Stem Cell Transplantation

Stem Cell Transplantation
Header Stem Cell Transplantation Subhead Michael Pulsipher, MD

HLA and Donor Issues An 18-month-old child with ALL in second remission is referred for transplantation. Which would be the best donor for this child? A. The child’s own sorted cord blood (cell dose 5X10^6/kg) B. A 55-year-old female unrelated donor, 7/8 match (willing to donate marrow or peripheral blood stem cells) C. A cord blood unit matched at 4/6 antigens: cell dose 5.4x106/kg D. A 40-year-old male unrelated donor matched at 8/8 loci (only willing to donate peripheral blood stem cells) E. A cord blood unit matched at 6/6 antigens (HLA A, B, DRB1) with a cell dose of 4.0x106/kg

Human Leukocyte Antigen Groups (HLA, Chromosome 6)
© 2012 Terese Winslow LLC, U.S. Govt. has certain rights

HLA Loci and Known Alleles
Class I (A, B, C) Found on almost all cells (except some neurons) HLA-A HLA-B HLA-C Class II (DR, DQ, DP) Found on antigen-presenting cells, B cells DRB DQB DPB DRB 3,4, , 15, 21

Minor HLA Antigens—If it were only as simple as HLA
Minor H Antigens Encoded by Autosomal Genes HA-1 – HA-7 A2-1 – A2-4 B7-1 – B7-6 A3, A11, A29, B44, B65, Cw7 Minor H Antigens Encoded by the Y chromosome HLA-A2-HY HLA-A1-HY HLA-B7-HY B8-1

Approach to HLA by Stem Cell Source

Stem Cell Sources—Different Ways to Grow a New Bone Marrow
Reported Sources Fetal Liver Cells Single or small numbers of “stem cells” iPSCs Umbilical Cord Blood (UCB) Bone Marrow (BM) Cytokine Mobilized Peripheral Blood Mononuclear Cells (PBMC)

Bone Marrow—the Traditional Source

Other Sources—Peripheral Blood Mononuclear Cells and Umbilical Cord Blood

Hematopoietic Cell Sources—Content of the Product Dictates Uses
Autologous Transplant (High Dose or Mega-Dose Therapy) Bone Marrow (risk with harvest) Cytokine Mobilized Peripheral Blood Mononuclear Cells (PBMC, quick engraftment) Manipulation of either source to remove cancer cells or alter immune response Winner—PBMC! Allogeneic Transplant Umbilical Cord Blood (few T-cells, increased risk of rejection and slow engraftment, can use safely with more HLA mismatches, less chronic GVHD) Bone Marrow (Intermediate T-cells numbers, intermediate rejection and GVHD) PBMC (More T-cells, rapid engraftment, less early transplant morbidity, probably more chronic GVHD) Winner—?

Allogeneic Transplants for Age ≤ 20 years, Registered with the CIBMTR
Slide 10: Annual numbers for unrelated donor transplants have increased in the last two decades for patients younger than 21. Transplants with umbilical cord blood have contributed significantly to this trend during the last decade. In 2010 and 2011, 43% of all unrelated donor transplants utilized umbilical cord blood grafts for this patient population. The use of peripheral blood among related donor transplants are decreasing in the last decade among this patient population.

Levels of Matching

Key Considerations Donor/HLA
HLA match trumps everything Single allele/antigen mismatch is all that is allowed for BM/PBSC (7/8) Cord Blood allows 4/6 matches 6-7/8 better, high cell dose helps with mismatches BM is preferred in pediatrics over PBSC Data especially strong for nonmalignant disorders PBSC results in faster engraftment, more GVHD, used for reduced intensity regimens and second HCT

Screening a Donor Need Assent, beware parental bias
Challenge if recipient unknown or difficult relationship Avoid risks to donor health Donors with underlying disorders should be assessed by experts to avoid risk Screened for transmissible diseases HIV, HBV, HCV, syphilis, WNV, Chagas, etc.

Other Considerations for Donor Choice
Assent/Consent—if an 18+yo sib is equivalent to younger, choose the adult Blood type matching helps/not necessary CMV negative donors for negative recipients Positive for positive may be better Gender match or male to female good: avoid multiparous females Donor/recipient size mismatch can be a problem Max from donor 20mL/kg, goal CD34+/kg >3-5x10^6 Cord dose >3x10^7 TNC/kg, can use 2 cords Outcomes better with 1 cord if dose OK (less GVHD)

Clinical Differences Between Stem Cell Sources—T-cell Content Key

Which is syngeneic, which is allogeneic, who is the better donor?

Major Increases in Risk occur with Pre-transplant Comorbidities
Active infection/inflammation Non-recovery of counts pre-HCT (prolonged neutropenia) Non-remission MRD positivity Underlying organ damage Pulmonary, Hepatic, Cardiac, Renal—all risks Performance Status (low KS/LPS) Psychiatric Disorder requiring significant therapy Some of these issues can be addressed with reduced intensity regimen approaches

Implications of Reduced Intensity

Current Practice: Preparative Regimens
Unpublished evidence suggests myeloablative approaches superior to RIC for AML/MDS Busulfan-based regimens (adult data) Retrospective evidence suggests TBI-based approaches better for ALL iBFM trial testing this Non-malignant disorder prep regimens vary RIC for HLH, RIC whenever possible Some disorders require reduced, minimal, or no prep FA—sensitive to TBI, chemotherapy SCID—Sib donors, no prep needed, URD, less prep may be possible.

Allogeneic Conditioning Regimens

Preengraftment (Day +1 to +30)
11/11/2018 Preengraftment (Day +1 to +30) Patient Presentation 6 yo female with h/o AML s/p MUD now day +9 WBC 0.1 LFTs normal. BUN 13, Cr 0.2 Temp 40C. RR 40s. O2 Sat 90% CXR: Fine patchy bilateral infiltrate BP: 100/50

11/11/2018 Preengraftment (Day +1 to +30) Case 1

11/11/2018 Preengraftment (Day +1 to +30) Begins with conditioning until engraftment (day 30) Severe neutropenia (ANC <100) Severe lymphopenia (ALC <100) Hypogammaglobulinemia (IgG < 400) Severe GI mucosal disruption

Phases of Predictable Opportunistic Infections
11/11/2018 Phases of Predictable Opportunistic Infections Adapted from Van Burik, Freifeld. Clinical Oncology, 3rd Edition. Philadelphia: Churchill Livingstone; 2004:942)

Prevention & Prophylaxis
11/11/2018 Prevention & Prophylaxis HSV/VZV Acyclovir 500 mg/m2 IV or PO tid CMV If CMV quant-PCR elevated GCV or foscarnet pre-emptive therapy Salvage therapy with Viral-specific T-cells Fungal Fluconazole or voriconazole Echinocandins often used Posaconazole approved for prophylaxis

Prevention & Prophylaxis
11/11/2018 Prevention & Prophylaxis PJP Septra “load” pre-HCT Restart day +30 Other meds Pentamidine Dapsone Atovaquone Bacterial ? Antibiotics ? Levofloxacin IVIG Replace for low IVIG levels <400mg/dL

Key Infection Considerations
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 cGVHD adds to risk Use of and dose of steroids critical risk factor Doses <1mg/kg and qod dosing can decrease risk

Acute Graft-vs-Host Disease
Usually diagnosed before day +100 Typically occurs near time of engraftment Almost always involves skin Also involves intestine, liver, or lung Substantial cause of morbidity and mortality

Palmar and Solar Erythema

Puritic Maculopapular Rash

Basal Keratinocyte Apoptosis

Basal Intestinal Crypt Apoptosis

Generalized erythroderma with bullae
Acute GVHD Staging Stage Skin Liver Gut 1 Rash on <25% Bili 2-3 mg/dl Diarrhea ml/m2/d 2 Rash on 25-50% Bili mg/dl Diarrhea ml/m2/d 3 Rash on >50% Bili mg/dl Diarrhea >883ml/m2/d 4 Generalized erythroderma with bullae Bili >15 mg/dl Severe abdominal pain

Acute GVHD Grading Grade Skin Liver Gut 1 2 3 4 Stage I-II none
Stage II-III 4 Stage IV

Acute GVHD Prophylaxis
Most use calcineurin inhibitors (tacro/CSP) + MTX given days 1,3, 6 +/- 11 for sib/URD BM/PBSC Or Mycophenylate mofetil (MMF) for cords Other agents in combination: sirolimus, ATG, post-tx cyclophosphamide, T-cell depletion Complete removal of T-cells problematic Excess infections, rejection, relapse

Primary Acute GVHD Therapy
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

Case Scenario An 8-year-old child with AML 6 months post-transplant comes to clinic complaining of a maculo-papular rash on arms and legs, dry, irritated eyes, and a persistent cough. His mother has noticed that he gets winded much more quickly than he used to. Which investigation is most likely to yield a diagnosis? A. Blood PCR for CMV B. Bronchiolar lavage to rule out pneumocystis infection C. Pulmonary function tests and high resolution CT D. Galactomannan test for fungus E. Upper GI endoscopy

Chronic GVHD Diagnosed after day 100 (2m sometimes) Immunodeficiency
Skin- lichen planus poikiloderma Scleroderma Sicca syndrome Hepatic- vanishing bile ducts Pulmonary- bronchiolitis obliterans GI- esophageal strictures, fat malabsorption

Cumulative incidence of discontinuation of immune suppression after the diagnosis of cGVHD shown with OS. Cumulative incidence of discontinuation of immune suppression after the diagnosis of cGVHD shown with OS. Republished with permission of the American Society of Hematology, from Blood, Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease, Jacobsohn, et al, 118, 16, 2011; permission conveyed through Copyright Clearance Center, Inc. ©2011 by American Society of Hematology

OS by risk factors included in multivariate analysis.
Republished with permission of the American Society of Hematology, from Blood, Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease, Jacobsohn, et al, 118, 16, 2011; permission conveyed through Copyright Clearance Center, Inc. ©2011 by American Society of Hematology

Standard Therapy for Chronic GVHD
Prednisone 1 mg/kg/day Taper to 1 mg/kg/every other day over 6 weeks Prolonged course, usually tapered over one year One half have resolution of GVHD Median duration of treatment is 2 years for responding patients

Salvage treatment for chronic GVHD
MMF FK506 Thalidomide Plaquenil Pentostatin Methotrexate Rituximab PUVA Extracorporeal photopheresis Experimental Low dose-IL-2 Mesenchymal Stem Cells Ruxolitinib (Jack inhibitors) Ibrutinib for cGVHD (breakthrough)

Case Scenario A 10 year old by undergoes stem cell transplantation for CML. The graft is T-Cell depleted as part of an NIH sponsored IRB approved research protocol. Day 145 post transplant the patient develops severe cervical lymphadenopathy and splenomegaly. The most likely diagnosis is: A. Relapsed CML in accelerated phase. B. Secondary Hodgkin disease. C. PTLD. D. Toxoplasmosis. E. Transfusion acquired HIV.

Post-Tx Lymphoproliferative Disorder
Occurs within a few months after BMT Highly associated with T-cell Depletion Product depletion techniques that preserve B-cells CD34+ selection In vivo depletion (ATG, less with campath) Therapy that is highly T-cell suppressive ATG for resistant GVHD Treatment IS withdrawal, rituxan, cyclophosphamide, EBV-targeted cytotoxic T-lymphocytes (CTLs)

Venoocclusive Disease (VOD, also sinusoidal obstruction syndrome, SOS)
11/11/2018 Venoocclusive Disease (VOD, also sinusoidal obstruction syndrome, SOS) Typically in first 14 days of transplant, up through day +30 About 25% patients affected 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

Venoocclusive Disease ctd.
11/11/2018 Venoocclusive Disease ctd. Signs and Sx: Weight gain RUQ pain (capsular distention) Hyperbilirubinemia Plt refractory Ascites (capillary leak) Renal Insufficiency Pulmonary Edema

Venoocclusive Disease ctd.
11/11/2018 Venoocclusive Disease ctd. Management: Fluid management Maintain intravascular volume Manage renal failure Consider antithrombotic agents (e.g. defibrotide)

Postengraftment (Days 30-100)
11/11/2018 Transplant-associated Thrombotic Microangiopathy (TA-TMA) 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. Postengraftment (Days )

Patient Presentation 6 year old day +64 out from TBI-based allogeneic transplant Presents to the ER with confusion Short tonic-clinic seizure witnessed in the ED Loss of vision noted What are key clinical facts you need to know?

11/11/2018 Postengraftment (Days )

11/11/2018 Posterior Reversible Encephalopathy Syndrome (PRES) 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 Postengraftment (Days )

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 Sequelae of pre-HCT Rx and GVHD Cardiac related to XRT and anthracylines GVHD effect on lungs, QoL Emerging Evidence of TBI effect on children < 3 at HCT

Hematopoietic Cell Transplantation: Current Indications
Cancer Treatment Allows high dose chemotherapy Immunological platform Replacement or “Resetting”of a Dysfunctional Hematopoietic/Immune System Absent vs. aberrant function Gene Therapy Only useful if the gene can be delivered by hematopoietic cells

The Big Decisions: Chemotherapy vs. Transplant—Auto vs. Allo
Autologous: TRM <1% at most centers. CR1 if better outcome/ difficult salvage Fertility/ immune suppression/ late effects Allogeneic: TRM 5-20% GVHD morbidity/QOL chief concerns Would want a 15% advantage over chemotherapy/autologous options

Causes of Death after Unrelated Donor Transplants done in 2010-2011

Indications for Hematopoietic Stem Cell Transplants for Age ≤ 20 years, in the US, 2011
Slide 9: In the pediatric population, allogeneic transplants are performed more often than autologous transplants. In 2011, allogeneic transplants performed in patients younger than 20 were for acute leukemias (43%) and non-malignant indications (35%). Among other non-malignant indication, primary immunedeficiencies and hemoglobinopathies are the most common indications. Autologous transplants were mostly performed for treatment of lymphoma and solid tumors in this patient population.

Indications for ALL HCT (Allo only)
CR1 Primary induction failure Hypodiploidy (<44 chromosomes) Persistent MRD after consolidation CR2 Early BM relapse (<36m from dx, esp if on rx) Late BM relapse if MRD+ after reinduction Any T-cell or Ph+ BM relapse CR3—any relapse

Survival after HLA-identical Sibling Donor Transplants for ALL, Age < 20 years, 2001-2011
Slides 28-29: Among young patients with ALL, for whom chemotherapy has a high success rate, allogeneic transplantation is generally reserved for patients with high-risk disease (i.e. high leukocyte count at diagnosis and the presence of poor-risk cytogenetic markers), who fail to achieve remission or who relapse after chemotherapy. Among the 2,188 patients younger than 20 receiving an HLA-matched sibling transplant for ALL between 2001 to 2011, the 3-year probabilities of survival were 67% ± 2%, 55% ± 2 %, and 26% ± 3% for patients with early, intermediate, and advanced disease, respectively. The corresponding probabilities of survival among the 3,271 recipients of an unrelated donor transplant were 64% ± 2%, 47% ± 1%, and 31% ± 3%.

Survival after Unrelated Donor Transplants for ALL, Age < 20 years, 2001-2011

Indications for AML HCT
CR1 Induction failure Mono-7, Mono-5, Del 5q, High AR flt-3/ITD+ Persistent MRD after induction (experimental) Most recent approach Sibling donor, pt with intermediate/HR disease CR2, CR3—any relapse Auto BMT? CBF or M3 AML with late relapse (>12m from dx) and clean marrow (PCR negative)

Survival after HLA-identical Sibling Donor Transplants for AML, Age < 20 years, 2001-2011
Slide 26: Among 1,785 patients younger than 20 with AML between 2001 and 2011, the 3-year probabilities of survival following transplant for early, intermediate, and advanced disease were 66% ± 1%, 57% ± 4%, and 35% ± 3%, respectively.

Indications for CML/MDS/JMML HCT
Resistance/failure of TKIs Good donor with strong family preference Significant growth failure with TKIs Advanced phase MDS Any child with MDS Adults “low risk” MDS: wait until progression JMML Trying to define “better actors”, currently omit Noonan’s syndrome (germline mut PTPN11) Careful with NF1 pts, they may have CNS tumors, peripheral nerve sheath tumors

Indications for Lymphoma
NHL Relapsed Disease (attempt auto) For lymphoblastic treat similar to ALL (allo) Allo role for resistant or relapse after auto HL Auto for relapsed/resistant disease Allo can salvage auto failures if disease responsive

Figure 2 The probability of event-free survival after allogeneic and autologous transplantation for Non-Hodgkin lymphoma: Diffuse Large Cell (1A), Lymphoblastic (1B), Burkitt (1C) and Anaplastic (1D). Biology of Blood and Marrow Transplant , DOI: ( /j.bbmt ) © This content is licensed under Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND)

Survival after Autologous Transplants for Hodgkin Lymphoma, 2001-2011
Slide 35: Transplantation for Hodgkin Lymphoma (HL) is indicated in patients who have failed initial chemotherapy or radiation therapy. Survival after HCT for HL depends on disease response to previous salvage therapy. Among the 8,343 patients receiving autotransplants for HL between 2001 and 2011, the 3-year probabilities of survival were 85% ± 1%, 74% ± 1%, and 58% ± 2% for patients in complete remission, with chemosensitive, and with chemoresistant disease, respectively.

Survival after Allogeneic Transplants for Hodgkin Lymphoma, 2001-2011
Slide 36: Allogeneic HCT for HD is generally performed in patients who experience disease relapse after receiving multiple lines of therapy including autotransplant or who have refractory disease and an available HLA-matched donor. Among 545 patients receiving allotransplants for HD between 2001 and 2011, the 3-year probabilities of survival were 48% ± 3% and 41% ± 4% after sibling and unrelated donor transplants, respectively.

Indications for Solid Tumors
Neuroblastoma Documented Improvement for High Risk CR1 patients Evidence that tandem transplants improves EFS Brain Tumors Good data for use in <3yo to avoid XRT Data in medulloblastoma, CNS germ cell tumors for relapsed disease Responsiveness, resectability, XRT important Other Tumors Role for Ewings, relapsed HR Wilms, Rhabdo unsure Responsive HR germ cell tumors (relapsed) and HR retinoblastoma, some evidence of benefit with auto

Indications for Non-malignant Disorders
BM failure or lineage insufficiency Severe aplastic anemia, Fanconi Anemia, SDS, DC, CAMT, TAR, DBA, others RBC: SSD, Thalassemia WBC: KS, LAD Immune Deficiencies/Dysregulation SCID, WAS, CD40L def (hyper IgM), CGD, IPEX, others HLH, CA-EBV

Survival after Allogeneic Transplants for SAA, 2001-2011
Slide 34: Allogeneic HCT is the treatment of choice for young patients with severe aplastic anemia and available HLA-matched sibling donor. Among the 2,763 patients receiving HLA-matched sibling donor HCT for severe aplastic anemia between 2001 and 2011, the 3-year probabilities of survival were 88% ±1% for those younger than 20 years and 76% ± 1% for those 20 years of age or older. Among the 1407 recipients of unrelated donor HCT, the corresponding probabilities of survival were 70% ± 2% and 63% ± 2%.

HCT as Gene Therapy Inborn Errors of Metabolism Hurler Syndrome MPS-IH
X-Adrenoleukodystrophy (X-ALD) Metachromatic Leukodystrophy Many others

Best of Luck on your Test!
Future of HCT Targeting cellular therapies CART NK Cells BiTE BiNK Combined therapies with immunomodulators Cells can cure cancer

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