BMT supportive Flashcards
plt engraftment
> 20 without transfusions
mucositis risk factors -4
Melphalan, Etoposide, TBI 12-14 Gy; methotrexate
mucositis prevention -3
Good oral hygiene: saline or sodium bicarbonate
Ice chips: beneficial in patients receiving melphalan
Palifermin: beneficial in autologous patients receiving TBI/cyclophosphamide/etoposide (NOT STUDIED WITH BEAM)
% patients with Grade 3/4 mucositis
duration of Grade3/4mucositis
opioidinfusions&totalparenteralnutrition
Palifermin is NOT BENEFICIAL -3
- Multiple myeloma patients with melphalan 200 mg/m2
- Allogeneic HSCT patients in bu/cy pts (some evidence to use for cy/tbi but should not be test question)
- BEAM
acute GVHD risk factors -6
HLA disparity
HLA matched unrelated donors (HR 1.66)
HLA mismatched related donors (HR 1.74)
HLA mismatched unrelated donors (HR 2.0)
Source & dose of stem cells
peripheral blood > bone marrow > ?cord blood
Increased CD34+ associated with increased
GVHD
Older age of host or donor
Conditioning regimen
Higher dose of TBI increased risk of acute
GVHD
TBI containing regimen vs. no TBI (HR 1.49)
Sex mismatch
Highest with parous females donating to males
Female donor and male recipient (HR 1.14)
CMV infection - cause-and-effect unclear
protective acute GVHD risk factors - 2
Conditioning regimen
Antithymocyte globulin is protective (HR 0.77)
Diagnosis of CML (HR 0.87)
Acute GVHD Prevention -5
Donor selection - best histocompatible match
Single agent immunosuppression (not used much)
Cyclophosphamide; cyclosporine; methotrexate
Combination immunosuppression Cyclosporine + Methotrexate Tacrolimus + Methotrexate Cyclosporine + Mycophenolate Tacrolimus + Sirolimus
T-cell depletion – in vivo or ex vivo
Palifermin – negative trial
acute GVHD px - MRD
csa + MTX vs fk +MTX
CSA + MTX
-better OS 57 vs 47 even though worse aGVHD
acute GVHD px - MUD
csa + MTX vs fk +MTX
FK + MTX
-same OS, less aGVHD
Does replacing MTX with MMF in combo with CSA or FK work?
NO
MTX in acute GVHD ADR -2
mucositis
delays engraftment
CLL and cord blood SCT’s use MMF for aGVHD px. why is that?
delayed engraftment
why use single agent cyclophos for aGVHD px?
reduced cGVHD to 10% at 2 years
ADR comparison:
Siro + FK vs FK + MTX
more rapid engraftment and less mucositis with siro
more VOD and thrombotic microangiopathy
Cyclosporine aGVHD px ADR -3
Nephrotoxicity
Neurotoxicity
Trough level 150-450 ng/mL
Tacrolimus aGVHD px ADR -3
Nephrotoxicity
Neurotoxicity
Trough level 5-20 ng/mL (5-10 ng/mL with sirolimus)
Sirolimus aGVHD px ADR -3
TMA
Hepatotoxicity
Trough level 3-12 ng/mL
Mycophenolate aGVHD px ADR -3
GI toxicity
Myelosuppression
? AUC; trough levels don’t correlate in all HSCT trials
Methotrexate aGVHD px ADR -3
Mucositis
Delayed engraftment
Dose reduce or hold in renal or hepatic dysfunction; fluid collections; severe mucositis
Initial Treatment of Acute GVHD -3
Grade I - Skin Only (less than 25%)
Initially manage with topical corticosteroids
Grade II – IV
Methylprednisolone 2 mg/kg/day
CR in 25-40% of patients; ORR 50%
Taper by 10%/week after 1-2 weeks if patient responds (typically 6-12 weeks of therapy)
Grade I or II GVHD
Retrospective data suggests 1 mg/kg/day is effective (minimize toxicity)
Combination Initial Therapy for Acute GVHD - no benefit -3
Anti-thymocyte globulin, Daclizumab, Infliximab
Combination Initial Therapy for Acute GVHD - possible benefit -3
Beclomethasone (BDP) in stage 1, isolated gut GVHD
- more rapid steroids
Mycophenolate – based on BMT CTN 0302 Trial
CR = 60%; OS at 9 months 64%
Higher CR and OS than Etanercept, Denileukin diftitox, and Pentostatin (CR 26-53% and OS 47-49%)
Steroid Refractory Acute GVHD definition -3
Progression after 3 days of methylprednisolone
No change after 7 days of methylprednisolone
Incomplete response after 14 day
Steroid Refractory Acute GVHD treatment
no standard of care (unlikely test question)
Chronic GVHD Risk Factors -6
Prior grade III-IV acute GVHD (HR 1.42)
HLA disparity between host and donor
MUD (HR 1.3)
MMRD (HR 1.24)
MMUD (HR 1.57)
Peripheral blood > bone marrow (HR 1.74)
Older age of host or donor
Sex mismatch
Female : male (HR 1.37)
Donor leukocyte infusion
chronic GVHD can effect virtually any organ. examples? -9
- dry eyes
- mucositis
- nail dystrophy
- skin
- deep muscle / joint
- liver
- lung - bronchiolitis obliterans
- autoimmune
- endocrine / metabolic
Mild Chronic GVHD (10% of pts that develop cGVHD)
NOT TESTABLE
Involves only 1 or 2 organs/sites (except the lung) with no clinically significant functional impairment (maximum score of 1 in all affected organs/ sites)
Moderate Chronic GVHD (30%)
NOT TESTABLE
Involves at least 1 organ/site with clinically significant but no major disability (maximum score of 2 in any affected organ/ site OR 3 or more organs/sites with no clinically significant functional impairment (max score of 1 in all affected organs/sites) OR a lung score of 1
Severe Chronic GVHD (60%, 2yr OS 50%)
NOT TESTABLE
Indicates major disability caused by cGVHD – score of 3 in any organ site. A lung score of 2 or greater will also be considered severe cGVHD
Initial Therapy of Chronic GVHD -MILD
Topical therapy
Initial Therapy of Chronic GVHD -MODERATE OR SEVERE -3
Prednisone 1 mg/kg/day- taper to every other day (NOTE NOT BID)
Prednisone + calcineurin inhibitor (not strong evidence)
May benefit patients with platelet < 100 x 109/L
Prednisone + other agents is not beneficial
No benefit to addition of mycophenolate, thalidomide, hydroxychloroquine
Topical Therapy for Chronic GVHD - Skin
Topical steroids;
topical calcineurin inhibitors;
PUVA;
UVA;
UVB
Topical Therapy for Chronic GVHD - Gastro- intestinal
Topical steroids (budesonide or beclomethasone)
Topical Therapy for Chronic GVHD - Liver
Ursodiol
Topical Therapy for Chronic GVHD - Lung
Inhaled steroids
Topical Therapy for Chronic GVHD - Oral
Topical steroids (dexamethasone, prednisolone, clobetasol, fluocinonide)
Topical tacrolimus ointment;
Topical cyclosporine rinse;
topical azathioprine rinse
Topical Therapy for Chronic GVHD - Eye
Artificial Tears;
topical steroids;
topical cyclosporine
Topical Therapy for Chronic GVHD - Vaginal
Topical steroids
Topical tacrolimus or pimecrolimus
2nd Line Therapy of Chronic GVHD -treatment
NO SOC
NOT TESTABLE
Patient history with prior therapies
Agents with non-overlapping toxicities
Patient preference
2nd Line Therapy of Chronic GVHD - when to consider
PROBABLY NOT ON TEST
Progression or new clinical manifestations on prednisone 1 mg/kg/day x 2 weeks
No improvement despite treatment for 4-12 weeks
Unable to taper prednisone < 1 mg/kg/day within 3 months or symptoms worsen during a taper < 0.5 mg/kg/day
Inability to tolerate therapy
extracorporeal photopheresis indx -2
skin and lung cGVHD
Bacterial px > 100 days (streptococcus pneumoniae) indx and dose -2
Allogeneic recipients with chronic GVHD (AIII)
Penicillin 500 mg BID or 1000 mg daily
Bacterial day 0 – 100 indx and dose -2
Consider fluoroquinolone with antipseudomonal
activity with anticipated neutropenia > 7 days
Levofloxacin (BI) or Ciprofloxacin (BII)
Yeast (Candida) Prophylaxis - auto
Prolonged neutropenia and mucosal damage from intense conditioning regimen,
graft manipulation,
recent purine analog exposure
Fluconazole 400 mg/day conditioning
through engraftment
Yeast (Candida) Prophylaxis - allo
Fluconazole 400 mg/day conditioning through day +75 (AI)
Itraconazole (CI)
Micafungin (BI)
Posaconazole (BI)
Voriconazole (BI)
Allogeneic Mold Prophylaxis (Aspergillus, Fusarium, Mucor) - PRE ENGRAFTMENT
Prolonged neutropenia
higher with cord blood or BMT
lower with peripheral blood and RIC transplant
Risk is higher with prolonged neutropenia prior to HSCT
Prophylaxis
micafungin 50 mg (BI)
Allogeneic Mold Prophylaxis (Aspergillus, Fusarium, Mucor) -POST ENGRAFTMENT
Immunodeficiency caused by GVHD and its treatment
higher risk include MUD, MMRD, and haploidentical
Prophylaxis
posaconazole 200 mg PO TID (BI)
Alternative: voriconazole 200 mg PO BID (BII)
VORI VS FLUC for alloHSCT px
NO DIFFERENCE
caveat: used aggressive monitoring that most centers don’t use
Pneumocystis jiroveci Prophylaxis - auto indx - 5
Hematologic malignancies,
intense conditioning regimens,
graft manipulation (t-cell depletion),
recent purine analog therapy (BIII),
—engraftment x 3 to 6 months after HSCT (CIII), OR longer if ongoing immunomodulatory therapy (ex. imides in MM)
Pneumocystis jiroveci Prophylaxis -allo
Engraftment x 6 months after HSCT, longer if patients continue to receive immunosuppressive drugs or have chronic GVHD (AII)
how long to continue VZV px in allo?
Routine acyclovir 800 mg PO BID during first year (BI) or 6 months after discontinuation of all immunosuppression (CIII)
CMV Prophylaxis
-No OS improvement
Ganciclovir 5 mg/kg/ dose IV BID x 5-7 days,
then once daily through day 100- start at engraftment (AI)
CMV Preemptive Therapy - allo
Ganciclovir 5 mg/kg/ dose IV BID 2 wk; or x 7 days+5 mg/kg/daily x2 wks; may go thru day 100
CMV Preemptive Therapy - auto
Consider monitoring until day + 60 in patients at risk (TBI, alemtuzumab, purine)
CMV Pneumonia tx
Ganciclovir 5 mg/kg/dose IV BID x 21 days + IVIG 500 mg /kg IV QOD x 21 days (NOTE: ADDED IVIG)
Maintenance x several weeks; longer if immunosuppression must be continued
CMV tx -Enteritis, esophagitis, hepatitis, retinitis, marrow infection
Ganciclovir 5 mg/kg/dose IV BID x 14-21 days or until resolution of process
Maintenance x several weeks; longer if immunosuppression must be continued
Varicella zoster virus tx
Acyclovir 10 mg/kg q 8 h x 7 -14 days;
Valacyclovir
Adenovirus tx
Taper / withdrawal immunosuppression
more in kids, cord blood tx
Human Herpes Virus 6 tx
Ganciclovir, cidofovir, foscarnet have in vitro activity
cord blood tx
Respiratory syncytial virus tx
Aerosolized ribavirin x 7-10days + IVIG (if LRI)
Influenza tx
Oseltamivir 75 – 150 mg BID x 10 days
BK virus tx
Hyperhydration
Taper / withdrawal immunosuppression
Cidofovir for hemorrhagic cystitis
Invasive Fungal Infection (IFI) Treatment Candidemia
Neutropenic: caspofungin / micafungin / liposomal amphotericin x 14 days + resolution of neutropenia (ESPECIALLY IF ON AZOLE)
Non-neutropenic: echinocandin preferred if recent azole exposure
Invasive Fungal Infection (IFI) Treatment Candidiasis
Neutropenic: liposomal amphotericin / caspofungin
Non-neutropenic: echinocandin preferred if recent
azole exposure; moderate to severe illness; at high
risk for infection due to C. glabrata or C. krusei
IFI Treatment –Invasive Aspergillosis
Voriconazole (survival advantage at 12 weeks over amphotericin B deoxycholate 71% vs. 58%)
Withdrawal/reduction in corticosteroids
A. terreus should received amphotericin B
IFI Treatment –Fusarium
Amphotericin B; voriconazole; posaconazole
IFI Treatment –Mucormycosis
Liposomal amphotericin B + echinocandin x 3 weeks, then posaconazole 200 mg PO QID
recommended vax - all 6mo later except MMR is 24 mo -8
PCV, TDap, haem inf, meningococcal, polio, hep B, influenza, MMR
Sinusoidal Obstruction Syndrome Veno-Occlusive Disease (VOD) - incidence and presentation
9-18%; mortality rate of severe VOD with supportive are alone was 84%
bilirubin > 2 mg/dL;
weight gain > 2-5% of baseline; hepatomegaly/right upper quadrant pain;
ascites
Sinusoidal Obstruction Syndrome Veno-Occlusive Disease (VOD) - Prevention
reduced intensity conditioning
target dosing of busulfan to AUC < 1500 Mol/min
ursodiol 12 mg/kg/day (myeloablative only) RR 0.34 (CI 0.17-0.66)
Sinusoidal Obstruction Syndrome Veno-Occlusive Disease (VOD) - Treatment
supportive care
defibrotide (compassionate use only)
Can you give a live vaccine to someone with GVHD?
NO
what is last immune cell to fully reconstitute?
CD4 T cell
Transplant Associated Thrombotic Microangiopathy (TMA) - incidence and presentation -4
2.5-25%; median survival ~ 39%
thrombocytopenia;
microangiopathic hemolysis (schistocytes, inc LDH, inc indirect bilirubin, dec haptoglobin)
renal dysfunction;
neurologic complications
Transplant Associated Thrombotic Microangiopathy (TMA) -treatment -4
best supportive care
decrease or discontinue calcineurin inhibitor and/or sirolimus
Plasma exchange – response rates of 40-60%
Rituximab – case reports
pulmonary sx - Idiopathic Pneumonia Syndrome
onset: Day 20-50
sx: Pneumonia, dyspnea, fever, non-productive cough, hypoxia
tx: Methylprednisolone 2 mg/kg/day THEN taper + Etanercept x 8 doses
pulmonary sx - Diffuse Alveolar Hemorrhage
onset: Day 12 - 19
sx: Shortness of breath, hypoxia, cough
tx: Methylprednisolone 2 mg/kg/day OR 1 g/m2/day
pulmonary sx - Periengraftment respiratory Distress Syndrome
onset: Day 4-7 post engraftment
sx: Fever, cough, dyspnea, rash, weight gain, edema
tx: Supportive care, Discontinue filgrastim, Prednisone 1 mg/kg/day THEN rapid taper
pulmonary sx - Bronchiolitis Obliterans Organizing Pneumonia
onset: Before day 100 (2-12 months)
sx: Fever, dry cough, shortness of breath
tx: Prednisone 1 mg/kg/day, tapered over 3-6 months
pulmonary sx - Bronchiolitis Obliterans
onset: 7-15 months
sx: Dry cough, dyspnea, wheezing; (NO fever)
tx: Prednisone 1-1.5 mg/kg/day taper over 6-12 months
Renal Complications - onset and presentation
6-12 months after HSCT
idiopathic, but may also be TMA, glomerulonephritis, nephrotic syndrome, radiation nephritis
Renal Complications - Treatment (for hypertension and CKD) mgmt
ACEI
ARB
secondary cancer screening - if TBI and chest irradiation
mammography at age 25 or 8 years after radiation, which ever is later, no later than age 40
secondary cancer screening - Chronic GVHD
screen for oral / pharyngeal cancer
Treatment of Late Complications - oral
Discontinue medications that cause oral dryness
Artificial saliva substitutes, sugar – free candy/ gum
Sialogogues (pilocarpine / cevimeline); oral hygiene
Treatment of Late Complications - C/V
Hypertension – manage per JNC 7
Hyperlipidemia – manage per NCEP III
Diabetes – insulin for short-term use; sulfonylurea, metformin and sitagliptin
Treatment of Late Complications -Thyroid
Thyroid hormone replacement (levothyroxine)
Treatment of Late Complications - Male hypogonadism
If symptomatic (low libido, erectile dysfunction, fatigue, bone loss) and low testosterone may use testosterone replacement
Treatment of Late Complications - Primary ovarian failure
Vaginal hypoestrogenism – topical estrogen / lubricant
Hormone replacement therapy until age of normal
menopause – estradiol + cyclic medroxyprogesterone (35yo different risk profile than 55yo)
Treatment of Late Complications - Skeletal Complications -osteoporosis - PREVENTION -4
Calcium 1200 mg / day + Vitamin D 800-2000 IU daily
LABS (25 hydroxyvitamin D > 30 ng/mL)
Weight bearing exercise
fall prevention
smoking cessation
Treatment of Late Complications - Skeletal Complications - osteoporosis - TREATMENT -3
Bisphosphonate
Hormone replacement therapy if deficient
2nd line: teriparatide, denosumab, raloxifene
Treatment of Late Complications - Iron Overload -4
Treatment considered if ferritin > 2500 ng/mL or
hepatic iron > 7 mg/g dry weight
Goal ferritin < 500 – 1000 ng/mL
Phlebotomy if hematocrit > 38%
Deferoxamine, deferiprone, deferasirox may be considered although there is no evidence in HSCT patients and significant risk of toxicity
