Hematopoietic Cell Transplant (HCT)

Types of transplant:

Allogeneic HCT:

• Infusion of hematopoietic cells (CD34⁺) from a HLA-compatible donor after cytotoxic conditioning to eradicate disease and enable engraftment.

• Used in order to deliver high doses of chemotherapy + “graft vs. tumor” (GVT) effect

  • GVT affect: immune-mediated cytotoxic effect exerted by donor-derived immune cells against the recipient’s neoplastic cells following allo-HCT

• ~30-50% of allo-HCT develops with acute GVHD (aGVHD)

• Most commonly used for high-risk or relapsed hematologic malignancies (high-risk AML, high-risk MDS, ALL) and non-malignant uses include severe aplastic anemia, Hemoglobinopathies (sickle cell disease, β-thalassemia major), congenital immunodeficiencies, etc.

• Leads to 5-year disease free survival rates of 30-55% when done during 1st remission

Autologous HCT:

• Hematopoietic cells collected from the patient prior to high-dose chemo are infused back into the patient after administration of the preparative regimen, with the primary goal of "rescuing" hematopoietic function that is damaged by the chemotherapy

• GVHD is rare

• Most commonly used for chemosensitive diseases such as multiple myeloma, followed by NHL and HL, and some solid tumors (neuroblastoma and testicular germ cell tumors)

• Leads to 5-year disease free survival rates of 45-65% when done during 1st remission

• Auto-HCT is associated with less morbidity and mortality but greater risk of disease relapse compared to allo-HCT

Pre-Transplant Evaluation:

• Confirmation of diagnosis and disease status

  • Cytogenetics/molecular testing, MRD, etc.

• ABO/Rh typing

  • ABO incompatibility is not a contraindication to transplantation

• Performance status (ECOG/KPS)

• Comorbidity index:

  • Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI)

• Organ function (pulmonary, cardiac, renal, hepatic)

• Infectious disease screening (CMV, HBV, HCV, HIV)

• Psychosocial evaluation/ support systems

• Human leukocyte antigens (HLA) typing for allogeneic candidates

Donor Selection (for allo-HCT):

• The preferred donor is an HLA-matched sibling. If unavailable, matched unrelated donors, haploidentical family members, or umbilical cord blood may be considered.

• Donor age and health are important predictors of outcome.

• HLA matching:

  • Critical to minimize graft failure and GVHD.

  • Major Histocompatibility Complex (MHC) Locus is a region on the short arm of chromosome 6 that contains genes encoding cell surface glycoproteins including the HLA class I (HLA-A, HLA-B, HLA-C) and HLA class II (HLA-DR, HLA-DQ, HLA-DP).

  • Related donor:

    • HLA genes are inherited as haplotypes (one from each parent). Therefore, there is a 25% chance that full sibling would be HLA matched.

    • HLA-matched sibling donors are preferred over HLA-matched unrelated donors because they share more non-HLA genetic background → fewer minor histocompatibility antigen differences → lower risks of GVHD and improved outcomes

    • Haploidentical means half-matched HLA genotype

      • Parent is 100% and sibling is 50% likely to be a haploidentical donor.

  • Unrelated donor:

    • ~30-75% of patients find an optimal (8/8) HLA-matched unrelated donor

      • Highest rates: white non-Hispanic/European descent

      • Lowest rates: Black and minority populations

• ABO Blood Groups:

  • Hematopoietic stem cells do not express ABO, therefore, ABO matching is not required for transplantation.

    • Residual donor RBCs or plasma antibodies can still lead to incompatibilities, resulting in hemolysis (immediate or delayed) or delayed RBC recovery (pure red cell aplasia).

  
  

Sources of graft/stem cells:

Graft source is chosen based on disease, patient comorbidities, and urgency.

• Peripheral Blood:

  • Requires plerixafor (CXCR4 antagonist) ± GCSF/GMCSF (mobilize CD34+ cells) followed by leukapheresis

  • Preferred source of graft (ease of collection, reduced cost, better safety, faster engraftment)

    • Similar rate of aGVHD, higher rate of cGVHD

  • Hypocalcemia and cramping may occur due to citrate toxicity

    • Supplemental calcium is typically given during leukapheresis 

• Bone Marrow:

  • Requires multiple BM aspirations from bilateral posterior iliac crests

  • Generally quick turnaround time to transplant (from donor to recipient)

    • Cryopreservation is possible, but not preferred

• Umbilical Cord Blood (UCB):

  • Has less mature T cells (HLA matching is less stringent) → less risk of GVHD

  • lower hematopoietic cells (CD34⁺) → Higher rate of graft rejection/failure

    • Engraftment time is longer

    • Use of two cords (to achieve adequate number of CD34+ cells) reduces risk of failure/rejection and shortens engraftment time

Conditioning Regimens:

• Conditioning intensity is tailored to disease type, patient age, comorbidities, and remission status.

• Eradicate any remaining disease, create space for engraftment, and immunosuppress the host to prevent graft rejection (for allo-HCT).

• Patients with severe combined immunodeficiency (SCID) often require no preparative regimen before HCT because they lack a functional immune system

• Categories:

  • Myeloablative regimens:

    • Cause irreversible marrow aplasia and requires replacement stem cells

    • Preferred for younger, fit patients with aggressive disease.

    • Common regimens:

      • Cyclophosphamide + Total body irradiation (TBI)

      • Cyclophosphamide + Busulfan

      • Fludarabine + Busulfan

  • Non-myeloablative regimens/ low-intensity:

    • Less myelosuppression

    • For older or frail patients, or those with indolent disease.

    • Provide a graft vs. tumor (GVT) effect, with similar anti-cancer outcomes and less toxicity compared to myeloablative regimens

    • Lower non-relapse mortality but higher relapse rates compared to myeloablative regimen

Transplant Procedure:

• After conditioning, donor hematopoietic cells (from peripheral blood/BM/UCB) are infused.

• Engraftment is monitored by blood counts and chimerism analysis (for allo-HCT).

  • Chimerism analysis is a test used after HCT to determine what proportion of a patient’s blood or BM cells come from the donor vs the recipient.

Post-Transplant Care:

• Intensive supportive care is required until engraftment.

• Monitoring for GVHD (in allo-HCT), infections and organ toxicities.

• Long-term follow-up to address late adverse effects, cGVHD and disease relapse.

Complications:

GVHD:

• Mediated by B cells (mostly in cGVHD) and T cells reacting against host cells

• Major cause of non-relapse mortality.

• Acute GVHD:

  • Usually develops within the first 100 days after HCT (mostly in 2-6 weeks)

  • Commonly affects the skin (maculopapular rash), GI tract (N/V, anorexia, diarrhea, ileus), and liver (jaundice, hyperbilirubinemia)

    • May be diagnosed with biopsy, not absolutely required if clinical findings are classic

  • Treatment:

    • Prednisone 1-2 mg/kg/day ± topical steroids for skin or GI disease

    • Steroid-refractory aGVHD:

      • Ruxolitinib (JAK-2 inhibitor): The only FDA-approved category 1 agent

      • Antithymocyte globulin (ATG) is listed as an alternative option

• Chronic GVHD:

  • Presents more indolently

  • Clinical features that mimic autoimmune/connective tissue diseases:

    • Sclerotic skin changes, lichen planus-like oral lesions, dry eyes, bronchiolitis obliterans, esophageal involvement

  • Treatment:

    • Prednisone ± calcineurin inhibitor ± topical/inhaled steroids

    • May need to re-escalate immunosuppression if had been tapering

    • Steroid-refractory cGVHD:

      • Ruxolitinib (category 1)

      • Ibrutinib, Belumosidil, Axatilimab (FDA-approved)

    • May need to re-escalate immunosuppression if had been tapering

• Prophylaxis:

  • Immunosuppression with calcineurin inhibitor (cyclosporine, tacrolimus) + antimetabolite (MTX, Mycophenolate Mofetil)

    • ± post transplant cyclophosphamide (PTCy), ATG, abatacept

Autoimmune:

• Common autoimmune complications:

  • Autoimmune cytopenias (Hemolytic anemia, ITP, neutropenia)

  • Thyroid disorders

  • Neuromuscular diseases (Myasthenia gravis)

  • Rheumatologic diseases (RA, vasculitis, scleroderma-like syndromes)

  • Skin manifestations (Vitiligo, psoriasis)

• Treatment: Immunosuppression 

Infection:

• Significant cause of morbidity and mortality due to immunosuppression from transplant or GVHD ppx/treatment

• Vaccination:

  • Normal Ab titers from previous vaccinations usually downtrends post transplant, will need revaccination.

  • Live vaccines are usually given after 2 years to avoid complications.

• Bacterial:

  • Before engraftment:

    • Fluoroquinolone is often given if prolonged (> 7–10 days) or high‐risk neutropenia is expected

  • After engraftment:

    • Consider Bactrim (+ PJP ppx) and penicillin if at risk for infection

• Fungal:

  • Antifungal ppx is standard, typically with fluconazole

    • Typically continued until 75 days post transplant

  • Consider mold coverage (voriconazole/posaconazole) for higher risk patients (GVHD, prolonged neutropenia)

• Viral:

  • HSV:

    • Prophylaxis: Acyclovir, valacyclovir, Famciclovir

      • Begin with conditioning and continue during neutropenia or until mucositis resolves (typically at least 30 days post-HCT)

      • Consider extended prophylaxis for those with ongoing immunosuppression or cGVHD.

    • Treatment: Acyclovir, valacyclovir, Famciclovir, Foscarnet (for refractory/resistant infections)

  • VZV:

    • Consider VZV prophylaxis for at least 1 year after allo-HCT

    • If cGVHD or ongoing immunosuppression:

      • Zoster vaccine may be administered after the end of antiviral prophylaxis

        • 12–18 months after allo-HCT

        • 3–12 months after auto-HCT

  • CMV:

    • Mostly involves GI tract or lungs

    • Prophylaxis with Letermovir for up to day 100-200 post-HCT in CMV seropositive allo-HCT recipients

      • Not associated with bone marrow suppression (unlike ganciclovir or valganciclovir)

    • Treatment:

      • Ganciclovir

      • Maribavir: for refractory/resistant infections

      • Foscarnet: Nephrotoxic and requires monitoring of electrolytes

• Iatrogenic (due to conditioning regimen):

  • Hemorrhagic cystitis ← Cyclophosphamide

  • Parotiditis ← Total body irradiation

  • Oral mucositis

    • Usually requires analgesia

  • Veno-Occlusive Disease/ Sinusoidal Obstruction Syndrome (VOD/SOS):

    • Life-threatening complication of HCT/certain chemo regimens

    • Toxic injury to the liver sinusoidal endothelial cells → necrosis and detachment → obstruction of small hepatic venules and sinusoids → post-sinusoidal portal HTN and impaired hepatic blood flow

    • Associated with Antibody Drug Conjugates (ADC) with calicheamicin

      • Inotuzumab ozogamicin

      • Gemtuzumab ozogamicin

    • Prophylaxis: Urosodiol

      • Recommended for all patients undergoing allo-HCT

      • Start before conditioning and continue for several months post-HCT.

    • Treatment:

      • Defibrotide: Only FDA-approved treatment for moderate-severe cases

• Pulmonary complications:

  • Idiopathic pneumonia syndrome

  • Restrictive lung disease

    • Cryptogenic organizing pneumonia (COP)

      • Treated with steroids

  • Obstructive lung disease

    • Bronchiolitis obliterans

      • Treated with increased immunosuppression

Timeline of common complications:

• Pre-engraftment (less than 30 days following HCT)

  • Neutropenia:

    • Leukocyte count starts to recover after 1-3 weeks post-HCT (usually later if UCB is used)

    • Administration of GCSF post-HCT reduces the duration of neutropenia and often shortens hospitalization but does not improve overall survival or infection-related mortality.

      • Platelet count usually lags behind by days to weeks.

    • Engraftment syndrome:

      • Occurs during neutrophil recovery after HCT due to release of pro-inflammatory cytokines (TNF, IL-1)

      • Common symptoms: Fever, skin rash, pulmonary infiltrates or edema, diarrhea, and hepatic or renal dysfunction

      • Must be differentiated from aGVHD and infectious complications

      • Steroids are mainstay of treatment

  • Mucositis

  • Infections:

    • HSV, gram- bacteria, gram+ bacteria from GI tract, Candida, Aspergillus

• Post-engraftment (days 30 to 100)

  • aGVHD tends to occur here

    • Drugs used for GVHD ppx (cyclosporine/tacrolimus) can cause TMA

  • Characteristic infections: CMV, PJP, aspergillus

• Late phase (>100 days) 

  • cGVHD tends to occur here

  • Characteristic infections: VZV, aspergillus, PJP, other encapsulated bacteria

Graft Failure:

• Usually due to host immune system rejecting donor marrow 

• The greater disparity in HLA antigens, the higher chance of rejection

• Other potential causes:

  • Prior exposure to stem cell poisons

  • Marrow damage during processing/storage

  • Drug toxicity after HCT

  • Viral infections

• Prognosis of hematologic malignancies that relapse after HCT is extremely poor

• Post-HCT maintenance therapies:

  • Multiple myeloma: Lenalidomide

  • Hodgkin Lymphoma: Brentuximab Vedotin