Bone Marrow Transplant

Emily Serata

Definitions

  • Autologous Stem Cell Transplant (AutoSCT): patient’s own stem cells.
  • Allogeneic Stem Cell Transplant (AlloSCT): HLA-compatible donor.
  • Matched Related Donor (MRD): HLA-compatible family member.
  • Matched Unrelated (MUD): from NMDP database.
  • Mismatched Donor (MMD): Mismatching HLA.
  • Haploidentical: most common parent, sibling, offspring.
  • Syngeneic Stem Cell Transplant (SynSCT): identical twin, functionally ~ AutoSCT.
  • Umbilical Cord Blood Transplant (UCBSCT): HSCTs from umbilical cord following delivery, frozen and banked (generally not enough for an adult person).
  • Donor specific antibodies (DSAs): antibodies produced by transplant recipient targeting HLA antigens from donor organ.

Indications for BMT 

  • 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 – can induce graft vs. leukemia), sometimes for MDS, CML, ALL, CLL, lymphomas; nonmalignant indications include aplastic anemia, immunodeficiency, hemoglobinopathy).

Recipient and Donor Selection

  • Recipient: Generally younger (<75), fit (ECOG 0-1), few comorbidities; 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, younger, sibling over non-sibling (less minor HLA mismatch), male donor (prevent Y antigen mismatch), nulliparous female (less minor HLA mismatch).
  • Graft source: peripheral HSCs harvested via apheresis after G-CSF (higher chronic GvHD rates) vs. HSCs from bone marrow (more difficult, lower yield, and possibly high relapse rate).

Choosing the Match 

  • Molecular typing of MHC-I (HLA-A, HLA-B, HLA-C) and MHC-II (HLA-DRB1, HLA-DQB1) of donor and recipient.
  • Matched sibling donor (MSD) > Matched unrelated donor (MUD) > Haploidentical/mismatched unrelated donors (MMUD).

Common Conditioning Regimens 

  • Myeloablative (MAC) regimens: cause irreversible pancytopenia/destruction bone marrow in preparation for HSC transplant – TBI-based vs. Busulfan-based regimens.
  • Non-myeloablative (NMA) regimens: produce minimal cytopenia - Fludarabine+ regimens - Reduced intensity (RIC): used for older patients with comorbidities, do not fit into MAC/NMA - Fludarabine+ regimens.

Complications

Non-infectious 

  • Oral Mucositis: peaks day +6-12; PPX with ice chips during infusion of high dose melphalan (“cryotherapy”) - treatment 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; 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, Rituximab.
  • 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

  • Neutropenic Fever: common, manage as per Neutropenic Fever section.
  • Neutropenic enterocolitis (typhlitis): polymicrobial necrotizing infection most commonly of cecum 2/2 GPC/GNR/Anaerobes (Clostridium septicum)/fungi (Candida), S/Sx: fever, N/V, lower abdominal pain, diarrhea +/- blood; Dx CT w oral and IV contrast; Tx initial ABX with Zosyn or cefepime/metro, maybe carbapenem, fungal coverage if febrile >72 hours; 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, Nocardia.
  • 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.).
  • Common respiratory and enteric viruses: Flu, COVID, RSV, adenovirus.
  • Fungi: Candida (esp. neutropenia with mucositis), aspergillus (prolonged neutropenia), toxoplasmosis.
  • Early Post-Engraftment: Engraftment until ~ +100; risk factors: impaired cellular and humoral immunity especially when immunosuppressed for GvHD.
  • Late post-engraftment: after day +100; risk factors: impaired cellular and humoral immunity.
  • Infectious PPX:
    • Bacterial: Fluoroquinolone until ANC>500 (levo or cipro).
    • Viral: HSV, VZV: (val)acyclovir 6-12M for allo SCT.
    • CMV: CMV seropositive recipients get Letermovir.
    • Fungal: Usually fluconazole in pre-engraftment period, those with prolonged neutropenia or GvHD requiring immunosuppression may need coverage for molds with posaconazole.
    • PJP: Bactrim starting after engraftment then for ~6 months (autoSCT) or ~12 months (alloSCT); high variability.
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