Long Term Recovery Life After Transplantation

Transcription

1 Long Term Recovery Life After Transplantation Long-Term Follow-Up (LTFU) 1 Questions? LTFU@seattlecca.org Caring for BMT Survivors There is a projection of 500,000 survivors in the US by the year 2030 Survivors are typically cared for by their home oncologist after discharge from the transplant center and eventually, by their primary care physicians About 50% of allogeneic BMT survivors will develop chronic GVHD, a rare and difficult-to-treat multi-organ syndrome involving tissue inflammation and fibrosis that often results in permanent organ dysfunction BMT survivors can be medically challenging as more than 90% of them have at least one chronic health condition Mission of Long-Term Follow Up To provide life-long medical consultation to hematopoietic stem cell transplant recipients (and their physicians) that were treated at The Hutchinson Center (FHCRC) and the Seattle Cancer Care Alliance (SCCA). 6/12/2018 Clinical LTFU Activities Prepare patients for departure home Provide telephone consultation with patients and referring physicians Evaluate LTFU patients on site in clinic visits Evaluate results of studies done at home LTFU support group Research LTFU Activities Send yearly questionnaires and keep track of health outcomes of survivors Conduct research protocols relating to chronic GVHD treatment and other long-term problems 1

2 LTFU Telemedicine Nursing Office Our LTFU Patient Charts LTFU Telemedicine Close to 60 phone calls/week Half are from patients, half are from local providers About half of callers have questions that can be answered within RN scope of practice About half go to rounds for LTFU Attending input with RNs communicating recommendations back to local providers Telemedicine Rounds Improved Early Survival Study Compared to N = 1418 vs Showed in day 200 nonrelapse mortality by 60% Showed in overall mortality by 41% Long-term Survival Odds Among 2 year disease-free survivors, subsequent survival: 90% at 5 years 85% at 10 years 80% at 15 years Among 5 year disease-free survivors, subsequent survival: 80% at 20 years Gooley TA et al. NEJM 2010; 363: 2091 Slide courtesy of Dr. Flowers Socie et al, NEJM 1999 Bhatia et al, BLOOD 2007 Martin et al, JCO 2010 Slide courtesy Dr. Flowers 2

3 Return to Work 100 day survival 1 year survival 5 year survival Current SCCA Survival 89% 65% 35% SCCA survival rates are typically better than most transplant centers About 70% of our BMT Survivors return to work/school Transplant Related Mortality Relapse is the number one cause of late transplant related mortality in autologous AND allogeneic patients. Other causes of late death are second cancers, infections, chronic GVHD, respiratory diseases and cardiovascular diseases. Life after Transplant The majority of long-term survivors recover to a new normal that is acceptable to them. VERY FEW make it through transplant without some degree of long-term changes that affect health and well-being. The minority of long-term survivors suffer serious morbidity post-transplant to a degree that causes chronic disability and/or suffering. Was it worth it? Long-Term Complications A surprising 95% of patients answered affirmatively with either a 4 which means Quite a Bit or a 5 which means Very Much on a 1-5 scale when asked to agree with the following statement: Having a transplant was worth it. Neurologic Endocrine Sexual Fertility Renal/Urinary Musculoskeletal Dental Ocular Emotional Chronic GVHD Infection Relapse New malignancy Pulmonary Cardiac 3

4 Neurologic Endocrine: Diabetes Learning Disabilities Higher risk with: Prior cranial irradiation Intrathecal chemotherapy Younger age at time of transplant Psychometric testing to assess problem School support for specialized learning plans Cognitive Dysfunction Poor memory, concentration, wordfinding difficulty Biggest dip around day 80 Patients recover until one year post-transplant Residual cognitive impairment can be assessed with Neuropsych testing and managed with behavioral interventions Reported in 7.6% of HSCT survivors and 3.1% of siblings Exposure to TBI is associated with an increased risk along with greater BMI and older age Endocrine: Thyroid Endocrine: Growth and Development Risk factors Most frequent in patients receiving total body irradiation (29%) Occurs in about 14 % of those receiving chemo only More frequent after cranial irradiation Common with I-131 containing regimens Screening Thyroid testing annually for life Symptoms Fatigue Depression Weight gain Sleep disturbances Dry skin Thinning hair Diagnosis Elevated TSH Reduced Thyroxine Treatment Thyroid replacement hormone Risk Factors for impaired growth Cranial irradiation Total body irradiation Age less that 6 years at time of transplant Underlying Fanconi s Anemia Treatment Growth Hormone: Stimulates growth of epiphyseal cartilage and bone Greatest response to treatment results when started before the height drops to below the third percentile Early use allows for longer period of treatment/growth Endocrine: Puberty Sexuality: Men Chemotherapy Cytoxan only: If prepubertal at time of transplant, normal progression of puberty Busulfan: Evidence of primary ovarian failure in girls and decreased sex hormone production in some boys Need to be follow closely from 12 years of age TBI Delayed sexual development in 46% of girls and 56% of boys Sex hormones (estrogen and testosterone) necessary for the promotion of pubertal growth spurt and sexual maturation The expertise of an endocrinologist is needed Manifestations: Elevated FSH levels Azospermia Low testosterone levels Decreased libido Premature ejaculation Impotence Management: Annual testing of free and total testosterone Treatment with testosterone may be warranted after risks/benefits explored 4

5 Manifestations Permanent ovarian failure common in most patients Elevated FSH and LH levels and decreased estradiol are common Both sexuality and bone health adversely affected Decreased libido, vaginal dryness, hot flashes, night sweats, vaginal atrophy and adhesions, emotional and cognitive changes, sexual dysfunction, discomfort with intercourse Sexuality: Women Management: Annual testing of estradiol level Systemic hormonal therapy for some women may be warranted after risks/benefits carefully explored Topical estrogens may relieve some symptoms and improve sexual function Fertility BMT survivors are 36X more likely to report no conception as compared to their sibling(s) Most patients will require fertility specialist to get pregnant and all patients should be treated as high risk once they get pregnant Newer therapies can help preserve fertility in advance of BMT Lead time for egg harvest is down to two weeks Fertility: Pregnancy Outcomes Renal/Urinary 1522 Disease-Free Survivors were studied for pregnancy and birth outcomes 146 Pregnancies in 76 patients 115 Live births to 67 patients Birth defects in line with general population, however, LBW and pre-term labor higher and spontaneous abortion higher (TBI)? Cancer risk in offspring d/t patient s own disease/risk factors or pretreatment damage to sperm Theoretical risk of relapse when pregnant d/t immunosuppressed state during pregnancy Bladder Late hemorrhagic cystitis d/t BK virus, polyome virus or adenovirus Women with vaginal/vulvar cgvhd can get frequent UTIs Kidney Renal impairment from CNIs, antibiotics, TBI or underlying disease (MM) Hemolytic Uremic Syndrome Nephrotic syndrome related to cgvhd Musculoskeletal: Osteoporosis and Osteopenia Risk Factors: Steroid Use Hypogonadism Radiation Inactivity Incidence Up to 40% of patients have reduced bone mass density at oneyear after transplant Management DEXA scan at one year and yearly if on prednisone/at risk Bisphosphonates Calcium/Vitamin D supplementation Hormonal therapy for select patients Weight-bearing exercise Musculoskeletal: Avascular Necrosis Incidence Reported in 4-10% of patients Hip most common site Most patients have >1 joint affected Risk Factors Steroid use TBI Male gender Older age AML or AA diagnoses Diagnosis MRI gold standard Treatment Core decompression for early-stage AVN Joint replacement 5

6 Musculoskeletal: Body Composition Loss of mean muscle mass as compared to healthy siblings Even if weight the same, percent fat mass is higher than lean body mass percent From outside, patient can look healthy, or even underweight, but this leads to metabolic issues Sibling Weight 70kg LBM 47kg BMI 24 PFM 28.6% BMT Survivor Weight 62kg LBM 37kg BMI 23 PFM 34% Dental Decreased salivary gland function and increased sensitivity, tooth decay, and gingivitis Avoid elective dental work in the first 6 months and while immunosuppressed, including routine cleaning (d/t risk of seeding pathogens) Use fluoride rinse and or gel and good oral hygiene Risk of osteonecrosis with bisphosphonate use If dental work is needed during first 6 months or if immunosuppressed: Prophylactic (and possibly post-procedure) antibiotics Dental dam, high-flow suction Ocular: Cataracts Emotional Risk factors: TBI Steroid use Cranial irradiation Incidence About 40% of TBI patients About 20% of non-tbi patients Long term prednisone use doubles incidence Affects children and adults Treatment Surgery Patients report many emotional issues after transplant: uncertainty, fatigue, reduced attention span, STML, depression, sexual dissatisfaction, low self-esteem and PTSD No significant different between BMT survivors and those given maintenance chemotherapy Physical recovery happens earlier than psychologic or work recovery Transplant-related distress slower to resolve in allogeneic vs autologous patients and those with poorer social supports By 5 years, most survivors report good psychologic health in addition to minimal physical symptoms and return to work Fatigue, lack of energy, sexual dissatisfaction remain longterm problems for many survivors Increased Risk Of Developing Chronic GVHD CHRONIC GVHD Prior acute GVHD Greater HLA disparity Increasing patient age Female donor/male patient Peripheral blood stem cells versus bone marrow Donor Lymphocyte Infusion 35 6

7 Chronic GVHD Incidence Acute vs Chronic GVHD: Timing Approximately 50% of allogeneic patients will develop chronic GVHD Onset is generally 75 days to 2 years post transplant. Uncommon for first diagnosis of cgvhd to be after 2 years If new symptoms common to GVHD present after 2 years in a patient with no GVHD, suspect other causes Acute Tends to be near time of engraftment Chronic Tends to be after day +75 Acute vs Chronic GVHD: Presentation Acute vs Chronic GVHD: Sites Acute Tends to be abrupt onset Tends to be angry Tends to demand attention Chronic May be insidious May be explained away May be less obvious Acute Skin Gut Liver Chronic Skin Oral Liver Lung Ocular Genital (F>M) Joints/Fascia Gut Labs (Eos, Plts) Acute vs Chronic GVHD: Treatment Acute HD Steroids as a short course, followed by a rapid taper Will resolve (over weeks to months) or become refractory After resolution, no permanent damage Refractory difficult to treat, may result in death Chronic HD Steroids as a longer course, followed by slow taper Steroid-sparing agent Will resolve (over months to years) or become refractory or progressive with additional sites After resolution, may leave permanent damage Refractory and progressive difficult to treat, may result in death 7

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9 Chronic GVHD of the Eye 50 Chronic GVHD Oral Exam Lacy patch? Keratotic patch? Erythema? Ulcers? Mucoceles? 9

10 5 years post-transplant 9 years post-transplant GVHD: Other Manifestations Esophageal webs, strictures or stenosis Vaginal scarring and stenosis with painful intercourse or inability to have intercourse Penile changes Thrombocytopenia, eosinophilia, inflammatory marker elevation Pericardial or pleural effusions Nephrotic syndrome, ascites, peripheral neuropathy and myasthenia gravis Decrease The Risk Of Chronic GVHD Compliance with immunosuppressive medication Avoid sunburns Avoid infections 10

11 May Require Treatment for 3-5 Years and with Multiple Lines of Therapy Systemic Therapy Prednisone Cyclosporine (Neoral) Tacrolimus (FK-506) Mycophenolate Mofetil (Cellcept) Sirolimus (Rapamycin) Methotrexate Rituxan PUVA Extracorporeal Photophoresis Imatinib Azothiaprine (Immuran) Local Therapy Vaginal/Vulvar Oral Skin Ocular Lung Gut Immunosuppression Increased infections Osteoporosis Avascular necrosis Diabetes Cataracts Nephrotoxicity Deconditioning Depression Effects of Treatment Infection: Immune Reconstitution Takes about 6 months post-autologous Takes about 12 month post-allogeneic Longer if chronic GVHD present as immune reconstitution not complete until off all IST Longer if on maintenance therapy (fairly common after autologous transplant) Re-vaccination Patients retain varicella immunity after transplant if present prior to transplant BUT all other immunity to vaccine preventable diseases is erased Typically, re-vaccination begins at one-year mark, although occasionally earlier if certain parameters are met Inactivated vaccines are given first; live vaccines are given later Flu shot can be given at 6 months post-transplant and should be given annually for life If seen at SCCA for one-year appointment, we give first doses (5-7 shots) and provide a written plan and schedule for boosters Boosters can be challenging to obtain in community due to lack of availability and guidelines regarding vaccines for the general population (weird for adults to need baby shots) Vaccine Schedule Vaccine >12m >14m >16m >18m >22m >24m >25m >60m H. Influenzae Type B X X X Meningococcal X X Pneumococcal (Prevnar 13) X X X? Pneumococcal (Pneumovax) X Polio X X X Hepatitis A X X Hepatitis B X X X HPV, age 9-26 X X X Pertussis-Tetanus-Diptheria Tdap Td Td Measles-Mumps-Rubella X rule Zostavax (shingles) age >60 seropositive ONLY rule X Infection: Common Pathogens Sinus Infections More common with chronic GVHD Sepsis More common if central line Pneumonias and Viral URIs CMV reactivation Monitored if at high risk Fungal Infections Most common if on prolonged high dose steroids Varivax (chicken pox) Seronegative ONLY rule X X 11

12 Prevention of Infection Patients follow safe living guidelines Pneumocystis prophylaxis for the first 6 months and Varicella Zoster prophylaxis for the first year after transplant or as long as on immunosuppression Hand hygiene Common Questions Asked Questions Often Asked Time after Transplant *The general guidelines below may not apply to your All Patients Not Receiving Receiving case. You must discuss with your physician to assess if Receiving Immunosupressiosupression Immuno- these rules apply to you. Less than 6 Immunosupression Months 6 months to 6 months to More than 1 1 year 1 year year School No No No Ok Hot tubs (1) No Ok(1) No No Swimming (1) (avoid head submersion & diving, use sun No Ok(1) No Ok screen) Gardening (digging in soil); mowing the lawn; raking No No No No leaves Having plants in the home (not handling) Ok Ok Ok Ok Making/kneading yeast breads No Ok Ok Ok Relapse of Disease Most common in first 1-2 years but there have been late relapses at 10+ years Poor prognosis if relapse is in first year Monitor for relapse BCR/ABL testing in CML patients, Ph+ ALL patients Myeloma labs for MM patients Withdrawal of IST, standard chemotherapy or radiation (for localized disease), donor lymphocyte infusion, immunotherapy or a 2 nd transplant are options Subsequent Malignancies Solid t-mds/aml PTLD Timing Median 4.2 years after HSCT Median 3 years after HSCT Median 2-4 months after HSCT Plateau No plateau Plateau at 10 years Greatly reduced risk after 10 years Plateau at 10 years Risk factors Autologous OR Allogeneic HSCT Age <10 at time of HSCT TBI >1200 cgy Smoking history Autologous HSCT Pre-HSCT diagnosis of MM, NHL or HD Exposure to alkylators, topoisomerase inhibitors, radiation prior to HSCT Older age at time of HSCT TBI Allogeneic HSCT Age <10 at time of HSCT EBV proliferation after HSCT Intensive immunosuppression Mismatched related donor Pre-HSCT diagnosis of immune deficiency ATG use any time during HSCT process T-cell depletion Unrelated donor Multiple HSCTs GVHD EBV sero-mismatch Incidence 3.8% to 8.8% at 20 years 0.8% to 6.3% at 20 years 1.4% to 3.22% at 20 years Excess risk as Standardized Incidence Ratio (SIR) SIR: the ratio of observed cancer cases in an HSCT cohort to expected cancer cases in the general population of a similar age and gender Table compiled from: Baker at al, 2003; Bhatia, 2013; Adhikari et al, 2015; Vaxman, Ram, Gafter-Gvili, Vidal, Yeshurun, Lahav & Shpilberg, 2015; Berger et al, 2018; Danylesko & Shimoni, 2018; Dyer et al, 2016 Subsequent Malignancies: Prevention Pre-transplant Transplant regimen selection Post-transplant Choose the least amount of IST that controls chronic GVHD and taper at the first opportunity Avoid needless CT scans In women on HRT, use progestin + estrogen, not estrogen alone Vaccinate against Hepatitis B and HPV Healthy lifestyle choices Proper diet, exercise, maintain healthy weight Avoid all forms of tobacco/secondary tobacco Alcohol in moderation if alcohol is used Sun safe practices Subsequent Malignancies: Early Detection Screening Early (PTLD and MDS) Frequent monitoring of CBCs Autologous patients need a BMA at one year and whenever falling counts cannot be explained/corrected In select patients, EBV monitoring serially after transplant Late (MDS and Solid Malignancies) Annual CBC with reflexive BMA PRN Annual mammograms and breast MRI (for >40, and age 25 or +8 years from TBI, whichever comes first) Annual Pap Smear and HPV DNA test Annual dental exams (every 6 months if persistent oral GVHD, on IST >2years, hx oral field XRT, <age 10 at time of transplant, and/or are male) Annual full-body naked skin exams Annual screening for thyroid cancer If persistent GERD or new dysphagia, upper GI endoscopy If Hepatitis B positive, consider liver US every 6 months Plus all the standard cancer screenings 12

13 Oral Cancers Pulmonary Late-onset pulmonary complications occur in 7-26% of patients Infections need to be ruled out first in a patient presenting with pulmonary issues TBI is a major risk factor PFTs are done pre-transplant and then at one-year post as well as with new cgvhd or pulmonary symptoms Common late pulmonary issues are: Bronchiolitis Obliterans (BO), Cryptogenic Organizing Pneumonia(COP) or Idiopathic Pneumonitis (IPS) Cardiac Incidence of Cardiovascular (CV) Events is Increased after HCT Increased Risk of: Cardiovascular Events Hypertension Hyperlipidemia HCT Control s Chow E et al, Ann Int. Med 2011 Internet Resources Want to Learn More? FHCRC LTFU Web Site CIBMTR Post-Transplant Guidelines ges/index.aspx Pediatric Survivorship Guidelines National Marrow Donor Program

14 A Final Thought My name is Ric Packard. I live in Pocatello, ID. I had a transplant in June of 2012 for AML. It saved my life and allowed me to go kayaking today with my grandchildren. I just can't say enough about the nurses at SCCA and UW. It was so hard for so long and they were so patient and kind. I probably never thought I was as sick as I was because the staff was so positive and pleasant. Having AML was the best experience of my life because it, out of necessity, brought me closer to my wife and my God. Thank you all again and again and again... 14