table 13 post-transplant evaluation
2. post-transplant evaluations

This is a recommended evaluation schedule.  
See Tables 9 - 12 for pre-transplant evaluations. Additional lab instructions in Table 15.  
| Comment                                                | Days                                                                                                                                                             | Years                       | Annual                                         |      |      |           |    |    |
|--------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|------------------------------------------------|------|------|-----------|----|----|
| **28                                                   | 56                                                                                                                                                               | 84                          | 180                                            | 1    | 1.5  | x 5 years |    |    |
| Ph (-) ALL                                             | BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical   judgment |                             |                                                |      |      |           |    |    |
| Chimerism                                              | Clinical                                                                                                                                                         | x                           | x                                              |      |      |           |    |    |
| Pathology                                              | Clinical                                                                                                                                                         | x                           | x                                              | x    | x    | x         | x  | x  |
| Flow cytometry                                         | Clinical                                                                                                                                                         | x                           | x                                              | x    | x    | x         | x  | x  |
| Cytogenetics                                           | Clinical                                                                                                                                                         | *If abnormal pre-transplant | *See  commen t                                 |      |      |           |    |    |
| Disease                                                | Specimen/ Test/ Imaging                                                                                                                                          | Clinical/  Research         | *See                                           | *See |      |           |    |    |
| comment                                                | commen t                                                                                                                                                         | *See                        | *See                                           | *See | *See |           |    |    |
| comment                                                | comment                                                                                                                                                          | comment                     | comment                                        |      |      |           |    |    |
| FISH for clonal                                        | Clinical                                                                                                                                                         | *If abnormal pre-transplant | *See  commen                                   |      |      |           |    |    |
| abnormalities                                          | t                                                                                                                                                                | *See                        | *See                                           |      |      |           |    |    |
| comment                                                | commen t                                                                                                                                                         | *See                        | *See                                           | *See | *See |           |    |    |
| comment                                                | comment                                                                                                                                                          | comment                     | comment                                        |      |      |           |    |    |
| Peripheral blood Chimerism                             | Clinical                                                                                                                                                         | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |      |      |           |    |    |
| 56, 84, 180, and 1 year                                |                                                                                                                                                                  |                             |                                                |      |      |           |    |    |
| T and B cell subsets (CD3,  CD4, CD8, B and NK  cells) | Clinical                                                                                                                                                         | x                           | x                                              |      |      |           |    |    |
| GVHD evaluation                                        | Clinical                                                                                                                                                         | See text for details        | x                                              |      |      |           |    |    |  
| Comment                                               | Days                                                                                                                                                                                                                                                                                                                                                                     | Years                      | Annual                                         |      |      |           |    |    |
|-------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|------------------------------------------------|------|------|-----------|----|----|
| **28                                                  | 56                                                                                                                                                                                                                                                                                                                                                                       | 84                         | 180                                            | 1    | 1.5  | x 5 years |    |    |
| Ph (+) ALL                                            | BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical x x x x x x x FISH for bcr/abl and other  Clinical x x x x x x x clonal abnormalities |                            |                                                |      |      |           |    |    |
| Disease                                               | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                                                                  | Clinical/  Research        |                                                |      |      |           |    |    |
| PCR for bcr/abl, p.190 and                            | Clinical                                                                                                                                                                                                                                                                                                                                                                 | x                          | x                                              | x    | x    | x         | x  | x  |
| p.210 breakpoints                                     |                                                                                                                                                                                                                                                                                                                                                                          |                            |                                                |      |      |           |    |    |
| Peripheral blood Chimerism                            | Clinical                                                                                                                                                                                                                                                                                                                                                                 | **Needed on Day 7, 14, 28, | **See table 14 for peripheral blood chimerisms |      |      |           |    |    |
| 56, 84, 180, and 1 year                               |                                                                                                                                                                                                                                                                                                                                                                          |                            |                                                |      |      |           |    |    |
| T and B cell subsets(CD3,  CD4, CD8, B and NK  cells) | Clinical                                                                                                                                                                                                                                                                                                                                                                 | x                          | x                                              |      |      |           |    |    |
| PCR for bcr-abl, p.190 and                            | Clinical                                                                                                                                                                                                                                                                                                                                                                 | *If Bone Marrow not        |                                                |      |      |           |    |    |
| p.210 breakpoints                                     | obtained, reflexive testing for  FHCRC patients only                                                                                                                                                                                                                                                                                                                     | *See  commen t             | *See                                           | *See |      |           |    |    |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                                                                 | *See                       | *See                                           | *See | *See |           |    |    |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                                                                  | comment                    | comment                                        |      |      |           |    |    |
| GVHD evaluation                                       | Clinical                                                                                                                                                                                                                                                                                                                                                                 | See text for details       | x                                              |      |      |           |    |    |  
| Comment                                               | Days                                                                                                                                                                                                                                                                                                                          | Years                       | Annual                                         |      |      |           |
|-------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|------------------------------------------------|------|------|-----------|
| **28                                                  | 56                                                                                                                                                                                                                                                                                                                            | 84                          | 180                                            | 1    | 1.5  | x 5 years |
| AML                                                   | BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  commen t |                             |                                                |      |      |           |
| Disease                                               | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                       | Clinical/  Research         | *See                                           | *See |      |           |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                      | *See                        | *See                                           | *See | *See |           |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                       | comment                     | comment                                        |      |      |           |
| FISH for clonal                                       | Clinical                                                                                                                                                                                                                                                                                                                      | *If abnormal pre-transplant | *See  commen                                   |      |      |           |
| abnormalities                                         | t                                                                                                                                                                                                                                                                                                                             | *See                        | *See                                           |      |      |           |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                      | *See                        | *See                                           | *See | *See |           |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                       | comment                     | comment                                        |      |      |           |
| Peripheral blood Chimerism                            | Clinical                                                                                                                                                                                                                                                                                                                      | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |      |      |           |
| 56, 84, 180, and 1 year                               |                                                                                                                                                                                                                                                                                                                               |                             |                                                |      |      |           |
| T and B cell subsets(CD3,  CD4, CD8, B and NK  cells) | Clinical                                                                                                                                                                                                                                                                                                                      | x                           | x                                              |      |      |           |
| GVHD evaluation                                       | Clinical                                                                                                                                                                                                                                                                                                                      | See text for details        | x                                              |      |      |           |  
| Comment                                               | Days                                                                                                                                                                                                                                                                                                                                         | Years                                                | Annual                                         |      |      |           |
|-------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|------------------------------------------------|------|------|-----------|
| **28                                                  | 56                                                                                                                                                                                                                                                                                                                                           | 84                                                   | 180                                            | 1    | 1.5  | x 5 years |
| MDS/ MPD                                              | BM aspirate *see biopsy  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  commen t |                                                      |                                                |      |      |           |
| Disease                                               | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                                      | Clinical/  Research                                  | *See                                           | *See |      |           |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                                     | *See                                                 | *See                                           | *See | *See |           |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                                      | comment                                              | comment                                        |      |      |           |
| FISH for clonal                                       | Clinical                                                                                                                                                                                                                                                                                                                                     | *If abnormal pre-transplant                          | *See                                           |      |      |           |
| abnormalities                                         | commen t                                                                                                                                                                                                                                                                                                                                     | *See                                                 | *See                                           |      |      |           |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                                     | *See                                                 | *See                                           | *See | *See |           |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                                      | comment                                              | comment                                        |      |      |           |
| BM biopsy Pathology                                   | Clinical                                                                                                                                                                                                                                                                                                                                     | *For pts. with evidence or  history of myelofibrosis | *See  commen t                                 | *See | *See |           |
| comment                                               | commen t                                                                                                                                                                                                                                                                                                                                     | *See                                                 | *See                                           | *See | *See |           |
| comment                                               | comment                                                                                                                                                                                                                                                                                                                                      | comment                                              | comment                                        |      |      |           |
| Peripheral blood Chimerism                            | Clinical                                                                                                                                                                                                                                                                                                                                     | **Needed on Day 7, 14, 28,                           | **See table 14 for peripheral blood chimerisms |      |      |           |
| 56, 84, 180, and 1 year                               |                                                                                                                                                                                                                                                                                                                                              |                                                      |                                                |      |      |           |
| T and B cell subsets(CD3,  CD4, CD8, B and NK  cells) | Clinical                                                                                                                                                                                                                                                                                                                                     | x                                                    | x                                              |      |      |           |
| GVHD evaluation                                       | Clinical                                                                                                                                                                                                                                                                                                                                     | See text for details                                 | x                                              |      |      |           |  
| Comment                                              | Days                                                                                                                                                                                                                                                                                                                                                                                    | Years                        | Annual                                         |         |         |           |              |              |
|------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|------------------------------------------------|---------|---------|-----------|--------------|--------------|
| **28                                                 | 56                                                                                                                                                                                                                                                                                                                                                                                      | 84                           | 180                                            | 1       | 1.5     | x 5 years |              |              |
| CML                                                  | BM aspirate *see biopsy  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical x x x x x x x FISH for bcr-abl and other  Clinical x x x x x x x clonal abnormalities |                              |                                                |         |         |           |              |              |
| Disease                                              | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                                                                                 | Clinical/  Research          |                                                |         |         |           |              |              |
| PCR for bcr-abl, and p.210                           | Clinical                                                                                                                                                                                                                                                                                                                                                                                | *If abnormal pre-transplant, |                                                |         |         |           |              |              |
| breakpoint                                           | Reflexive testing for FHCRC  patients only                                                                                                                                                                                                                                                                                                                                              | *See                         | *See                                           | *See    | *See    | *See      | *See         | *See comment |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                 | comment                      | comment                                        | comment | comment |           |              |              |
| BM biopsy Pathology                                  | Clinical                                                                                                                                                                                                                                                                                                                                                                                | *If abnormal pre-transplant  | *See                                           | *See    | *See    | *See      | *See comment |              |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                 | comment                      | comment                                        |         |         |           |              |              |
| Peripheral blood Chimerism                           | Clinical                                                                                                                                                                                                                                                                                                                                                                                | **Needed on Day 7, 14, 28,   | **See table 14 for peripheral blood chimerisms |         |         |           |              |              |
| 56, 84, 180, and 1 year                              |                                                                                                                                                                                                                                                                                                                                                                                         |                              |                                                |         |         |           |              |              |
| T and B cell subsets(CD3,                            | Clinical                                                                                                                                                                                                                                                                                                                                                                                | x                            | x                                              |         |         |           |              |              |
| CD4, CD8, B and NK cells)                            | *See                                                                                                                                                                                                                                                                                                                                                                                    | *See                         | *See                                           | *See    | *See    | *See      | *See comment |              |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                 | comment                      | comment                                        | comment | comment |           |              |              |
| PCR for bcr-abl, and p.210                           | Clinical                                                                                                                                                                                                                                                                                                                                                                                | *If abnormal pre-transplant  |                                                |         |         |           |              |              |
| breakpoint                                           | AND bone marrow not                                                                                                                                                                                                                                                                                                                                                                     |                              |                                                |         |         |           |              |              |
| obtained, Reflexive testing for  FHCRC patients only |                                                                                                                                                                                                                                                                                                                                                                                         |                              |                                                |         |         |           |              |              |
| GVHD evaluation                                      | Clinical                                                                                                                                                                                                                                                                                                                                                                                | See text for details         | x                                              |         |         |           |              |              |  
| Comment                                              | Days                                                                                                                                                                                                                                                                                                                                                                                                                           | Years                       | Annual                                         |         |         |           |              |      |              |
|------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|------------------------------------------------|---------|---------|-----------|--------------|------|--------------|
| **28                                                 | 56                                                                                                                                                                                                                                                                                                                                                                                                                             | 84                          | 180                                            | 1       | 1.5     | x 5 years |              |      |              |
| CLL                                                  | BM aspirate *see biopsy  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment |                             |                                                |         |         |           |              |      |              |
| Disease                                              | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                                                                                                                        | Clinical/  Research         |                                                |         |         |           |              |      |              |
| FISH for clonal                                      | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See      | *See         | *See | *See comment |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                     | comment                                        | comment | comment |           |              |      |              |
| abnormalities                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                |                             |                                                |         |         |           |              |      |              |
| BM biopsy Pathology                                  | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | x                           | x                                              | x       | x       | x         |              |      |              |
| Peripheral blood Chimerism                           | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |         |         |           |              |      |              |
| 56, 84, 180, and 1 year                              |                                                                                                                                                                                                                                                                                                                                                                                                                                |                             |                                                |         |         |           |              |      |              |
| T and B cell subsets(CD3,                            | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | x                           | x                                              |         |         |           |              |      |              |
| CD4, CD8, B and NK cells) Flow cytometry             | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | *If peripheral blood        |                                                |         |         |           |              |      |              |
| involvement pre-transplant  AND bone marrow not done | *See                                                                                                                                                                                                                                                                                                                                                                                                                           | *See                        | *See                                           | *See    | *See    | *See      | *See comment |      |              |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                     | comment                                        | comment | comment |           |              |      |              |
| Quantitative Ig levels                               | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See      | *See         | *See | *See comment |
| comment                                              | comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                     | comment                                        | comment | comment |           |              |      |              |
| β-2 microglobulin                                    | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | x                           | x                                              |         |         |           |              |      |              |
| LDH                                                  | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | x                           | x                                              | x       | x       | x         | x            |      |              |
| Imaging CT chest, abdomen, pelvis                    | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | *Day 56 only if abnormal pretransplant                             | *See                                           | x       | x       | x         | x            | x    |              |
| (neck if indicated)                                  | comment                                                                                                                                                                                                                                                                                                                                                                                                                        |                             |                                                |         |         |           |              |      |              |
| GVHD evaluation                                      | Clinical                                                                                                                                                                                                                                                                                                                                                                                                                       | See text for details        | x                                              |         |         |           |              |      |              |  
| Comment                                     | Days                    | Years               | Annual   |    |     |           |
|---------------------------------------------|-------------------------|---------------------|----------|----|-----|-----------|
| **28                                        | 56                      | 84                  | 180      | 1  | 1.5 | x 5 years |
| HL - No history of  BM  involvement Disease | Specimen/ Test/ Imaging | Clinical/  Research |          |    |     |           |
| BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  comment comment FISH for clonal  Clinical *If abnormal pre-transplant *See  *See  comment comment abnormalities Peripheral blood Chimerism Clinical **Needed on Day 7, 14, 28,  **See table 14 for peripheral blood chimerisms 56, 84, 180, and 1 year T and B cell subsets(CD3,  Clinical x x CD4, CD8, B and NK cells) Quantitative Ig levels Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment β-2 microglobulin Clinical x x LDH Clinical x x x x x x Imaging CT chest, abdomen, pelvis Clinical *Day 56 only if abnormal pretransplant *See  x x x x x comment (neck if indicated) GVHD evaluation Clinical See text for details x                                             |                         |                     |          |    |     |           |  
| Comment                                 | Days                    | Years               | Annual   |    |     |           |
|-----------------------------------------|-------------------------|---------------------|----------|----|-----|-----------|
| **28                                    | 56                      | 84                  | 180      | 1  | 1.5 | x 5 years |
| HL - History of BM  involvement Disease | Specimen/ Test/ Imaging | Clinical/  Research |          |    |     |           |
| BM aspirate *see biopsy  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment FISH for clonal  Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment abnormalities BM biopsy Pathology Clinical x x x x x Peripheral blood Chimerism Clinical **Needed on Day 7, 14, 28,  **See table 14 for peripheral blood chimerisms 56, 84, 180, and 1 year T and B cell subsets(CD3,  Clinical x x CD4, CD8, B and NK cells) Quantitative Ig levels Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment β-2 microglobulin Clinical x x LDH Clinical x x x x x x Imaging *See  CT chest, abdomen, pelvis Clinical *Day 56 only if abnormal pretransplant x x x x x comment (neck if indicated) GVHD evaluation Clinical See text for details x                                         |                         |                     |          |    |     |           |  
| Comment                                                                                                                                                                                                                                                                                                                                                                                                                                       | Days                    | Years                             | Annual   |         |         |           |              |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-----------------------------------|----------|---------|---------|-----------|--------------|----|
| **28                                                                                                                                                                                                                                                                                                                                                                                                                                          | 56                      | 84                                | 180      | 1       | 1.5     | x 5 years |              |    |
| NHL - No history of  BM  involvement Disease                                                                                                                                                                                                                                                                                                                                                                                                  | Specimen/ Test/ Imaging | Clinical/  Research               |          |         |         |           |              |    |
| BM aspirate* If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment  Chimerism Clinical x x Pathology Clinical x x Flow cytometry Clinical x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  comment comment Peripheral blood Chimerism (CD3+) Clinical *Days 56 and 180 only if <50%  x *See  x *See  x on day 28 comment comment |                         |                                   |          |         |         |           |              |    |
| *see separate  section for  additional PCR  on Mantle Cell  and Follicular  NHLs in  suspected CR                                                                                                                                                                                                                                                                                                                                             | Chimerism (CD33+)       | Clinical                          | x        |         |         |           |              |    |
| Chimerism (NK CD56+)                                                                                                                                                                                                                                                                                                                                                                                                                          | Clinical                | Optional for outside institutions | x        |         |         |           |              |    |
| Flow cytometry                                                                                                                                                                                                                                                                                                                                                                                                                                | Clinical                | * If peripheral blood             |          |         |         |           |              |    |
| involvement pre-transplant  AND bone marrow not done                                                                                                                                                                                                                                                                                                                                                                                          | *See                    | *See                              | *See     | *See    | *See    | *See      | *See comment |    |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                                       | comment                 | comment                           | comment  | comment | comment |           |              |    |
| β-2 Microglobulin                                                                                                                                                                                                                                                                                                                                                                                                                             | Clinical                | x                                 |          |         |         |           |              |    |
| LDH                                                                                                                                                                                                                                                                                                                                                                                                                                           | Clinical                | x                                 | x        | x       | x       | x         |              |    |
| Imaging CT of chest, abdomen, pelvis                                                                                                                                                                                                                                                                                                                                                                                                          | Clinical                | *If abnormal pre-transplant       | *See     | x       | x       | x         | x            | x  |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                                       |                         |                                   |          |         |         |           |              |    |
| (neck if indicated)                                                                                                                                                                                                                                                                                                                                                                                                                           |                         |                                   |          |         |         |           |              |    |
| GVHD evaluation                                                                                                                                                                                                                                                                                                                                                                                                                               | Clinical                | See text for details              | x        |         |         |           |              |    |  
| Comment                                                                                                                                                                                                                                                                                                                                                                                                                        | Days                    | Years                       | Annual                                         |         |         |           |              |      |              |              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-----------------------------|------------------------------------------------|---------|---------|-----------|--------------|------|--------------|--------------|
| **28                                                                                                                                                                                                                                                                                                                                                                                                                           | 56                      | 84                          | 180                                            | 1       | 1.5     | x 5 years |              |      |              |              |
| NHL -- History of BM  involvement  Disease                                                                                                                                                                                                                                                                                                                                                                                     | Specimen/ Test/ Imaging | Clinical/  Research         |                                                |         |         |           |              |      |              |              |
| BM aspirate *see biopsy  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment |                         |                             |                                                |         |         |           |              |      |              |              |
| *see separate  section for  additional PCR  on Mantle Cell  and Follicular  NHLs in  suspected CR                                                                                                                                                                                                                                                                                                                              | FISH for clonal         | Clinical                    | *If abnormal pre-transplant                    | *See    | *See    | *See      | *See         | *See | *See         | *See comment |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                 | comment                     | comment                                        | comment | comment |           |              |      |              |              |
| abnormalities                                                                                                                                                                                                                                                                                                                                                                                                                  |                         |                             |                                                |         |         |           |              |      |              |              |
| BM biopsy Pathology                                                                                                                                                                                                                                                                                                                                                                                                            | Clinical                | x                           | x                                              | x       | x       | x         |              |      |              |              |
| Peripheral blood Chimerism                                                                                                                                                                                                                                                                                                                                                                                                     | Clinical                | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |         |         |           |              |      |              |              |
| 56, 84, 180, and 1 year                                                                                                                                                                                                                                                                                                                                                                                                        |                         |                             |                                                |         |         |           |              |      |              |              |
| Flow cytometry                                                                                                                                                                                                                                                                                                                                                                                                                 | Clinical                | *If peripheral blood        |                                                |         |         |           |              |      |              |              |
| involvement pre-transplant  AND bone marrow not done                                                                                                                                                                                                                                                                                                                                                                           | *See                    | *See                        | *See                                           | *See    | *See    | *See      | *See comment |      |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                 | comment                     | comment                                        | comment | comment |           |              |      |              |              |
| T and B cell subsets(CD3,                                                                                                                                                                                                                                                                                                                                                                                                      | Clinical                | x                           | x                                              |         |         |           |              |      |              |              |
| CD4, CD8, B and NK cells) Quantitative Ig levels                                                                                                                                                                                                                                                                                                                                                                               | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See      | *See         | *See | *See comment |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                        | comment                 | comment                     | comment                                        | comment | comment |           |              |      |              |              |
| β-2 microglobulin                                                                                                                                                                                                                                                                                                                                                                                                              | Clinical                | x                           | x                                              |         |         |           |              |      |              |              |
| LDH                                                                                                                                                                                                                                                                                                                                                                                                                            | Clinical                | x                           | x                                              | x       | x       | x         | x            |      |              |              |
| Imaging CT chest, abdomen, pelvis                                                                                                                                                                                                                                                                                                                                                                                              | Clinical                | *Day 56 only if abnormal pretransplant                             | *See                                           | x       | x       | x         | x            | x    |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                                        |                         |                             |                                                |         |         |           |              |      |              |              |
| (neck if indicated)                                                                                                                                                                                                                                                                                                                                                                                                            |                         |                             |                                                |         |         |           |              |      |              |              |
| GVHD evaluation                                                                                                                                                                                                                                                                                                                                                                                                                | Clinical                | See text for details        | x                                              |         |         |           |              |      |              |              |  
| Comment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Days                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Years               | Annual   |    |     |           |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|----------|----|-----|-----------|
| **28                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | 56                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 84                  | 180      | 1  | 1.5 | x 5 years |
| Mantle Cell  NHL in  suspected CR Disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Specimen/ Test/ Imaging                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Clinical/  Research |          |    |     |           |
| BM aspirate *in addition to complete NHL restaging  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment PCR for t(11:14) Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment Peripheral blood *in addition to complete NHL restaging PCR for t(11:14) Clinical *If abnormal pre-transplant  AND bone marrow not done *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                     |          |    |     |           |
| Follicular Cell  NHL in  suspected CR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | BM aspirate *in addition to complete NHL restaging  ** If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment PCR for t(14:18) Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment Peripheral blood *in addition to complete NHL restaging PCR for t(14:18) Clinical *If abnormal pre-transplant  AND bone marrow not done *See  *See  *See  *See  *See  *See  *See commentcomment comment comment comment comment comment |                     |          |    |     |           |  
| Comment                                                                                                                                                                                                                                                                                                                                                                                                          | Days                    | Years                       | Annual                                         |         |         |              |              |      |              |              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-----------------------------|------------------------------------------------|---------|---------|--------------|--------------|------|--------------|--------------|
| **28                                                                                                                                                                                                                                                                                                                                                                                                             | 56                      | 84                          | 180                                            | 1       | 1.5     | x 5 years    |              |      |              |              |
| MM Disease                                                                                                                                                                                                                                                                                                                                                                                                       | Specimen/ Test/ Imaging | Clinical/  Research         |                                                |         |         |              |              |      |              |              |
| BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment |                         |                             |                                                |         |         |              |              |      |              |              |
| Omit  SPEP/IFIX and  UPEP/IFIX for  non-secretory  MM                                                                                                                                                                                                                                                                                                                                                            | FISH for chrom. 13 (and | Clinical                    | *If abnormal pre-transplant                    | *See    | *See    | *See         | *See         | *See | *See         | *See comment |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        | comment | comment |              |              |      |              |              |
| other clonal) abnormalities                                                                                                                                                                                                                                                                                                                                                                                      |                         |                             |                                                |         |         |              |              |      |              |              |
| Peripheral blood Chimerism                                                                                                                                                                                                                                                                                                                                                                                       | Clinical                | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |         |         |              |              |      |              |              |
| 56, 84, 180, and 1 year                                                                                                                                                                                                                                                                                                                                                                                          |                         |                             |                                                |         |         |              |              |      |              |              |
| T and B cell subsets(CD3,                                                                                                                                                                                                                                                                                                                                                                                        | Clinical                | x                           | x                                              |         |         |              |              |      |              |              |
| CD4, CD8, B and NK cells) SPEP and IFIX                                                                                                                                                                                                                                                                                                                                                                          | Clinical                | x                           | x                                              | x       | x       | x            |              |      |              |              |
| Quantitative Ig levels                                                                                                                                                                                                                                                                                                                                                                                           | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See         | *See         | *See | *See comment |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        | comment | comment |              |              |      |              |              |
| β-2 microglobulin                                                                                                                                                                                                                                                                                                                                                                                                | Clinical                | x                           | x                                              | x       | x       | x            |              |      |              |              |
| Cryoglobulins, C-reactive                                                                                                                                                                                                                                                                                                                                                                                        | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See comment |              |      |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     |                                                |         |         |              |              |      |              |              |
| protein, viscosity                                                                                                                                                                                                                                                                                                                                                                                               |                         |                             |                                                |         |         |              |              |      |              |              |
| Urine Protein/creatinine clearance                                                                                                                                                                                                                                                                                                                                                                               | Clinical                | x                           | x                                              | x       | x       | x            |              |      |              |              |
| UPEP and IFIX                                                                                                                                                                                                                                                                                                                                                                                                    | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See         | *See comment |      |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        |         |         |              |              |      |              |              |
| Imaging Complete skeletal survey                                                                                                                                                                                                                                                                                                                                                                                 | Clinical                | x                           | x                                              |         |         |              |              |      |              |              |
| Skeletal MRI                                                                                                                                                                                                                                                                                                                                                                                                     | Clinical                | x                           | x                                              |         |         |              |              |      |              |              |
| GVHD evaluation                                                                                                                                                                                                                                                                                                                                                                                                  | Clinical                | See text for details        | x                                              |         |         |              |              |      |              |              |  
| Comment                                                                                                                                                                                                                                                                                                                                                                                                          | Days                    | Years                       | Annual                                         |         |         |              |              |      |              |              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-----------------------------|------------------------------------------------|---------|---------|--------------|--------------|------|--------------|--------------|
| **28                                                                                                                                                                                                                                                                                                                                                                                                             | 56                      | 84                          | 180                                            | 1       | 1.5     | x 5 years    |              |      |              |              |
| Waldenstrom's  Macroglobulinemia Disease                                                                                                                                                                                                                                                                                                                                                                                                                  | Specimen/ Test/ Imaging | Clinical/  Research         |                                                |         |         |              |              |      |              |              |
| BM aspirate * If CR documented at one year, and there is recovery of normal blood counts, bone marrow after one year may be obtained based on clinical judgment Chimerism Clinical x x Pathology Clinical x x x x x x x Flow cytometry Clinical x x x x x x x Cytogenetics Clinical *If abnormal pre-transplant *See  *See  *See  *See  *See  *See  *See comment comment comment comment comment comment comment |                         |                             |                                                |         |         |              |              |      |              |              |
| Omit SPEP/IFIX  and UPEP/IFIX  for non-secretory  Waldenstrom's  Macroglobulinemia                                                                                                                                                                                                                                                                                                                                                                                                                  | FISH for chrom. 13 (and | Clinical                    | *If abnormal pre-transplant                    | *See    | *See    | *See         | *See         | *See | *See         | *See comment |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        | comment | comment |              |              |      |              |              |
| other clonal) abnormalities                                                                                                                                                                                                                                                                                                                                                                                      |                         |                             |                                                |         |         |              |              |      |              |              |
| Peripheral blood Chimerism                                                                                                                                                                                                                                                                                                                                                                                       | Clinical                | **Needed on Day 7, 14, 28,  | **See table 14 for peripheral blood chimerisms |         |         |              |              |      |              |              |
| 56, 84, 180, and 1 year                                                                                                                                                                                                                                                                                                                                                                                          |                         |                             |                                                |         |         |              |              |      |              |              |
| T and B cell subsets(CD3,                                                                                                                                                                                                                                                                                                                                                                                        | Clinical                | x                           | x                                              |         |         |              |              |      |              |              |
| CD4, CD8, B and NK cells) SPEP and IFIX                                                                                                                                                                                                                                                                                                                                                                          | Clinical                | x                           | x                                              | x       | x       | x            |              |      |              |              |
| Quantitative Ig levels                                                                                                                                                                                                                                                                                                                                                                                           | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See         | *See         | *See | *See comment |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        | comment | comment |              |              |      |              |              |
| β-2 microglobulin                                                                                                                                                                                                                                                                                                                                                                                                | Clinical                | x                           | x                                              | x       | x       |              |              |      |              |              |
| Cryoglobulins, C-reactive                                                                                                                                                                                                                                                                                                                                                                                        | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See comment |              |      |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     |                                                |         |         |              |              |      |              |              |
| protein, viscosity                                                                                                                                                                                                                                                                                                                                                                                               |                         |                             |                                                |         |         |              |              |      |              |              |
| Urine Protein/ creatinine                                                                                                                                                                                                                                                                                                                                                                                        | Clinical                | x                           | x                                              | x       | x       | x            |              |      |              |              |
| clearance UPEP and IFIX                                                                                                                                                                                                                                                                                                                                                                                          | Clinical                | *If abnormal pre-transplant | *See                                           | *See    | *See    | *See         | *See comment |      |              |              |
| comment                                                                                                                                                                                                                                                                                                                                                                                                          | comment                 | comment                     | comment                                        |         |         |              |              |      |              |              |
| Imaging CT chest, abdomen, pelvis                                                                                                                                                                                                                                                                                                                                                                                | Clinical                | *Day 56 only if abnormal pretransplant                             | comment                                        | x       | x       | x            | x            | x    |              |              |
| *See                                                                                                                                                                                                                                                                                                                                                                                                             |                         |                             |                                                |         |         |              |              |      |              |              |
| (neck if indicated)                                                                                                                                                                                                                                                                                                                                                                                              |                         |                             |                                                |         |         |              |              |      |              |              |
| GVHD evaluation                                                                                                                                                                                                                                                                                                                                                                                                  | Clinical                | See text for details        | x                                              |         |         |              |              |      |              |              |
table 13 post-transplant evaluation
table 14 post-transplant peripheral blood

This is a recommended evaluation schedule. See Tables 9 - 12 for pre-transplant evaluations, table 13 for post-transplant evaluations.  
Additional lab instructions in Table 15.  
| Disease               | Test                                    | Clinical/  Researc h   | Comment     | Days   | 1   |    |    |    |    |
|-----------------------|-----------------------------------------|------------------------|-------------|--------|-----|----|----|----|----|
| Year                  |                                         |                        |             |        |     |    |    |    |    |
| 7                     | 14                                      | 28                     | 56          | 84     | 180 |    |    |    |    |
| All  Diseas es        | *If donor NK cell infusion is occurring |                        |             |        |     |    |    |    |    |
| Chimerism (CD3+)      | Clinical                                | on Day +7, obtain chimerism sample preNK cell infusion                        | *See  comme | x      | x   | x  | x  | x  | x  |
| nt                    |                                         |                        |             |        |     |    |    |    |    |
| *If donor NK cell infusion is occurring  on Day +7, obtain chimerism sample preNK cell infusion                       |                                         |                        |             |        |     |    |    |    |    |
| Chimerism  (CD33+)    | Clinical                                | *See  comme            | x           | x      | x   | x  | x  | x  |    |
| nt                    |                                         |                        |             |        |     |    |    |    |    |
| *If donor NK cell infusion is occurring  on Day +7, obtain chimerism sample preNK cell infusion                       |                                         |                        |             |        |     |    |    |    |    |
| Chimerism (NK  CD56+) | Clinical                                | *See  comme            | x           | x      | x   | x  | x  | x  |    |
| nt                    |                                         |                        |             |        |     |    |    |    |    |
table 13 post-transplant evaluation
table 15 additional lab instructions

Note: All bone marrow tests are done on aspirate unless specifically identified as biopsy. All instructions apply to both pre- and post-transplant evaluations unless identified otherwise.  
Off-site providers may use local facilities for the tests.  
| Specimen / Test                                                                      | Type                                  | Instructions                                                 | Lab Name                                                       | Contact Information                                                      |
|--------------------------------------------------------------------------------------|---------------------------------------|--------------------------------------------------------------|----------------------------------------------------------------|--------------------------------------------------------------------------|
| Bone marrow Chimerism                                                                | Clinical                              | 1-3mL bone marrow in                                         | Clinical Immunogenetics                                        | Seattle Cancer Care Alliance                                             |
| green-top tube                                                                       | Lab                                   | (206) 288-7700                                               |                                                                |                                                                          |
| Pathology                                                                            | Clinical                              | 2mL bone marrow in                                           | SCCA Pathology Lab                                             | Seattle Cancer Care Alliance                                             |
| (aspirate)                                                                           | EDTA/ formalin                        | (206) 288-1355                                               |                                                                |                                                                          |
| Clinical                                                                             | 1cm bone marrow in                    |                                                              |                                                                |                                                                          |
| Pathology (biopsy)                                                                   | formalin OR mounted in  paraffin      | SCCA Pathology Lab                                           | Seattle Cancer Care Alliance (206) 288-1355                    |                                                                          |
| Flow Cytometry                                                                       | Clinical                              | 2mL bone marrow in greentop tube                                                              | UW Hematopathology Lab                                         | Seattle Cancer Care Alliance (206) 288-7060                              |
| Cytogenetics                                                                         | Clinical                              | 3mL bone marrow in greentop tube                                                              | SCCA Cytogenetics Lab                                          | Seattle Cancer Care Alliance (206) 288-1390                              |
| FISH                                                                                 | Clinical                              | 2mL bone marrow in greentop tube                                                              | SCCA Cytogenetics Lab                                          | Seattle Cancer Care Alliance (206) 288-1390                              |
| PCR for bcr-abl  and p190 and/or  p210                                               | Clinical                              | 3mL bone marrow in  lavender-top tube Label "protocol 2230"  | UW Molecular                                                   | Mailstop G7-800 825 Eastlake Ave,                                        |
| Hematopathology Lab                                                                  | East Seattle, WA 98109 (206) 288-7060 |                                                              |                                                                |                                                                          |
| Clinical                                                                             | 2mL bone marrow in                    | UW Molecular                                                 | Mailstop G7-800 825 Eastlake Ave,                              |                                                                          |
| lavender-top tube                                                                    | Hematopathology Lab                   | East Seattle, WA 98109 (206) 288-7060                        |                                                                |                                                                          |
| Peripheral blood Chimerism  (CD3+), (CD33+)  NK(CD56+) PCR for t(11:14) or  t(14:18) | Clinical                              | 10mL blood in green-top  tube for Flow sorting, then  to CIL | UW Hematopathology Lab, routed to Clinical  Immunogenetics Lab | Mailstop G7-800 825 Eastlake Ave,  East Seattle, WA 98109 (206) 288-7060 |
| Flow Cytometry                                                                       | Clinical                              | 10mL blood in green-top                                      | UW Hematopathology Lab                                         | Seattle Cancer Care Alliance                                             |
| tube                                                                                 | (206) 288-7060                        |                                                              |                                                                |                                                                          |
| T and B cell                                                                         | Clinical                              | 1mL blood in lavender-top                                    | UW Hematopathology Lab                                         | Seattle Cancer Care Alliance                                             |  
Volumes represent desired amounts.  
| Specimen / Test                                                                 | Type                                  | Instructions                                          | Lab Name                          | Contact Information                         |
|---------------------------------------------------------------------------------|---------------------------------------|-------------------------------------------------------|-----------------------------------|---------------------------------------------|
| subsets(CD3,  CD4, CD8, B and  NK cells)                                        | (206) 288-7060                        |                                                       |                                   |                                             |
| SPEP/IFIX                                                                       | Clinical                              | 3mL blood in red-top tube                             | UW Department of                  | University of Washington                    |
| Laboratory Medicine                                                             | (800) 713-5198                        |                                                       |                                   |                                             |
| Quantitative Ig                                                                 | Clinical                              | 3mL blood in red-top tube                             | SCCA Alliance Lab                 | Seattle Cancer Care Alliance                |
| Levels                                                                          | (206) 288-2057                        |                                                       |                                   |                                             |
| β-2 Microglobulin                                                               | Clinical                              | 3mL blood in red-top tube                             | UW Department of                  | University of Washington                    |
| Laboratory Medicine                                                             | (800) 713-5198                        |                                                       |                                   |                                             |
| LDH                                                                             | Clinical                              | 3mL blood in red-top tube                             | SCCA Alliance Lab                 | Seattle Cancer Care Alliance (206) 288-2057 |
| PCR for bcr-abl  and p190 and/or  p210                                          | Clinical                              | 7mL blood in lavender-top  tube Label "protocol 2230" | UW Molecular                      | Mailstop G7-800 825 Eastlake Ave,           |
| Hematopathology Lab                                                             | East Seattle, WA 98109 (206) 288-7060 |                                                       |                                   |                                             |
| Clinical                                                                        | 5mL blood in lavender-top             | UW Molecular                                          | Mailstop G7-800 825 Eastlake Ave, |                                             |
| tube                                                                            | Hematopathology Lab                   | East Seattle, WA 98109 (206) 288-7060                 |                                   |                                             |
| PCR for t(11:14) or  t(14:18) ZAP - 70 by Flow  cytometry (pre-transplant only) | Clinical                              | 5mL blood in green-top                                | UW Hematopathology Lab            | Mailstop G7-800 825 Eastlake Ave,           |
| tube                                                                            | East Seattle, WA 98109 (206) 288-7060 |                                                       |                                   |                                             |  
See Standard Practice Guidelines for *T and B cell subsets* Outside institutions may use VNTR analysis (sex- matched transplants) or sex chromosome FISH-analysis (sex-mismatched transplants) for chimerism analysis.
table 13 post-transplant evaluation
xii. drugs irradiation and marrow

1. **Description**
Cyclophosphamide is an alkylating agent which prevents cell division primarily by cross linking DNA strands. Cyclophosphamide is cell cycle non-specific. Cyclophosphamide is not stem cell toxic.  
2. Storage and Administration Cyclophosphamide for injection is commercially available in 2000 mg vials, which are reconstituted with 100 ml sterile water for injection. The concentration of the reconstituted product is 20 mg/ml. The calculated dose will be diluted further in 250-500 ml of Dextrose 5%
in water. Each dose will be infused over 1-2 hr (depending on the total volume).  
3. **Side Effects and Toxicity**
Clinical toxicities of cyclophosphamide include alopecia, nausea and vomiting, headache and dizziness, hemorrhagic cystitis, cardiotoxicity, immunosuppression, myelosuppression, pulmonary fibrosis, increased hepatic enzymes and syndrome of appropriate anti-diuretic hormone (SIADH).
table 13 post-transplant evaluation
b. mesna

1. Description Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the oxazaphosphorine (cyclophosphamide and iphosphamide). It has no intrinsic cytotoxicity and no antagonistic effects on chemotherapy. Mesna binds with acrolein, the urotoxic metabolite produced by the oxazaphosphorine, to produce a non-toxic thioether and slows the rate of acrolein formation by combining with 4-hydroxy metabolites of oxazaphosphorine.
table 13 post-transplant evaluation
2. storage and administration

Mesna is commercially available in 200 mg, 400 mg and 1000 mg vials containing a 100mg/ml solution. Each dose of Mesna will be diluted further in 50 ml of normal saline to be infused over 15 min. Mesna dose will be based on the CY dose being given but can be omitted when the CY dose is less than 1000 mg/m2(or 33.3 mg/kg). The total daily dose of Mesna is equal to 100% of the total daily dose of cyclophosphamide.
table 13 post-transplant evaluation
3. side effects and toxicity

At the doses used for uroprotection Mesna is virtually non-toxic. However, adverse effects, which may be attributable to Mesna, include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint or limb pain, hypotension and fatigue.
table 13 post-transplant evaluation
c. fludarabine

1. **Description**
Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and Ribonucleotide nuclease.
table 13 post-transplant evaluation
2. dosage and administration

Fludarabine monophosphate is commercially available as a 50 mg/vial, which is reconstituted with 2 ml of sterile water, resulting in a 25mg/ml solution. The desired dose is further diluted to concentrations of 0.04-1 mg/ml in normal saline or 5% dextrose (50-100ml) for injection and will be administered by IV infusion over 30 minutes or longer.  
Fludarabine will be administered by IV infusion over 30 minutes in a dose of 30 mg/m2/day on days -6 to -2.
table 13 post-transplant evaluation
3. side effects and toxicities

The dose of fludarabine used in this protocol is nonmyeloablative; however, it can cause severe immunosuppression particularly in the CD4+ T cell compartment. Immunosuppression increases the risk of infection, which can be life threatening. In addition, clinical toxicities of fludarabine monophosphate include: myelosuppression, primarily lymphopenia and granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, stomatitis, diarrhea, somnolence, fatigue, peripheral neuropathy, mental status changes, cortical blindness, hepatocellular toxicity with elevation in serum transaminases, neurotoxicity and interstitial pneumonitis. These effects are reversible when the drug is discontinued. Immunosuppression observed with the use of fludarabine increases the risk of infection which can be life-threatening.
table 13 post-transplant evaluation
d. total body irradiation

TBI given at high doses in conventional transplants may cause nausea, vomiting, diarrhea, temporary hair loss, and painful swelling of the salivary glands for a few days. TBI may destroy normal marrow cells in addition to the cancer cells. The doses of TBI (200-300 cGy) used in this protocol is about one-sixth of that used in conventional transplant protocols, and severe acute side effects have so far not been observed. TBI has been associated with causing sterility and there is a risk of major genetic damage to any children conceived after transplantation. There is a risk that a small percentage of patients may develop a secondary cancer resulting from this treatment.
table 13 post-transplant evaluation
e. tacrolimus 1. description

Tacrolimus, also known as FK-506, is a macrolide immunosuppressive agent. Tacrolimus inhibits lymphocytes by forming a complex with FKBP-12, calcium, and calmodulin, leading to the decrease in the phosphatase activity of calcineurin. Calcineurin mediates the first intracellular signal required for T-cell activation after antigen recognition by the T-cell receptor. This drug is used with corticosteroids for prophylaxis of organ rejection in patients receiving allogeneic liver transplants and for prophylaxis of GVHD in the setting of HCT. It is also used for immunosuppression after kidney, cardiac, pancreas, pancreatic islet cell and small bowel transplantation. This drug is well-absorbed orally. It is metabolized in the liver by unknown mechanisms, but demethylation and hydroxylation have been proposed based on in vitro studies. The metabolized products are excreted in the urine.  
b. Intravenous Sterile solution of 5 mg/ml ampules in polyoxyethylated castor oil (Cremophor FCL).  
Diluted in D5W in glass or other non-PVC container.  
Final dilution volume: 50-250 ml dependent upon patient size and Tacrolimus dose.  
Infusion time:
o Pediatrics (<30 kg) - 22-24 hours (continuous infusion 0.03 mg/kg/day). Convert to twice daily oral dosing once therapeutic levels achieved.  
o Adults and Pediatrics (>30 kg) - single daily IV dose of 1 mg over 1-2 hours.  
Convert to twice daily oral dosing once therapeutic levels achieved.
table 13 post-transplant evaluation
2. dosage and administration a.

Tacrolimus capsules - 0.5 mg, 1 mg or 5 mg capsules. (There is currently no liquid solution available.)
For better absorption, it is recommended that Tacrolimus capsules be taken on an empty stomach.  
Tacrolimus should not be taken with grapefruit juice as it may increase blood levels.  
If patient vomits within one hour of oral administration, repeat dose.  
If vomiting persists, switch to IV administration.  
c. Conversion from IV to PO dosing of tacrolimus.  
Patients should be converted to an oral dose at 4 times the IV dose to be given in divided (Q 12 hour) doses. For children aged < 6 years old who have sub-therapeutic levels, the dose interval may need to be reduced to every 8 hours.  
See **Section X.A.3.c** for information about administration and dosage adjustments.
table 13 post-transplant evaluation
f. mycophenolate mofetil

1. Description MMF is the morpholinylethylester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B and T lymphocytes is blocked and antibody production is inhibited.
table 13 post-transplant evaluation
2. storage and administration

MMF is available in an oral and an intravenous formulation. The oral formulation is supplied in 250mg hard gelatin capsules and can be stored at room temperature. MMF for IV
administration is supplied as a lyophilized powder in a glass vial containing the equivalent of 500mg.
table 13 post-transplant evaluation
3. side effects and toxicity

1. Precautions: MMF has been studied extensively among patients after nonmyeloablative HCT. Previous clinical studies in patients after allografting suggest that the principal adverse reactions associated with the administration of MMF include nausea, vomiting, neutropenia, diarrhea, and on one occasion bloody diarrhea. In the setting of marrow transplantation, several etiologic factors may contribute to alterations in gastrointestinal and hematologic parameters. MMF has an increased incidence of digestive system adverse events, including GI tract ulceration, and hemorrhage (3% of patients receiving MMF). GI tract perforations have rarely been observed. Most patients in these studies were also on other drugs known to be associated with these complications. Up to 2% of patients receiving MMF for prevention of rejection developed severe neutropenia (ANC <500). The development of neutropenia may be related to MMF itself, concomitant medications, viral infections or some combination of these causes. MMF dose adjustments will be made if clinically indicated if in the opinion of the attending physician, no other cause is thought to be responsible for the abnormality. These adjustments should be
table 13 post-transplant evaluation
3. side effects and toxicities

Renal - Rise in serum creatinine, hemolytic uremic syndrome.  
Neurological - Peripheral: paresthesia, tremor. Central: seizures, headache, insomnia, dizziness, depression, confusion, hallucinations, psychosis, myoclonus, neuropathy, agitation.  
Gastrointestinal - Nausea, vomiting, anorexia, constipation, diarrhea.  
Cardiovascular - Hypertension, myocardial hypertrophy.  
Endocrine - Hyperglycemia, hyper/hypokalemia, hypophosphatemia, hypomagnesemia.  
Integument - Itching, rash.  
Hematologic - Leukocytosis, thrombocytopenia, leukopenia, anemia, PTLD,
thrombotic microangiopathy.  
Liver - Abnormal liver function tests.  
Ocular - Blurred vision, photophobia.  
Respiratory - Pleural effusion, atelectasis, cough, dyspnea. Musculoskeletal - Arthralgia.  
discussed with the principal investigator and documented in the medical records and the clinical reporting form (CRF). Dose adjustments are described in Section X.A.3.b.
table 13 post-transplant evaluation
xiii. infectious disease prophylaxis and

Patients will receive prophylaxis for pneumocystis carinii pneumonia (PCP), varicella zoster virus
(VZV), herpes simplex virus (HSV), and encapsulated bacterial and fungal organisms per Standard Practice Guidelines. Recommendations are listed in **Appendix B** of the protocol. Highlights include:
1. Sulfamethoxazole/trimethoprim should be started pre-transplant, discontinued on day -2, and reinstituted at Day +30 only if the ANC >500 for three consecutive days; use alternative prophylaxis if ANC <500 by Day+30.  
2. Acyclovir should be provided to all transplant patients except those having both negative HSV and VZV serostatus. For duration, refer to chart in **Appendix B**
3. Fluconazole should be given until Day +75
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xiv. graft-versus-host disease a. diagnosis

1. Refer to **Appendices C and D** for diagnosis and to Standard Practice Guidelines for latest treatment recommendations for acute and chronic GVHD, respectively 2. Prophylaxis with daily Bactrim and acyclovir must continue while receiving immunosuppression for Acute GVHD >Grade II or Chronic Extensive GVHD
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b. stopping rules for gvhd

A stopping rule is provided that will stop the study if there is evidence that the incidence of grade III/IV acute GVHD is greater than 25% within the first 100 days after HCT. Details of the rule are described in Section XVI.
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xv. evaluation and endpoint definitions

This is a Phase I/II study using nonmyeloablative conditioning (FLU, CY, TBI), HLAhaploidentical marrow as the stem cell source, potent post-transplantation immunosuppression
(CY, MMF, tacrolimus), followed by a single NK cell infusion early after HCT.
table 13 post-transplant evaluation
b. definition of endpoints 1.

a. Definition: Death in any patient for whom there has not been a diagnosis of relapse or disease progression.  
2. Relapse:
a. Definition: Presence of malignant cells in marrow (>5% blasts by morphology), peripheral blood (circulating blasts), or extramedullary sites (enlarging lymphadenopathy, soft tissue masses) not evident at the time of HCT. Presence of new or recurrent cytogenetic abnormalities in patients who have previously cleared this abnormality.  
b. Evaluation: Testing for recurrent malignancy will be performed using disease-specific, established testing methods, including but not limited to: marrow and peripheral blood morphology, immunophenotyping, cytogenetics, and molecular assays; peripheral blood counts and tumor markers; radiological evaluation (CT, MRI, PET scans); and biopsyproven disease.  
3. Progression:
Definition: Advancement of malignancy after HCT despite previous achievement of stable disease (**Table 16**).
table 13 post-transplant evaluation
4. acute gvhd

a. Definition: Acute GVHD will be defined by the criteria outlined in **Appendix C.** b. Evaluation: GVHD will be assessed by a by a single clinician using the criteria in Appendix C. Biopsy for confirmation of diagnosis of skin, liver and GI tract GVHD will be performed as indicated.  
c. The time to onset of GVHD and the number and types of immune suppressant therapies will be determined.  
5. Chronic GVHD:
a. Definition: Chronic GVHD is defined by criteria outlined in **Appendix D.** b. Evaluation: Chronic GVHD endpoints will include:
i. Extent (limited or clinical extensive) of GVHD
ii. Duration of immune suppression in months after diagnosis iii. Number of cycles of immune suppressant therapy iv. Need for immune suppressive agents other than first line therapy  
| Table 16: Definitions of Disease Progression  Multiple  Myeloma or Plasma  Cell  Leukemia  Increasing bone pain or  Increase in serum/urine monoclonal protein by 25% or  Increase in circulating or bone marrow blasts by 25% CLL, NHL,  Hodgkin  Lymphoma  New sites of lymphadenopathy or  Increase of ≥ 25% in lymph node size (assessed by CT scan)  Blood or marrow involvement with clonal B cells (lymphoma)  Increase of ≥ 25% marrow involvement or  Increase of ≥ 25% blood involvement of lymphocytes > 50x103 /μl) with  clonal B-cells (CLL) CML  Inability to control platelet or granulocyte counts  Increase in baseline number of metaphases demonstrating the Ph+  chromosome by 25%  Any other new cytogenetic abnormality  Transformation to accelerated phase or blast crisis MDS, AML  Aberrant myeloblasts may clear only slowly from the marrow after nonmyeloablative HCT. Thus, the presence of residual (<5%) MDS or AMLcells  early post-HCT cannot in and of itself be considered evidence for relapse.  However, if subsequent marrows show an increase in abnormal cells >5%,  this will be considered progressive disease.   |
|---|
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6. engraftment

a. Time to ANC >500/uL on the first of three consecutive days.  
b. *Mixed chimerism*: 5-95% donor T-cells (CD3+) in peripheral blood. c. *Full donor chimerism*: > 95% donor CD3+ T-cells in peripheral blood. d. *Donor engraftment*: Having mixed or full donor chimerism. e. *Increasing donor chimerism:* a 20% absolute increase in the CD3+ T-cell chimerism compared to the previous months' chimerism evaluation.  
f. *increasing donor chimerism*: a 20% absolute decrease in the CD3+ T-cell chimerism compared to the previous months' chimerism evaluation.  
g. *Low donor chimerism*: <40% CD3+ T-cells after HCT on two consecutive evaluations within a 4 week period. The two evaluations must be at least 14 days apart. Low donor chimerism should always be confirmed with repeat blood T-cell and granulocyte chimerism analysis. VNTR analyses or FISH studies (in sex mismatched patients) of sorted peripheral blood CD3+ T-cells will be used to quantify chimerism. The same assay should be used for a given patient for repeated studies of chimerism. VNTR and FISH analyses will also be performed on marrow aspirates. Therapeutic decisions (i.e. donor lymphocyte infusion) will be made based on the results of sorted T-cell studies of *peripheral blood.*
h. *Rejection*: the inability to detect, or less than 5% donor T-cells (CD3) as a proportion of the total T-cell population after nonmyeloablative HCT.  
i. *Graft failure*: grade IV thrombocytopenia and neutropenia after Day +21 that lasts > 2 weeks and is refractory to growth factor support.
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xvi. statistical analysis

This is a phase I/II study with an initial dose escalation for the targeted NK cell dose, followed by a single cohort phase II at the identified safe dose.  
If a patient initially enrolls on this study but is unable to receive a donor NK cell infusion for any reason, the patient will not be included in the statistical analyses for DLT criteria, graft failure, GVHD, relapse, or NRM and they will be considered off-study.  
Reasons for not receiving a donor NK cell infusion include, but are not limited to: 1) Patient being actively treated for hyperacute GVHD requiring additional systemic immunosuppressive therapy (other than prophylactic tacrolimus and MMF) 2) Patient receiving >0.25 mg/kg equivalent prednisone dose prior within one day of donor NK
cell infusion; 3) Any patient medical concerns or issues that prohibit infusion of the NK cell product 4) Any donor medical concerns or issues that prohibit collection of the NK cell product
table 13 post-transplant evaluation
phase i

Two possible targeted doses of NK cells are defined: 2.5x106 cells/kg and 5x106 cells/kg. Three patients will be initially entered at the lower dose level. If none of the 3 experience DLT (as defined below) within 28 days of the donor NK cell infusion, then escalation to the higher dose level will occur. If 1 of the 3 patients experiences DLT then an additional 3 patients will be enrolled at the lower dose level, and if no additional DLTs are observed then escalation to the higher dose may occur. If a 2nd DLT is observed at the lower dose level in any number of patients, then the study will be suspended pending review by our DSMB and consideration of a protocol amendment to establish a lower dose level.  
At the higher dose level, the first 6 patients enrolled will be considered part of 'phase I'. If no more than 1 DLT is observed among these 6, then 'phase II' enrollment will commence at this dose level and continue for an additional 29 patients. If a 2nd DLT is observed in the first 6 patients, then the lower dose level will be considered the phase II dose and the additional phase II enrollment of 29 patients will commence at that dose level, provided that at least 6 patients have been enrolled with no more than 1 DLT.  
During the phase I enrollment period, patients may be enrolled at the current dose level pending completion of the 28 day observation period for the final patient required to permit dose escalation, provided that at least 2 patients at the current dose level have completed the 28 day observation period without DLT.
table 13 post-transplant evaluation
dlt is defined as having

52 2) Grade IV regimen-related toxicity (based on Adapted CTC);
3) Grade IV acute GVHD 4) Non-relapse mortality
table 13 post-transplant evaluation
phase ii

The phase II efficacy evaluation will target a total enrollment of 35 patients: the 6 patients enrolled during phase I plus the additional 29 patients enrolled during phase II. All patients receiving NK cell infusions during phase II will be counted, even if the infused cell dose does not meet the targeted dose established in phase I. The sample size is chosen to provide adequate power to evaluate a possible reduction in the 1-year relapse rate from the historical reference rate of 55% observed in previous studies. With 35 patients, we have approximately 80% power to detect a 20% reduction in the 1-year relapse rate, at a 1-sided 0.10 level of significance. This power calculation is intended only as an approximate point of reference. Because of the heterogeneity of the patient populations, relapse rates are not likely to be directly comparable, and further analysis taking this heterogeneity into account will be required in order to determine the potential effectiveness of the regimen.  
Stopping rules will be imposed for:  
Day 200 NRM with a threshold rate of 25%
Day 100 grade III/IV acute GVHD, with a threshold rate of 25%, or Day 100 graft failure, with a threshold rate of 10%.
The limits for NRM and GVHD are somewhat higher than the rates observed in the previous haploidentical donor studies, but we are allowing for the possibility that a decrease in early relapse might lead to a modest increase in these adverse endpoints yet still yield a better overall outcome. The study will stop at any time that there is reasonable evidence that the true rate of these events exceeds the threshold rate. Reasonable evidence will be taken to mean that the lower bound of a 1-sided 80% confidence interval exceeds the threshold. Operationally, the stopping rules would be triggered by the number of patients experiencing the event in question as outlined below:  
Day 200 NRM (25% threshold): 5/10, 8/20, or10/30 patients Day 100 grade III/IV acute GVHD (25% threshold): 5/10, 8/20, or10/30 patients Day 100 graft failure (10% threshold): 3/10, 4/20, or 5/30 patients
These stopping rules will be evaluated at least every 10 patients. Both the patients and events observed among the 6 patients enrolled during phase I will 'count' for purposes of evaluating the stopping rules. The operating characteristics of these rules are in **Table 17** below.  
| True rate of day 200 NRM   |                         |              |             |     |    |
|----------------------------|-------------------------|--------------|-------------|-----|----|
| or day 100 GVHD            | Average N at  stopping1 |              |             |     |    |
| 0.3                        | 55%                     | 25           | .15         | 61% | 23 |
| 0.35                       | 74%                     | 20           | .20         | 83% | 18 |
| 0.4                        | 89%                     | 16           | .25         | 94% | 14 |
| 0.45                       | 96%                     | 13           | .30         | 99% | 11 |
| Probability of  stopping1  | Average N at  stopping1 | True rate of | Probability |     |    |
| graft failure              | of                      |              |             |     |    |
| stopping1                  |                         |              |             |     |    |  
1 estimated from 10,000 Monte Carlo simulations Enrollment may continue pending evaluation of these endpoints at the 10 patient benchmarks; however, the outcome of subsequently enrolled patients may not override the stopping rule if triggered by patients currently enrolled. Other endpoints will include evaluation of rejection, overall survival, chronic extensive GVHD, the contribution of KIR ligand alloreactivity to relapse risk, and the effects of a donor NK cell infusion on post-transplant immune reconstitution.
table 13 post-transplant evaluation
xvii. data safety and monitoring

The principal investigators (PI) will monitor this study, with oversight by a Data Safety and Monitoring Board (DSMB), the Protocol and Data Monitoring Committee (PDMC) and the Institutional Review Board (IRB). The PI reviews toxicity data weekly for the first 100 days after HCT, and outcome data for each individual patient at a minimum of 3 months after HCT.  
Serious adverse events are reported to the trial coordinator, the study nurse or directly to the PI within 72 hours of the event during the initial 28 days after NK infusion. An official report of an adverse event is faxed to the coordinating center within seven days during the initial 28 days and up to day 180 post HCT. The adverse event report is reviewed by PI. If the adverse event meets the FHCRC criteria for reporting, then an official signed report is submitted to the FHCRC Institutional Review Office (IRO). All deaths, regardless of the cause, are reported to the IRB. This protocol has a DSMB responsible for monitoring patient safety on this clinical trial. The DSMB meets twice a year and all outcome data is reviewed including all adverse events reported to the FHCRC IRO. The DSMB confirms that the trial has not met any stopping rules and reviews any patient safety problems necessitating discontinuation of the trial. A report from the DSMB is submitted to the FHCRC IRB as well as the trial coordinators/local PIs of this protocol. Furthermore, the FHCRC also has a PDMC that reviews the progress of the protocol with respect to the monitoring plan at the time of each annual renewal. As with initial review, annual IRB review and approval is also required.  
With respect to safety, patients are monitored for the development of GVHD, myelosuppression, infections and rejection. All patients, regardless of diagnosis, will be considered in the safety analysis. GVHD events will be closely monitored and severity of GVHD graded. Formal stopping rules for GVHD grades III-IV and graft failure before day 100, and NRM before day 200 are provided.  
Flow of information concerning clinical trial participants originates with the clinicians and nurses in the clinic or referring clinicians at other institutions and is transmitted to the FHCRC Trial Coordinator. At the FHCRC, health care providers and rotating attending physicians assess patients and record their observations regarding toxicity and response outcomes in the medical record. This documentation is extracted by the study nurse within 140 days +/- after HCT via chart review and collection of copies of source documents and entered into a hard copy or electronic Case Report Form (CRF). The PI reviews the official CRF and primary source documents. After the CRFs are verified, they are signed by the PI. Thus, multiple health care providers provide independent observations and participate in monitoring this trial. The PI may be a clinician for some patients entered on this trial. However, assessments are the sum total of the primary health care provider (fellow or physician assistant), floor or outpatient nurse and the PI or other attending clinician involved with the patient averting possible conflict of interest having the PI as the attending clinician for protocol patients. If determination of adverse events is controversial, co-investigators will convene on an ad hoc basis as necessary to review the primary data and render a decision.
table 13 post-transplant evaluation
b. plans for assuring compliance

The adverse event reporting will follow the FHCRC Guidelines for serious adverse event (SAE)
reporting (**Appendix E**). These guidelines detail the expedited reporting requirements and definitions of particular events. All SAEs that meet expedited reporting criteria are reported to the IRO within 10 days by the investigator, trial coordinator, or research nurse upon learning of the event. A completed SAE report form, signed by the PI, must be received by the IRO within 10 calendar days. The PI reviews all SAEs and annual reports at the time of submission. For patients being cared for at the FHCRC, health care providers communicate with the PI, trial coordinator or research nurses as events occur triggering subsequent reporting. All serious adverse events are reported to the IRB at the time of annual renewal and at the Mixed Chimerism Meeting. The PI for a study is responsible for this reporting and the IRO assures adverse event reporting on an annual basis. The PI in the annual application for grant continuation will summarize reports of toxicities. Furthermore, stopping rules and interim analysis provides an additional safeguard for adverse event analysis and reporting in this protocol. All collaborating PIs have fulfilled all NIH requirements for training in human subjects' protection.  
In regards to monitoring for the FDA, all acute adverse event monitoring will occur until 28 days after the NK cell infusion. We will plan to report all unexpected SAEs and grades 3-4 infusional reactions in an expedited fashion. We plan to expedite reporting on any patient with an ANC < 500 by day 28 after NK cell infusion. In addition, we will plan to include a separate listing of infusional toxicities, in addition to other required elements, in our annual reports to the FDA.  
Duration for monitoring GVHD, relapse, and survival for purposes of reporting *to the FDA* will be for **1 year after transplant.** At FHCRC, we will continue collecting long-term follow-up data for many years for our internal use.
table 13 post-transplant evaluation
c. plans for assuring that

The procedure of CD3+ depletion and CD56+ selection will be performed under an investigatorsponsored IND, with FDA oversight. Serious and unexpected adverse experiences must be reported to the IND holder and the Principal Investigator. The IND holder and the principal investigator must report all serious and unexpected adverse events to the IRB, the FDA and the Miltenyi Biotec, Inc. Any temporary or permanent suspension, as determined by the PI, IRB, or PDMC, of this clinical research trial will be reported to the NCI grant program director by the PI.  
1. Unexpected and related fatal or life-threatening events are reported to FDA by phone or FAX
within 7 calendar days.  
2. A written report will be sent to FDA within15 calendar days for any serious unexpected adverse events for which is a reasonable possibility that the event may have been caused by study device.  
3. All serious adverse events occurring during this study, whether or not attributed to study drug, will be included in the IND holder's annual IND report to FDA.
table 13 post-transplant evaluation
d. plans for assuring data

This protocol has a DSMB that is responsible for reviewing protocol data and safety endpoints. The DSMB meets on a twice-yearly basis, reviews a report of appropriate endpoint data, and compiles a report that is submitted to the IRB, PDMC Chairman, and Protocol Office.  
55 At the FHCRC, health care providers and rotating attending physicians assess patients and record their observations in the medical record. This documentation is extracted by one of the study nurses at 100 days after HCT via chart review and entered into an electronic Case Report Form (CRF). The study nurses also continue to follow patients after day 100, review source documentation, and complete CRFs at 6 month and then yearly intervals per protocol. The CRFs are printed directly from the database, and the PI reviews the CRFs and the primary source documents for data accuracy. When the CRFs are verified, the PI signs them, and the data are incorporated into a central database by the data manager. Thus, multiple health care providers provide independent observations and participate in assessments on this trial. The study has dedicated nurses who at a minimum follow patients to confirm eligibility; reporting of adverse events; reporting of events, which are part of the safety-monitoring plan, and protocol adherence. The PI, data coordinators, and research nurses are responsible for review and maintenance of all patient records to ensure data integrity and protocol adherence.
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xviii. records

Clinical records will be maintained as confidentially as possible. Data will be collected maintained by Clinical Statistics. The investigator will ensure that data collected conform to all established guidelines for coding, collection, key-entry and verification. Each patient is assigned a unique patient number to assure patient confidentiality. Any publication or presentation will refer to patients by this number and not by name. The licensed medical records department, affiliated with the institution where the patient receives medical care, maintains all original inpatient and outpatient chart documents. Patient research files are kept in a locked room. They are maintained by the FHCRC data collection staff, which is supervised by an A.R.T. Access is restricted to personnel authorized by the Division of Clinical Research. Information gathered from this study regarding patient outcomes and adverse events will be made available to the Federal Drug Administration and to Miltenyi Biotec, Inc. All precautions to maintain confidentiality of medical records will be taken.
table 13 post-transplant evaluation
xix. projected target accrual

| TARGETED / PLANNED ENROLLMENT                     | Number of Subjects   |       |       |
|---------------------------------------------------|----------------------|-------|-------|
| Ethnic Category                                   | Sex / Gender Females | Males | Total |
| Hispanic or Latino                                | 0                    | 1     | 1     |
| Not Hispanic or Latino                            | 14                   | 20    | 34    |
| Ethnic Category Total of All Subjects*            | 14                   | 21    | 35    |
| RACIAL CATEGORIES American Indian / Alaska Native | 1                    | 0     | 0     |
| Asian                                             | 0                    | 2     | 1     |
| Native Hawaiian or Other Pacific Islander         | 0                    | 0     | 0     |
| Black or African American                         | 1                    | 2     | 1     |
| White                                             | 12                   | 17    | 33    |
| Racial Categories: Total of All Subjects*         | 14                   | 21    | 35    |
| FHCRC Version 02/23/2016                          | 56                   |       |       |
table 13 post-transplant evaluation
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50. Savani BN, Mielke S, Adams S, et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia. 2007;21:2145-2152.  
51. Kim DH, Won DI, Lee NY, Sohn SK, Suh JS, Lee KB. Non-CD34+ cells, especially CD8+
cytotoxic T cells and CD56+ natural killer cells, rather than CD34 cells, predict early engraftment and better transplantation outcomes in patients with hematologic malignancies after allogeneic peripheral stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:719-728.  
52. Lewalle P, Triffet A, Delforge A, et al. Donor lymphocyte infusions in adult haploidentical transplant: a dose finding study. Bone Marrow Transplant. 2003;31:39-44.
table 13 post-transplant evaluation
appendices

page  
| A   | ABO Incompatibility Guidelines………………………………………………………………………… 61                     |
|-----|-----------------------------------------------------------------------------------|
| B   | Infectious Disease Guidelines………………………………………………………………………….. 63                    |
| C   | Grading of Acute GVHD………………………………………………………………………………… 64                           |
| D   | Evaluation of Chronic GVHD…………………………………………………………………………… 65                        |
| E   | Study Coordinator's Manual……………………………………………………………………………. 67                       |
| F   | Core Case Report Form………………………………………………………………………………… 71                           |
| G   | Patient Demographics and Registration Form……………………………………………………….. 72              |
| H   | Notice of Death…………………………………………………………………………………………... 76                           |
| I   | Serious Adverse Event Report Form…………………………………………………………………...77                   |
| J   | The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 9/07/10………………………….79 |
| K   | Adapted Common Toxicity Criteria ……………………………………………………………………..81                   |
| L   | Coordinating Center Functions ………………………………………………………………………... 89                   |
| M   | Research Specimens.…………………………………………………………………………………... 91                          |
| N   | Intrathecal Therapy Administration.…………………………………………………………………... 96                |
table 13 post-transplant evaluation
abo incompatibility guidelines red blood

Occasional patients may have antibodies directed against red blood cell antigens found on the donor's cells. These are generally ABO or Rh antigens, although incompatibility with other red cell antigens identified by donor-recipient crossmatch may occur. If the recipient shows an anti-donor RBC antibody titer of  1:32, the RBC content of the marrow product must be reduced to  20mL in order to avoid a hemolytic transfusion reaction when the product is infused. Incompatible marrow products  600 mL will be RBC depleted by processing through an apheresis instrument and recovering marrow mononuclear cells (MNC) containing  20mL of residual RBC. Incompatible marrow products < 600 mL will undergo RBC depletion by the starch sedimentation method. Refer to the Clinical Coordinator's Patient Information Sheet for instructions regarding management of a specific patient.  
Post transplant blood component support will be according to Standard Practice Guidelines. Timing: Every attempt should be made to infuse red cell depleted marrow products within 2 hours of depletion. Expected Results: Red blood cell depleted marrow products will contain < 20ml residual red blood cells and  80% recovered marrow MNC.
table 13 post-transplant evaluation
red blood cell - incompatibility

Occasional donors may have antibodies directed against red blood cell antigens (ABO, Rh, or other antigen system) found on the recipient's cells. The risk of hemolysis of recipient red cells immediately after transplant may occur if the donor antibody titer is  1:256 and the volume of infused plasma (for recipient  20 kg) is > 200mL. If the donor antibody titer is  1:256 the marrow product must be plasma reduced to a final volume of  200 mL (for recipient  20 kg). For recipients
< 20 kg, see the Standard Practice Manual for guidelines regarding final plasma-reduced marrow volumes (see flowsheet below). Due to the high number of lymphocytes in the marrow inoculum, recipients of minor ABO mismatched products may also be at risk for a delayed type of hemolysis that can be severe. *Refer to the Clinical Coordinator's Patient Information Sheet for instructions* regarding management of a specific patient. Post transplant blood component support will be according to Standard Practice Guidelines.  
Timing: Every attempt should be made to infuse plasma-depleted PBMC within 2 hours of depletion. Expected Results: The plasma depletion should not affect the nucleated cell recovery.
table 13 post-transplant evaluation
red blood cell - bidirectional

Patients undergoing transplants for bidirectional RBC incompatibility should be managed according to both algorithms shown below. Most red cell depletion techniques also deplete plasma from the marrow component with no additional cell loss. *Refer to the Clinical Coordinator's Patient Information* Sheet for instructions regarding management of a specific patient.
post transplant blood component support
red blood cell - bidirectional

MAJOR ABO INCOMPATIBLE
1:32  
  
  
  
< 20ml RBC total  Infuse without modification
> 20ml RBC total  RBC depletion of component to  20 mL
Recipient antiDonor titer  
1:16  
  
  
  
Infuse without modification  
  
  
  
  
  
  
  
MINOR ABO INCOMPATIBLE  
  
  
  
  
Plasma depletion of component to  200 mL (recipient  20 kg). See  
  
Standard Practice Manual for volume guidelines for recipient < 20 kg)
Donor antiRecipient titer  
  
INFECTIOUS DISEASE GUIDELINES
Herpes Simplex and Varicella Zoster Virus Prevention and Treatment Herpes Simplex and Varicella Zoster Virus CMV Prevention: Surveillance and Preemptive Therapy  
$$\frac{\left|\overrightarrow{\mathrm{{Eaa}}}\right|}{\left|\overrightarrow{\mathrm{{A}}}\right|}$$  convervention.pdf  
  
CMV Disease: Diagnosis and Treatment  
cmvdiseasetreatmen t.pdf
post transplant blood component support
1 introduction the quantum quantum

Pneumonia / Pneumocystis Jiroveci Prophylaxis  
**Acknowledgement**
$\textsf{OMgSi}$.
pneumocystisjiroveci Antibiotic Prophylaxis for Encapsulated Bacteria in Allogeneic Patients with Chronic GvHD
Requiring Immunosuppressive Therapy Antibiotic Prophylaxis for Encap Bacteria
post transplant blood component support
appendix c grading of acute

Diarrhea
+1  1000 ml of liquid stool/day*( 15ml of stool/kg/day)†
+2 >1,000 ml of stool/day*(> 15ml of stool/kg/day)† +3 >1,500 ml of stool/day*(> 20ml of stool/kg/day)†
+4 2,000 ml of stool/day*( 25ml of stool/kg/day)†  
| No gut or liver involvement +1 gastrointestinal involvement and/or +1 liver involvement   |                                                                                                |
|-------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|
| Grade III                                                                                 | +2 to +4 gastrointestinal involvement and/or +2 to +4 liver involvement with or without a rash |
| Grade IV                                                                                  | Pattern and severity of GVHD similar to grade 3 with extreme constitutional  symptoms or death |  
*In the absence of infectious/medical cause
†For pediatric patients
post transplant blood component support
severity of gvhd (grade)

Grade I +1 to +2 skin rash  
No gut or liver involvement  
Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional  
symptoms or death  
_______________  
a From "Graft-vs-host disease" Sullivan, Keith M. *Hematopoietic Cell Transplantation* Ed: D. Thomas, K. Blume, S.  
Forman, Blackwell Sciences; 1999, pages 518-519  
| Severity of Individual Organ Involvement (stage)   |                                                                                                                                                                                                       |                                                              |
|----------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| Skin                                               | +1                                                                                                                                                                                                    | a maculopapular eruption involving less than 25% of the body |
| +2                                                 | a maculopapular eruption involving 25-50% of the body surface                                                                                                                                         |                                                              |
| +3                                                 | generalized erythroderma                                                                                                                                                                              |                                                              |
| +4                                                 | generalized erythroderma with bullous formation and often with  desquamation                                                                                                                          |                                                              |
| Liver                                              | +1                                                                                                                                                                                                    | bilirubin (2.0-3.0 mg/100 ml)                                |
| +2                                                 | bilirubin (3-5.9 mg/100 ml)                                                                                                                                                                           |                                                              |
| +3                                                 | bilirubin (6-14.9 mg/100 ml)                                                                                                                                                                          |                                                              |
| +4                                                 | bilirubin > 15 mg/100 ml                                                                                                                                                                              |                                                              |
| Gut                                                | Diarrhea is graded +1 to +4 in severity. Nausea and vomiting and/or  anorexia caused by GVHD is assigned as +1 in severity The severity of gut involvement is assigned to the most severe involvement |                                                              |
|                                                    | noted. Patients with visible bloody diarrhea are at least stage +2 gut and                                                                                                                            |                                                              |
post transplant blood component support
appendix d evaluation of chronic

In all cases, concomitant processes (i.e. infections or drug reactions) must be ruled out. Karnofsky or Lansky Clinical Performance scores, 60%, > 15% weight loss, and recurrent infections are usually signs of clinical extensive chronic GVHD. Abnormalities that could indicate chronic GVHD are categorized by organ systems as listed below.  
| categorized by organ systems as listed below. Skin Erythema, dryness, pruritus, pigmentary changes (i.e. hyperpigmentation, vitiligo),  mottling, papulosquamous plaques, nodules, exfoliation, macular-papular or  urticarial rash, scleroderma, morphea (one or several circumscribed, indurated  and shiny lesions) Nails Ridging, onychodystrophy, onycholysis Hair Premature graying, (scalp hair, eyelashes, eyebrows), thinning scalp hair,  alopecia, decreased body hair Mouth Dryness, burning, gingivitis, mucositis, striae, atrophy, erythema, lichenoid  changes, ulcers, labial atrophy or pigmentary changes, tooth decay, tightness  around the mouth Eyes Dryness, burning, blurring, gritty eyes, photophobia, pain Vagina/vulva Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid  changes not included Liver Elevated liver function tests not due to other causes (alkaline phosphatase  3x  upper limit of normal, AST or ALT 4x upper limit of normal or total serum bilirubin   2.5; in the absence of chronic GVHD involving other organs, liver biopsy is  required to confirm diagnosis) Lung Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on  exertion, history of recurrent bronchitis or sinusitis GI Anorexia, nausea, vomiting, weight loss, dysphasia, odynophagia,  malabsorption Fasciitis Stiffness and tightness with restriction of movement, occasionally with swelling  pain, cramping, erythema and induration, most commonly affecting forearms,  wrists and hands, ankles, legs, and feet, inability to extend wrists without flexing  the fingers or the elbows, contractures Serositis Chest pain or cardiopulmonary comprise due to pericarditis or pleuritis Muscle Proximal muscle weakness, cramping Skeletal Arthralgia of large proximal girdle joints and sometimes smaller joints   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
post transplant blood component support
laboratory testing and diagnostic indicators

| Eye       | Schirmer's test with a mean value  5mm at 5 minutes, or symptomatic with  values of 6-10mm or keratitis detected by slit lamp examination          |
|-----------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| Liver     | Elevated liver function tests not due to other causes (see definition of clinical  limited and extensive chronic GVHD)                              |
| Lung      | New obstructive lung defect defined as FEV1 < 80% of predicted with either an  FEF 25-75 <65% of predicted or RV >120% of predicted, or a decrease of  FEV1/FVC by > 12% within a period of less than 1 year. A diagnosis of  bronchiolitis obliterans requires negative microbiological tests from  bronchoalveolar lavage and evidence of air trapping by high resolution endexpiratory and end-inspiratory CAT scans o the chest. A thoracoscopic lung  biopsy may be necessary in order to confirm the diagnosis of bronchiolitis  obliterans in patients who have obstructive lung disease without air trapping when  chronic GVHD involving other organs is absent                                                                                                                                                     |
| Esophagus | Esophageal web formation, stricture or dysmotility demonstrated by barium  swallow, endoscopy or manometry                                          |
| Muscle    | Elevated CPK or aldolase, EMG findings consistent with myositis                                                                                     |
| Blood     | Thrombocytopenia (usually 20,000-100,000/l), eosinophilia,  hypogammaglobulinemia, hypergammaglobulinemia, and autoantibodies occur in  some cases |  
_________________
a From Standard Practice Guidelines for "Chronic Graft-versus-Host Disease Classification at the time of presentation" developed by Long Term Follow-Up at the FHCRC
post transplant blood component support
appendix e study coordinator's manual

The mixed chimerism protocols have been opened to multiple sites to increase the referral base and accrual. Because of this expansion of collaborators, the data collection procedures are being revised. The procedure manual was created to assure consistency of data reporting across the centers and to assure compliance with regulations. General expectations of collaborators are that they will comply with appropriate regulatory requirements, specified protocol requirements, and provide outcome data. The manual translates working procedures for study coordination. Its goal is to describe the procedures with sufficient clarity to ensure that all study centers will use the same procedures and follow-up schedules for participant data management and reporting. Changes to the manual and relevant forms will be made as soon as practical and will become effective on receipt of the revised procedures at the study centers, unless otherwise noticed.
post transplant blood component support
ii. institutional review board review

All research protocols proposed for use that involves human subjects must be reviewed and approved by the Institutional Review Board (IRB) prior to implementation. New protocols will undergo review at the FHCRC IRB and then will be distributed to sites that wish to participate for their IRB's review. For Centers that have a Federal Wide Assurance (FWA), formal collaboration includes submission of a form 310 and a copy of the IRB approved protocol and consent forms to the FHCRC. For sites without a FWA, an FWA form needs to be filed. Once the paperwork is submitted to the Office for Human Research Protection, the approval process can take up to a couple of months, and must be completed before collaboration on a protocol can begin.  
In addition, all amendments and/or revisions to on-going, approved activities must be submitted for review and approved prior to implementation at an institution. No revisions may be implemented at outside institutions without the prior approval of the FHCRC Principal Investigator. The FHCRC and the local site's IRB must review all protocol activities at least once annually. This must be done within 365 days of the last review regardless of the policies of the institution. A copy of annual renewal approvals must be received for collaboration to continue for the next year.
post transplant blood component support
iii. registrations

Collaborating Institutions: The principal investigator of the collaborating institution who will register the patient with the FHCRC will identify eligible patients. Registration will include completion of the eligibility checklist/demographic form. This form will be faxed (206-667-5378) prior to treatment initiation. Patients should be registered prior to treatment initiation for valid registration
post transplant blood component support
iv. reporting adverse events

The following guidelines are the minimum serious adverse event (SAE) reporting guidelines for Category 1 and 2 studies conducted at the Fred Hutchinson Cancer Research Center.
post transplant blood component support
expedited reporting requirements

All unexpected and serious adverse events which may be due to study treatment or intervention must be reported to the FHCRC Institutional Review Office as soon as possible but within at least 10 calendar days of the investigator learning of the event.