Donor and Patient Safety Committee Recipient & Product Adverse Events: FY 2015 Quarter 3

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1 Product HPC Cord IC Collection Date Product Infusion CTCAE Event (grade) 03/28/11 5/11/15 Respiratory, thoracic, and mediastinal disorders; respiratory failure, grade 4 Date of Event Serious Unexpected Cord ID Recipient ID Description 5/11/15 Yes No The recipient was a nine year old male, who was O positive, CMV antibody positive, and weighed 28 kg, with acute myelogenous leukemia (AML). He received a single HPC, Cord (CBU) transplant on May 11, The CBU was collected March 28, The infant was male. The product was O positive, and plasma and red blood cell reduced. The CBU was shipped on April 30, Current Status Relationship Date of DPSM Closed Unrelated 8/7/15 DPSM Action DPSM Closure ID Type Sex Plasma RBC TC Process Product Volume O+ Male NA NA NA NA O+ Male Reduced Reduced Wash 25 ml The recipient had a complicated pre-transplant history that included induction failure for AML and invasive pulmonary aspergillosis infection (January 2015) that required a right pneumonectomy (February 24, 2015) complicated by wound dehiscence. Post-surgery he required ventilator support for four weeks as recovery was complicated by air leak requiring second look surgery. He received treatment of amphotericin and micafungin that continued to time of transplant. He was also reported to have moderate to severe obstructive lung disease with poor lung reserve and poor pulmonary function test with forced expiratory volume (FEV) of 34% on April 19, He received a reduced intensity preparative regimen of fludarabine and melphalan with tacrolimus and mycophenolate mofetil (MMF) as graft versus host disease (GVHD) prophylaxis. The recipient received pre-medications of hydrocortisone, acetaminophen, diphenhydramine, and mannitol. The CBU was washed prior to infusion. The product was thawed at 0720 on May 11, 2015, was washed and arrived to the floor at The CBU infusion began on May 11, 2015 at 1022 and was completed at Pre-transplant vital signs were temperature of 36.6 Celsius, heart rate 151 beats per minute, respiration rate 36 breaths per minute, blood pressure (BP) of 111/68 mmhg, and O2 saturation of 100% on room air. The recipient remained afebrile during the infusion and all other vital signs remained stable. The volume of the infused CBU product was 49 ml and contained 1.96 ml of red blood cells. Post thaw, the total nucleated cell count was 98 x 10^7 with a dose of 3.4 x 10^7 and viability of 82% by trypan blue. No adverse events occurred with the infusion. 1

2 The recipient was noted to be febrile to 38.2 Celsius on May 11, 2015 at 2020 and tachycardic to 150s/160s beats per minute (greater than nine hours post infusion). pressure remained stable. Antibiotics of piperacillin and tobramycin were started. His work of breathing further progressed with tachypnea and grunting. Due to the recipient's recent transplant and immunocompromised state with systemic inflammatory response syndrome (SIRS) presentation, he was given a 20 ml/kg volume bolus and transferred to the pediatric intensive care unit (PICU) for further management at 0319 on May 12, The recipient on exam at transfer was noted to have slightly coarse breath sounds in left lung but otherwise good air movement and mild nasal flaring with grunting and mild tachypnea. Plan included differential of possible SIRS due to immunocompromised state or development of systemic infection as a result of history of pulmonary aspergillosis. The recipient blood cultures drawn on May 11, 2015 at 2020 were positive for Staphylococcus aureus from both lumens of the central catheter. The CBU culture was negative. An aspergillosis galactomannan assay level drawn May 11, 2015 at 0445 was (previous level of on April 29, 2015). The recipient required two liters of oxygen via nasal cannula in the PICU and while he remained in the PICU with respiratory concerns, the fever resolved. On May 15, 2015, the recipient was diagnosed with veno-occlusive disease (VOD) and started on defibrotide. On May 26, 2015, treatment of foscarnet was initiated for treatment of a HHV6 positive plasma PCR and subsequently the recipient required continuous renal replacement therapy (CRRT) on May 27, 2015 due to kidney failure related to foscarnet. The recipient remained on defibrotide. He was intubated on May 27, 2015 due to increased respiratory distress with hypoxia. On May 28, 2015, the recipient remained in the PICU with multi-system failure. On June 13, 2015, this recipient expired; clinical cause of death was reported as "HHV6 pneumonia, as a consequence of immunosuppression from bone marrow transplantation, as a consequence of acute myelogenous leukemia. The Cord Bank (CBB) indicates the CBU was negative for both aerobic and anaerobic organisms at 14 days. There were no unexpected events or deviations that impacted product sterility. The Transplant Center (TC) indicates a CTCAE of respiratory, thoracic, and mediastinal disorders; respiratory failure, grade 4. The TC classifies the event as serious (life-threatening), not unexpected and unlikely related. The NMDP Medical Monitor (MM) indicates a CTCAE of respiratory, thoracic and mediastinal disorders; respiratory failure; grade 4. The MM classified the event as serious (life-threatening), not unexpected, and unrelated. Additional MM comments include very complicated subject with multiple 2

3 HPC- Cord IC /15/98 & 02/06/08 5/13/15 Nervous System Disorders, Intracranial hemorrhage, grade 4 5/13/15 Yes No SPUCMAL & infections and respiratory failure. The event surrounding the infusion was a grade 4, and likely from the staph infection and not related to the CBU infusion. Death appears to have been from the HHV6 pneumonia This recipient is an eight year old male weighing 33.7 kg with acute lymphocytic leukemia (ALL) who received a double CBU transplant initiated on May 13, His history is notable for graft failure following a single CBU transplant on March 9, His ALL was complicated by CNS involvement, and multi-drug resistant Escherichia coli (E. Coli) following intussusception surgery in January He was also receiving steroids at time of double cord transplant for continued graft versus host disease (GVHD) treatment. Recipient has no cardiac history and Lansky score of 100% and comorbidity score of zero when admitted for this transplant. Closed Probably 8/15 Per the Cord Bank (CBB), the CBU SPUCMAL was a 5/6 match collected December 15, 1998 from a male infant. CBU post processing total nucleated count (TNC) of 176 x 10^7 and TNC dose of 5.6 x 10^7/ recipient kg. The CBU had a post-processing viability of 89%. The product bacterial and fungal cultures were negative and there was no noted infectious disease marker concerns with a normal hemoglobinopathy screen. Final product volume was 170 ml. The CBB indicated no noted problems in collection, processing, cryopreservation, storage, packing, and/or shipment of the CBU. ID Type Sex Plasma RBC TC Process O- Male NA NA NA SPUCMAL A- Male Replete Replete Wash The CBU was thawed and washed per Rubenstein method prior to infusion. The pre-processing hematocrit was 42% and the post-processing hematocrit 11.9%. The product was thawed starting at 1020 on May 13, 2015 and ended at TC CBU cultures were negative. 3 The recipient preparatory regimen started May 8, 2015 and included fludarabine, antithymocyte globulin (ATG), and total body irradiation (TBI) of 2 Gy. Cultures drawn May 8, 2015 due to fever during ATG were negative for growth. The recipient received pre-medications of acetaminophen, diphenhydramine, and hydrocortisone at 1130 on May 13, His vital signs prior to transplant included a temperature of 37 Celsius, heart rate of 88 beats per minute, respiration rate of 21 breathes per minute, blood

4 pressure of 133/90 mmhg and oxygen saturation of 100% on room air. Of note, his pre-transplant creatinine was 0.37 mg/dl. The infusion of the CBU began at 1220 on May 13, 2015 with infusion rate of approximately 6 ml / minute. Approximately ten minutes into infusion, the recipient complained of an intense headache. The BP at this time was 168/106. The infusion was paused and the recipient was treated with hydralazine with little effect and subsequently furosemide. TC reports 60 ml of product had been infused at this point. See table below with BP readings. Date Time Systolic Diastolic Comments 5/10/ /11/ /11/ /12/ /12/ /13/ /13/ /13/ infusion start 5/13/ /13/ Intense headache 5/13/ /13/ /13/ /13/ /13/ Infusion restarted 5/13/ /13/ infusion complete 5/13/ /13/ /13/ The infusion was restarted minutes later at a slower pace. At 1325, the BP was noted to be 155/105 and the recipient had two episodes of emesis. Another dose of hydralazine was administered and the BP started to trend down. The infusion was completed at A volume of 136 ml was 4

5 infused. Headache resolved following the infusion completion. The physicians indicate the recipient maintained normal mental status throughout the product infusion. The platelet level drawn at 0452 on May 13, 2015 was 17 X 10^9 / L. The recipient replacement parameter was 20 X 10^9 / L and one unit of O positive platelets were given at The next platelet count drawn was at 1637 on May 13, 2015 was 64 X 10^9 / L (post-adverse event). The recipient creatinine level drawn at 1637 was 0.61 mg/dl. At approximately 1520, about two hours after the infusion, the recipient was found unresponsive, head deviated toward the left, eyes deviated upward and to the right, globally hypertonic, and shaking. A code was called. O2 saturations were in the 80 % range. Ativan 2 mg per IV were administered to break the seizure. A stat head CT showed a 2.4 x 2.3 cm intraparenchymal hemorrhage (IPH) in the right parietal lobe with surrounding subarachnoid blood and vasogenic edema. The recipient was transferred to the pediatric intensive care unit (PICU) for further monitoring. On arrival to PICU, the recipient was noted to be postictal, stuporous, with poor respiratory effort and a Glasgow Coma Scale score of 7. The recipient was electively intubated at 1730 on May 13, An MRI completed May 14, 2015 confirmed the CT findings and includes "constellation of findings of the parenchymal abnormalities and arterial abnormalities can be seen with complicated posterior reversible encephalopathy syndrome (PRES). Other differential considerations include vasculitis (etiology related to post treatment toxicity from chemotherapy/radiation changes versus graft versus host disease (GVHD) with a case report of this noted in the American Journal of Neurology. A viral encephalitis can also demonstrate these findings but appears less likely based on clinical history. Lastly, a coagulopathy superimposed on any of these findings may result in the intracranial hemorrhage." There were no recipient cultures drawn at the time of event, but it is noted there were no active infections. 5 Per TC medical records dated May 18, 2015, TC indicates neurology team felt findings were suggestive of vasospasm. The location of the bleed is in an atypical anatomic location for hypertensive bleed. Per BMT physician, with appreciation of the neurology team s assessment, the etiology of bleed is likely secondary to combination of low counts and vasospasm. An EEG completed May 13, 2015 at 1939 was abnormal. There is diffuse slowing of the background indicative of a nonspecific moderate encephalopathy. In addition, there was subtle focal slowing with superimposed sharp waves over the right parieto-occipital region, which may indicate an underlying

6 structural or functional abnormality, as well as risk for seizures. However, no electrographic seizure activity was seen during this baseline study." On May 14, 2015, the recipient received the second CBU infusion without complications. The recipient was extubated on May 14, 2015 and transferred back to the BMT unit on May 17, At transfer he was doing well and back to baseline with no neurologic deficit. There has been no further reports of mental status changes or seizures. The Transplant Center (TC) reported a CTCAE of nervous system disorders; intracranial hemorrhage; grade 4. The TC classified the event as serious (lifethreatening), not unexpected and unlikely related. The NMDP MM reported a CTCAE of nervous system disorders; intracranial hemorrhage, grade 4. The MM classified the event as serious (life-threatening), not unexpected, and possibly related. Additional MM comments include: suffered a stroke related to vasospasm and low platelets (17,000 per TMS review). Subsequent recovery reported with no deficits. 6