appendix h management guidelines for
table h3 asbmt icans consensus

| Neurotoxicity  Domain                                   | Grade 1                                                                                                                                                  | Grade 2                                                                                                                                  | Grade 3                                                         | Grade 4                                                                                                  |
|---------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| 0 (patient is  unarousable and  unable to perform  ICE) |                                                                                                                                                          |                                                                                                                                          |                                                                 |                                                                                                          |
| ICE score1                                              | 7-9                                                                                                                                                      | 3-6                                                                                                                                      | 0-2                                                             | Patient is  unarousable or  requires vigorous  or repetitive tactile  stimuli to arouse.  Stupor or coma |
| Depressed levels                                        | Awakens  spontaneously                                                                                                                                   | Awakens to voice                                                                                                                         | Awakens only to                                                 |                                                                                                          |
| of consciousness2                                       | tactile stimulus  Any clinical  seizure focal or  generalized that  resolves rapidly or  nonconvulsive  seizures on EEG  that resolve with  intervention | Life-threatening  prolonged seizure  (> 5 min); or  repetitive clinical  or electrical  seizures without  return to baseline  in between |                                                                 |                                                                                                          |
| Seizure                                                 | N/A                                                                                                                                                      | N/A                                                                                                                                      | Deep focal motor  weakness such as  hemiparesis or  paraparesis |                                                                                                          |
| Motor findings3                                         | N/A                                                                                                                                                      | N/A                                                                                                                                      | N/A                                                             |                                                                                                          |  
| Neurotoxicity  Domain                                                                                                                                | Grade 1   | Grade 2   | Grade 3                             | Grade 4   |
|------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|-----------|-------------------------------------|-----------|
| Diffuse cerebral  edema on  neuroimaging;  Decerebrate or  decorticate  posturing; or  cranial nerve VI  palsy; or  papilledema; or  Cushing's triad |           |           |                                     |           |
| Elevated  intracranial  pressure  (ICP)/cerebral  edema                                                                                              | N/A       | N/A       | Focal/local edema  on neuroimaging4 |           |  
Treatable causes of neurologic dysfunction, such as infection or hemorrhage should be ruled out. Common manifestations of neurotoxicity (e.g., confusion, seizure, aphasia), can also be seen with infection, electrolyte imbalances, metabolic acidosis, uremia, concomitant medication use (e.g., narcotics), and other medical conditions. Other causes for such symptoms should be considered. MRI and CT scans of the brain are usually negative for any anatomical pathology that would account for the neurotoxicity symptoms observed in subjects treated with CAR T cell therapy, although rare cases of reversible T2/fluid attenuation inversion recovery (FLAIR) MRI hyperintensity involving the thalami, dorsal pons, and medulla, and cerebral edema have been reported.[70]
For subjects who have neurologic toxicity in the present of CRS, the CRS should be managed following the guidelines provided in **Figure H1**. Neurotoxicity should be evaluated following the guidelines in Figure H2. For concurrent CRS and neurotoxicity, the most aggressive intervention recommended by either guideline should be employed (if the recommendations for steroid doses differ, use the highest dose and/or frequency). For subjects with grade 4 neurotoxicity with cerebral edema, high-dose corticosteroids, hyperventilation and hyposmolar therapy has been recommended.[70]
Note: Tocilizumab is not recommended for the treatment of neurotoxicity related to CAR T cell therapy unless CRS or MAS/HLH is also present. Results from 2 studies, one of preemptive use of tocilizumab, shortly after anti-CD19 CAR T cell therapy in relapsed/refractory NHL subjects,[71] and the other mandatory use of tocilizumab at first fever (≥ 38.5 °C) in pediatric ALL patients treated with anti-CD19 CAR T cells,[59]
demonstrated that early tocilizumab use either increased overall neurotoxicity and grade ≥ 3 neurotoxicity rates (85% vs 62% overall; 35% vs 26% grade ≥ 3) or provided no improvement in neurotoxicity rates, respectively. These findings support the hypothesis that tocilizumab does not improve any may worsen isolated neurotoxicity.[71]
Neurotoxicity management guidelines are provided in **Figure H2**  
| NT Grade2   | Corticosteroids and Antiseizure Medications                                                                                                                                                                                                                                                                                                                                                                                          |
|-------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1     | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours  or more after infusion, observe patient. If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours  for 2 to 3 days.                                                                                                                                                                          |
| Grade 2     | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days, or longer for persistent symptoms.  Consider taper for a total steroid exposure of greater than 3 days. Steroids are not recommended for  isolated Grade 2 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency |  
| Grade 3   | Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 to 20 mg IV every 6 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to  methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper  within 7 days). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose  methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and  cyclophosphamide 1.5 g/m2.   |
|-----------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Grade 4 Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 20 mg IV every 6 hours.  
If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1-2 g, repeated every 24 hours if needed; taper as clinically indicated).  
If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and may consider cyclophosphamide .
appendix i
management guidelines for cytopenias management

Guidelines below refer to filgrastim use, but filgrastim biosimilars or pegfilgrastim may also be used where filgrastim use is specified below according to investigator discretion and local institutional practice. Patients should not receive filgrastim within 2 weeks of CAR T cell infusion. Beginning 2 weeks (day 15) after CAR T cell infusion, filgrastim may be administered according to local institutional practice to address neutropenia. Neutropenia is expected within 4 weeks of CAR T cell infusion and does not require filgrastim support, though filgrastim may be used between as early as day 15 after CAR T cell infusion at discretion of investigators. For persistent neutropenia at any individual post-infusion time point beyond 4 weeks, minimum support should include the following:  
x If ANC less than 500/mm3 (grade 4), administer filgrastim x 1, re-check within one week.  
x If ANC is less than 500/mm3 on re-check, administer daily filgrastim and re-check within one week.  
x If ANC is less than 500/mm3 after daily filgrastim x 1 week, bone marrow biopsy should be performed to assess etiology of persistent neutropenia.
Filgrastim may be administered for chronic neutropenia between 500/mm3 and 1000/mm3
(grade 3) but is not required by the protocol. If ANC is not consistently greater than 1000 by week 6 after CAR T cell infusion, bone marrow biopsy should be performed to assess the etiology of chronic neutropenia.
appendix i
management guidelines for thrombocytopenia

Bone marrow biopsy to assess the etiology of thrombocytopenia should be performed if platelets are consistently less than 25,000/mm3 (grade 4) at week 6 after CAR T cell infusion, less than 50,000/mm3 (grade 3) at week 12 after CAR T cell infusion.
appendix i
guidelines for stem cell re-infusion

Prolonged cytopenias have been reported after CAR T cell therapy. Cryopreserved autologous stem cells can be used to restore normal hematopoiesis in the circumstances defined below. The efficacy of this approach has not been well established, and the impact of this approach on the efficacy of CAR T cell therapy has not been studied. The use of cryopreserved autologous stem cells in this protocol will be considered in the following circumstances:  
1. Grade 4 thrombocytopenia with bleeding complications occurring more than 6 weeks after CAR T cell infusion 2. Grade 4 neutropenia lasting more than 6 weeks after CAR T cell infusion and not responding to or continuing to require growth factor support 3. Grade 3 or 4 cytopenias lasting more than 12 weeks post infusion 4. At ANY TIME in a patient with life threatening bleeding or infectious complications that in the view of the treating physician could only be reversed with rapid hematologic reconstitution.  
5. Protracted transfusion requirements beyond 12 weeks post infusion not attributable to other causes.  
6. Other indications as discussed with the protocol chairs and medical monitors.
The BMT CTN 1902 Protocol Chairs and Officer must be consulted prior to stem cell infusion. Prior approval from the BMT CTN Protocol Chairs or Office is required prior to stem cell re-infusion. Prior to stem cell reinfusion all patients should have the following tests performed to assess for other potential factors contributing to the cytopenias:
1. Viral PCR: HHV6, CMV, EBV, Adeno, Parvovirus  
2. Thyroid function tests 3. Iron Studies 4. CRP and ESR 5. Bone marrow aspirate and biopsy to assess overall cellularity, adequacy of iron stores, myeloma burden, and to evaluate for myelodysplasia, hemophagocytosis, large granular lymphocyte (LGL) leukemia (by flow cytometry and morphology), and clonal cytogenetic abnormalities.  
6. Autoimmune panel: ANA, ANCA panel, Antiplatelet antibodies, Coombs 7. Aspirate and biopsy samples should be sent to central biorepository
appendix j references
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appendix k investigator's signature
guidelines for stem cell re-infusion

Phase II Multicenter Trial of anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for Multiple Myeloma Patients with Sub-Optimal Response After Autologous Hematopoietic Cell Transplantation and Maintenance Lenalidomide
appendix k investigator's signature
bmt ctn protocol 1902 version

I have read all pages of this clinical study protocol. I agree to conduct the study as outlined in the protocol and to comply with all the terms and conditions set out therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and applicable local regulations. I will also ensure that subinvestigator(s) and other relevant members of my staff have access to copies of this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions of these documents.  
Principal Investigator: Signature:  
  
  
  
Printed Name: