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10.12 storage and stability

Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light
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10.13 palifermin (kepivance)

Palifermin is a human recombinant keratinocyte growth factor (KGF) used to reduce the incidence and duration of severe oral mucositis. Palifermin is commercially available and will be purchased by the Clinical Center Pharmacy. 10.13.1 Formulation storage intravenous powder for solution: 6.25 mg add sterile water for injection to vial for a final concentration of 5 mg/mL, gently swirl, do not shake or vigorously agitate vial destroy reconstituted solution after 1 hour if left at room temperature or 24 hours if refrigerated 10.13.2 Administration add sterile water for injection to vial for a final concentration of 5 mg/mL, gently swirl, do not shake or vigorously agitate vial give reconstituted solution immediately or destroy after 1 hour if left at room temperature or 24 hours if refrigerated do not filter reconstituted solution during preparation or administration if heparin is used to maintain the i.v. line, flush with saline prior to and after the dose to prevent binding to heparin palifermin should not be used during or within 24 hours preceding or following myelotoxic therapy administration 10.13.3 Dose and schedule
- 60 g/kg intravenously push
- daily for three days starting day -9 pre-ASCT (i.e. days -9, -8 and -7) - then for three additional daily doses on days +1, +2 and +3 of ASCT  
10.13.4 Drug interaction
In vitro and *in vivo* data suggest that palifermin binds to unfractionated as well as low-molecularweight heparins, and licensed product information therefore recommends that such combinations should be used with care, although the clinical relevance is unclear. 10.13.5 Toxicity 90  
The following adverse events were found in excess in the palifermin group over the control group in randomized studies and may be related to palifermin administration: Rash, pruritus, erythema, cough, edema, taste changes or taste loss, coating of the tongue, sensation of increased tongue thickness, rhinitis, arthralgia, perianal pain, numbness, paresthesia
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11 references

1. Jemal, A., et al., *Cancer statistics, 2009.* CA Cancer J Clin, 2009. 59(4): p. 225-49. 2. Canellos, G.P., et al., Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med, 1992. 327(21): p. 1478-84. 3. Moskowitz, C.H., et al., *A 2-step comprehensive high-dose chemoradiotherapy second-line* program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood, 2001. 97(3): p. 616-23.  
4. Josting, A., et al., Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin's disease. Ann Oncol, 2002. 13 Suppl 1: p. 112-6. 5. Linch, D.C., et al., *Dose intensification with autologous bone-marrow transplantation in* relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet, 1993. 341(8852): p. 1051-4. 6. Schmitz, N., et al., *Aggressive conventional chemotherapy compared with high-dose* chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet, 2002. 359(9323): p. 2065-71. 7. Josting, A., et al., New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol, 2002. 20(1): p. 221-30. 8. Brice, P., et al., *Analysis of prognostic factors after the first relapse of Hodgkin's disease in* 187 patients. Cancer, 1996. 78(6): p. 1293-9. 9. Bonfante, V., et al., Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. J Clin Oncol, 1997. 15(2): p. 528-34. 10. Sureda, A., et al., Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol, 2001. 19(5): p. 1395-404. 11. Sureda, A., et al., *Prognostic factors affecting long-term outcome after stem cell* transplantation in Hodgkin's lymphoma autografted after a first relapse. Ann Oncol, 2005. 16(4):
p. 625-33. 12. Bierman, P.J., et al., High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: long-term follow-up in 128 patients. Ann Oncol, 1993. 4(9): p. 767-73. 13. Nademanee, A., et al., *High-dose chemotherapy with or without total body irradiation* followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin's disease: results in 85 patients with analysis of prognostic factors. Blood, 1995. 85(5): p. 1381-90.  
14. Horning, S.J., et al., High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices. Blood, 1997. 89(3): p. 801-13.  
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15. Sweetenham, J.W., et al., *High-dose therapy and autologous stem-cell transplantation for* adult patients with Hodgkin's disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation.  
Lymphoma Working Party. J Clin Oncol, 1999. 17(10): p. 3101-9.  
16. Lazarus, H.M., et al., Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol, 1999. 17(2): p. 534-45.  
17. McLaughlin, P., et al., *Rituximab chimeric anti-CD20 monoclonal antibody therapy for* relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol, 1998. 16(8): p. 2825-33.  
18. Cheson, B.D., *Radioimmunotherapy of non-Hodgkin lymphomas.* Blood, 2003. 101(2): p.  
391-8. 19. Witzig, T.E., et al., *Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of* relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol, 1999. 17(12): p. 3793-803. 20. Witzig, T.E., et al., *Randomized controlled trial of yttrium-90-labeled ibritumomab* tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol, 2002. 20(10): p. 2453-63.  
21. Kaminski, M.S., et al., *Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (antiCD20) antibody.* N Engl J Med, 1993. 329(7): p. 459-65.  
22. Kaminski, M.S., et al., Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood, 2000. 96(4): p. 1259-66. 23. Weaver, C.H., et al., *High-dose fractionated total-body irradiation, etoposide, and* cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma. J Clin Oncol, 1994. 12(12): p. 2559-66. 24. Horning, S.J., et al., *Fractionated total-body irradiation, etoposide, and cyclophosphamide* plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol, 1994. 12(12): p. 2552-8. 25. Bearman, S.I., et al., *Regimen-related toxicity and early posttransplant survival in patients* undergoing marrow transplantation for lymphoma. J Clin Oncol, 1989. 7(9): p. 1288-94. 26. Press, O.W., et al., *Radiolabeled-antibody therapy of B-cell lymphoma with autologous* bone marrow support. N Engl J Med, 1993. 329(17): p. 1219-24.  
27. Press, O.W., et al., *Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous* stem cell transplantation for relapsed B cell lymphomas. Lancet, 1995. 346(8971): p. 336-40. 28. Liu, S.Y., et al., Follow-up of relapsed B-cell lymphoma patients treated with iodine-131labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol, 1998. 16(10): p. 32708.  
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29. Press, O.W., et al., *A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide,*
cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood, 2000. 96(9): p. 2934-42.  
30. Nademanee, A., et al., *A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in* combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood, 2005.  
106(8): p. 2896-902.  
31. Devizzi, L., et al., High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation. J
Clin Oncol, 2008. 26(32): p. 5175-82.  
32. Krishnan, A., et al., *Phase II trial of a transplantation regimen of yttrium-90 ibritumomab* tiuxetan and high-dose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol, 2008. 26(1): p. 90-5. 33. Queen, C., et al., *A humanized antibody that binds to the interleukin 2 receptor.* Proc Natl Acad Sci U S A, 1989. 86(24): p. 10029-33. 34. Waldmann, T.A., et al., *The interleukin-2 receptor: a target for monoclonal antibody* treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood, 1993. 82(6): p. 1701-12.  
35. Waldmann, T.A., et al., *Radioimmunotherapy of interleukin-2R alpha-expressing adult Tcell leukemia with Yttrium-90-labeled anti-Tac.* Blood, 1995. 86(11): p. 4063-75. 36. Kreitman, R.J., et al., *Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB2) in patients with hematologic malignancies.* J Clin Oncol, 2000. 18(8): p. 1622-36.  
37. Decaudin, D., et al., Radioimmunotherapy *of refractory or relapsed Hodgkin's lymphoma* with 90Y-labelled antiferritin antibody. Anticancer Drugs, 2007. 18(6): p. 725-31.  
38. Schnell, R., et al., *Treatment of refractory Hodgkin's lymphoma patients with an iodine131-labeled murine anti-CD30 monoclonal antibody.* J Clin Oncol, 2005. 23(21): p. 4669-78.  
39. Engert, A., et al., A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5- SMPT-dgA) in patients with refractory Hodgkin's lymphoma. Blood, 1997. 89(2): p. 403-10. 40. Cheson, B.D., et al., *Revised response criteria for malignant lymphoma.* J Clin Oncol, 2007. 25(5): p. 579-86. 41. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Vardiman, J.W and IARC, WHO Classification of Tumours of Haematopoietic *and Lymphoid* Tissues. Fourth ed. 2008.  
42. Breitenstein, B.D., Jr., Fry, S.A. and Lushbaugh, C.C., *DTPA therapy: The U.S.*
Experience 1958-1987, in *The Medical Basis of Radiation Accident Preparedness*. 1990, Elsevier Science Publishing Co., Inc. p. 397-406.  
43. Raubitschek, A., A Phase I Trial of Intravenously administered yttrium-90 chimeric T84.66 anti-CEA antibody in patients with metastatic CEA producing malignancies.  
44. Kalkwarf, D.R., et al., 1976 Hanford americium exposure incident: urinary excretion of trace metals during DTPA treatments. Health Phys, 1983. 45(4): p. 937-47.  
45. Education, O.R.I.f.S.a., *Calcium DTPA Informational Material Package Insert* 2002. 46. Dudley, H.R., et al., Pathologic changes associated with the use of sodium ethylene diamine tetra-acetate in the treatment of hypercalcemia; report of two cases with autopsy findings. N Engl J Med, 1955. 252(9): p. 331-7.  
47. Chag, C.C., et al., Karnofsky Performance Status Revisited: Reliability, Validity, and Guidelines. 1984. 2(3): p. 187-193.
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12 appendices

12.1 APPENDIX A:  WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF LYMPHOID
TUMORS.
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table 3 who classification of

Precursor B-cell neoplasm Precursor B-lymphoblastic leukemiallymphoma (precursor B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemialsmall lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (± villous lymphocytes)
Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma (± monocytoid B cells) Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphomas Primary effusion lymphoma.  
Burkitt lymphoma/Burkitt-like lymphoma T-cell and NK-cell neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic lymphomalleukemia (precursor T-cell acute lymphoblastic leukemia)
Mature (peripheral) T-cell neoplasms T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLY-I+)
Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic V 6 T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Anaplastic large cell lymphoma, T-/null-cell, primary cutaneous type Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, T-Inull-cell, primary systemic type Hodgkin lymphoma (Hodgkin disease)
Nodular lymphocyte-predominant Hodgkin lymphoma. Classic Hodgkin lymphomas Nodular sclerosis Hodgkin lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin lymphoma Mixed cellularity Hadgkin lymphoma Lymphocyte-depletion Hodgkin lymphoma Italic type denotes more common clinical entities. WHO = World Health Organization; MALT =
mucosa-associated lymphoid tissue; NK = natural killer; HTLV-I = human T-cell lymphotrophic
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12.3 appendix c ecog performance

| ECOG Performance Status Scale Grade Descriptions 0 Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous  1 activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all selfcare, but unable to carry out any work activities. Up and about  2 more than 50% of waking hours. 3 In bed >50% of the time. Capable of only limited self-care,  confined to bed or chair more than 50% of waking hours. 4 100% bedridden. Completely disabled. Cannot carry on any  self-care. Totally confined to bed or chair. 5 Dead.   |
|---|  
APPENDIX D:  ABNORMALITIES ENCOUNTERED IN MDS THAT CAN CONTRIBUTE TO THE
12.4 DIAGNOSIS
The diagnosis of Myelodysplasia will be made by an independent investigator of the Laboratory of Pathology, NCI taking into consideration the totality of the clinical, pathological, flow cytometric and cytogenetic information described below and present in a particular individual's evaluation  
| Blood findings                                                                                                                                                   | Bone marrow findings                                         |                                                                 |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|-----------------------------------------------------------------|
| Disease                                                                                                                                                          | Unicytopenia or bicytopenia'                                 | Unilineage dysplasia: ≥ 10% of the cells in one myeloid lineage |
| Refractory cytopenias with unilineage dysplasia (RCUD)                                                                                                           | No or rare blasts (<1%) 2                                    | <% blasts                                                       |
| Refractory anaemia (RA); Refractory neutropenia (RN);                                                                                                            | <15% of erythroid precursors are ring sideroblasts           |                                                                 |
| Refractory thrombocytopenia (RT)                                                                                                                                 | Anaemia                                                      | 215% of erythroid precursors are ring sideroblasts              |
| Refractory anaemia with ring sideroblasts (RARS)                                                                                                                 | No blasts                                                    | Erythroid dysplasia only                                        |
| <% blasts                                                                                                                                                        |                                                              |                                                                 |
| Cytopenia(s)                                                                                                                                                     | Dysplasia in ≥10% of the cells in ≥ two myeloid lineages     |                                                                 |
| Refractory cytopenia with multilineage dysplasia (RCMD)                                                                                                          | No or rare blasts (<1%) 2                                    | (neutrophil and/or erythroid precursors and/or megakaryocytes)  |
| <% blasts in marrow                                                                                                                                              |                                                              |                                                                 |
| No Auer rods                                                                                                                                                     |                                                              |                                                                 |
| <1x10%L monocytes                                                                                                                                                | No Auer rods                                                 |                                                                 |
| ±15% ring sideroblasts                                                                                                                                           |                                                              |                                                                 |
| Unilineage or multilineage dysplasia                                                                                                                             |                                                              |                                                                 |
| Refractory anaemia with excess blasts-1 (RAEB-1)                                                                                                                 | Cytopenia(s)                                                 |                                                                 |
| <5% blasts 2                                                                                                                                                     | 5-9% blasts 2                                                |                                                                 |
| No Auer rods                                                                                                                                                     | No Auer rods                                                 |                                                                 |
| <1x10 9 L monocytes                                                                                                                                              |                                                              |                                                                 |
| Cytopenia(s)                                                                                                                                                     | Unilineage or multilineage dysplasia                         |                                                                 |
| Refractory anaemia with excess blasts-2 (RAEB-2)                                                                                                                 | 5-19% blasts                                                 | 10-19% blasts                                                   |
| Auer rods ± 3                                                                                                                                                    |                                                              |                                                                 |
| Auer rods ± 3                                                                                                                                                    |                                                              |                                                                 |
| <1x10% monocytes                                                                                                                                                 | Unequivocal dysplasia in less than 10% of cells in one       |                                                                 |
| Myelodysplastic syndrome - unclassified (MDS-U)                                                                                                                  | Cylopenias                                                   |                                                                 |
| $1% blasts 2                                                                                                                                                     | or more myeloid cell lines when accompanied by a cytogenetic |                                                                 |
| abnormality considered as presumptive evidence for a diagnosis                                                                                                   |                                                              |                                                                 |
| of MDS (See Table 5.04)                                                                                                                                          |                                                              |                                                                 |
| <% blasts                                                                                                                                                        |                                                              |                                                                 |
| MS associated with isolated del(5q)                                                                                                                              | Anaemia                                                      | Normal to increased megakaryocytes with hypolobated nuclei      |
| < 5% blasts                                                                                                                                                      |                                                              |                                                                 |
| Usually normal or                                                                                                                                                |                                                              |                                                                 |
| increased platelet count                                                                                                                                         | Isolated del(5q) cytogenetic abnormality                     |                                                                 |
| No or rare blasts (<1%)                                                                                                                                          | No Auer rods                                                 |                                                                 |
| 1 Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.                                                               |                                                              |                                                                 |
| 3 If he marrow myeloblast percentage is <5% but there are 2-4% myeloblasts in the blood, the diagnostic classification is RAEB 1. Cases of RCUD and RCMD with 1% |                                                              |                                                                 |
| myeloblasts in the blood should be classified as MDS, U.                                                                                                         |                                                              |                                                                 |
| ³ Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB 2.                                                   |                                                              |                                                                 |  
The following is derived from the "WHO Classification of tumours of Haematopoietic and lymphoid tissues" 4th Edition. International Agency for Research on cancer  
  
  
uninucleate with lobulated nuclei)
Table 5.04 Recurring chromosomal abnormalities and their frequency in the myelodysplastic syndromes at diagnosis.  
|  Abnormality     |
|------------------|
| Unbalanced       |
| +8*              |
| -7 or del(7q)    |
| -5 or del(5q)    |
| del(20q)'        |
| -Y*              |
| i(17q) or t(17p) |
| -13 or del(13q)  |  
  
cytogenetic abnormality in the absence of morphologic criteria is not considered definitive evidence for MDS. In the setting of persistent cytopenias of undetermined origin, the other abnormalities shown are considered presumptive evidence of MDS in the absence of definitive morphologic features.  
90
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12.5 appendix e protocol for

Patients will undergo mobilization with filgrastim (Neupogen, Amgen) and plerixafor
(Mozobil, Genzyme). The filgrastim will be administered as a single daily dose in a dose range of 10-15.9 ug/kg/day subcutaneously for 5-6 days (see Table below for sliding-scale filgrastim dose schedule). The filgrastim doses for days 1-4 may be given between 8:00A.M. to 5:00 P.M. The filgrastim that is administered on day 5, and if necessary day 6, will be combined with a concurrent dose of plerixafor 240 mcg/kg subcutaneously. On days 5 and 6, both drugs must be given approximately six hours prior to starting apheresis. Predictable side effects of filgrastim, including headache, bone pain, and myalgia, will be treated as appropriate.
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filgrastim administration

Filgrastim will be administered according to a vial-based algorithm to reduce wastage and increase the total filgrastim dose given to lighter weight donors in order to improve CD34 yields.1  
  
CD34 cell yield per liter processed as a function of pre-apheresis CD34 cell count in 220 NMDP donors.  
1Vasu S, Leitman SF, Tisdale JF, et al. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. Blood 2008; 112:2092-100  
| Subject Weight   | Total Filgrastim Dose   | Dose /kg (range)      |                |
|------------------|-------------------------|-----------------------|----------------|
| 38 - 48 kg       | 600 mcg                 | (12.5 to 15.8 mcg/kg) |                |
| 49 - 56 kg       | 780 mcg                 | (13.9 to 15.9 mcg/kg) |                |
| 57 - 60 kg       | 900 mcg                 | (15.0 to 15.8 mcg/kg) |                |
| 61 - 67 kg       | 960 mcg                 | (14.3 to 15.7 mcg/kg) |                |
| 68 - 108 kg      | 1080 mcg                | (10.0 to 15.9 mcg/kg) |                |
| > 109 kg         |                         | 1200 mcg              | (11.0 or less) |
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plerixafor administration

| Subject Weight   | Total Plerixafor Dose                                 |
|------------------|-------------------------------------------------------|
| < 90 kg          | calculate dose at 240 mcg/kg                          |
| > 90 kg          | 24,000 mcg (flat dose, equal to one full 1.2-mL vial) |
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stem cell collection by apheresis

Peripheral blood stem cell (PBSC) collection will be performed in the Dowling Apheresis Clinic of the Department of Transfusion Medicine (DTM). A DTM physician is within the immediate vicinity of the procedure or available within one minute by pager. The minimum CD34 dose that must be collected in order to proceed with a single autologous transplantation is 2 x 106/kg. When feasible, based on the mobilization response of the donor, a higher dose of >4 x106 CD34 cells/kg will be targeted, to permit more than one cycle of high dose chemotherapy with autologous stem cell rescue. The volume processed per apheresis procedure will be determined by DTM medical staff on the day of apheresis, based on peak CD34 cell mobilization response to filgrastim and optimum and minimum CD34 cell dose needed (see graph below). Volume processed will range from 12 to 25 liters per procedure for 1 to 3 consecutive daily procedures, not to exceed a total of 75 liters over 3 days. Collections will be performed with use of a dual-access continuous-flow apheresis device (Spectra Apheresis System, Caridian). Most donors will require a central double lumen apheresis catheter. Donors will receive continuous intravenous calcium prophylaxis to prevent citrate toxicity during apheresis, in accordance with standard DTM policies.