Bone Marrow Transplant

Chelsie Sievers

Michael Kaminski

Definitions

  • Autologous Stem Cell Transplant (AutoSCT):
  • Allogeneic Stem Cell Transplant (AlloSCT):
    • Matched Related Donor (MRD)
    • Matched Unrelated (MUD): from NMDP database
    • Mismatched Donor (MMD)
    • Haploidentical: most common parent or sibling
  • Syngeneic Stem Cell Transplant (SynSCT): identical twin, functionally ~ AutoSCT
  • Umbilical Cord Blood Transplant (UCBSCT): HSCTs from umbilical cord following delivery, frozen and banked
  • Donor specific antibodies (DSAs): testing recipient for Abs against HLAs of donors >> increased risk of graft failure from DSAs

Indications for Transplant 

  • AutoSCT: multiple myeloma (most common) and other plasma cell disorders, relapsed lymphomas, solid tumors (germ cell tumors, pediatric tumors)
  • AlloSCT: malignancies including AML (most common), sometimes for MDS, CML, ALL, CLL, lymphomas; nonmalignant indications include aplastic anemia, immunodeficiency, hemoglobinopathy)
    • Important reason for AlloSCT in AML is graft vs leukemia effect whereby donated cells eliminate remnant AML tumor cells following myelo-ablative conditioning

Recipient and Donor Selection

  • Recipient: Generally younger (<70), fit (ECOG 0-1), fewer comorbidities but variable by institution and attending; pretransplant: infectious studies (Hepatitis A/B/C, EBV, CMV, HSV, HTLV-1, toxo); T+S, DSAs, TTE, PFTs; psychosocial evaluation
  • Donor: all else being equal: better match is preferred (see below), younger is preferred, sibling preferred over non-sibling (less minor HLA mismatch), male donor (prevent Y antigen mismatch), nulliparous female (less minor HLA mismatch)
  • Graft source: most commonly peripheral HSCs harvested via apheresis after donor receives G-CSF for ~4 days, but higher chronic GvHD rates; alt is HSCs from bone marrow but more difficult, lower yield, and possibly high relapse rate, may be preferred for non-malignant SCT indications due to less GvHD; in pediatric population and very rarely adults can use umbilical cord blood HSCs

Choosing the Match 

  • Molecular typing of MHC-I (HLA-A, HLA-B, HLA-C) and MHC-II (HLA-DRB1, HLADQB1) of donor and recipient.
    • MRD: fully matched is 10/10
    • MUD: fully matched is 10/10; NOTE may also type HLA-DPB1 so maybe 12/12;
    • MMD: 8-9/10 match, more GvHD and graft failure
    • Haploidentical: 5/10 match; cyclophosphamide on transplant days +3 and +4 decreases GvHD and graft failure, maybe more graft vs tumor via NK cells
  • MUDs chosen from banks, inequities in ability to find match based on race of recipient (white more likely to find match in bank, African American least likely

Common Conditioning Regimens 

  • Myeloablative (MAC) regimens: Chemo +/- RT destroys recipient bone marrow
    • AutoSCTs: MM (high dose melphalan); Lymphoma (BEAM-BCNU, Etoposide, Ara- C, Melphalan); Solid tumors (MEC-Melphalan, Etoposide, Carboplatin)
    • AlloSCTs: Cy/TBI (Cyclophosphamide, Total Body Irradiation); Bu4/Cy (Busulfan x4 days, Cyclophosphamide, MESNA); Flu/Bu x4 (Fludarabine, Busulfan x4 days)
  • Reduced intensity (RIC)/non-myeloablative (NMA) regimens: gentler for less fit patients, lower treatment related morbidity/mortality but higher relapse rates
    • Common RIC regimens: Flu/Mel (Fludarabine + Melphalan), Flu/Bu2 (Fludarabine + Busulfan x2 days)
    • Common NMA regimens: Flu/TBI; TLI/ATG (Total Lymphoid Irradiation + Anti- Thymocyte Globulin)
  • Toxicities: Mucositis, N/V/D, Rash, Alopecia, Peripheral Neuropathy

Complications

Non-infectious 

  • Oral Mucositis: peaks day +6-12; PPX with ice chips during infusion of high dose melphalan (“cryotherapy”); Tx with topical/IV pain meds
  • Diarrhea: non-oral mucositis vs Acute GvHD vs Infectious (C diff, CMV, etc)
  • Engraftment Syndrome: days-weeks after neutrophil recovery;
    • Pathophysiology: PMN recovery >> cytokine storm >> vascular leak
    • S/Sx: fever, tachycardia, rash, pulmonary edema, LE edema; AKI, transaminitis;
    • Dx of exclusion after infectious wu negative and aGvHD ruled out HEMATOLOGY-ONCOLOGY 247
    • Tx: 1 mg/kg steroids with rapid taper
  • Graft Failure: Rejection of donor stem cells, primary (never engrafted) vs secondary (engrafted then failed); Dx by measuring donor/recipient chimerism; Tx: some form of repeat transplant, growth factors, intensive immunosuppression
  • Hepatic Sinusoidal Obstruction:
    • Days-weeks following transplant in up to 15% of pts
    • Pathophysiology: hepatic sinusoidal endothelial injury >> inflammation, coagulation cascade activation >> obstructs hepatic veins >> portal HTN and organ failure; inc. risk if liver disease and MAC and previous treatment with gemtuzumab-ozo
    • Dx: EBMT diagnostic criteria: Bili>2 plus 2 of: hepatomegaly, weight gain >5%, ascites, also get RUQ US w doppler
    • PPX: UDCA; Tx: possibly defibrotide if severe
  • Idiopathic Pulmonary Syndrome: umbrella term including peri-engraftment respiratory distress syndrome (PERDS)
    • Days 30-90
    • Pathophysiology: alveolar injury 2/2 direct toxicity >> cytokine release >> alloreactive T cells >> noninfectious pneumonitis, edema resembling ARDS >> fever and hypoxia
    • Dx: CXR: diffuse infiltrates, maybe bronch and BAL
    • Tx: supportive +/- prednisone 1 mg/kg or pulse 1 g/d, etanercept 2nd line
  • Other pulmonary complications: DAH (early) versus bronchiolitis obliterans syndrome (BOS) and cryptogenic organizing PNA (COP) (late)
  • Post-transplant Lymphoproliferative Disorders (PTLD)
    • Pathophysiology: EBV reactivation iso immunosuppression>>clonal B cell proliferation; S/Sx with fever, wt loss, fatigue, LAD
    • Dx: EBV PCR, possibly Biopsy
    • Tx: reduce immunosuppression, maybe ritux
  • Graft vs Host Disease (GvHD):
    • Acute GvHD: usually day <100; increased risk with more HLA mismatch, older donor, female donor/male recipient, peripheral blood SCT>Marrow
      • Pathophysiology: donor T cells in graft attack recipient tissues (Th1-mediated), proliferate and persist to transition to chronic inflammation and tissue damage most pronounced in skin (maculopapular rash, desquamation), luminal GI tract (diarrhea), liver (cholestatic predominant liver injury)
      • Dx: rule out infectious causes of rash/diarrhea, possibly skin biopsy; grading
      • Tx: depends on severity; Grades 1-4; Grade 1: topical steroids (skin cream/ointment vs PO nonabsorbable steroid for luminal GI); Higher grades: IV steroids (IV methylpred 1-2 mg/kg), maybe MMF, etanercept, ruxolitinib
    • Chronic GvHD: generally >100 days post alloSCT, incidence ~40%, risk factors similar to aGvHD
      • Pathophysiology: chronic inflammation 2/2 Th2/auto Ab production >> acellular fibroproliferative scleroderma-like picture; skin: rashes and skin thickening, alopecia, dystrophic nails; arthralgias/inflamed joints; mouth/eyes: xerostomia and keratoconjunctivitis sicca; luminal GI: N/V, malabsorption, dysmotility, stricture; hepatic: cholestasis; pulmonary: DOE, non-productive cough, bronchiolitis obliterans; marrow: cytopenias
      • Dx: NIH consensus criteria for Dx and grading: mild/moderate/severe; biopsy
      • Tx: Mild: topical steroids when able (skin/luminal GI); Moderate-Severe: steroids +/-immunosuppressive agents like ruxolitinib (JAK inhibitor), belumosudil (ROCK2 inhibitor), cyclophosphamide, tac
    • GvHD PPX: day ~ -3 onward, common agents include tac/MTX, tac/sirolimus, MMF; maybe add post-transplant cyclophosphamide

Infectious

  • Pre-Engraftment: Day 0 until ~ +30; risk factors: neutropenia, mucositis/lines
    • Neutropenic Fever: common, manage as per Neutropenic Fever section
    • Neutropenic enterocolitis (typhlitis): polymicrobial necrotizing infection most commonly of cecum 2/2 GPC/GNR/Anaerobes (Clost septicum)/fungi (Candida), S/Sx: fever, N/V, lower abdominal pain, diarrhea +/- blood; Dx CT w oral and IV contrast; Tx intitial ABX with zosyn or cefe/metro, maybe carbapenem, fungal coverage if febrile >72 hrs; surgery consult if concern for perf
    • Line infections: S/Sx: erythema, pain of catheter insertion site, usually pathogens are skin flora (Staph, Strep)
    • Bacteria: GPCs, GNRs, GI Strep species
    • Viruses:
      • CMV (check weekly PCR post allo-SCT, PPX with letermovir, Tx with IV ganciclovir or PO valganciclovir)
      • EBV (weekly PCR post allo-SCT, if VL >1000 on 2 occasions can Tx with preemptive ritux to reduce risk of PTLD;
      • HSV (esp with mucositis)
      • Common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.) o
    • Fungi: Candida (esp. neutropenia with mucositis), aspergillus (prolonged neutropenia)
  • Early Post-Engraftment: Engraftment until ~ +100; risk factors: impaired cellular and humoral immunity especially when immunosuppressed for GvHD
    • Bacteria: GPCs, GNRs
    • Viruses: CMV (pneumonitis, diarrhea/colitis, retinitis, hepatitis), EBV (PTLD); BK or adeno (hemorrhagic cystitis); HSV or HHV-6 related encephalitis, common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.)
    • Fungi: Candida, Molds like aspergillus; PCP (esp with prolonged steroids for GvHD)
  • Late Post-Engraftment: after day +100; risk factors: impaired cellular and humoral immunity
    • Bacteria: Encapsulated bacteria Strep pneumonia, H flu, Neisseria (sinusitis, PNA); Nocardia (PNA +/- skin), Listeria (diarrhea, meningitis)
    • Viruses: CMV (pneumonitis, diarrhea/colitis, retinitis, hepatitis), EBV (PTLD, hepatitis); BK or adeno (hemorrhagic cystitis); JC (PML), HSV or HHV-6 (encephalitis, hepatitis), VZV (shingles, hepatitis, encephalitis), common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.)
    • Fungi: Molds like aspergillus (PNA, invasive rhinosinusitis); Cryptococcus (PNA, skin, encephalitis); PCP (PNA, esp with prolonged steroids for GvHD)
    • Parasitic: toxoplasmosis (PNA, encephalitis)
  • Infectious PPX:
    • Bacterial: Fluoroquinolone until ANC>500 (levo or cipro) o Viral
      • HSV, VZV: (val)acyclovir 6-12M depending on auto vs allo SCT, immunosuppression (allo)
      • CMV: CMV seropositive recipients get letermovir PPX
    • Fungal: Usually fluconazole in pre-engraftment period, those with prolonged neutropenia or GvHD requiring immunosuppression may need coverage for molds with voriconazole or posaconazole
    • PCP: Bactim starting after engraftment then for ~6 months (autoSCT) or ~12 months (alloSCT); high variability
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