Supplementary Data File for Manuscript titled:

Establishment of Definitions and Review Process for Consistent Adjudication of Cause-Specific Mortality AfterAllogeneicUnrelated Donor Hematopoietic Cell Transplant

By Hahn, et al

Supplementary Table 1Clinical data included in Data Summaries and Reviewed by the Consensus Panel for Adjudication of Cause-Specific Death

Main Data Category / Detailed Data Reviewed
Recipient Demographics / Age, gender, race/ethnicity, height, weight, BMI, CMV serologic status, KPS/LPS
Disease / Diagnosis (AML, ALL, MDS), date of diagnosis, WBC count at diagnosis and pre-HCT, blasts in marrow and blood at diagnosis and pre-HCT, disease status
Transplant / Conditioning regimen drugs/radiation and intensity/dose, donor age, gender, CMV serologic status, year of HCT, GvHD prophylaxis regimen, graft source (blood or marrow)
Outcomes / Date of neutrophil and platelet engraftment, chimerisms, all reported causes of death, autopsy reports (if available), date of last follow-up or death, acute and chronic GvHDdate of onset, stage, grade, organ involvement and treatments, disease response and date of assessment after HCT, and date of interstitial pneumonitis, acute respiratory distress syndrome, bronchiolitis obliterans, pulmonary hemorrhage, veno-occlusive disease/ sinusoidal obstructive syndrome, avascular necrosis, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, infections, second cancers and other organ impairments
Legend BMI: body mass index, CMV: cytomegalovirus, KPS/LPS: Karnofsky/Lansky performance score, AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, MDS: myelodysplastic leukemia, WBC: white blood cell, HCT: hematopoietic cell transplantation, GvHD: graft-versus-host disease

Supplementary Table 2: Summary of the reclassification of the reported primary cause of death after adjudication

Transplant Center CSD / Percent of Transplant Center CSD with which the Consensus Panel
agreed (blue) or adjudicated (white)by First / Second Cohort
Disease / GvHD / Infection / Organ Failure / Other
Disease / 99.6 / 98.8 / 0 / 0 / 0 / 0.6 / 0.4 / 0.6 / 0 / 0
GvHD / 12 / 7 / 80 / 91 / 6 / 0 / 2 / 0 / 0 / 2
Infection / 24 / 14 / 13 / 30 / 54 / 44 / 7 / 9 / 3 / 3
Organ Failure / 21 / 22 / 14 / 22 / 12 / 14 / 48 / 28 / 6 / 14
Other / 22 / 37 / 12 / 11 / 14 / 3 / 19 / 18 / 34/ 32

In each cell, the first number is the percent of cases the CP agreed with the TC for Cohort 1,

and the second number is the percent of cases the CP agreed with the TC for Cohort 2.

Supplementary Table 3: Statistical measures of agreement by category of primary cause of death

Transplant Center Primary Cause of Death / FirstCohort / SecondCohort
Bias
Index * / Prevalence Index ** / Bias Index * / Prevalence Index **
Disease / .12 / .42 / .10 / .44
GvHD / .04 / .09 / .09 / .10
Infection / -.03 / .09 / -.07 / .08
Organ Failure / -.07 / .09 / -.08 / .04
All Other Causes / -.05 / .03 / -.04 / .03
* Proportion of the cohort which the consensus panel moved into (positive value) or out of (negative value) the reported cause of death category
** Proportion of the whole cohort (first or second) in the cell where the Transplant Center and Consensus Panel agreed on each cause of death (eg, both the reported and adjudicated primary cause of death was ‘Disease”)

SupplementaryTable 4: Examples of Actual Clinical Scenarios where the Consensus Panel adjudicated cause(s) of death differently than what was reported by the Transplant Center

TC reported Cause Specific Death / CP Adjudicated Cause Specific Death / Brief Patient Characteristics / GvHD / Infections / Other Outcomes / Comments
Disease / Organ Failure / 41 yr old F, MDS early disease (2% marrow blasts pre-HCT), BuFluATG conditioning / None / None / ARF, pulmonary failure/intubated, cardiac arrest / Died ~ day 21,
TC reported disease progression on day 2 post-HCT due to worsening cytopenias/transfusion dependence, however this was during the normal neutropenic period. Autopsy confirmed no evidence of MDS in marrow, patient died of multi-organ failure (cardiac, renal, pulmonary) with no evidence of GVHD or infections pre-mortem or on autopsy
GvHD / Disease / 44 yr old F, AML in CR1, Bu+other conditioning / Acute GvHD maximum grade IV (skin stage 1, GI stage 4, liver stage 0) / Pneumonia / None / AML relapse ~ day 90, withdrew immuno-suppression then developed severe acute GvHD and pneumonia, died ~ day 170
Organ Failure / Disease / 63 yr old M, AML PIF, FluMel conditioning / None / Bacteremia, sepsis / No disease evaluation or chimerism performed post HCT / No autopsy, died ~ day 18;
Pre-HCT bone marrow with >90% blasts, failed multiple induction attempts
Other/ Unknown / Disease / 50 yr old M, AML, Bu+TBI / None / None / None / No autopsy, died ~day 7; 68% marrow blasts pre-HCT, no disease evaluation post-HCT
GvHD,
Infection / Infection,
GvHD / 55 yr old M, AML in CR1, Cy+TBI conditioning / Acute GvHD maximum grade III (skin stage 3, GI stage 3, liver stage 0) / Fusarium (BAL and autopsy) / Continuous CR documented post HCT and at autopsy;
Pulmonary emboli / Died ~ day 55, Autopsy confirmed Fusarium pulmonary infection, with superimposed multiple pulmonary emboli, bone marrow remission, GvHD present on autopsy but not severe
Infection,
GvHD / GvHD,
Infection / 36 yr old F, MDS advanced disease (>10% blasts pre-HCT), Cy+TBI conditioning / Acute GvHD maximum grade IV (skin stage 4, GI stage 4, liver stage 4, ocular) / Pseudomonas / None / Died ~ day 21, Autopsy confirmed no evidence of MDS in marrow, severe multi-organ GvHD treated with 4thline agents, Pseudomonas lung infection detected in autopsy only
Infection,
GvHD / GvHD,
Infection / 50 yr old M, MDS early disease (<5% blasts pre-HCT), Bu+Cy conditioning / Acute GvHD maximum grade IV (skin stage 1, GI stage 3, liver stage 4) / Bacteremia/sepsis / CR documented post HCT; Pneumothorax / No autopsy, died ~ day 75; severe GvHD treated with 4th line agents; bacteremia/sepsis contributed to death but was terminal event
Organ Failure,
GI Hemorrhage / GvHD,
Infection / 22 yr old M, ALL in CR1, Cy+TBI conditioning / Acute GvHD maximum grade III, progressed to extensive severe chronic GvHD (GI) / Aspergillusfumigatus isolated from lung cultures / Continuous CR documented post HCT / No autopsy, died ~ day 300;
GI hemorrhage was due to severe GI GvHD; Fungal pneumonia contributed but patient was not intubated and on appropriate antifungal treatment
Organ Failure / GvHD,
Infection / 5 yr old M, AML PIF, CyThioTBI / Acute GvHD maximum grade IV (skin stage 4, GI stage 3, liver stage 0) progressed to extensive moderate chronic GvHD (skin, GI, lung) / MRSA2 months before death; Polyoma virus, RSV, HHV6 all from lung cultures within 1 month before death / CR documented post-HCT;
Transbronchial biopsy led to respiratory failure and intubation / No autopsy, died ~ day 160;
Severe acute GvHD treated with 4th line agents, progressed to chronic GvHD (including lung) led to multiple pulmonary viral infections in the setting of extensive immuno-suppression and lung GvHD
Organ Failure / Infection / 45 yr old F AML in CR1, FluMel conditioning / None / Pseudomonas and RSV / Continuous CR documented post HCT; CHF / No autopsy, died ~ day 120;
Organ Failure (pulmonary) was due to viral and bacterial pneumonia
Organ Failure / Infection,
Organ Failure / 15 yr old M, ALL in CR2, Cy+TBI conditioning / None / HHV6, EBV, Influenza A (cultures and autopsy) / Continuous CR documented post HCT and autopsy;
VOD, ARF, hemorrhagic cystitis / Died ~ day 25, autopsy confirmed pulmonary failure main cause of death (Influenza); VOD resolved before death but ongoing renal impairment (organ failure contributed); remission marrow
Other (Pulmonary Hemorrhage),
Infection / Infection,
GvHD / 44 yr old F, ALL Relapse 1, Cy+TBI conditioning / Acute GvHD maximum grade III (skin stage 3, GI stage 0, liver stage 0) / Aspergillusfumigatus (BAL and autopsy) / CR documented post-HCT; Pulmonary hemorrhage / Died ~ day 180;
Autopsy confirmed fungal pneumonia, pulmonary hemorrhage possibly due to BAL, on-going skin GvHD treated with 4th line agents contributed to death; remission marrow

SupplementaryTable 5: Examples of Actual Clinical Scenarios where the Consensus Panel adjudicated cause(s) of death was the same as what was reported by the Transplant Center

TC reported Cause Specific Death / CP Adjudicated Cause Specific Death / Brief Patient Characteristics / GVHD / Infections / Other Outcomes / Comments
Infection / Infection / 9 yr old F AML in CR2, BuCy conditioning / Acute GvHD maximum grade II (skin stage 3, GI stage 0, liver stage 0) / Polyoma virus infection (blood, kidneys), CMV (lung culture), Toxoplasma in brain and multiple other organs at autopsy / Continuous CR documented post HCT / Died ~ day 50, autopsy;
GvHD was mild/moderate on 1st line agents and non-life-threatening, Toxoplasma must have been colonized pre-HCT since patient was not discharged home post-HCT
Infection,
GvHD / Infection,
GvHD / 64 yr old M, AML in CR1, Bu+Cy conditioning / No acute GvHD, extensive mild chronic GvHD (skin, oral) treated with topical and systemic corticosteroids / Bacterial sepsis and pneumonia / Continuous CR documented post HCT / No autopsy, died ~ day 200;
GvHD was present but not severe, still on immuno-suppression at death; sudden onset sepsis/community acquired pneumonia
Infection,
GvHD / Infection,
GvHD / 53 yr old F, AML PIF with 90% marrow blasts pre-HCT, Cy+TBI conditioning / Acute GvHD maximum grade III (skin stage 2, GI stage 0, liver stage 3) / Candida (spleen, lung) / CR documented post HCT / Died ~ day 75 Autopsy confirmed yeast/fungal infection in spleen, lung and other organs, GvHD was present on autopsy but limited to liver only and not severe, remission marrow
GvHD,
Infection / GvHD,
Infection / 57 yr old M, MDS advanced disease (>10% marrow blasts pre-HCT) Bu+Other conditioning / Acute GvHD maximum grade IV (skin stage 2, GI stage 4, Liver stage 3) / MRSA and VRE / CR documented post HCT; ARF not requiring dialysis / Died ~ day 110, autopsy confirmed severe multi-organ GvHD and bacterial infection
GvHD / GvHD / 52 yr old M, AML PIF with 3% marrow blasts, 10% marrow cellularity, WBC <1.0 pre-HCT, Cy+TBI conditioning / Acute GvHD maximum grade IV (skin stage 4, GI stage 4, liver stage 0) / None / Cardiac arrest, no bone marrow or chimerisms performed post-HCT / No autopsy, died ~ day 40; severe GI GvHD led to hemodynamic instability and likely resulted in terminal cardiac arrest
Organ Failure / Organ Failure / 49 yr old M, AML PIF, Cy+TBI conditioning / Acute GvHD maximum grade II (skin stage 2, GI stage 1, Liver stage 0) / None / Seizures due to toxic tacrolimus levels / No autopsy, died ~ day 30; patient died of TRM even though patient had 40% blasts pre-HCT and no marrow evaluation post-HCT, GvHD was not life-threatening
Organ Failure / Organ Failure / 64 yr old F, AML in CR2, FluMel conditioning / Acute GvHD maximum grade I (skin stage 2, GI stage 0, liver stage 0) / None / VOD, ARF, seizures, mental status changes, no bone marrow or chimerisms performed post-HCT / No autopsy, died ~ day 30; multi-organ failure, no infections, mild acute GvHD was non-contributory