12:21:32 – Allogeneic Stem Cell Transplant for Malignancy

Summary

Key Points

  • Allo-SCT (allogeneic stem cell transplant) is a medical procedure to eradicate high-risk hematologic malignancies using conditioning therapy in the form of chemotherapy with or without radiation, followed by IV infusion of donor-derived hematopoietic stem cells
  • Over the past 60 years, allo-HCT (allogenic hematopoietic cell transplant) has evolved from an experimental procedure to the standard of care for a wide range of hematologic malignancies. Allo-SCT remains the only potential curative option for many patients
  • Continuum of care for allo-SCT recipients includes pretransplant candidacy assessment, conditioning therapy, peritransplant care, and ongoing posttransplant care
  • Patients and potential donors undergo comprehensive evaluation before transplant
  • High-dose chemotherapy, with or without total body irradiation, is administered over several days immediately preceding stem cell infusion to eradicate residual malignancy and create a tolerant environment for donor hematopoietic cells
  • Immunosuppressive and prophylactic medications are initiated in the peritransplant period
  • The posttransplant period after allo-SCT is associated with severe myelosuppression, immunosuppression, and risk of GVHD (graft-versus-host disease), infection, and various organ toxicities
  • Important posttransplant care considerations include hematopoietic support, GVHD prophylaxis and surveillance, management of organ toxicities, prevention/management of infection, and ongoing monitoring and follow-up
  • After disease relapse, GVHD is a principal cause of morbidity and mortality after allo-SCT
  • The risk of disease relapse is highest during the first 6 to 12 months after transplant. The risk of disease relapse after allo-SCT depends on underlying disease and pretransplant disease status
  • Survival after allo-SCT largely depends on underlying malignancy, since disease relapse remains a major driver for mortality

Alarm Signs and Symptoms

  • Allo-SCT recipients are chronically immunocompromised, potentially for life. Infections in allo-SCT recipients should be managed aggressively including consultations with transplant physician and infectious disease specialist
  • GVHD is a common and potentially life-threatening complication of allo-SCT. Common symptoms of GVHD are nausea, vomiting, diarrhea, skin rash, and jaundice. Prompt evaluation and initiation of immunosuppressive therapies such as high-dose steroids are important to control GVHD

Basic Information

Terminology

  • Allo-SCT (allogeneic stem cell transplant) is a medical procedure to eradicate high-risk hematologic malignancies using conditioning therapy in the form of chemotherapy with or without radiation, followed by IV infusion of donor-derived hematopoietic stem cells. HCT (hematopoietic cell transplant) and HSCT (hematopoietic stem cell transplant) are other terms used in reference to the process of stem cell transplant
    • There are 3 main sources of hematopoietic stem cells for allo-SCT:
      • Mobilized peripheral blood stem cells
      • Bone marrow stem cells
      • Cord blood units
    • Common donors are family members such as a sibling, parent, or child, as well as unrelated donors from bone marrow transplant registries such as Be The Match, operated by the National Marrow Donor Program
  • “Allogeneic” refers to the use of stem cells derived from a donor, in contrast to an autologous stem cell transplant, which uses the patient’s own stem cells. Allo-SCT is the focus of this clinical overview.
  • Conditioning regimens are treatments consisting of high-dose chemotherapy with or without total body irradiation administered to the patient before stem cell infusion to eradicate any residual malignancy and create a receptive environment for donor-derived stem cells
    • There are several types of conditioning regimens:
      • MAC (myeloablative conditioning): higher-intensity regimens associated with profound pancytopenia that is long lasting and usually irreversible unless hematopoiesis is restored by infusion of hematopoietic stem cells
      • NMA (nonmyeloablative) NMA conditioning: lower-intensity regimens causing pancytopenia that is reversible without need for hematopoietic cell infusion
      • RIC (reduced-intensity conditioning): regimens that do not meet criteria for MAC or NMA conditioning and can cause pancytopenia of variable duration; generally followed by stem cell infusion, although pancytopenia may not be irreversible without
  • TRM (transplant-related mortality) is patient death due to allo-SCT–related complications before disease relapse
    • Common causes of TRM are GVHD (graft-versus-host disease), organ toxicity, and infections
  • GVHD
    • Common complication of allo-SCT associated with significant morbidity and mortality; GVHD is a result of abnormal immune reactions from the transplanted donor immune cells to the recipient, leading to tissue injury and inflammation

Background Information

  • Over the past 60 years, allo-HCT (allogeneic hematopoietic cell transplant) has evolved from an experimental procedure to the standard of care for a wide range of hematologic malignancies
  • Despite significant advances in systemic chemotherapy and targeted agents, these treatments are not curative for the majority of hematologic malignancies, including acute leukemia and myelodysplastic syndrome. Allo-SCT remains the only potential curative option for many patients
  • More than a million allo-HCTs have been completed, and utilization of allo-HCT is rapidly increasing with advancements in HLA typing, newer RIC regimens, and improvement in prevention and treatment of GVHD
  • Donor availability used to be a major challenge for members of racial and ethnic minority groups. The use of partially HLA-matched family (haploidentical) or unrelated donors with posttransplant cyclophosphamide in the past 5 years has significantly improved access to allo-HCT for these patients
  • Disease relapse after allo-HCT remains a major issue, which is being addressed by rapid advances in adoptive cell therapies and posttransplant maintenance strategies
  • GVHD treatment and prevention have also seen significant evolution, with 3 drugs (ibrutinib, ruxolitinib, belumosudil) for treatment and 1 drug (abatacept) for prevention of GVHD approved by FDA

Risk Models and Risk Scores

  • Various risk score calculators are available for use in predicting mortality and survival outcomes after allo-SCT: DRI (Disease Risk Index), HCT-CI (Hematopoietic Cell Transplantation-Comorbidity Index), and EBMT (European Group for Blood and Marrow Transplantation) risk score are among the most widely used
  • Recommendations regarding use of one risk score calculator over another cannot be made, and clinicians should use these tools along with other patient- and transplant-related variables to assess individual risks and benefits of allo-HCT
  • DRI
    • Web-based calculator to estimate overall survival after allo-SCT
    • DRI accounts for pretransplant disease control, remission status, and various cytogenetic and molecular abnormalities
  • HCT-CI (hctci.org)
    • Calculate impact of preexisting comorbidities on mortality after allo-SCT
    • Comorbidities used in HCT-CI: pulmonary disease, cardiac disease, hepatic disease, renal disease, other malignancies, diabetes, cerebral vascular disease, rheumatologic disease, peptic ulcer disease, psychiatric disturbances, infection history, inflammatory bowel disease, obesity
  • EBMT risk score
    • Prediction tool for transplant-related mortality and 5-year survival after allo-SCT
    • Factors used in EBMT risk score: donor type, disease stage, recipient age, sex matching, time from diagnosis to allo-SCT

Treatment

Approach to Treatment

  • Goal of treatment is to cure the underlying hematologic malignancy
  • Continuum of care for allo-SCT (allogeneic stem cell transplant) includes:
    • Pretransplant candidacy assessment
    • Conditioning (immediately before transplant)
    • Peritransplant care
    • Posttransplant care (early, up to 3 months and late, after 3 months)

Treatment Procedures

Pretransplant Candidacy Assessment

  • Success of allo-SCT depends on underlying disease status, patient comorbidities, and choice of donor
  • Common indications for allo-SCT in adult patients:
    • AML (acute myeloid leukemia)
      • Intermediate or high-risk AML per European LeukemiaNet Classification
      • Relapsed or refractory AML
      • Favorable-risk AML with persistent measurable residual disease
      • Secondary or therapy-related AML
    • ALL (acute lymphoblastic leukemia)
      • Relapsed or refractory ALL
      • ALL in remission with persistent measurable residual disease
      • High-risk ALL in first complete remission
    • CML (chronic myeloid leukemia)
      • Chronic phase CML with history of intolerance/resistance of multiple tyrosine kinase inhibitors
      • Accelerated or blast phase CML
    • MDS (myelodysplastic syndrome)
      • Intermediate-/high-risk MDS per Revised International Prognostic Scoring System
      • Therapy-related MDS
    • MPN (myeloproliferative neoplasm)
      • Intermediate-/high-risk MPN (primary myelofibrosis, chronic myelomonocytic leukemia)
      • Relapsed/refractory MPN
      • Secondary myelofibrosis
    • Lymphoma
      • Relapsed or refractory lymphoma after autologous SCT or chimeric antigen receptor T-cell therapy
      • Relapse or refractory T-cell lymphoma
      • Lymphoma in second or later relapse
    • CLL (chronic lymphocytic leukemia)
      • Relapsed or refractory CLL after multiple lines of therapies
      • Transformation to high-grade lymphoma (Richter syndrome)
    • Listing is nonexhaustive, and individual patient- and disease-related factors should be considered when selecting candidates for allo-SCT
  • Disease status
    • Pretransplant disease control is essential for the success of allo-SCT. Most patients with hematologic malignancies being considered for allo-HCT (allogeneic hematopoietic cell transplant) require therapies to minimize the disease burden
    • Patients with acute leukemia in complete remission without measurable residual disease have the best outcomes after allo-SCT
    • Patients with persistent disease should be offered additional therapies before transplant procedures are started
  • Patient evaluation
    • Typically, patients who meet disease criteria for allo-SCT undergo a comprehensive evaluation at a transplant center
    • There are no universal guidelines for patient evaluation; each center has individualized selection criteria
    • A comprehensive physical examination and organ function testing are conducted to assess patient comorbidities that are likely to impact transplant outcomes. Use of validated risk scores such as DRI (Disease Risk Index), HCT-CI (Hematopoietic Cell Transplantation-Comorbidity Index), or EBMT (European Group for Blood and Marrow Transplantation) risk scores may help in counseling patients regarding risks and benefits of allo-SCT
    • Baseline chest radiograph, pulmonary function testing, and a study of cardiac function (echocardiogram or multiple gated acquisition scan) are typically obtained
    • Additional testing based on individual’s risk factors, such as cardiac stress test, imaging studies, physical therapy evaluation, psychiatric and geriatric evaluation, or drug screen may be conducted
    • Laboratory studies include HLA testing, blood type and screen, cytomegalovirus serology, assessment of prior exposure to various infectious agents
    • Patient is evaluated by social worker to determine caregiver support
    • Psychosocial factors taken into consideration include psychiatric history, cognitive ability to consent for allo-SCT, substance use disorder history, caregiver requirements, ability to stay close to transplant center for at least 3 months, and adequate financial resources including insurance authorization for transplant
    • Pretransplant depression is associated with increased mortality after allo-SCT
    • Young patients should receive guidance and support for fertility preservation measures
    • Advance care planning should be completed before allo-SCT to ensure patient’s wishes are honored and appropriate health power of attorney is in place
  • Contraindications
    • There are no universally accepted absolute contraindications to allo-SCT; any patient with a medical indication for transplant should be evaluated by a transplant specialist to determine overall suitability and candidacy
  • Donor selection
    • The degree of HLA match between recipient and donor is the most important factor during donor selection. Higher HLA mismatch is associated with increased risk of GVHD (graft-versus-host disease) and posttransplant mortality
    • Initial donor HLA typing is done with peripheral blood mononuclear cells or buccal swab
    • Donors submit completed health history screening questionnaires to the registry or transplant center
    • Once a potential donor is selected by a transplant center, the donor undergoes comprehensive physical and laboratory assessment, which includes testing for a wide range of infections
    • Standard peripheral blood stem cell collection procedure involves administration of GCSF (granulocyte colony-stimulating factor) over several days, followed by 1 or 2 days of apheresis in the outpatient setting. In contrast, most bone marrow harvesting is done without GCSF in the operating room with general anesthesia
    • The following HLA alleles/antigens are tested for donor selection:
      • Class I: HLA-A, HLA-B, HLA-C
      • Class II: HLA-DRB1, HLA-DQB1, HLA-DP1
    • An HLA-identical sibling donor is preferred over other donor sources, given reduced risk of GVHD and enhanced survival after allo-SCT
    • In the absence of an appropriate sibling donor, a matched unrelated donor or haploidentical donor can be used, given comparable outcomes. A registry search is conducted electronically for an unrelated donor. Non-White patients have a lower chance of finding a fully matched registry donor compared with White patients of European descent
    • If multiple HLA-matched donors are available, the following factors are considered for selection of the donor: CMV (cytomegalovirus) serotype, ABO type, age, sex, weight discrepancy, presence of anti-HLA antibodies, history of pregnancies, willingness to provide requested stem cell source (peripheral blood versus bone marrow)
    • In the absence of an HLA-matched donor, a partially HLA-matched donor (haploidentical family donor or mismatched registry donor) or cord blood units can be used for allo-SCT
    • When other factors are comparable, a younger donor is preferred over an older donor
    • Source of stem cell (bone marrow versus mobilized peripheral blood stem cells) is determined by transplant physician based on underlying disease type and donor willingness

Conditioning (Immediately Before Transplant)

  • High-dose conditioning therapy is administered over multiple days immediately preceding stem cell infusion to eradicate residual malignancy and create a tolerant environment for donor hematopoietic cells. Treatment generally consists of various chemotherapy agents with or without total body irradiation. This treatment is generally given in the hospital but can be administered on an outpatient basis with appropriate infrastructure
  • Central line access is required for conditioning chemotherapy and hematopoietic cell infusion
  • Conditioning regimens are highly protocol dependent, are not standardized, and vary widely among transplant centers
  • MAC (myeloablative conditioning) is associated with lower risk of disease relapse but higher TRM (transplant-related mortality). MAC is preferred for patients younger than 65 years without significant comorbidities and for patients who have high-risk malignancies such as myeloid neoplasms or acute lymphoblastic leukemia
  • RIC (reduced-intensity conditioning) is preferred for older individuals or patients with comorbidities who are not eligible for MAC
  • Commonly used chemotherapeutic drugs for conditioning include busulfan, fludarabine, thiotepa, cytarabine, melphalan, carmustine, treosulfan, and cyclophosphamide
  • Patients receive multiple antiemetics to prevent chemotherapy-induced nausea and vomiting

Peritransplant Period

  • Day of stem cell infusion is called “Day 0”
  • Patients receive IV hydration and premedications (eg, acetaminophen, H1-blocker) followed by cell infusion under gravity. Depending on total volume of graft, infusion takes 30 to 90 minutes
  • Patients are monitored for 1 to 2 hours after cell infusion for any infusion reaction. ABO-mismatched transplant may result in hemolytic reaction, and renal function is monitored closely
  • Patients start immunosuppressive medications (eg, thymoglobulin, calcineurin inhibitor) a few days before Day 0 for GVHD prevention. Patients may receive additional immunosuppressive medications (eg, methotrexate, mycophenolate mofetil, cyclophosphamide) during the peritransplant period for GVHD prevention. GVHD prevention regimens are center dependent
  • Prophylactic antimicrobial agents are started with conditioning chemotherapy and should be continued until patient is no longer taking immunosuppressive medications after allo-SCT

Posttransplant Period

  • The posttransplant period can be divided into early (up to 3 months) and late (after 3 months) phases
  • Allo-SCT is associated with severe myelosuppression and various organ toxicities from high-dose conditioning chemotherapy. Patients are severely immunocompromised during the first 3 months after transplant and require close monitoring and broad antimicrobial prophylaxis
  • In the late posttransplant period, allo-SCT recipients remain at risk for multiple transplant-related complications such as GVHD, disease relapse, secondary cancers, infertility, and osteoporosis. They should be followed up closely at the transplant center at least until cessation of immunosuppression without active GVHD or disease relapse
  • Recipients of allo-SCT experience excess mortality relative to the general population, even a decade after transplant. Major causes of late mortality are disease relapse, GVHD, organ toxicity, and secondary malignancy
  • Important posttransplant care considerations include:
    • Hematopoietic support
      • Transplant recipients need transfusional support until engraftment takes place
    • GVHD
      • Major source of morbidity and mortality after allo-SCT
      • Prophylaxis typically initiated in the peritransplant period and continued into the posttransplant period
      • GVHD surveillance is part of ongoing posttransplant follow-up
    • Organ toxicities
      • Organ toxicities are common after allo-SCT
      • Surveillance for early posttransplant and late organ toxicities is part of ongoing posttransplant follow-up
    • Infections
      • Infections are common after allo-SCT and another major source of morbidity and mortality
      • Prophylaxis is typically initiated in the peritransplant period and continued into the posttransplant period
      • Immunizations play an important role in infection prevention
      • Prevention and management of infections are part of ongoing posttransplant follow-up
    • Ongoing monitoring and follow-up
      • Ongoing close follow-up with a transplant specialist is vital, and many centers have dedicated long-term transplant survivorship clinics
      • Focus is on disease surveillance/monitoring for relapse and prevention/management of complications

Nondrug and Supportive Care

  • Hematopoietic support
    • All patients require transfusion support early after allo-SCT until transplanted cells engraft sufficiently to support hematopoiesis
      • Typical engraftment period for neutrophils after allo-SCT is 14 to 21 days
      • Platelet engraftment takes 20 to 40 days, depending on graft source and underlying disease
      • Patients may require transfusions of packed RBCs for 2 to 3 months or longer after allo-SCT. This period is longer in a subset of patients who receive major ABO-mismatched transplants
        • ABO incompatibility is classified as major, minor, or bidirectional
          • Major ABO-incompatible SCT (eg, from a type A, type AB, or type B donor to a type O recipient) is characterized by the presence of anti–donor blood group antibodies in recipient plasma
          • Minor ABO incompatibility (eg, from a type O donor to a type A, type B, or type AB recipient) is characterized by the passive transfer of incompatible blood group antibodies from the donor to the recipient
          • In bidirectional ABO incompatibility (eg, type A donor to a type B recipient), both major and minor incompatibilities are present
    • Typical transfusion thresholds are hemoglobin of 7 g/dL or lower for packed RBC transfusion and platelet count of 10,000/µL or less for platelet transfusion. Higher transfusion thresholds may be required for patients with a history of cardiac disease, bleeding, or thrombosis
    • In the peritransplant period, patients should only receive leukoreduced, CMV serotype– matched, irradiated blood products to reduce the risk of alloimmunization, transfusion-associated GVHD, and CMV transmission

Drug Therapy

  • GCSF (granulocyte colony-stimulating factor)
    • GCSF use after allo-SCT varies from center to center. It is associated with modest improvement in time to neutrophil engraftment without significant impact on infection-related mortality, GVHD rates, or long-term survival
    • Patients who experience slow hematologic reconstitution, such as recipients of an umbilical cord graft or posttransplant cyclophosphamide, may benefit from prophylactic GCSF or GM-CSF (granulocyte-macrophage colony-stimulating factor) administration starting 5 to 7 days after graft infusion. Administration should be continued until neutrophil engraftment is complete
  • GVHD prophylaxis
    • Choice of GVHD prophylaxis regimens remains nonstandardized and highly center dependent, with wide variation between centers
    • Multiple immunosuppressive drugs such as antithymocyte globulin, calcineurin inhibitor (tacrolimus, cyclosporine), mycophenolate mofetil, methotrexate, and sirolimus are given in the peritransplant period for GVHD prophylaxis
    • Recently, there has been increasing use of posttransplant cyclophosphamide for GVHD prevention in the setting of HLA-mismatched donor allo-SCT
    • Involvement of an SCT-trained pharmacist is key in managing multiple drug interactions and monitoring various drug levels during this period
    • A calcineurin inhibitor or sirolimus is generally continued for 4 to 6 months after transplant and slowly tapered off in absence of GVHD. Mycophenolate mofetil is generally continued until day 35 when cyclophosphamide has been administered to prevent GVHD after transplant
  • Infection prophylaxis
    • Patients should receive routine prophylaxis against bacterial, viral, and fungal pathogens, depending on the phase of transplantation
    • Letermovir is given to prevent CMV reactivation during the 3 months after allo-SCT
    • Patients with acute GVHD on high-dose steroids should receive mold prophylaxis
    • Various societies have published guidelines on this topic, but specific drugs, dosages, and duration may vary based on center-specific protocols
    • A comprehensive discussion of infection prophylaxis in allo-SCT is beyond the scope of this clinical overview
    • Commonly used prophylactic antimicrobials:
      • Antibacterials: fluoroquinolones (eg, levofloxacin), cephalosporins (eg, cefuroxime), penicillin
      • Antivirals: letermovir, acyclovir, valacyclovir
      • Antifungals: azoles (eg, fluconazole, posaconazole, voriconazole)
    • Antimicrobial prophylactic drugs are typically continued until the patient is no longer taking immunosuppressive medications and has completed posttransplant immunizations
  • Immunizations
    • Allo-SCT recipients may lose protection from common pathogens for which they have previously received immunizations
    • Patients receive a full set of repeated childhood immunizations in addition to standard age-appropriate vaccines after allo-SCT. Immunizations are started 3 to 6 months after allo-SCT
    • It is advisable to check vaccine response by serology testing, as many patients will require repeated boosters to sustain protective immune responses
    • Live virus vaccines (eg, measles-mumps-rubella) are given 12 months after patient is no longer taking immunosuppressive medications or at least 24 months after SCT, whichever is longer, to reduce the risk of vaccine-associated infection
    • Immunization before allo-SCT is not utilized because of the immunocompromised status of the recipient in most situations in light of active hematologic malignancy

Persistent or Recurrent Disease

  • The risk of disease relapse is greatest during the first 6 to 12 months after transplant Patients should be monitored with regular scans and bone marrow biopsies as dictated by underlying disease
  • Preemptive therapies such as targeted agents (FLT-3 [FMS-like tyrosine kinase 3] inhibitors [sorafenib, midostaurin, gilteritinib] or IDH1/2 [isocitrate dehydrogenase] inhibitors [enasidenib, ivosidenib]) and immunomodulatory drugs (azacitidine, decitabine) may be given as maintenance therapy to selected patients to reduce the relapse risk after allo-HCT
  • The risk of disease relapse after allo-SCT depends on underlying disease and pretransplant disease status. Relapse incidence ranges from 40% to 70% for patients with acute leukemia, and outcomes for these patients remain poor
  • Outcomes of relapsed disease after allo-SCT depend on disease type, duration from transplant, and patient’s performance status and response to subsequent salvage therapy
  • Relapsed disease after allo-SCT requires salvage therapy to control disease. Among patients who are eligible for curative intent therapies, subsequent treatment options include DLI (donor lymphocyte infusion) and second allo-SCT
    • DLI is infusion of fresh or cryopreserved peripheral blood lymphocytes from the original SCT donor. The underlying principle is to enhance graft-versus-disease effect
    • DLI may result in durable remissions for 10% to 25% of patients who experience relapse after allo-SCT
    • Outcomes of DLI versus second allo-SCT appear to be comparable according to registry-based analysis

Admission Criteria

  • Utilization of inpatient care during allo-SCT depends on center-specific protocols and available infrastructure
  • Some centers with an established outpatient allogeneic transplant program administer conditioning chemotherapy, stem cell infusion, and posttransplant monitoring in the outpatient setting and only admit patients to manage complications
  • Typical complications that require inpatient admission include neutropenic fever, severe mucositis, organ toxicity, clinically significant bleeding or thrombosis, moderate to severe GVHD, and relapsed disease
  • At centers without established outpatient allo-SCT programs, patients remain admitted from the start of conditioning therapy until stable neutrophil engraftment and resolution of any serious transplant-related complications have occurred, which can typically take 2 to 3 weeks or longer after stem cell infusion

Follow-up

Monitoring

  • Focuses on:
    • Disease surveillance
    • Prevention/management of complications:
      • GVHD (graft-versus-host disease)
      • Organ toxicities, including early posttransplant and late toxicities
      • Infections
  • Patients should be followed up at a transplant center, given the unique early and late complications of allo-SCT. Local oncologist or primary care physician can assist with routine laboratory monitoring and provide interim supportive care as needed in coordination with transplant physician
  • Monitoring frequency and parameters
    • Peritransplant period: patients are seen on daily basis from start of conditioning regimen through stable engraftment and resolution of any early chemotherapy-related toxicities. Daily CBC and comprehensive metabolic panel should be obtained during this period
    • Early posttransplant (engraftment through first 100 days after transplant): patients are seen 2 to 3 times per week. Weekly CMV (cytomegalovirus) and Epstein-Barr virus blood polymerase chain reaction assays should be performed during this time
    • Late posttransplant (beyond day 100 after transplant): patients are typically seen every 1 to 3 months during the first 2 years and then every 6 to 12 months over the long term
  • Disease surveillance:
    • Frequency of disease monitoring may vary depending on underlying disease status and center-specific protocols
    • Typically, patients undergo bone marrow biopsy every 4 to 6 months during the first 2 years after transplant
    • Peripheral blood donor chimerism should be monitored on a monthly basis during the first 6 months after allo-SCT and then less frequently per institutional standards
    • Type and screen is repeated at varied frequency until conversion to donor ABO blood type
    • Routine imaging surveillance every 3 to 6 months for patients with lymphoma or baseline extramedullary disease is suggested for the first 2 years after allo-SCT
    • Given multiple drug interactions and variable pharmacokinetics, serum levels of tacrolimus, cyclosporine, and sirolimus should be monitored to adjust dosage

Complications

GVHD

  • General information
    • GVHD is a result of abnormal immune reactions of the transplanted donor immune cells to the recipient, leading to tissue injury and inflammation
    • It can affect any organ, with highest risk during the first 3 to 6 months after allo-SCT
    • After disease relapse, GVHD remains the principal cause of morbidity and mortality after allo-SCT
    • A comprehensive discussion of GVHD management is beyond the scope of this clinical overview
  • Acute GVHD
    • The incidence of overall acute GVHD is 30% to 50%, and incidence of severe GVHD is 10% to 20% after allo-SCT. The use of peripheral blood stem cell graft, MAC (myeloablative conditioning), and an unrelated or partially HLA-matched donor are some of the factors associated with increased risk of acute GVHD
    • Immunosuppression is administered in the peritransplant period and sometimes continued into the posttransplant period for GVHD prophylaxis; prophylactic measures reduce but do not eliminate risk of developing GVHD
    • The risk for acute GVHD is highest during the first 3 months after allo-SCT, but it can appear later, especially in the few weeks after discontinuation of immunosuppression. Common manifestations of acute GVHD are skin rash, diarrhea, nausea, vomiting, and jaundice
    • A clinical diagnosis of acute GVHD in most situations is based on typical organ-specific manifestations (Table 1) and exclusion of other possible causes. Classical GVHD-associated pathologic changes in tissue biopsy (interface dermatitis in skin GVHD, ductopenia in liver GVHD, apoptotic cells and crypt loss in gastrointestinal GVHD) are needed in many cases to confirm the diagnosis
    • Attempt should be made for a tissue biopsy whenever feasible for pathologic diagnosis of GVHD; however, preemptive therapy with steroids should be initiated for patients with severe acute GVHD
    • Once acute GVHD is established, severity of disease in each involved organ system (skin, liver, gut) is staged from 0 to 4 (see Table 1), and an overall grade of acute GVHD severity (I to IV) can be assigned based on organ system staging. Several grading systems are in use; Table 2 shows one widely used system
    • Grade I acute GVHD (ie, isolated stage 1-2 skin symptoms) can be managed with topical steroids alone (eg, triamcinolone or hydrocortisone)
    • First line treatment for grades II to IV or persistent grade I acute GVHD is systemic corticosteroid therapy
      • Practice varies in terms of preferred agent, dosing, and route for corticosteroid therapy. While older US and current European GVHD guidelines recommend initial dosing with methylprednisolone, 2 mg/kg/day, or prednisone, 2 to 2.5 mg/kg/day, use of lower dosing (eg, methylprednisolone or prednisone, 1 to 2 mg/kg/day ) is also common and is supported by trial data and other recent GVHD guidelines
      • IV methylprednisolone should be used for patients with severe gastrointestinal GVHD who are not able to tolerate oral medications
      • Steroids are tapered over 3 to 4 weeks for patients who have steroid-responsive acute GVHD
    • For gastrointestinal GVHD, nonabsorbable oral steroids (eg, budesonide, 9 mg daily, or beclomethasone, 2 mg 4 times a day) can be given in conjunction with systemic corticosteroids
    • Patients with progression of disease by day 5 or no response by day 7 are considered to have glucocorticoid-resistant acute GVHD
      • Treatment of steroid-resistant GVHD is ruxolitinib, 5 to 10 mg twice a day, with steroid taper as tolerated based on superior overall response rate compared with best available therapy
      • Referral to a well-designed clinical trial should be considered for these patients
    • Other options for steroid-refractory acute GVHD include extracorporeal photopheresis, alfa1-antitrypsin, infliximab, thymoglobulin, sirolimus, and pentostatin; success rates are variable
    • Acute GVHD requiring second line therapy is a highly morbid condition with 1-year survival of 52%. Increasing patient age, serum bilirubin, abdominal pain with stage 4 gastrointestinal GVHD, and low serum albumin are associated with increased mortality after acute GVHD
    • These patients need supportive care with antiemetics and antimotility agents along with nutritional support (tube feedings, total parenteral nutrition) and enhanced antimicrobial prophylaxis, given the higher risk of infection
  • Chronic GVHD
    • Chronic GVHD is a major cause of morbidity and mortality during the first 2 years after allo-SCT. Major risk factors for chronic GVHD include history of acute GVHD, peripheral blood stem cell graft, unrelated donor, and use of MAC.
    • Chronic GVHD can affect any organ, but skin, lungs, and gastrointestinal tract are the main sites where typical manifestations are observed (Table 3)
    • Management of chronic GVHD is based on number and severity of affected organs. Multidisciplinary team consisting of transplant physician, organ-specific consultant, nurses, and professionals in support services such as nutritionists, physical therapists, and pharmacists is key in optimal management of chronic GVHD
    • Mild or limited chronic GVHD is treated with local or topical therapies, whereas advanced or severe chronic GVHD requires immediate systemic immunosuppression to prevent life-threatening consequences
    • Systemic corticosteroid (prednisone, 1 to 2 mg/kg/day or equivalent) is generally considered standard first line therapy for chronic GVHD. Approximately half of patients with chronic GVHD will require an additional immunosuppressive agent for sustained control and weaning of steroids. Ruxolitinib, 10 mg twice daily, with steroid taper is preferred treatment for such patients based on superior response rate compared with best available therapy in a phase 3 study
    • Other treatments available for steroid-refractory/dependent chronic GVHD are ibrutinib, belumosudil, and extracorporeal photophoresis
    • Risk factors associated with increased mortality after chronic GVHD: involvement of 3 or more organs or any organ with severity score higher than 2; thrombocytopenia less than 100,000/µL and skin involvement of more than 50% of body surface area
May 18, 2026 | Posted by in GENERAL | Comments Off on 12:21:32 – Allogeneic Stem Cell Transplant for Malignancy

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