Outline. Introduction. Introduction. Introduction. Introduction 27/03/61. Hematologic Stem Cell Transplantation (HSCT)

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1 Outline Hematologic Stem Cell Transplantation (HSCT) Trai Tharnpanich B.Pharm, BCOP, BCP Faculty of medicine, Mahidol university Department of pharmacy, Siriraj hospital 1 Introduction Sources of HSCT and mobilization strategies Types of HSCT s Maintenance therapy Common complications from BMT and management Pharmacist role 2 Introduction Introduction Allogeneic HSCT Normal cells Progenitor cells 3 malignant cells 4 Introduction Introduction Autologous HSCT Normal cells CMT Normal cell Progenitor cells Mature cells malignant cells 5 6 1

2 Introduction Introduction 7 8 HSCT process Indications Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication Malignancies Acute & chronic leukemia Lymphoma Multiple myeloma Myelodysplasia Testicular cancer Pediatric tumors Non-malignancies Genetic disorders (thalassemia, sickle cell anemia Combined immunodeficiency disorders 9 10 Donor and Histocompatibility Testing Autologous transplantation Own hematopoietic stem cell Syngeneic transplantation identical twin serves as the donor Allogeneic transplantation Genetic not identical but share some common tissue antigens Donor and Histocompatibility Testing Allogeneic transplantation : Matched sibling or related donor (MRD) Mismatched sibling or related donor (MMRD) Haploidentical transplantation Matched unrelated donor (MUD) Mismatched unrelated donor (MMUD)

3 Human Lymphocyte antigen Human Lymphocyte antigen HLA matching Class I antigen : HLA-A, -B, -C Endogenous antigen to T-cell Class II antigen : HLA-DR, -DP, -DQ Exogenous antigen Comparison of immunologic source of stem cells Relative risk Allogeniec Syngeneic Autologous Relapse GVHD Others complication Indications Hematologic stem cell transplantation process Disease/Condition Allogeneic Autologous Acute leukemia (myeloblastic; lymphoblastic) + + Chronic myelogenous leukemia + - Chronic lymphocytic leukemia + + Myelodysplastic syndrome + - Non Hodgkin Lymphoma + + Hodgkins Disease - + Selected solid tumors (testicular ca, pediatric tumors) - + Amyloidosis - + Neuroblastoma - + Aplastic anemia + - Severe combined immunodeficiency Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication 18 3

4 Patient Evaluation Donor evaluation Complete history and physical exam Complete blood count and serum chemistry Virology study Blood group and HLA typing Disease specific parameter CXR, EKG, Cardiac function, CT scan Complete history and physical exam Complete blood count and serum chemistry Virology study HLA issue Matching donor and recipient based on HLA antigen Hematologic stem cell transplantation process Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication Anatomic source of stem cell Hematopoietic stem cells serve as mother cells of erythrocytes, leukocytes, platelets Hematopoietic stem cells are rare cell composing less than 0.01% of all bone marrow cell Hematopoietic stem cell are found in 1. Bone marrow 2. Peripheral blood 3. Umbilical cord blood Anatomic source of stem cell 1. Bone marrow Anatomic source of stem cell 2. Peripheral blood (PBSCs) Obtained by multiple aspirations from anterior and posterior iliac crests The donor is under general anesthesia Procedure ~ 1hr (10-20 ml/kg ; max 1500 ml) Collected by procedure called leukopheresis (Apheresis) Mobilization techniques are required HD-CTX + G-CSF G-CSF +/- Plerixafor

5 Anatomic source of stem cell 2. Peripheral blood (PBSCs) P Anatomic source of stem cell 3. Umbilical cord blood GCSF mcg/kg OD D1-D4 Plerixafor (P) 240 mcg/kg/day on D4-7 DiPiro JT, et al. Pharmacotherapy Frequency of use difference stem cell sources Allogeneic (+) BM PB UCB (++) Increasing Increasing in frequency Autologous (+) (+++) NA Adequate stem cell collection BM/PB TWC : 3-5 x 10 8 cell/kg of recipients CD34+ : 3-5 x 10 6 cell/kg of recipients UCB TWC : 3-5 x 10 7 cell/kg of recipients CD34+ : 3-5 x 10 5 cell/kg of recipients BM = Bone marrow PB = Peripheral blood UCB = Umbilical cord blood Hematologic stem cell transplantation process Approaches to eradicate malignant cells Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication Toxicity

6 Conditioning regimen Myeloablative conditioning regimens Goal : To kill as many malignant as possible AlloHSCT : prevent graft rejection Usually include anticancer drugs given at very high dose Total-body irradiation (TBI) is used for eradicate malignant cell located in inaccessible area via CMT Myeloablative conditioning regimens Preoperative regimen Regimen Days CyTBI (gold standard) Cyclophosphamide + Total body Irradiation (total dose = 1200 cgy) BuCy (gold standard) Busulphan PO (IV) + Cyclophosphamide BEAM BCNU Etoposide Ara-C Melphalan 60 mg/kg/d IV q24h x 2d fractionated daily (ex. = 200 cgy bid x 3d) 1mg/kg/dose PO (0.8mg/kg/dose IV) q6h x4d 50mg/kg/d IV q24h x 4d 300 mg/m 2 IV 200 mg/m 2 Q12H 200 mg/m 2 Q24H 140 mg/kg/day IV -5, -4-3, -2, -1-9, -8, -7, -6-5, -4, -3, , -4, -3, -2-5, -4, -3, Reduced intensity conditioning regimens (RIC) Goal : Suppress immune system prevent graft rejection Rational of RIC based on assumption that most of tumor cell kill in AlloHSCT as result of Graft-Versus- Tumor effect (GVT) 34 Reduced intensity conditioning regimen (FYI) Hematologic stem cell transplantation process Preoperative regimen Regimen Days Cyclophophamide Fludarabine Fludarabine Melphalan Fludarabine Busulfan ATG (horse) 60 mg/kg IV Q24H 25 mg/m 2 IV Q24H mg/m 2 IV Q24H mg/m 2 IV Q24H 30 mg/m 2 IV Q24H 1 mg/kg/dose PO Q6H x 8 doses 10 mg/kg/day IV Q24H -7, -6-5 to -1-6 to to -5-6, -5-4 to Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication 36 6

7 Immunosuppressant For AlloHSCT Prevention of rejection Achieved immunosuppressive of conditioning regimen Required to eradicated host immune system Prevention GVHD Achieved with long-term immunosuppressant Initiated prior to infusion stem cell until > 6 mo of HSCT or resolve GVHD Required to suppress donor immune Hematologic stem cell transplantation process Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication Merten J. HSCT/BMT. ACCP/ASHP Oncology Pharmacy Preparatory Review Course Infusion of stem cell Day of infusion of stem cell referred as day 0 May be infusion of Fresh : AlloHSCT Thawed : cryopreserved AlloHSCT or AutoHSCT Infused via central line Cryopreserved may be associated with DMSO toxicity Nausea, Bradycardia, Garlic like odor Separate to over several days to avoid toxicity Engraftment Engraftment indication ANC > 0.5 x 10 9 cells/l Plt > 20 x 10 9 cells/l Sustained for 3 consecutive day Time to engraftment PBSC > BMSC > UCB Engraftment Evidence DNA analysis Donor sex chromosome Donor blood group Thalassemia patient Normal Hb, Hct, Reticulocyte count Donor hemoglobin typing Malignancy patients No evidence of previous malignancy Hematologic stem cell transplantation process Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication

8 BMT complication Nausea/Vomiting Mucositis VOD or SOS Graft versus host diseases(gvhd) Acute Chronic Infection Prophylaxis Mucositis Epidemiology Impact to patients Substantial clinical and economic impact of mucositis after HCT stratified by severity Increase in febrile days Increase in infection rates Days of injectable narcotic therapy Length of hospital stay Total inpatient charges Nutrition status Mucositis Frequency: Standard-Dose Chemotherapy 40% Mucositis Frequency: Radiation for Head and Neck Cancer 80% Mucositis Frequency: BMT with High-Dose Chemotherapy and/or Radiation Pre-Conditioning 75% Mucositis Pain QOL Patient nutrition Systemic infection Morbidity and mortality Cost of care 60% Peterson DE, et al. Ann Oncol. 2011;22: Sonis ST, et al. J Clin Oncol 2001;19: % Mucositis Reported Mucositis Not Reported 25% 45 Gabriel DA, et al. Semin Oncol Dec;30(6 Suppl 18): Narcotic therapy TPN Mucositis Tx Length of hospital stay Total inpatient charges 46 Initiatio n Signaling Amplification Ulceration Healing Risk factors 1. Co-morbidities/poor performance status 2. CMT Melphalan, BU, etoposide or TBI 3. Poor oral hygiene 4. Combined chemotherapy and radiation 5. Prolonged pre-transplant steroid treatment 6. Genetic abnormalities Lower MTHFR activity S.T. Sonis.Oral Oncology 45 (2009) Niscola P, et al. Haematologica 2007;92:

9 Oral mucositis Grading Guideline Grade CTCAE version Asymptomatic or mild symptoms; intervention not indicated Moderate pain; not interfering with oral intake; modified diet indicated Severe pain; interfering with oral intake Life-threatening consequences; urgent intervention indicated Death Grade WHO oral mucositis scale 2 None Oral soreness, erythema Oral erythema, ulcers, solid diet tolerated Oral ulcers, liquid diet only Oral alimentation impossible Score NIDCR 3 None Erythema Single ulcer <1 cm A few ulcers 1 cm Multiple ulcers >1 cm Slough 1. CTCAE June 14, Sonis ST, Elting LS, Keefe D, et al.cancer 2004;100(9 suppl): National Institute of Dental and Craniofacial Research 49 Lalla RV, et al. Cancer May 15;120(10): Prevention Prevention choices Pre-transplant oral screening Oral procedures completed prior to HCT Palifermin Basic oral hygiene Avoid alcohol-based mouth rinses Use non-medicated mouth rinses 4-6 times/day incorporating saline, sterile water, or sodium bicarbonate Brush with soft toothbrush 2-3 times/day ± toothpaste Oral cryotherapy Low-level laser therapy Tomblyn M, et al. Bio Blood Marrow Transplant 2009;15: Peterson DE, et al. Ann Oncol 2011;22: Lalla RV, et al. Cancer May 15;120(10): Palifermin Oral cryotherapy Human keratinocyte growth factor Targets epithelial cells lining the mouth and gastrointestinal tract Positive trial Autologous HCT included TBI/Etoposide/Cy regimen Palifermin 60 mcg/kg IV daily for 3 days before conditioning regimen and for 3 days following HCT Negative trial Allogeneic setting with TBI-based conditioning (Sub gr. + in CY/TBI) MM patients receiving melphalan 200 mg/m 2 Goldberg JD, et al. BMT 2013;48: Peterson DE, et al. Ann Oncol 2011;22: Hensley ML et al. J Clin Oncol 2009:27: pts with MM received melphalan 200 mg/m 2 followed by autologous HCT Oral cryotherapy vs RT NSS rinses 30 mins before and for 6 h after Bone Marrow Transplantation (2006) 37,

10 Result Preventions Palifermin Utilized for high-dose CMT with TBI followed by autologous HCT Oral cryotherapy Mephalan high dose (>200mg/m2) 30 mins before until 6 hrs after Low-level laser therapy Utilized for high-dose CMT with or without TBI Bone Marrow Transplantation (2006) 37, Lalla RV, et al. Cancer May 15;120(10): Papas AS, et al. Bone Marrow Transplant Apr;31(8): Treatment Stamatic cocktail Pain management Supportive care with goal of symptom relief Topical preparations have demonstrated limited benefit for oral mucositis Evaluate for TPN Oral drug administration Lalla RV, et al. Cancer May 15;120(10): Sinusoidal obstruction syndrome (SOS) SOS mechanism High dose-cmt damages sinusoidal endothelial cells and hepatocytes Activated injured cells Cytokines and adhesion molecules Damage the endothelium Fibrin deposit and cellular debris occlusion Ischemia Hepato-renal syndrome Multi-organ failure 59 World J Transplant ; 2(2): Ho V. Bone Marrow Transplant.2008;41: ; Carreras E. Blood.1998;92:

11 Risk factors Clinical Presentation Patient Factors Disease Factors Transplant Factors Pre-existing liver disease Iron overload Older HCT recipient age Younger HCT recipient age (< 8 years old) Poor performance status Female gender Glutathione S-transferase gene variants Advanced stage of malignancy History of abdominal radiation Prior HCT Cumulative exposure of cytotoxic agents Recent exposure of gemtuzumab ozogamicin Allogeneic > autologous HCT Myeloablative HCT TBI or cyclophosphamide containing regimen High exposure of BU, CTX and Etoposide Donor-recipient human leukocyte antigen (HLA) disparity Concomitant azoles, sirolimus, methotrexate Onset within 3 weeks after HCT Symptoms Hepatomegaly + RUQ pain Jaundice Ascites Rapid Wt. In severe SOS Multi-organ failure Confusion Bleeding Renal failure Cardiac failure Pulmonary failure World J Transplant ; 2(2): Ho V. Bone Marrow Transplant.2008;41: ; Carreras E. Blood.1998;92: McDonald G. Hepatology. 2010;51: Diagnosis/Staging/Prognosis SOS prevention Stage Symptom Medication (Diuresis, pain or fluid or sodium restriction) Complete resolution Mild X X Moderate Severe X Prognosis TRM by 4-fold All-cause mortality rate in severe SOS with MOF before day +100 is close to 100% 63 Reduced intensity conditioning Medication Defibatide Ursodeoxycholic acid Heparin LMWH TDM Busulfan World J Transplant ; 2(2): Bone Marrow Transplantation (2008) 41, SOS Prevention Dose recommended Defibrotide 10-25mg/kg/day IV OD from D 0 until D +21 Ursodeoxycholic acid mg or 6-12 mg/kg PO BID from D -1 until D +80 Treatment Supportive care Sodium and fluid restriction Judicious Platelet transfusion Renal replacement therapy Oxygen support Pain management World J Transplant ; 2(2): Bone Marrow Transplantation (2008) 41, McDonald G. Hepatology. 2010;51:

12 Treatment Defibrotide RCT multicenter, international phase III 102 patients (adult n=58; children n=44) with severe SOS received defibrotide 6.25mg/kg IV q6h daily (median 22 days) Compared with 32 historical control patients 100-day OS: 38% vs. 25% (P<0.034) 100-day CR: 24% vs. 9% (P=0.013) Similar incidence of hemorrhagic AEs (65% vs. 69%) Infection prophylaxis Estimated immune recovery Richardson P, et al. Blood 2014;Abstr Bone Marrow Transplantation (2009) 44, Opportunistic pathogens Infection prophylaxis Pathogen Medication Remark Bacteria -Gram neg. (Pseudomonas aeru.) - Streptococcus pneumoniae PCP Antipseudomonal Ciproflaxacin 500 mg po BID Levofloxacin 500 mg po OD Streptococcus pneumoniae: allogeneic recipients with ongoing cgvhd Penicillin 500 mg BID or 1000 mg daily Bactrim SS po OD or DS po three times/wk (+Toxo) Dapsone 50 mg PO BID or 100 mg PO QD Aerosolized pentamidine 300 mg q 3-4 weeks D 0 until engraftment or initiation of empiric antibiotics for FN Auto. 6 mo. after HSCT Allo. 3-6 mo. after discon. Immunosuppressives Can cause delay of neutrophil recovery Bone Marrow Transplantation (2009) 44, Biol Blood Marrow Transplant. 2009; 15: Infection prophylaxis Infection prophylaxis Pathogen Medication Remark Fungal -Yeast - Mold Azoles Fluconazole 400 mg po OD Itraconazole 200 mg BID Posaconazole 200 mg po TID Prolonged neutropenia: Micafungin 50 mg IV OD Prophylaxis in the setting of GVHD: Posaconazole 200 mg PO TID Voriconazole 200mg PO BID Auto.D 0 to until engraftment ( 7 day after ANC >1000) Allo. D 0 to at least D +75 Risk Pre-engraftment: Prolonged neutropenia Sourse of stem cell: Cord blood or bone marrow > peripheral blood Reduced Intensity Post-engraftment Immunodeficiency caused by GVHD and treatment for it. Unrelated donor HLA-mismatched donor or haploidentical. Pathogen Medication Remark Viral -HSV, VZV CMV Acyclovir mg po BID or 250 mg/m2/dose IV q 12 hr. Valacyclovir 500 mg po OD Ganciclovir 5 mg/kg/dose IV BID x 5-7 days OD Foscarnet 60 mg/kg IV BID x 7 days, followed by mg/kg IV OD Acyclovir 800 mg PO QID valacyclovir 2 gm PO TID HSV D 0 until engraftment or (-)mucositis VZV D 0 to at least 12 mo. or at least 6 mo. after discontinue immunosuppressive medications Treatment Acyclovir 10 mg/kg IV Q 8H for 7-14 days, or 2 days after cessation of new lesion Starting at time of engraftment D +100 Treatment Ganciclovir induction for 7-14 days at reactivation of CMV continue until the indicator test is neg. and maintenance of 2 weeks. Foscarnet: Same dose

13 GVHD GVHD from Allogeneic HCT Skin, Liver and GI Not specific Acute GVHD Risk of HVHD MSD Grade II IV : 35-40% Grade III-IV : 20% MUD Grade II IV: > 50% Grade III-IV: 35% Median time to onset Myeloablative: D +17 Reduced intensity: D +90 HLA disparity HLA matched unrelated donors (HR 1.66) HLA mismatched related donors (HR 1.74) HLA mismatched unrelated donors (HR 2.0) Source of stem cells Peripheral blood > Bone marrow > Cord blood Dose of CD34+ cells Acute GVHD Staging and Grading Organ Incidence Clinical Diagnosis Skin 75% MP rash, erythematous rash palms and soles cheeks, backs of ears, neck, and back/upper trunk. Liver 20% Cholestatic jaundice GI 50% Lower Gut: Secretory diarrhea, Cramping Upper Gut: Anorexia, nausea, and dyspepsia Biopsy 77 Bone Marrow Transplant. 1995; 15:

14 Medications GVHD Prevention Blood. 1998; 92: , Blood. 2000; 96: , Bone Marrow Transplant. 2004; 34:621-5., Biol Blood Marrow Transplant.2010;16: GVHD Prevention Combination immunosuppression Related donors CSA + MTX Tacrolimus (FK506)+ Sirolimus (Non BU based regimen) Unrelated donors FK506 + MTX Calcineurin inh. + MMF in some reduced intensity conditioning regimens CSA level (ng/ml) % change in dose CSA dose adjustment Very low Normal High Very high < >550 Increase 10 25% No change 25-50% dose reduction OR if no toxicity, consider holding 1 dose and resume when level < 250 with 25-50% dose reduction Hold dose and resume when level < 250 with 50 75% dose reduction Blood. 1998; 92: , Blood. 2000; 96: , Bone Marrow Transplant. 2004; 34:621-5., Biol Blood Marrow Transplant.2010;16: FK dose adjustment Treatment 1 st line = methylprednisolone 1-2 mg/kg/day (or equivalent dose prednisone) Tapering by 0.2 mg/kg/day q 3-5 days Nonabsorbable Corticosteroids may has benefit in stage I isolated gut GVHD D 50 Treatment failure rate was not statistically different, but D 80 treatment failure rate was improved HR =0.55; p=0.02 OS at 1 year: 71% VS 58% ;HR 0.54; P = Blood. 1998; 92: Blood. 2007; 109:

15 Steroid-refractory for agvhd 2 nd line for agvhd 1. Progression after 3 days 2. No change after 7 days of grade III GVHD or 14 days of grade II GVHD 3. Incomplete response after 14 days of Tx Chronic GVHD (cgvhd) Grading Occurs in about 50% No have most organ specific Risk factor Prior grade III-IV agvhd (HR 1.42) HLA disparity HLA matched unrelated donors (HR 1.3) HLA mismatched related donors (HR 1.24) HLA mismatched unrelated donors (HR 1.57) Source of stem cells 2 year survival 97% 2 year survival 86% 2 year survival 62% Blood. 2011; 117: Biol Blood Marrow Transplant. 2005; 11: Mild cgvhd Topical Tx Treatment Moderate to severe cgvhd 3 organs or with a score of 2 in any one organ Systemic Tx Systemic Tx: Prednisone 1 mg/kg/day Steroid-refractory for cgvhd 1. Progression while on treatment for 2 weeks 2. No improvement despite treatment for 4-12 weeks 3. Inability to taper steroid Prednisone < 1 mg/kg/day within 3 months The Symptoms worsen during a taper below 0.5 mg/kg/day 4. Inability to tolerate therapy Biol Blood Marrow Transplant. 2005; 11: Biol Blood Marrow Transplant. 2005; 11:

16 2 nd line for cgvhd Drug interaction Busulfan, CTX and Etoposide Immunosuppressive Cyclosporine, Tacrolimus, Sirolimus and MMF Infection prophylaxis Azoles, Quinolones and Macrolides Supportive care PPIs, NK1 receptor blockers 91 Glotzbecker B, at al.biol Blood Marrow Transplant Jul;18(7): Pharmacist role Conclusions Check Prescription s Immunosuppressive Supportive care medication Sequencing of medication Pre transplant Conditioning regimen Stem cell infusion Infection prophylaxis Engraftment Immunosuppressive TDM of CMT and Immunosuppressive Drug interaction BMT complication Hematologic stem cell transplantation process Initial consult to established appropriateness BMT/HSCT Patient evaluation Donor evaluation Collection stem cells Immunosuppressant Infusion of stem cell Monitoring and management complication BMT complication Nausea/Vomiting Mucositis VOD or SOS Graft versus host diseases(gvhd) Acute Chronic Infection Prophylaxis

17 The END Thank you 97 17