| What is the bone marrow? | Spongy matrix in center of bones, contains stem cells, factory at which cellular components of blood are made.
Red marrow located (all bones of children, and only axial skeleton in adults) while yellow marrow in appendicular of adults. |
| What is a bone marrow transplant? | Replaces a pts unhealthy stem cells in bone marrow w/ healthy ones from a donor, completely different from transfusion which is a temporary symptomatic fix, while BM transplant gives ability to renew blood cells (not just for 3 months)
Types include autologous transplant, and allogenic transplant |
| What are indications for BM transplant? | Autologous (malignancies [multiple myeloma, NHL, HL, AML, neuroblastoma, ovarian cancer, germ-cell tumor], non malignant [autoimmune, amyloidosis])
Allogenic (malignancies [AML, ALL, CML, myelodysplasia, myeloproliferative, NHL, HL, MM, juvenile CML], non-malignant [aplastic anemia, PNH, fanconi's anemia, anemia, thalassemia major, SCA, immunodeficiency, Wiskott, inborn metabolism error, congenital neutropenia]) |
| What are types of allogenic bone marrow transplant? | Matched related sibling donor, matched unrelated donor, mismatched donor (Haploidentical related donor), cord blood. |
| How is matching of donors? | According to HLA in chrmsm 6, 6/6 match if HLA A,B and DRB1. 8/8 if A, B, C, and DRB1. 10/10 if A, B, C, DRB1, DQB1. 12/12 if A, B, C, DRB1, DQB1, DPB1. |
| What are pts assessment pre-transplant? | Pre-transplant (30 days prior except disease baseline (7-15 days) and pregnancy (7 days). Should do CBC, coagulation, blood type, biochem, viral serology [CMV, EBV, HIV,VZV, HSV, toxopl, syphilis, HBV, HCV], pregnancy test, CXR and resp function test, ECG, MRD, dental evaluation, psychiatric evaluation, nutritional assessment)
Risk Factors (older age, Karnofsky index <80% general condition, remission from disease, donor other than identical sibling, any HLA difference, CMV serology different from donor, comorbidities, iron overload) |
| How is donor selection and assessment? | We look first for HLA-identical sibling, then 10/10 unrelated donor [look at donor age, CMV matching and ABO matching], then at 9/10 unrelated donor [cord blood, HLA-mismatched...]
Assessment (CBC, complete biochem, BG, viral serology, pregnancy test, CXR, ECG, psych evaluation) |
| What are contraindications for HSCT (hematopoietic stem cell transplant)? | Active infection/inflammation
Non-recovery of counts pre-HCT (prolonged neutropenia)
Non-remission
MRD positivity
Underlying organ damage
Pulmonary (FEV1, DLCOc <50%), Hepatic (LFTs >5x ULN, T bil >2), Cardiac (EF <50%), Renal (GFR < 70)—all risks
Performance Status (low KS/LPS)
<90 falls off, <60 major decline
Psychiatric Disorder requiring significant therapy
Some of these issues can be addressed with reduced intensity regimen approaches |
| How is collection, processing and storage in HSCT? | Goal is to transfer hematopoietic stem cells (HSC) along with appropriate doses of key immune cells from donor to recipient
Cells types that matter and are often measured
CD34+ cells
T-cells (CD3)
B-cells (CD19)
NK Cells (CD16, CD56)
Cell numbers that are used to choose doses
CD 34 cells/kg recipient weight
Total Nucleated Cells (TNC) or mononuclear cells (MNC)/kg recipient weight
Progenitor sources (bone marrow, peripheral stem cells, umbilical cord) |
| How is marrow collection done? | Surgical day procedure
Marrow extracted from pelvis (Iliac crest) using a hollow needle
Anesthesia is used to minimize pain.
Most patients will go home the same day.
Many experience lower back pain and stiffness for several days.
The marrow stem cells will completely regenerate in 4-6 weeks. |
| How is peripheral blood stem cell collection? | Allows collection of stem cells through the blood rather than bone
A Stem cells mobilizer (G-CSF +/- Mozobil) must be taken for 4-6 days prior to extraction to mobilize the stem cells to peripheral blood
A Peripheral stem cells collection by Apheresis
The whole process may take several hours.
Side effects include:
Headache
Hypocalcemia during procedure
muscle aches during a week prior to collection. |
| How do doses of stem cells vary by source? | Autologous:
Target >2x106 CD34 cells/kg recipient wt
Allogenic:
Bone marrow, PBSC matched related and unrelated donors
Target >4-5x106 CD34 cells/kg recipient wt
Can go higher, debate about upper limit re GVHD concerns
T-cell depleted/haploidentical
Target >10-20x106 CD34+ cells/kg recipient wt
Target <1x105 CD3+ cells/kg recipient wt
Cord Blood
Target >4x107 TNC/kg single unit
For highly mismatched >5x107/kg recipient wt
Multiple units as needed for at least 3x107/kg recipient wt
No advantage to 2 units if single unit dose adequate, more GVHD with 2 units |
| What types of processing are needed? | Goal: deliver the correct dose of key cells and minimize reactions
1. ABO incompatibility:
RBC depletion of bone marrow necessary for major mismatches
A&B blood cannot be transfused into non-compatible types
Plasma depletion can be done for minor mismatches
PBSC generally have low RBC content
Small amounts of incompatible RBCs can be tolerated
2. In Vitro T-cell Depletion:
CD34+ selection :Removal of all cells except CD34+ cells
CD3+ depletion, CD3+/CD19+ depletion |
| What is cryopreservation? | Autologous collections and cord blood all cryopreserved with DMSO (Dimethyl Sulfoxide)
Premedication and counseling needed regarding infusion reactions
Hypo/hypertension, bitter taste, odor
Allogeneic infusions sometimes need cryopreservation
Infusion should occur within 72 hours, better within 48
With donor recipient scheduling issues, cryopreservation an option, generally efficacious |
| What are clinical differences between stem cell sources? | . |
| How is the transplant process? | 5 steps, conditioning, stem cell infusion, neutropenic phase, engraftment phase, and post-engraftment period. |
| How is the conditioning step of transplant? | The conditioning period typically lasts 7-10 days except in Multiple Myeloma .
The purposes are (by delivery of chemotherapy and/or radiation) to eliminate malignancy
to provide immune suppression to prevent rejection of new stem cells create space for the new cells
Radiation and chemotherapy agents differ in their abilities to achieve these goals. |
| How are current allogenic preparative regimens? | Unpublished evidence suggests myeloablative approaches superior to RIC for AML/MDS
Busulfan-based regimens (adult data)
Bu/Cy, Bu/Fludarabine, Treosulfan
Retrospective evidence suggests TBI-based approaches better for ALL
Prospective iBFM trial testing this
TBI ≥1200cGy in 6 or 8 fractions + cyclophosphamide, VP-16, or thiotepa
Non-malignant disorder prep regimens vary
RIC for HLH—flu/melphalan, RIC whenever possible
Some disorders require reduced, minimal, or no prep
FA—sensitive to TBI, some approaches 300cGy, others low dose chemo
SCID—Sib donors, no prep needed, URD, less prep may be possible. |
| How are current autologoues preparative regimens? | All autologous regimens are high dose
Disease specific (especially if targeted at CNS)
Neuroblastoma
Carbo/Etop/Mel (CEM), Thio/Cy, Bu/Mel, 131I-MIBG
Tandem procedures
CNS Tumors
Carbo/thio tandem, Carbo/thio/etop
Lymphoma
BEAM (BCNU/Etop/Ara-C/Mel) |
| How is stem cell infusion? | Infusion - 20 minutes to an hour, varies depending on the volume infused. The stem cells may be processed before infusion, if indicated. Depletion of T cells can be performed to decrease GVHD.
Premedication with acetaminophen and diphenhydramine to prevent reaction.
Infused through a CVL, much like a blood transfusion.
Anaphylaxis, volume overload, and a (rare) transient GVHD are the major potential complications involved.
Stem cell products that have been cryopreserved contain dimethyl sulfoxide (DMSO) as a preservative and potentially can cause renal failure, in addition to the unpleasant smell and taste. |
| How is neutropenic phase in SCT? | During this period (2-4 wk), the patient essentially has no effective immune system.
Healing is poor, and the patient is very susceptible to infection.
Supportive care and empiric antibiotic therapy are the mainstays of successful passage through this phase. |
| How is engraftment phast in SCT? | During this period (several weeks), the healing process begins with resolution of mucositis and other lesions acquired. In addition, fever begins to subside, and infections often begin to clear. The greatest challenges at this time are management of GVHD and prevention of viral infections (especially CMV). |
| How is post-engraftment phase in SCT? | This period lasts for months to years. Hallmarks of this phase include the gradual development of tolerance, weaning off of immunosuppression, management of chronic GVHD, and documentation of immune reconstitution. |
| What are key considerations in transplant in terms of complications? | Transplant approach affects immune recovery
Cord blood, T-cell Depl., ATG use= prolonged IS
Marked increase in viral reactivation/infection
CMV, Adeno, EBV, HHV-6, HSV—surveillance essential
Occurrence of aGHVD or cGVHD adds to risk
Use of and dose of steroids critical risk factor
Doses <1mg/kg and qod dosing can decrease risk
Infection increases the risk of all complications we will discuss |
| What is aGVHD? | Usually diagnosed before day +100
Typically occurs near time of engraftment
Almost always involves skin
Pruritic Maculopapular rash
Also can involve intestine, liver, or eye
Substantial cause of morbidity and mortality |
| How is aGVHD staging? | . |
| How is aGVHD grading? | . |
| How is aGVHD prophylaxis? | Most use calcineurin inhibitors (tacro/CSP) +
MTX given days 1,3, 6 +/- 11 for sib/URD BM/PBSC
Some programs use Mycophenylate mofetil (MMF) instead of MTX
Mycophenylate mofetil (MMF) used for cords by most
Other agents that can be used: sirolimus, ATG, prednisone, post-transplant cyclophosphamide, T-cell depletion
Complete removal of T-cells
Excess infections, rejection, relapse can occur
Different types of depletion have different risks |
| What is aGVHD therapy? | Primary (Mild disease: limited skin rash alone
Optimize tacro or CSP levels, topical steroids
If progressive or multisystem
Prednisilone 2mg/kg/d
Steroid Refractory aGVHD (no response 3-7d)
No clearly superior second regimen
ECP, etanercept, infliximab, pentostatin
Poor prognosis due to infectious complications) |
| What is chronic GVHD? | Diagnosed after day 100:
Immunodeficiency
Skin- lichen planus⇨ poikiloderma
Vitaligo, hyperpigmentation
Scleroderma
Limited joint mobility
Sicca syndrome
Mouth ulceration/food sensitivity
Hepatic- vanishing bile ducts
Pulmonary- bronchiolitis obliterans
GI- esophageal strictures, fat malabsorption |
| What is std therapy of cGVHD? | Prednisone 1 mg/kg/day
Prolonged course, usually tapered over one year
One half have resolution of GVHD
Median duration of treatment is 2 years for responding patients
Salvage tx (MMF, FK506, Thalidomide, Plaquenil, Pentostatin, Methotrexate, Rituximab, PUVA
Extracorporeal photopheresis, Newer approaches, Low dose-IL-2, Mesenchymal Stem Cells ,Ruxolitinib (Jack inhibitors), Ibrutinib for cGVHD (breakthrough)) |
| What are veno-occlusive diseases (Sinosoidal obstruction syndrome SOS)? | Typically in first 14 days of transplant, up through day +30
About 25% patients affected, severe in 5-8%
Caused by endothelial damage in the hepatic venules → platelet deposition → hepatic congestion → cholestasis
Associated with Cy, Busulfan, and TBI
New data show sirolimus use is a risk when used with tacrolimus or cyclosporine |
| What are VOD S&S? | Weight gain
RUQ pain (capsular distention)
Hyperbilirubinemia
Plt refractory
Ascites (capillary leak)
Renal Insufficiency
Pulmonary Edema |
| How is VOD management? | Fluid management
Diuresis, keeping patients fluid negative
Challenges
Maintain intravascular volume
Manage renal failure
Defibrotide (Antithrombotic agent)
Indicated for VOD plus organ dysfunction
Special attention to coagulopathy |
| What is post-transplant lymphoproliferative disorder? | Occurs within a few months after BMT
Highly associated with T-cell Depletion
Product depletion techniques that preserve B-cells
CD34+ selection
CD3+ selection without CD19+ depletion
Cord blood with ATG
In vivo depletion (ATG, less with Alemtuzumab)
Therapy that is highly T-cell suppressive
ATG for resistant GVHD
Treatment
IS withdrawal, Rituximab, cyclophosphamide, EBV-targeted cytotoxic T-lymphocytes (CTLs) |
| What is transplant associated thrombotic microangiopathy (TA-TMA) | Postengraftement days(30 – 100)
Occurs when endothelial damage resulting from HCT causes microangiopathic hemolytic anemia and platelet consumption, resulting in thrombosis and fibrin deposition in the microcirculation.
The kidney is most commonly affected.
Patients present with anemia; thrombocytopenia; often schistocytes on blood smear; elevated LDH and decreased haptoglobin
Calcineurin inhibitors (especially + sirolimus), TBI, high-dose busulfan, and infections increase risk
Early Evidence that eculizumab (terminal complement inhibitor) can improve renal function. |
| What is posterior reversible encephalopathy syndrome (PRES)? | Postengraftment (Days 30-100)
Headache, confusion, seizures, and visual loss and most often caused by malignant hypertension.
In HSCT patients, the intractable hypertension and the associated PRES have been linked to the use of calcineurin-inhibitors (tacrolimus and cyclosporine).
The diagnosis of PRES is typically made on MRI imaging of the brain, which reveals a characteristic pattern of enhancement, commonly in the posterior circulation, which may be seen, but poorly on CT
Treatment: Control HTN, stop calcineurin inhibitors |
| What are late issues after HCT? | Two years after BMT, most common problem?
Relapse
Non-relapse events
Second malignancies: 2-6%, ⇧ in FA patients, assoc. c XRT
Growth failure: Rare, associated with TBI + CNS XRT
Endocrine issues: Hypothyroidism, Gonadal failure
Pre-HCT Rx and GVHD contribute significantly to late effects
Cardiac related to XRT and anthracylines
GVHD effect on lungs, QoL
Emerging Evidence of TBI effect on children < 3 at HCT |
