Vaccinations - Hematopoetic stem cell transplantation Prof.Dr. Zafer Gülbaş

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1 Vaccinations - Hematopoetic stem cell transplantation Prof.Dr. Zafer Gülbaş Departman Tarih

2 He is a member of the Turkish Society of Hematology, American Society of Hematology, European Group of Bone Marrow Transplantation, International Society of Cellular therapy. His clinical expertise lie in Diagnosis and treatment of hematologic malignancies and stem cell transplantation, cellular therapy and Geriatric Hematology. He is the founder and general secretary of Turkish Geriatric Hematology. Zafer Gulbas M.D. Dr. Gulbas currently serves as Director of Hematologic Oncology and Bone Marrow transplantation Department Anadolu Health Center Affiliated with John Hopkins Gebze-Turkey. He graduated in 1977 from the Hacettepe University Medical Faculty and he received internist and hematology degrees and he did his academic carrier at Anadolu University and Osmangazi University-Turkey. He worked at Bone Marrow Transplantation Department of Hadassah University, Israel, Bone Marrow Transplantation Department of Fred Hutchinson Cancer Research Center, Seattle, USA, Molecular Hematology and Treatment Department of MD Anderson Cancer Research Center USA and GMP cell processing laboratory of Princess Margeret Hospital Treatment Center, Canada.

3 ANADOLU HEALTH CENTER BONE MARROW TRANSPLANTATION PROGRAM Departman Tarih

4 started 2010 Departman Tarih

5 AHC- BMT PROGRAM Outpatient clinic Inpatient clinic: Two floor - 22 beds

6 AHC- BMT PROGRAM Apheresis Unit Cryopreservasation and Stem Cell processing laboratory HLA tissue typing laboratory Flow cytometry laboratory PCR laboratory

7 ASM- BMT PROGRAM Inpatient clinic

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11 Hepa-filtered including the individual rooms, nursing stations and corridors. Patients are encouraged to stay active throughout their hospitalization. Therefore, the hepa-filtration provides a safe environment for walking

12 ASM- BMT PROGRAM 6 physician 4 biolog 32 nurse 2 case manager 3 apheresis nurse 7 house keeping personel

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14 ASM- BMT PROGRAM Allogeneic BMT: HLA identical sibling BMT: Haploidentic BMT: Unrelated BMT: Autologous BMT:

15 NUMBER OF TRANSPLANTS BY TYPE TOTAL AUTOLOGUES ALLOGENEIK (HLA- MATCHED) HAPLOIDENTIC UNRELATED TOTAL

16 NUMBER OF TRANSPLANTS BY DIAGNOSIS AUTOLOGUES HLA-MATCHED UNRELATED HAPLOIDENTIK TOTAL Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Chronic Lymphocytic Leukemia Myelodysplastic Syndrome Hodgkin Lymphoma Non-Hodgkin Lymphoma Plasma Cell Disorders Aplastic Anemia Solid Tumors Skloderma Qualitative Platelet Disorder CMML Chronic Myeloproliferative Disorders TOTAL

17 NUMBER OF FOREIGN PATIENTS TOTAL AUTOLOGUES ALLOGENEIK (HLA- MATCHED) HAPLOIDENTIC UNRELATED TOTAL

18 NUMBER OF FOREIGN PATIENTS BY COUNTRY TOTAL AZERBAIJAN BULGARIA ROMANIA IRAQ TURKMENISTAN 1 1 UZBEKİSKAN 1 1 BAHRAIN RUSSIA IRAN LIBYA KAZAKHSTAN KYRGYZSTAN MACEDONIA 2 2 GEORGIA MOLDOVA 1 1 KOSOVA 1 1 ALBANIA 1 1 U.A.E 1 1 USA 1 1 UKRAINE TOTAL

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21 Autologous bone marrow transplant indications? Multiple Myeloma Hodgkin lymphoma Non hodgkin lymphoma Germ cell tumors

22 Allogeneic bone marrow transplant indications? Acute lymphoblastic leukemia(all) Acute myeloblastic leukemia (AML) Myelodysplastic syndrome(mds) Chronic myeloid leukemia (KML) Chronic lymphocytic leukemia(kll) Lymphoma Aplastic anemia

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30 Why we need vaccination?

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46 Regeneration of immune system

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54 Worldwide, > 50,000 HSCTs performed each year Vaccine preventable diseases: influenza, pneumococcus, varicella, Bordetella pertussis significant causes of morbidity, re-hospitalization and mortality after successful HSCT Invasive pneumococcal infections in 590/100,000 allogeneic & 199/100,000 autologous recipients per year, compared with 11.5/100,000 age-matched controls Kumar D, et al. Bone Marrow Transplant 2008.

55 Loss of immunity post-transplant ~ 50% of patients with positive tetanus & polio titers at the time of allogeneic HSCT will become seronegative at 1 year, with most unprotected against both by 2 years Ljungman P, et al. J Infect Dis In the absence of revaccination, the majority of allogeneic patients will become susceptible to measles, mumps & rubella by 3-5 years post-hsct Ljungman P, et al. Bone Marrow Transplant 2009.

56 Ljungman P, et al. Bone Marrow Transplant 2009; CIBMTR - EBMT, CDC, ASBMT, IDSA Vaccine CIBMTR (2009) Tdap, then Td x 2 doses IPV Hib (conjugate) Pneumococcal Three doses, 6-12 months Three doses, 6-12 months Three doses, 6-12 months Conjugated PCV*, three monthly doses, 3-6 months Then, PPV23 after 3 doses of PCV HepB Three doses, 6-12 months (for those with risk factors) MMR 24 months Inactivated influenza Live-attenuated varicella vaccine -Varivax??? - Zostavax? Yearly, 4-6 months 24 months (limited data) CDC (2000): NO, EBMT (2005): NO, CIBMTR (2009): selected patients * 13-valent (PCV-13), 2011 revision no safety data on the live, cold-adapted vaccine for intranasal administration serologic testing to determine need for vaccination (CIII) limited experience with use post-transplant; CII recommendation if >24 months posttransplant, without active GVHD, off immune suppression

57 Current post-transplant guidelines recommend immunization of all patient groups at fixed time points post-hsct.

58 Vaccine variables Timing Dosage Doses Route (IM, subcutaneous, intradermal) Conjugate Pathogen encountered as natural infection (VZV) vs. as vaccination pre-transplant (HBV) vs naïve (pneumococcus) Host (donor/recipient) variables Age Preexisting immunity (donor* & recipient) Graft type Time post-transplant Immune suppressive regimen (conditioning & immune suppression) Monoclonal antibodies GvHD * Vaccination of the donor has been shown to improve recipient post-transplant immunity in the case of tetanus toxoid, PCV7 and H. influenzae type b-conjugate vaccines.

59 What are the milestones of immune competence? 3 doses of IPV (219) & 3 doses of HepB (292) vaccine, if: CD4 > 200/µl In vitro T-cell response to phytohemagglutinin (PHA) at least 75% of the lower limit of normal IgG > 500mg/dL Off systemic immunosuppressive therapy, minimal/no GVHD Median age 24 (range ) at time of transplant Vaccinated median 23.4 months post-transplant 65% MRD, 9% MMRD, 25% MUD; 65% T-cell depleted 64% developed protective hepatitis B titers older age & prior chronic GvHD associated with vaccine nonreponse poorest response in MMRD subset 96% developed a > 4-fold response to all 3 polio serotypes, including recipients of an unrelated and/or T- cell depleted HCT Jaffe D, et al. Blood 2006.

60 127 HSCT recipients, adults & children ( ) median age 23, range % MRD, 5.5% MMRD, 42% MUD; 56% T-cell depleted Of 53 unmodified HSCTs, 26% developed cgvhd, 32% on IS at time of vaccination PCV7 (127) & HIB (115) vaccination median 1.1 years post-transplant; 81% vaccinated within 2 years 62% (79/127) responded to PCV7: 88% children vs. 44% adults (P<.001) 86% (99/115) responded to HIB: 96% children vs. 79% adults (P=.006) In patients > age 50, 58% (11/19) vaccinated AFTER reaching minimal milestones of immune competence (CD4 > 200/µL, IgG > 500mg/dL, PHA within 60% lower limit normal) responded to PCV7, vs. 0/8 vaccinated prior to milestones (P=.006) Higher numbers of circulating CD4 + CD45RA + T cells improved response to PCV7. Pao M, et al. Biol Blood Marrow Transpl 2008.

61 Influenza vaccination Influenza vaccination within the first 6 months following HSCT is associated with a poor serologic response to vaccine antigens. Engelhard D, et al. Bone Marrow Transplant Addition of GM-CSF to influenza vaccine resulted in a minor improvement in response to influenza B vaccine in HSCT recipients Pauksen K, et al. Clin Infect Dis In non-transplant patients with hematologic malignancy, 2 doses of influenza vaccine were not more effective than one. Ljungman P, et al. Br J Haematol 2005.

62 CLINICAL EFFICACY of influenza vaccination 177 transplant recipients (118 allo, 71%) followed for 1 year 134 were < 6 months post-transplant (unvaccinated) 25 (18.6%) developed influenza 43 eligible for vaccination (> 6 months post-transplant) 19 vaccinated: 2/19 (10.5%) developed influenza 24 unvaccinated: 12/24 (50%) developed influenza vaccine efficacy 80% (VE¼((r0 r1):r0) Machado CM, et al. Bone Marrow Transplant 2005.

63 The over/under approach to influenza vaccination No study has reported an increased risk for GVHD in association with influenza vaccination Data are limited, largely from heterogeneous groups of patients following traditional myeloablative conditioning Common practice: Vaccinate yearly, beginning > 4-6 months post-transplant Consider vaccination between 3-6 months post-transplant, in the context of widespread community activity, with a 2 nd dose at 6 months post-transplant Ensure vaccination of family members/close contacts of transplant recipients & healthcare workers (cocooning)

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65 Pneumococcal vaccination in SCT recipients Superiority of conjugate vaccine 64 donor/recipient pairs, randomized to PPV23 or PCV7 Pre-transplant vaccination of donor & 6-month posttransplant vaccination of recipient 0% vs 38.6% 55.6% vs 90.9%, P=.02 Kumar D, et al. Clin Infect Dis 2007.

66 Pneumococcal vaccination.is earlier better? 158 patients, 13 EBMT centers PCV7 x 3 months or 9 months post-transplant Primary endpoint: antibody level > 0.15µg/mL for each serotype at 1 month after 3 rd dose of PCV7 Noninferiority margin 20% early vaccination: 79% late vaccination: 82% (P=0.64) % with positive titers to all 7 serotypes at 24 months posttransplant early vaccination: 59% late vaccination: 85% (P=0.013) cgvhd & older donor age associated with poor response WHO threshold for response: >0.35 µg/ml 2011 update: PCV13 as replacement for PCV7 Ljungman P, et al. Bone Marrow Transplant Prospective open-label study underway Cordonnier C, et al. Clin Infect Dis 2009.

67 Pneumococcal vaccine updates: prime boost For patients who have previously received one or more doses of PPSV23, a single dose of PCV13 should be given one or more years after the last PPSV23 dose was received. For patients who require additional doses of PPSV23, the first such dose should be given no sooner than eight weeks after PCV13 and at least five years after the most recent dose of PPSV23. MMWR October 12, 2012.

68 Vaccines NOT recommended for the transplant recipient BCG (Bacillus Calmette-Guérin) (live) Oral poliovirus vaccine (live) Intranasal influenza vaccine (live) Cholera Typhoid, oral (live) Rotavirus (live, not licensed for adult use) Zostavax (live) Yellow fever vaccination contraindicated IF < 24 months, active GVHD, and/or on immunosuppression

69 New vaccines on the horizon Heat-inactivated varicella-zoster virus vaccine CMV vaccine

70 Recommended Vaccinations/Schedule Pneumococcal Conjugate (PCV) Recommended for use after HCT: Yes Time post-hct to initiate vaccine: 3-6 months No. of doses: 3-4 b Tetanus, Diphtheria, Acellular Pertussis c Recommended for use after HCT: Yes Time post-hct to initiate vaccine: 3-6 months No. of doses: 3 d Haemophilus Influenzae Conjugate Recommended for use after HCT: Yes Time post-hct to initiate vaccine: 6-12 months No. of doses:

71 Recommended Vaccinations/Schedule Meningococcal Conjugate Recommended for use after HCT: Follow country recommendations for general population Time post-hct to initiate vaccine: 6-12 months No. of doses: 1 Inactivated Polio Recommended for use after HCT: Yes Time post-hct to initiate vaccine: 6-12 months No. of doses:

72 Recommended Vaccinations/Schedule Recombinant Hepatitis B Recommended for use after HCT: Follow country recommendations for general population Time post-hct to initiate vaccine: 6-12 months No. of doses: 3 Inactivated Influenza Recommended for use after HCT: Yearly Time post-hct to initiate vaccine: 4-6 months No. of doses: 1-2 e Measles-Mumps-Rubella (live f, g ) Recommended for use after HCT: Measles: All children and seronegative adults Time post-hct to initiate vaccine: 24 months No. of doses: 1-2 h

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94 THANKS Departman Tarih

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97 Two checkpoints in the immune response, CTLA-4 and PD-1. The immune response consists of an initiation phase (A) and an effector phase (B). In the initiation phase, naive T cells recognize specific antigens associated with MHC molecules via TCR, but observable activation and proliferation require an additional costimulatory signal from CD28. CD28 is activated by engagement with the ligands CD80 or CD86, which are expressed exclusively on dendritic cells (DCs) and other professional antigen-presenting cells (APCs). CTLA-4, which has a higher binding affinity to CD80 and CD86 and is induced after the initial TCR recognition, inhibits the CD28-mediated costimulatory signal by sequestering CD80/CD86 ( off signal). CTLA-4 is a checkpoint molecule that determines whether a particular antigen should produce measurable T-cell proliferation and activation. In the effector phase, effector T-cell progenies developed from the initiation phase execute immune functions such as cytokine production and the killing of target cells. At this stage, the activation of effector cells via specific TCRs no longer requires a CD28-mediated costimulatory signal, and thus cytotoxic T cells (CTLs), for example, can affect any target cell bearing the antigen, even in the absence of CD80/CD86. However, the activated effector T cells are induced to express PD-1, which can inhibit TCR signaling if engaged with the ligands PD-L1 or PD-L2. PD-Ls are induced on normal tissue cells in response to IFNγ as on many cancers, thereby inhibiting effector T-cell activation and proliferation via PD-1. PD-1 is a checkpoint molecule that prevents potentially self-reactive effector T cells from attacking normal tissue cells

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99 Recommendations for Timing of Vaccination When Should Vaccines Be Administered to Immunocompetent Patients in Whom Initiation of Immunosuppressive Medications Is Planned? Vaccines should be administered prior to planned immunosuppression if feasible (strong, moderate). Live vaccines should be administered 4 weeks prior to immunosuppression (strong, low) and should be avoided within 2 weeks of initiation of immunosuppression (strong, low).* Inactivated vaccines should be administered 2 weeks prior to immunosuppression (strong, moderate)

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