What’s New in Data Management & Reporting- FAQs & Answers Janet Brunner-Grady, PA-C Tues. Feb. 19, 2019

Agenda Reporting # of mobilizations & products Autologous boosts/rescues Chimerism reporting MDS/MPN Multiple Myeloma Other

Reporting # of Mobilizations & Products

Mobilization Events A mobilization event is the planned administration of growth factors or systemic therapy designed to enhance the stem cell collection. If the donor requires an additional mobilization at a later date to collect additional product, this should be considered an additional mobilization event. If mobilization methods change (e.g., plerixafor added on second day of collection due to low CD34+ yield), this should be considered an additional mobilization event.

Examples of Mobilization Events An autologous patient was mobilized with G-CSF and underwent a two-day PBSC collection. This is considered one mobilization event. An autologous patient was mobilized with G-CSF & a peripheral CD34 count was low before the start of collection. The center added plerixafor in addition to the G-CSF. The patient’s cells were collected over the next two days. Question- Is this considered one or two mobilization events?

Examples of Mobilization Events- continued An autologous patient was mobilized with G-CSF & started their PBSC collection. The PBSC count was poor. No further collections were attempted & the patient was remobilized a week later with G-CSF & plerixafor. An adequate PBSC cell dose was collected over the next two days. This is considered two mobilization events.

Product Definitions Single product: Cells (e.g., CD34+ cells) collected from a single donor using the same mobilization cycle and collection method regardless of the number of collection days. Multiple products: Cells (e.g., CD34+ cells) collected using more than one mobilization technique and/or collection method.

Examples of Multiple Products Multiple Collection Methods A donor had a PBSC collection after mobilization with G-CSF & the product was cryopreserved. Three weeks later the donor had a marrow collection & both products were infused at the time of HCT. The number of products would be two. Change in Mobilization A donor mobilized with G-CSF had a PBSC collection, but the cell count was low. Plerixafor was added to the G-CSF mobilization & the donor continued their collections. The number of products would be two.

Examples of Multiple Products Re-mobilization A donor mobilized with G-CSF had a PBSC collection, but the cell count was low. No further collections were attempted & a week later the donor was re-mobilized with G-CSF and a second PBSC collection was performed. The number of products would be two.

Reporting Autologous Boosts/Rescues

Autologous “Boosts/Rescues” Performed for engraftment reasons following a HCT No hematopoietic recovery Partial hematopoietic recovery Graft failure Autologous boosts/rescues are HCTs Purpose is to restore hematopoiesis To reduce the reporting burden on centers forms do not start over

Autologous “Boosts/Rescues” Performed for any other reason would be reported as a subsequent HCT & forms would start over Indications include- Persistent primary disease Recurrent primary disease Planned second HCT, per protocol New malignancy Stable, mixed chimerism Declining chimerism

Reporting Multi-donor Chimerism

Reporting multi-donor chimerism Testing requires DNA markers (loci) that are informative for both the recipient & each donor Short Tandem Repeat (STR) polymorphisms are very useful for this purpose Each loci typically have more than two alleles

Reporting multi-donor chimerism What is a “polymorphism”? It’s a variation in the DNA that is too common to be due merely to a new mutation A polymorphism must have a frequency of at least 1% in the population

Reporting multi-donor chimerism Recipient before HCT Genetic Marker Identified Allele D3S1358 16 TH01 6 D21S11 30, 33 D18S51 14,19 Penta E 12, 14

Reporting multi-donor chimerism Genetic Marker Identified Allele D3S1358 14, 16 TH01 9, 10 D21S11 29, 31 D18S51 14, 15 Penta E 11

Reporting multi-donor chimerism Genetic Marker Identified Allele D3S1358 15 TH01 8, 10 D21S11 30, 33 D18S51 15, 18 Penta E 5, 14

Reporting multi-donor chimerism Recipient An informative allele is one the recipient has, but the donor(s) does not. Donor An informative allele is one the donor has, but the recipient does not.

Reporting multi-donor chimerism Non-informative alleles Both recipient & donor(s) share the same allele In the case of multiple donors, both donors share the same allele D R D D

Reporting multi-donor chimerism Recipient informative alleles (alleles the donors don’t possess) Genetic Marker Identified Allele TH01 6 D18S51 19 Penta E 12

Reporting multi-donor chimerism Donor 1 informative alleles (alleles the recipient doesn’t possess) Genetic Marker Allele D3S1358 14 TH01 9,10 D21S11 29,31 D18S51 15 Penta E 11

Reporting multi-donor chimerism Donor 2 informative alleles (alleles the recipient doesn’t possess) Genetic Marker Allele D3S1358 15 TH01 8,10 D21S11 ---- D18S51 15,18 Penta E 5

Reporting multi-donor chimerism Non-informative donor alleles include TH01 allele 10 D18S51 allele 15 Since both donors possess these two alleles, they cannot be used to determine the percentage of each donor post-HCT.

Reporting multi-donor chimerism Recipient after HCT Genetic Marker Identified Alleles D3S1358 14,15,16* TH01 8,9,10 D21S11 29,30*,31,33* D18S51 14*,15,18 Penta E 5,11,14* *An allele shared by one of the donors & the recipient (i.e., not informative)

Reporting multi-donor chimerism Questions to consider…… Q1 Is there evidence of one or two donors post-HCT? https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=303#ask Q2 Is there any evidence of recipient (host) post-HCT? https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=304#ask Q1- Two Q2- No- The recipient’s informative alleles (6,9,12) are not present!

Reporting multi-donor chimerism Chimerism results for a recipient of a double cord HCT must equal 100% STR results revealed: Donor 1 5% Donor 2 95% Host 0%

Reporting multi-donor chimerism F2100 r5 Reporting

Reporting multi-donor chimerism 5 95

Reporting multi-donor chimerism If you get the following STR result: Donor 1 = 100% Donor 2 = 0% Host = 0% You still must report both donors: Donor 1 = 100% (Host = 0%) Donor 2 = 0% (Host = 0%)

Reporting multi-donor chimerism 100

MDS/MPN Questions

Myeloproliferative Disorders Essential Thrombocytosis (ET) A myeloproliferative neoplasm (MPN) Characterized by sustained thrombocytosis (>/=450 x 109/L), increased # of large mature megakaryoctes in the marrow and episodes of thrombosis and/or hemorrhage. After many years, some ET patients may develop BM fibrosis associated with myeloid metaplasia. This is known as “post-ET myelofibrosis”.

Myeloproliferative Disorders Polycythemia Vera (PV) A myeloproliferative neoplasm (MPN) Characterized by increased production of RBCs independent of mechanisms that normally regulate eyrthropoiesis Virtually all have the JAK2 mutation

Myeloproliferative Disorders Polycythemia vera (PV) continued Three phases of PV Pre-polycythemic phase Characterized by borderline to mild erythrocytosis Polycythemic phase Significantly increased red cell mass Post-polycythemic myelofibrosis phase (post-PV MF) Cytopenias (including anemia) are associated with ineffective hematopoiesis, BM fibrosis, extramedullary hematopoiesis & hypersplenism

Myeloproliferative Disorders Recipients transplanted for post-ET MF or post-PV MF will be reported as ET or PV at diagnosis (F2402 r3 Q167) Report “yes” to Q212 (F2402 r3) - Did the recipient progress or transform to a different MDS/MPN subtype between diagnosis and the start of the preparative regimen? Report “Primary myelofibrosis” as the MDS/MPN subtype after transformation to Q213 (F2402 r3).

Multiple Myeloma

Multiple Myeloma Questions What is considered measurable disease? Serum M-protein >/= 1 g/dL and/or Urine M-protein >/= 200 mg/24 hours Free light chain levels may be used in place of the M-protein, provided the involved chain is >10 mg/dL & the κ/λ ratio is abnormal at diagnosis

Multiple Myeloma Questions What is Light Chain (LC) only myeloma? The malignant plasma cells make only the light chain (e.g., kappa or lambda) component of the antibody & not the heavy chain (e.g., IgG). The light chains are often excreted in the urine. LC only myeloma does not include oligo-secretory myeloma. What is non-secretory myeloma? The malignant plasma cells do not make a heavy or light chain resulting in no measurable protein in the blood or urine. There will be significant plasma cell burden in the bone marrow & evidence of end-organ damage. Non-secretory myeloma does not include oligo-secretory myeloma.

Multiple Myeloma Updates If a positive immunofixation is the only abnormality in a patient post-HCT who previously achieved a CR will not be considered progression! In the next revision of the Myeloma forms there will no longer be a near CR (nCR) response category!!

What Baseline to Use When… Determining disease status at time of HCT No relapse or progression at any time between diagnosis and 1st HCT: Use the disease parameters (DP) from diagnosis as the baseline. The next two slides detail what baseline to use when determining disease status at time of HCT (before the HCT occurs).

What Baseline to Use When… Patient was treated for a relapse or progression (R/P) in between diagnosis & 1st HCT: Use the disease parameters (DP) obtained at the time of relapse or progression (R/P) as the baseline (the baseline is reset to the time of the relapse or progression)

What Baseline to Use When… Determining disease response to HCT HCT planned as part of the initial therapy without a prior disease relapse or progression: Use disease parameters (DP) obtained at diagnosis The next few slides describe what baseline to use when determining the best response to HCT.

What Baseline to Use When… Determining best response to HCT Patient had a treated disease progression or relapse (R/P) prior to HCT: Use disease parameters (DP) obtained at time of the relapse or progression (R/P) The next few slides describe what baseline to use when determining the best response to HCT.

What Baseline to Use When…. Patient has not received any therapy within 6 months of HCT or has an untreated relapse or progression (R/P) Use the disease parameters (DP) obtained prior to the start of prep to determine best response to HCT.

What Baseline to Use When….. Recipient undergoes a Tandem transplant. Tandem transplants are considered part of “one” treatment plan. The baseline to use following the 2nd HCT would be the same baseline used for the 1st HCT provided there has not been a disease progression or relapse in between.

Summary of Which Baseline to Use When Determining Disease Status Has there been a relapse or progression? Disease Status at Time of HCT Disease Response to HCT No R/P DP at diagnosis Yes R/P (treated) DP at R/P Yes R/P (untreated) DP prior to the start of prep DP prior to start of prep R/P = relapse or progression, DP = disease parameters

Confirmatory Testing Requirements Includes SPEP/UPEP, serum/urine immunofixation & κ/λ free light chains Confirmatory testing does not apply to BM biopsies, skeletal surveys & other radiographic studies Reformatted, move bullet point up. TH 1/22/16

Confirmatory Testing Requirements Every disease response (sCR, CR, VGPR, PR & SD) requires two consecutive assessments (by the same method) made at any time before the initiation of any new therapy. Progressive disease (PD) & relapse from CR are a bit different…. PD & relapse from CR requires two consecutive assessments (by the same method) before classification, and/or the start of any new therapy.

Confirmatory Testing Requirements To report CR, both the serum & urine immunofixation must be negative as well as confirmed! Many institutions don’t obtain urine studies on a regular basis. CR may be reported as long as there is at least one negative serum & one negative urine immunofixation and one of them is confirmed.

Multiple Myeloma Complete Remission (CR) criteria

Multiple Myeloma Question- If a patient had a BMBx with <5% plasma cells prior to HCT, but did not meet the other CR criteria (e.g., + serum IFE for IgG lambda), can the same BMBx be used post-HCT when evaluating for CR status? Answer- Yes! A repeat BMBx is not needed since the plasma cells were already <5%.

MYELOMA CASE STUDY

Myeloma Case Study A 55 year old AA male is diagnosed with IgG lambda myeloma. Results of the initial work-up include: Serum M-spike = 4 g/dL (or 4000 mg/dL) 24-hr urine M-protein = 1000 mg/24 hr Bone marrow aspirate = 60% plasma cells Patient receives 2 cycles of Revlimid & Dex, then re-evaluated: Serum M-spike = 2000 mg/dL 24-hr urine M-protein = 195 mg/24 hr

Myeloma Case Study What is the patient’s disease response after two cycles of Rev/Dex? Very Good Partial Remission (VGPR) Partial Remission (PR) Stable Disease (SD) https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=305#ask Correct answer = B

Myeloma Case Study The patient’s PR status was confirmed with a 2nd measurement. The patient received two additional cycles of Rev/Dex & re-evaluated for disease response. Serum M-spike = 2900 mg/dL 24-hr urine M-protein = 600 mg/24 hr Bone marrow aspirate = 30% plasma cells Need to add info regarding the determination of progressive disease

Myeloma Case Study What is the patient’s disease response after a total of 4 cycles of Rev/Dex? Very Good Partial Response (VGPR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=306#ask Correct answer = D

Myeloma Case Study Patient is switched to Vincristine, Adriamycin & Decadron (VAD) and is re-evaluated after two cycles. Serum M-spike = 1400 mg/dL 24-hr urine M-protein = 190 mg/24 hr Bone marrow aspirate = 15% plasma cells The plan is to give IV Cytoxan mobilization. What is the patient’s disease response to the 2 cycles of VAD?

Myeloma Case Study The patient achieved a PR after two cycles of VAD. What studies were used as a baseline to make that determination? The studies obtained at diagnosis The studies obtained after first two cycles of Rev/Dex The studies obtained at time of progression https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=307#ask Correct answer = C

Myeloma Case Study The patient has undergone their autologous PBSC HSCT & has been evaluated monthly for the 1st three months post HSCT. Day +30 evaluation: Serum M-spike = 1000 mg/dL Serum immunofixation (+) for IgG lambda 24-hr urine M-protein = 190 mg/24 hrs Bone marrow biopsy = 7% plasma cells

Myeloma Case Study Day +60 evaluation: SPEP/UPEP- no monoclonal band Serum/Urine immunofixation (+) for IgG lambda 24-hr urine for M-protein = 90 mg/24 hrs

Myeloma Case Study Day +100 evaluation: SPEP/UPEP- no monoclonal band Serum/Urine immunofixation (+) for IgG lambda 24-hr urine for M-protein = 0 mg/24 hrs Bone marrow aspirate <5% plasma cells

Myeloma Case Study What is the best disease response to HCT that you would report at Day +100 for this patient? Stable Disease (SD) Partial Remission (PR) Very Good Partial Remission (VGPR) Near Complete Remission (nCR) Complete Remission (CR) https://tct.confex.com/tandem/2019/audiencepoll/ask.cgi?password=679322&Entryid=12048&EntryTable=Paper&Questionid=308#ask Correct answer = D (or VGPR once nCR is removed from the forms)

Other updates Forms due list for Corporate Studies & Registries Centers who participate in multiple studies (e.g., BMT-CTN, CMS, PIDTC, KGF, etc.) or Kite & Novartis CAR T-cell registries will now receive one forms due list on a monthly basis. The forms due list will be sent the first week of each month Study & registry forms will be held to the Due Date

Questions