 antagonist
-autologous stem cell mobilization in combo with G-CSF
Premedicate with H1 and H2 and leukotriene receptor blocker to prevent hypersensitivity rxn
Mycophenolate mofetil (Cellcept)
Immunosuppressant
-used instead of MTX in reduced intensity or non-myeloablative regimens to prevent GVHD
-less commonly used drug for GVHD prevention by depleting T-cells
Omidubicel-onlv (Omisirge)
Nicotinamide-modified allogeneic hematopoietic progenitor cell therapy
-used for expansion of umbilical cord blood cells leading to decreased time to neutrophil and plt recovery
Ruxolitinib (Jakafi)
JAK inhibitor
-used to tx steroid refractory GVHD
-dose adjust for crcl, plt, and bilirubin
-no adjustment needed for posaconazole, voriconazole, or fluconazole for the GVHD indication
ADR: myelosuppression, infxns (CMV), edema, LFTs, hemorrhage, HLD, high triglycerides
cGVHD: skin, oral, GI, liver, lung, MSK
Sirolimus (Rapamune)
mTOR inhibitor
-used to prevent GVHD
-can be used as immunosuppressant when pts develop TMA/MAHA with calcineurin inhibitors
-long t1/2 so monitor trough once weekly
-3A4 substrate- Dec from azoles
-DI with statins- rhabdo
-Increased risk of VOD
-thrombotic microangiopathy
-3-14 ng/mL
Tacrolimus (Prograf)
Calcineurin inhibitor
-used to prevent and tx GVHD
-renal toxicity, hypomagnesemia, hyperkalemia, and HTN
-requires TDM
-rarely causes PRES (posterior reversible encephalopathic syndrome)
-many DDIs as it is a 3A4 substrate
-5-15 ng/mL (5-10 if given with sirolimus)
-IV:PO 1:3-4
Thiotepa (Tepadina)
Alkylator
-used in CNS penetration in auto and allo conditioning regimens (good if leptomeningeal or parenchyma involvement)
-hyperpigmentation-excreted in sweat- BID skin cleansing during and x48h after therapy. Change linens
-DLTs: mucositis, neurotoxicity
-give after cyclophosphamide (prevents activation of cyclophosphamide
Indications for autologous HCT
-multiple myeloma
-Hodgkin’s lymphoma
-DLBCL
-systemic sclerosis
Indications for allogenic HCT
-multiple myeloma-not preferred
-Hodgkin’s lymphoma-not preferred
-DLBCL-no preferred
-AML
-MDS
-ALL
-CML, CLL
-severe aplastic anemia
-SSD
Mobilization methods autologous and allogeneic
Autologous:
-single agent G-CSF
-chemo (cyclophos or etoposide) + G-CSF
-plerixafor + G-CSF
Allogeneic:
-single agent G-CSF only
Myeloma mobilization
Single agent G-CSF 10-16 mcg/kg/d if all of the following
-no more than 1 prior line of chemo
-no prior Melphalan
-no more than 4 cycles lenolidamide and wait 2-4 weeks after last dose
-Use plerixafor if low CD34+ (<10)
-if prior lenalidomide:
-collect after no more than 2-4 cycles
-can use G-CSF + chemo + plerixafor
NHL mobilization
-single agent G-CSF has high failure rate
-plerixafor if low CD34+(<10)
-chemo based mobilization can be incorporated into planned salvage chemo
Which type of conditioning regimen is always used for autologous HCT?
Myeloablative
-allogeneic can use all three types depending on the situation- myeloablative is better for young/fit pts
Who gets myeloablative conditioning ?
-AML, MDS, ALL, CML
-young, low comorbidities
TBI based in ALL
Who gets reduced intensity or no myeloablative conditioning?
-older, significant comorbidities
-prior HCT
-CLL, NHL, HL, plasma cell disorders
Palifermin
Mucositis prevention for autologous HCT receiving HD-chemo + TBI
TBI antiemetics
High risk RT for Emesis
5HT3 + dex on day of and 1 day after
Sinusoidal obstruction syndrome prevention
Ursodiol 12 mg/kg/day through days 1-30 (or 1-90)
Risk fx: allogeneic, myeloablative, busulfan, ozogamicin, pre-existing liver injury, iron overload
Avoid hepatotoxins, APAP, azoles, progestins, estrogens
Sinusoidal obstruction syndrome treatment
Defibrotide 6.25 mg/kg iv Q6h x 21d (max of 60 days)
Most commonly occurs in first 3 weeks
GVHD prevention: myeloablative MRD or MUD
CNI + MTX +/- ATG
Consider cyclosporine for related and tacrolimus for unrelated donor
GVHD prevention: non-myeloablative
-CNI + mycophenolate +/- ATG
-CNI + post transplant cyclophosphamide
GVHD prevention: mismatched unrelated donor
CNI + MTX + abatacept
GVHD prevention: haploidenrical
Tacrolimus + mycophenolate + post transplant cyclophosphamide
GVHD prevention: umbilical cord blood
CNI + mycophenolate
avioid MTXd/t delayed engraftment
No ATG!!
Acute GVHD grade 1 (skin only)
-continue or restart immunosuppressant
-topical steroid
-antihistamine
-observation
Acute GVHD treatment grade II-IV
Continue/restart/increase immunosuppressant
AND
-skin/lower GI/liver: MP 1-2 mg/kg/d (use lower end for grade II)
grade II upper GI only:
-budesonide or beclomethasone + pred/MP 0.5-1 mg/kg/day
OR
Sirolimus ALONE (instead of steroids) for standard risk aGVHD
Steroid refractory acute GVHD
Ruxolitinib-Skin and GI (liver is less likely to respond)
chronic GVHD tx
Mild: topical steroid or pred 1 mg/kg/d
Mod-severe: pred 1 mg/kg/d this is lower than acute GVHD
Notice, not normal grading system like with aGVHD
Chronic GVHD bronchiolitis obliterates syndrome
Fluticasone + azithromycin + montolukast (FAM)
Note: most other pulmonary complicates are treated with steroids
Steroid refractory chronic GVHD
Belumosudil, ibrutinib, or Ruxolitinib
Bacterial ppx
-FQ day 0-30 (auto and allo)
-PCN: day >100 for allogeneic with chronic GVHD on immunosuppressive-CHRONIC NOT ACUTE, ALLO not auto (don’t get tripped up)
PJP ppx
-allogeneic through 6 months or longer if on immunosuppressive
-consider for autologous if heme ca, intensive conditioning, graft manipulation, or recent purine analog
-start at engraftment (could cause delayed engraftment if started right away)
-GVHD tx with steroid 20+ pred equivalents x4+wk
Candida ppx
-allogeneic: fluconazole 400 mg/d through at least day 75 (if low risk for mold infection)
-consider for autologous if prolonged neutropenia, mucosal damage (mucositis)graft manipulation, or recent purine analog
-can also use echinocandin
-remember to use mold agent instead of GVHD on tx
Mold ppx, aspergillus ppx
Mold:
allogeneic
-cord blood, haploidentical, bone marrow, prolonged neutropenia prior to HCT, prior IFI or GVHD on tx (use posaconazole) (DOESNT MATTER IF ACUTE V CHRONIC-unlike PCN)
-azole or echinocandin through duration of neutropenia or immunosuppressant tx
-mold active azoles include, posa, vori, isavu
Aspergillus:
-If allo and high risk aspergillus: posa or vori until at least day 75
-risk fxs: MMUD, UCB, haplo, prolonged neutropenia, GVHD on tx, exposed, prior aspergillus infxn, active heme ca
HSV and VZV ppx
HSV
-acyclovir for all seropositive allogeneic through duration of neutropenia/mucositis
-consider if seripositive autologous especially if mucositis
VZV
-acyclovir for all HCT for at least 1 year
therefore everyone need acyclovir for at least 1 year
CMV prevention
all allogeneic
1. Ppx: letermovir 480 mg (240 mg if w/ cyclosporin) for seropositive (R+) AND allogeneic (start day 0 or no later than. Day 28 and continue through day 100)
2. Preemptive: monitor through day 100 and initiate valganciclovir 900 mgPO x14 days then 900 mg daily x1-2 wks- if infxn (for asymptomatic pts with cmv on lab markers)
Treatment:
-ganciclovir, valganciclovor
-foscarnet
-maribavir (oral)
Tx of thrombotic microangiopathy
-decrease or stop CNI/ sirolimus
-change CNI/mTOR-I to other agents
-plasma exchange
-rituximab, Defibrotide, eculizumab
Autologous relapse prevention
Multiple myeloma: lenalidomide 10-15 mg QD for at least 2y start 3 months post transplant
bortezomib if can’t take ^
Mantle cell lymphoma: rituximab q8 wk x3 yr- if rituxan sensitive
Follicular lymphoma: rituximab q8 wk x4 doses- if rituxan sensitive
Hodgkin’s lymphoma: Brentuximab (unless already used and refractory) q3 wk x16- if one of the following:
-refractory to initial tx
-relapse <12 months
-extranodal dx at pre-transplant
DLBCL: rituximab is not recommended
CML or ph+ ALL: maybe bcr-abl tki
Allogenic relapse prevention
AML/MDS: consider sorafenib if FLT3-ITD AML (no Lenalidomide)
ALL ph+: BCR-ABl TKI
CML: consider BCR-ABL TKI
Late effects monitoring
-ophthalmic exam at 1 yr
-dental exam at 1 yr
-CV risk at 1 yr then annual (lipids, DM)
-renal at 6 mo, 1 yr, then annual
-BP every visit
-thyroid annual
-gyn at 1 yr (women)
-gonadal for men if symptoms
-BMD at 1 yr for all women and allogeneic pts
-avascular necrosis
-secondary cancers
No longer in workbook:
Lfts, Pfts, ferritin
Secondary cancers
Esophagus: endoscopy if persistent GERD/dysphasia
Oral: annual oral exam
Thyroid: annual exam
Breast: if TBI or chest RT- start screen at age 25 or 8 yr after RT- annual breast exam, mammogram and MRI
Cervix- annual pap and HPV test
Skin- annual skin exam
BEAM
BCNU (carmustine)
Etoposide
Cytarabine
Melphalan
For NHL and HL
Define engraftment
ANC > 500 x3 days
Plt > 20k w/o transfusion for 7 days
Vaccinations
-re-vaccinate 2 years after for live
-inactivated:
-3 months: Covid, hib, PCV13/15/20, polio
-6 months: diptherias, heps, meningitis, hpv
-12 months: PPSV23
-others: flu- 4 mo, zoster 50-70d (autologous only)
-NO LIVE if active immunosuppression and/or GVHD
-recipient no live 4 weeks or inactive 2 weeks before start of conditioning
-Donor* should avoid live for 4 weeks prior to stem cell harvest
Live:
COZY IV RM
Cholera, oral typhoid, zoster (zostavax), yellow fever, intranasal influenza. Varicella, rotavirus, MMR
Pros and cons of peripheral blood vs bone marrow
Also umbilical cord and haploidentical
Pros:
Peripheral blood
-faster engraftment
-lower graft failure
-ease of collection
Cons:
- higher risk of cGVHD
-umbilical cord is opposite: more graft rejection, but less GVHD
-haploidentical: less graft rejection, more GVHD
Goals # of stem cells to collect
2-5 x10^6 CD34+ cells/kg (minimum 2)
Plerixafor
Mobilization agent for autologous
ADR: diarrhea
Often good if <10 CD34+ cells
allogeneic RIC/NMA vs MA: which dx states get which?
RIC/NMA: CLL, HL, NHL, plasma cell disorders, prior HCT
MA: AML, MDS, ALL, CML
NMA v MA risk of graft rejection
Higher risk with NMA (relies on immunosuppression rather than ablation)
Conditioning regimens
MA: high doses of one or more alkylating agent or high dose TBI
RIC:
-<500cGy TBI as single fx or <800cGy as fractionated
-<9 mg/kg PO busulfan
-<140 mg/m2 Melphalan
-<10 mg/kg thiotepa
NMA:
-generally contains low dose TBI (</=200 cGy) and immunosuppressive chemo (Fludarabine, cyclophosphamide)
MA:
-BEAM
-BuCy
-BuFlu
-carmustine + thiotepa
-carbo + etop
-Cyclo/ TBI
-Flu/ TBI
-Flu/Cy/TBI
-Melphalan
RIC:
-Flu/Bu
-Flu/Cy
-Flu/Cy/TBI
-Flu/Cy/thiotepa/TBI
-Flu/Mel
NMA
-Flu/TBI
Role of ATG
Unclear
Guidelines rec for matched (MUD or MRD) at high risk of GVHD
Is G-CSF used after BMT to reduce neutropenic time
Yes- better evidence for autologous
Allogenic- more with cord blood
Tx of viruses post HCT
VZV: Iv acyclovir
Adenovirus: stop immunosuppression and use Cidofovir
Herpes virus 6: ganciclovir, foscarnet, Cidofovir
BK virus: hyper hydrate, decrease immune suppression, Cidofovir +/-probenecid
RSV: aerosolized ribavirin
Flu: neuraminidase inhibitors, tamiflu
Ifosfamide
DLT is renal toxicity and neurotoxicity
-renal tubular damage can cause fancomi syndrome
-hemorrhagic cystitis occurred with 4-6 weeks of administration
-hepatic metabolism to active metabolite —>renal elimination
-3A4 interactions- pro drug, inducers increase activation to active metabolite, inhibitors decrease activation
Who do we need GVHD prophylaxis in?
Allogeneic!
Dose adjusting tacro and cyclosporin
Scr 2-2.9x BL- 25% dose reduction
Scr >3x BL- 50% dose reduction
How long to continue tacro or cyclosporine
Begin tapering by 10% per week at day 50-100 if no aGVHD
Where does acute GVHD manifest?
Skin, liver, GI
Chronic can be other places (often we see fibrosis)
Who need sinusoidal obstructive syndrome ppx?
-Allogenic- especially if myeloablative
-busulfan
Others:
-pre-existing liver injury
-iron overload
-ozogamicin
-abdominal irradiation
-prior HCT
HCT late complications
-ocular
-oral
-lung
-liver
-cardiac
-renal
-genito-urinary (gyn exam in women at 1 yr and men with symptoms)
-endocrine
-skeletal (BMD at 1 yr for all women and allo HCT)
Low level laser therapy
Mucositis from HCT high dose chemo +/- TBI
Define Steroid refractory
aGVHD: progresses after 3-5 days or or doesn’t improve after 5-7 days
cGVHD: progresses after 1-2 weeks or doesn’t improve after 4-8 weeks
Other respiratory issues
Peri-engraftment respiratory distress syndrome
-discontinue filgrastim
-steroids 1 mg/kg/ day
idiopathic pneumonia syndrome
-Methylpred 2 mg/kg/d x7 d then taper
-eteracept
Diffuse alveolar damage
-steroids 2 mg/kg/d to 1 g/m2/d
bronchiolitus obliteruns organizing PNA
-pred 1 mg/kg/d tapered over 3-6 mo
bronchiolitus obliteruns syndrome
-pred 1-1.5 mg/kg/d taper over 6-12 mo
-FAM
Stem cell mobilization g-CSF and plerixafor dosing
G-CSF- max 10 mcg/kg
Plerixaphor: 0.24 mg/kg x1, ~11hours prior to collection (max 4 days)
Most common infections after allogenic HCT in first 30-100 days
HHv6, EBV, CMV
Preffered donor type
MRD>haploidentical >MUD> UBC>MMUD
Infusion of stem cells pearls
-premedication with h1, APAP, steroid for infusion rxn
-if cryopreserved beware DMSO toxicity (nausea, bradycardia, garlic smell x24h)
Sinusoidal obstructive syndrome
-can be “classical” or “late onset” (>21d)
-signs/symptoms: 2 of the following
-bili >2
-painful hepatomegaly
-Ascites
-wt gain >5% pre HCT
GVHD ppx- RIC
CNI + mycophenolate + post transplant cyclophosphamide
Organs likely to respond to respective second line agents for GVHD
aGVHD
Ruxolitinib: skin, GI
cGVHD
-Ruxolitinib: skin, GI, oral, liver, lung, MSK
-Belumosudil: skin, GI, oral, liver, lung, eyes, joint/fascia
-ibrutinib: skin, GI, oral
When to give tamiflu
<2 years post HCT- exposure during outbreak
75 bid x5d- tx
75 QD x10-14d- post exp ppx
Allo vs auto pros and cons
Autologous:
-decreases transplant related mortality
Allogenic:
-lower relapse rate
-graft v host effect
-graft free of contaminating tumor cells
Carmustine + thiotepa
PCNSL and NHL with CNS dx
Thiotepa + busulfan + cyclophosphamide
PCNSL and NHL with CNS dx
Most common type of infection in first few weeks after transplant
Gram positive
