Transplant conditioning regimens

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Autologous (auto) stem cell transplant

BEAC

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BEAC: BiCNU, Etoposide, Ara-C, Cyclophosphamide

Regimen

Phase III

Autologous blood stem cells are infused on day 0.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -7
• Etoposide (Vepesid) 800 mg/m2 IV once per day on days -6 to -3
• Cytarabine (Cytosar) 800 mg/m2 IV once per day on days -6 to -3
• Cyclophosphamide (Cytoxan) 35 mg/kg IV once per day on days -6 to -3

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day +1, continued until there are 3 consecutive days with ANC =1000
• Prophylaxis against opportunistic infections and management of febrile neutropenia per "active protocols"

References

1. Jo JC, Kang BW, Jang G, Sym SJ, Lee SS, Koo JE, Kim JW, Kim S, Huh J, Suh C. BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: comparative analysis of efficacy and toxicity. Ann Hematol. 2008 Jan;87(1):43-8. Epub 2007 Aug 21. link to original article contains protocol PubMed

BEAM

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BEAM: BiCNU, Etoposide, Ara-C, Melphalan

Regimen #1, Jo et al. 2008

Phase III

Autologous blood stem cells are infused on day 0.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
• Cytarabine (Cytosar) 400 mg/m2 IV once per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day +1, continued until there are 3 consecutive days with ANC =1000
• Prophylaxis against opportunistic infections and management of febrile neutropenia per "active protocols"

Regimen #2, Shimoni et al. 2012

Randomized Phase II, >20 per arm

Autologous blood stem cells are infused on day 0.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
• Cytarabine (Cytosar) 200 mg/m2 IV Q12H on days -5 to -2
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day +4 "until engraftment"
• Valacyclovir (Valtrex) (dose not specified) for one month
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months

Regimen #3, Stewart et al. 2006

Phase II

Autologous blood stem cells are infused on day 0.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 100 mg/m2 IV Q12H on days -5 to -2 (8 total doses)
• Cytarabine (Cytosar) 200 mg/m2 IV Q12H on days -5 to -2 (8 total doses)
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications:

• Patients <70 kg: Filgrastim (Neupogen) 300 mcg SC once per day starting on day +7 after stem cell transplant
• Patients >70 kg (reference did not clarify which dosage to use for patients who are exactly 70 kg): Filgrastim (Neupogen) 480 mcg SC once per day starting on day +7 after stem cell transplant
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID on Monday and Thursdays, until 6 months after BEAM

While ANC <500:

• Ciprofloxacin (Cipro) 500 mg PO BID
• Fluconazole (Diflucan) 100 mg PO once per day or mycostatin 500,000 units swish & swallow QID
• Acyclovir (Zovirax) 400 mg PO TID

Regimen #4, Josting et al. 2005

Phase II

Paper did not specify which day peripheral blood stem cells were administered.

• Carmustine (BiCNU) 300 mg/m2 IV once on day 1
• Etoposide (Vepesid) 150 mg/m2 IV Q12H on days 2 to 5 (8 total doses)
• Cytarabine (Cytosar) 200 mg/m2 IV Q12H on days 2 to 5 (8 total doses)
• Melphalan (Alkeran) 140 mg/m2 IV once on day 1

Regimen #5, Gisselbrecht et al. 2010

Non-randomized

This study randomized patients to R-ICE or R-DHAP, but all patients undergoing autologous transplant received BEAM

Autologous blood stem cells are infused on day 0, at least 24 hours after completion of BEAM.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
• Cytarabine (Cytosar) 200 mg/m2 IV once per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Regimen #6, Zinzani et al. 2003

Retrospective

• Carmustine (BiCNU) 300 mg/m2 IV once on day -7
• Etoposide (Vepesid) 200 mg/m2 IV BID on days -6 to -3
• Cytarabine (Cytosar) 200 mg/m2 IV BID on days -6 to -3
• Melphalan (Alkeran) 140 mg/m2 IV once on day -2

References

1. Retrospective: Zinzani PL, Tani M, Gabriele A, Gherlinzoni F, de Vivo A, Ricci P, Bandini G, Lemoli RM, Motta MR, Rizzi S, Giudice V, Zompatori M, Stefoni V, Alinari L, Musuraca G, Bassi S, Conte R, Pileri S, Tura S, Baccarani M. High-dose therapy with autologous transplantation for Hodgkin's disease: the Bologna experience. Haematologica. 2003 May;88(5):522-8. link to original article contains verified protocol PubMed
2. Zinzani PL, Tani M, Gabriele A, Gherlinzoni F, De Vivo A, Ricci P, Bandini G, Lemoli RM, Motta MR, Rizzi S, Guidice V, Zompatori M, Stefoni V, Alinari L, Musuraca G, Marchi E, Bassi S, Conte R, Pileri S, Tura S, Baccarani M. High-dose therapy with autologous transplantation for aggressive non-Hodgkin's lymphoma: the Bologna experience. Leuk Lymphoma. 2004 Feb;45(2):321-6. PubMed
3. Josting A, Sieniawski M, Glossmann JP, Staak O, Nogova L, Peters N, Mapara M, Dörken B, Ko Y, Metzner B, Kisro J, Diehl V, Engert A. High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study. Ann Oncol. 2005 Aug;16(8):1359-65. Epub 2005 Jun 6. link to original article contains protocol PubMed
4. Stewart DA, Bahlis N, Valentine K, Balogh A, Savoie L, Morris DG, Jones A, Brown C, Russell JA. Upfront double high-dose chemotherapy with DICEP followed by BEAM and autologous stem cell transplantation for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2006 Jun 15;107(12):4623-7. Epub 2006 Feb 7. link to original article contains protocol PubMed content property of HemOnc.org
5. Jo JC, Kang BW, Jang G, Sym SJ, Lee SS, Koo JE, Kim JW, Kim S, Huh J, Suh C. BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: comparative analysis of efficacy and toxicity. Ann Hematol. 2008 Jan;87(1):43-8. Epub 2007 Aug 21. link to original article contains protocol PubMed
6. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed
7. Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article PubMed

Bor-HDM

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Bor-HDM: Bortezomib, High Dose Melphalan

Regimen

Phase II

Autologous hematopoetic stem cell transplant on day 0.

• Bortezomib (Velcade) 1 mg/m2 IV once per day on days -6, -3, 1, 4
• Melphalan (Alkeran) 200 mg/m2 IV once on day -2

Supportive medications:

• "All patients received standard supportive care measures"

References

1. Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM). Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010 Jan 7;115(1):32-7. Epub 2009 Nov 2. link to original article contains verified protocol PubMed

Busulfan & Melphalan

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Regimen

Phase II

Day 0 is the day of transplantation.

• Busulfan (Myleran) 1 mg/kg PO q6h on days -6 to -4
• Melphalan (Alkeran) 70 mg/m2 IV bolus once per day on days -3 & -2

References

1. Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N; Japan Adult Leukemia Study Group. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood. 2013 Apr 18;121(16):3095-102. Epub 2013 Feb 14. link to original article Contains verified protocol PubMed

C-VAMP -> high-dose Melphalan (Alkeran)

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C-VAMP: Cyclophosphamide, Vincristine, Adriamycin, MethylPrednisolone

Regimen - multiple myeloma high-dose therapy

Phase III

Induction therapy

• Cyclophosphamide (Cytoxan) 500 mg IV once per day on days 1, 8, 15
  • Cyclophosphamide was omitted in patients with a serum creatinine >3.4 mg/dL
• Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4 (total dose per cycle: 1.6 mg)
• Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days (total dose per cycle: 36 mg/m2) on days 1 to 4
• Methylprednisolone (Solumedrol) 1000 mg/m2 (maximum dose per cycle of 1500 mg) PO/IV once per day on days 1 to 5

21-day cycles, given until maximal response was achieved. A minimum of 3 cycles given before stem cell harvest.

• Stem cell mobilization was performed with administration of Cyclophosphamide (Cytoxan) 2000 to 4000 mg/m2 IV with hydration and G-CSF on days 5 to 12

Melphalan (Alkeran) & transplant

• Melphalan (Alkeran) 200 mg/m2 IV (no additional details given)
• Peripheral blood stem cells infused on day 0, 24 hours after melphalan
• Methylprednisolone (Solumedrol) 1500 mg IV once per day on days 0 to 3

An alternative to the above melphalan option was:

• Bone marrow autograft
• Total body irradiation (TBI)
• Melphalan (Alkeran) 140 mg/m2 IV (no additional details given)
• Methylprednisolone (Solumedrol) 1500 mg IV once per day on days 0 to 3

Interferon alfa maintenance therapy

• Interferon alfa-2a (Roferon-A) 3 million units SC three times per week

References

1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article contains verified protocol PubMed

CBV

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CBV: Cyclophosphamide, BiCNU, VP-16

Regimen #1, Stiff et al. 1998; Damon et al. 2009

Phase II

• Carmustine (BiCNU) 15 mg/kg (maximum dose of 550 mg/m2) IV over 1 hour once on day -6
• Etoposide (Vepesid) 60 mg/kg IV over 4 hours once on day -4
• Cyclophosphamide (Cytoxan) 100 mg/kg IV over 2 hours once on day -2
• Autologous blood stem cells infused on day 0.

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day +4, to continue until ANC >5000 once or >1500 twice
• Levofloxacin (Levaquin) 500 mg PO once per day, starting on day +2, to continue until ANC =500
• Fluconazole (Diflucan) 200 mg PO once per day, starting on day +1, to continue until ANC =500
• Acyclovir (Zovirax) 200 mg PO TID, starting on day -2, to continue until 1 year after ASCT
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID on Saturday and Sunday, to continue until 3 months after ASCT

Regimen #2, Zinzani et al. 2003 (CVB)

• Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once per day on days -6 to -3
• Etoposide (Vepesid) 250 mg/m2 IV once per day on days -6 to -4
• Carmustine (BiCNU) 300 mg/m2 IV once on day -6

References

1. Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, Nademanee AP, Blume KG, LeBlanc M, Fisher RI. Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial. J Clin Oncol. 1998 Jan;16(1):48-55. link to original article contains verified protocol PubMed
2. Retrospective: Zinzani PL, Tani M, Gabriele A, Gherlinzoni F, de Vivo A, Ricci P, Bandini G, Lemoli RM, Motta MR, Rizzi S, Giudice V, Zompatori M, Stefoni V, Alinari L, Musuraca G, Bassi S, Conte R, Pileri S, Tura S, Baccarani M. High-dose therapy with autologous transplantation for Hodgkin's disease: the Bologna experience. Haematologica. 2003 May;88(5):522-8. link to original article contains verified protocol PubMed
3. Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. link to original article contains protocol PubMed

Cyclophosphamide (Cytoxan), Etoposide (Vepesid), TBI

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Regimen

Phase II

Autologous hematopoetic stem cell transplant on day 0.

• Cyclophosphamide (Cytoxan) 100 mg/kg IV over 1 to 2 hours once on day -2
• Etoposide (Vepesid) 60 mg/kg IV over 4 hours once on day -4
• Total body irradiation (TBI) with 150 cGy fractions given twice per day (fractions are at least 5 hours apart) x 8 fractions (total dose: 1200 cGy) over 4 days on days -8 to -5, with lung shielding for the final 600 Gy
  • Note: Table 1 of Stiff et al. 1998 lists the dosage of each fraction as being 120 cGy, in contrast to the body text under "treatment regimen" saying each fraction is 150 cGy. It is believed that the 150 cGy dose is correct since 8 fractions of this results in the correct total dose of 1200 cGy.

Supportive medications:

• Diphenhydramine (Benadryl) 25 mg (route not specified) once 2 hours before Etoposide (Vepesid) to prevent allergic reaction
• Hydrocortisone (Cortef) 100 mg (route not specified) once 2 hours before Etoposide (Vepesid) to prevent allergic reaction
• "Continuous bladder irrigation and vigorous hydration were used" to protect against hemorrhagic cystitis

References

1. Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, Nademanee AP, Blume KG, LeBlanc M, Fisher RI. Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial. J Clin Oncol. 1998 Jan;16(1):48-55. link to original article contains verified protocol PubMed

DHAP -> BEAC

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DHAP: Dexamethasone, High-dose Ara-C (cytarabine), cisPlatin
BEAC: BiCNU, Etoposide, Ara-C, Cyclophosphamide

Regimen, Velasquez, et al. 1988 (DHAP) & Philip, et al. 1991

Phase II

DHAP Induction Therapy

In Velasquez, et al. 1988, Ara-C/Cytarabine was originally administered "on the third day," but the regimen was subsequently modified so that it was given on day 2 after cisplatin.

• Dexamethasone (Decadron) 40 mg PO/IV over 15 minutes once per day on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours on day 2, starting when cisplatin infusion is complete; a second dose of Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours is given after the first one
• Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours on day 1, starting after 6 hours of prehydration

Supportive Medications:

• Normal saline solution with mannitol, 50 g/L, at 250 mL/hour IV over 36 hours starting on day 1 prior to cisplatin
• Metoclopramide (Reglan) 1 mg/kg "given routinely as antiemetics"
• Diphenhydramine (Benadryl) 25 mg IV "given routinely as antiemetics"

21 to 28 day cycles, depending on degree of myelosuppression, for a total of 2 cycles as follows: After 1 course of DHAP, if they did not have "clearly progressive disease," patients underwent bone marrow harvest. A second course of DHAP was administered starting 1 day after bone marrow harvest. At day 20 after the second course of DHAP, patients were restaged. Patients who showed a response and had bulky disease at initial relapse then started involved field radiotherapy on day 20 after the second course of DHAP for 5 days per week x 2 weeks. In the original Velasquez, et al. 1988 paper where DHAP was used on its own, treatment continued for 6 to 10 cycles in patient who responded to treatment.

BEAC conditioning & transplant

BEAC starts on day 35 after the second course of DHAP. Autologous blood stem cells are infused on day 0.

• Carmustine (BiCNU) 300 mg/m2 IV over 30 minutes once on day -13
• Etoposide (Vepesid) 100 mg/m2 IV twice per day on days -12 to -7
• Cytarabine (Cytosar) 100 mg/m2 IV twice per day on days -12 to -9
• Cyclophosphamide (Cytoxan) 35 mg/kg IV over 60 minutes once per day on days -12 to -9
• Mesna (Mesnex) 50 mg/kg IV every day on days -12 to -9 (optional)

References

1. DHAP portion: Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22. link to original article contains verified protocol PubMed
2. BEAC portion: Philip T, Chauvin F, Armitage J, Bron D, Hagenbeek A, Biron P, Spitzer G, Velasquez W, Weisenburger DD, Fernandez-Ranada J, et al. Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation. Blood. 1991 Apr 1;77(7):1587-92. link to original article contains verified protocol PubMed

High-dose Melphalan (Alkeran)

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Regimen - immunoglobulin light-chain (AL) amyloidosis

Phase II

Eligibility criteria: Biopsy-proven amyloid disease and =1 major organ involved, evidence of plasma cell dyscrasia, no heart failure or arrhythmia that cannot be medically managed, cardiac ejection fraction =40%, no pleural effusions, supine systolic blood pressure =90 mmHg, O2 saturation =95% on room air, lung diffusing capacity =50% predicted, SWOG performance status =2 unless due to neuropathy.

• Patients who fulfilled all of these criteria--=65 years old, cardiac ejection fraction =45%, and =2.5 x 10⁶ CD34+ cells/kg collected--received Melphalan (Alkeran) 200 mg/m2 total dose IV divided over two consecutive days
• Patients with at least one of these criteria-->65 years old, cardiac ejection fraction 40-44%, or with 2.0-2.5 x 10⁶ CD34+ cells/kg collected received Melphalan (Alkeran) 140 mg/m2 total dose IV divided over two consecutive days
• Autologous stem cell infusion occurs 24 to 72 hours after the last dose of melphalan

References

1. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. link to original article contains verified protocol PubMed

TAM6

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Regimen

Phase II

• Total body irradiation (TBI) with a total dose of 10 Gy over 3 days using twice per day fractions
• Cytarabine (Cytosar) 1500 mg/m2 IV Q12H x 2 days (total of 4 total doses)
• Melphalan (Alkeran) 140 mg/m2 IV

Peripheral stem cells are infused on day 0

Supportive medications: "Antimicrobial prophylaxis and use of G-CSF or erythropoietin were permitted according to physician decision."

References

1. Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; for the Groupe d'Etude des Lymphomes de l'Adulte (GELA). CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. link to original article contains verified protocol PubMed

V-BEAM

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V-BEAM: Velcade, BiCNU, Etoposide, Ara-C, Melphalan

Regimen, William et al. 2014

Phase II

Full details not available in abstract; to be added later.

• Bortezomib (Velcade) on days -11, -8, -5, -2
• Carmustine (BiCNU)
• Etoposide (Vepesid)
• Cytarabine (Cytosar)
• Melphalan (Alkeran)

References

1. William BM, Allen MS, Loberiza FR Jr, Bociek RG, Bierman PJ, Armitage JO, Vose JM. Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell transplantation for relapsed indolent non-Hodgkin lymphoma, transformed, or mantle cell lymphoma. Biol Blood Marrow Transplant. 2014 Apr;20(4):536-42. Epub 2014 Jan 14. link to original article PubMed

VMCP & BVAP -> high-dose Melphalan (Alkeran)

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VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone
BVAP: BiCNU, Vincristine, Adriamycin, Prednisone

Regimen - multiple myeloma high-dose therapy

Phase III

VMCP induction therapy

• Vincristine (Oncovin) 1 mg IV once on day 1
• Melphalan (Alkeran) 5 mg/m2 PO once per day on days 1 to 4
• Cyclophosphamide (Cytoxan) 110 mg/m2 PO once per day on days 1 to 4
• Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4

21-day cycles x 2 to 3 cycles, given in an alternating fashion with BVAP

BVAP induction therapy

• Vincristine (Oncovin) 1 mg IV once on day 1
• Carmustine (BiCNU) 30 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
• Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4

21-day cycles x 2 to 3 cycles, given in an alternating fashion with VMCP

VMCP and BVAP are given in an alternating fashion x a total of 4 to 6 cycles; patients with a WHO performance status <3, creatinine <1.7 mg/dL (150 µmol/L), and bone marrow (collected after cycle 4) with greater than 200 million nucleated cells/kg would proceed to melphalan, total body irradiation (TBI), and transplant:

Melphalan (Alkeran), TBI, and transplant

• Melphalan (Alkeran) 140 mg/m2 IV (no other details given about its administration)
• Total body irradiation (TBI) with a total dose of 8 Gy given over 4 days in 4 fractions, without lung shielding
• Autologous hematopoietic stem cell transplant after melphalan and TBI
• Interferon alfa treatment started after transplant when ANC >1500/mm3 and platelets >75,000/mm3

References

1. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article contains verified protocol PubMed

Z-BEAM

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Z-BEAM: Zevalin, BiCNU, Etoposide, Ara-C, Melphalan

Regimen, Shimoni et al. 2012

Randomized Phase II, >20 per arm

Autologous blood stem cells are infused on day 0.

• Rituximab (Rituxan) 250 mg/m2 IV once on day -14
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.5 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given after Rituximab (Rituxan)
• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
• Cytarabine (Cytosar) 200 mg/m2 IV Q12H on days -5 to -2
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day +4 "until engraftment"
• Valacyclovir (Valtrex) (dose not specified) for one month
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months

References

1. Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article PubMed
2. Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernsández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2013 Oct 25. [Epub ahead of print] link to original article PubMed

Allogeneic (allo) stem cell transplant

BEAM

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BEAM: BiCNU, Etoposide, Ara-C, Melphalan

Regimen

Phase II

Day 0 is the day of transplantation.

• Carmustine (BiCNU) 300 mg/m2 IV once on day -6
• Etoposide (Vepesid) 200 mg/m2 IV BID on days -5 to -2
• Cytarabine (Cytosar) 200 mg/m2 IV BID on days -5 to -2
• Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +7 and continued until engraftment
• GVHD prophylaxis with Tacrolimus (Prograf) and Methotrexate (MTX)
• "Prophylactic antibiotics"

References

1. Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. link to original article contains protocol PubMed

BFR

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BFR: Bendamustine, Fludarabine, Rituximab

Regimen, Khouri et al. 2014

Phase II

Day 0 is the day of transplantation.

• Bendamustine (Treanda) 130 mg/m2 IV over 60 minutes once per day on days -5 to -3
• Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days -5 to -3
• Rituximab (Rituxan) (for "those with B-cell disease") 375 mg/m2 IV once on days -13, -6, +1, +8
• See article for GVHD prophylaxis information

References

1. Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. link to original article contains verified protocol PubMed

Busulfan & Cyclophosphamide (BuCy)

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Regimen #1, Lee et al. 2013

Phase III

Day 0 is the day of transplantation.

• Busulfan (Myleran) 3.2 mg/kg IV once per day on days -7 to -4
• Cyclophosphamide (Cytoxan) 60 mg/kg IV once on days -3 and -2

Supportive medications:

• "Cyclosporine alone or cyclosporine plus methotrexate according to the discretion of the attending physician"
• Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC >3,000

Regimen #2, Copelan et al. 2013

Retrospective

This was a retrospective study from CIBMTR data; regimen and supportive medication details vary.

• Busulfan (Myleran)
• Cyclophosphamide (Cytoxan)

References

1. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains verified protocol PubMed
2. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. link to original article PubMed

Busulfan & Fludarabine (Flu/Bu; BuFlu)

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Regimen #1, Russell et al. 2002 (Flu/Bu)

Phase II

Day 0 is the day of transplantation.

• Fludarabine (Fludara) 50 mg/m2 IV once per day on days -6 to -2
• Busulfan (Myleran) 3.2 mg/kg (ideal body weight) IV once per day over 3 hours on days -5 to -2

Supportive medications:

• Phenytoin (Dilantin) "loading" PO/IV, dosed to maintain therapeutic levels of 40 to 80 umol/L on days -5 to -2
• Ciprofloxacin (Cipro) 500 mg PO BID as prophylaxis
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (dose not specified in reference, but assume 160/800 mg dose) PO 2 times a week as PCP prophylaxis
• No routine fungal prophylaxis
• No routine use of growth factors
• CMV negative blood

Acute GVHD prophylaxis:

• Antithymocyte globulin (Thymoglobulin, rabbit ATG) 0.5 mg/kg IV once on day -2; 2 mg/kg/day IV once on days -1 and 0 (total dose of 4.5 mg/kg)
• Cyclosporine modified (Neoral) or Cyclosporine non-modified (Sandimmune) PO/IV BID, with doses adjusted to maintain cyclosporine levels of 150 to 400 umol/L
• Methotrexate (MTX) 15 mg/m2 once on day 1; 10 mg/m2 once per day on days 3, 6, 11
• Folinic acid (Leucovorin) 5 mg started 24 hours after each dose of Methotrexate (MTX) and continued Q6H until 12 hours before the next dose of Methotrexate (MTX)

Regimen #2, Lee et al. 2013 (BuFlu)

Phase III

Day 0 is the day of transplantation.

• Busulfan (Myleran) 3.2 mg/kg IV once per day on days -7 to -4
• Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2

Supportive medications:

• "Cyclosporine alone or with methotrexate according to the discretion of the attending physician"
• Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC >3,000

References

1. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, Stewart D, Ruether JD, Morris D, Glick S, Gyonyor E, Andersson BS. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8(9):468-76. link to original article contains verified protocol PubMed
2. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, Lee JH, Lee WS, Park JH, Bae SH, Hyun MS, Kim DY, Kim SD, Min YJ, Lee KH. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013 Feb 20;31(6):701-9. Epub 2012 Nov 5. link to original article contains verified protocol PubMed

Cyclophosphamide and TBI

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Regimen, Copelan et al. 2013

Retrospective

This was a retrospective study from CIBMTR data; regimen and supportive medication details vary.

• Cyclophosphamide (Cytoxan)
• Total body irradiation (TBI)

References

1. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, Aljurf M, van Besien K, Bredeson C, Cahn JY, Costa LJ, de Lima M, Gale RP, Hale GA, Halter J, Hamadani M, Inamoto Y, Kamble RT, Litzow MR, Loren AW, Marks DI, Olavarria E, Roy V, Sabloff M, Savani BN, Seftel M, Schouten HC, Ustun C, Waller EK, Weisdorf DJ, Wirk B, Horowitz MM, Arora M, Szer J, Cortes J, Kalaycio ME, Maziarz RT, Saber W. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013 Dec 5;122(24):3863-70. Epub 2013 Sep 24. link to original article PubMed

Fludarabine and Low-dose TBI

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Regimen

Phase III

Day 0 is the day of transplantation.

• Fludarabine (Fludara) 30 mg/m2 IV once per day on days -4 to -2
• Total body irradiation (TBI) 2 Gy at a rate of 0.07 to 0.20 Gy/min on day 0

Supportive medications for GVHD prophylaxis:

• "Postgrafting immunosuppression consisted of cyclosporine or tacrolimus combined with mycophenolate mofetil," further details not specified

References

1. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, Langston AA, Pulsipher MA, Bredeson CN, Maziarz RT, Bruno B, Petersen FB, Maris MB, Agura E, Yeager A, Bethge W, Sahebi F, Appelbaum FR, Maloney DG, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010 Jun 10;28(17):2859-67. Epub 2010 May 3. link to original article contains verified protocol PubMed

Fludarabine, Busulfan, Cyclophosphamide

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Regimen, Glass et al. 2014 (DSHNHL R3)

Nonrandomized

This is described by the authors as a lymphoma-directed myeloablative conditioning regimen

Conditioning

• Fludarabine (Fludara) 25 mg/m2/day IV on days -8 to -4
• Busulfan (Myleran) 4 mg/kg/day PO or 3.2 mg/kg/day IV on days -6 to -4
• Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Day 0 is the day of transplantation

GVHD prophylaxis

• Tacrolimus (Prograf) 8 to 12 µg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
• Mycophenolate mofetil (CellCept) 1000 mg (route not specified) BID from day +1 to +28
• Antithymocyte globulin (Thymoglobulin, rabbit ATG) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose; option also to use ATG-Fresenius S at a higher dose of 10 mg/kg)

References

1. Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; on behalf of the German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 May 9. [Epub ahead of print] link to original article link to original protocol (in German) contains verified protocol PubMed

Fludarabine, Cyclophosphamide, & TBI for dUCB or haploidentical transplant

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dUCB: double Umbilical Cord Blood

Regimen #1, Brunstein et al. 2011 - dUCB transplantation

Phase II

Day 0 is the day of transplantation.

• Fludarabine (Fludara) 40 mg/m2 IV once per day on days -6 to -2 (total dose: 200 mg/m2)
• Cyclophosphamide (Cytoxan) 50 mg/kg IV once on day -6
• Total body irradiation (TBI) 2 Gy once on day -1

Supportive medications:

• Mesna (Mesnex) (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
• Filgrastim (Neupogen) 5 µg/kg SC once per day, starting on day +1, continued until ANC =2000/µL for 3 consecutive days

GVHD Prophylaxis

• Mycophenolate mofetil (CellCept) 1000 mg (route not specified) Q8H for patients >50 kg, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
  • Patients <50 kg received Mycophenolate mofetil (CellCept) 15 mg/kg (route not specified) Q8H, starting on day -3 "and continuing until day +30 or 7 days after engraftment, whichever was later"
• Cyclosporine A (Neoral vs. Sandimmune not specified, route not specified) with a goal trough of 200 to 400 ng/mL (starting date not specified) until day +100. Patients without GVHD had their dose tapered by 10% each week starting on day +101, with discontinuation of cyclosporine A around day +180 to +200.
• Tacrolimus (Prograf) (route not specified) with a goal trough level of 5 to 10 ng/mL could be substituted for cyclosporine.

Regimen #2, Brunstein et al. 2011 - Haploidentical

Phase II

Day 0 is the day of transplantation.

• Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2 (total dose: 150 mg/m2)
• Cyclophosphamide (Cytoxan) 14.5 mg/kg IV once on days -6 and -5
• Total body irradiation (TBI) 2 Gy once on day -1

Supportive medications:

• Mesna (Mesnex) (dose/route/schedule not specified) and "vigorous IV hydration for uroprotection."
• Filgrastim (Neupogen) 5 µg/kg SC once per day, starting on day +5, continued until ANC =1000/µL for 3 consecutive days

GVHD Prophylaxis

• Cyclophosphamide (Cytoxan) 50 mg/kg IBW IV over 1 to 2 hours once per day on days +3 (60 to 72 hours after marrow infusion) and +4
• Mycophenolate mofetil (CellCept) 15 mg/kg (maximum daily dose of 3000 mg; route not specified) Q8H, starting on day +5, continued until day +35 or longer at physician discretion if active GVHD was present
• Tacrolimus (Prograf) (route not specified) with a goal trough level of 5 to 10 ng/mL, starting on day +5, continued until day +180

References

1. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV;Blood and Marrow Transplant Clinical Trials Network. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-8. link to original article contains verified protocol PubMed