Chronic myeloid leukemia - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? See the main CML page for current regimens.

8 regimens on this page 8 variants on this page

Chronic phase, first-line therapy

Busulfan monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Galton 1953	1951	Case series
Tura et al. 1994 (MI400)	1986-1988	Phase 3 (C)	Interferon alfa-2a	Inferior OS
Allan et al. 1995	1986-1994	Phase 3 (C)	Interferon alfa-n1	Inferior OS

Chemotherapy

• Busulfan (Myleran) 4 mg PO once per day

Continued indefinitely

References

1. Galton DA. Myleran in chronic myeloid leukaemia; results of treatment. Lancet. 1953 Jan 31;264(6753):208-13. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. MI400: Tura S, Baccarani M, Zuffa E, Russo D, Fanin R, Zaccaria A, Fiacchini M; Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994 Mar 24;330(12):820-5. link to original article PubMed
3. Allan NC, Richards SM, Shepherd PC; UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. Lancet. 1995 Jun 3;345(8962):1392-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Hydroxyurea monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tura et al. 1994 (MI400)	1986-1988	Phase 3 (C)	Interferon alfa-2a	Inferior OS
Allan et al. 1995	1986-1994	Phase 3 (C)	Interferon alfa-n1	Inferior OS
Hehlmann et al. 2003 (CML-Study II)	1991-1994	Phase 3 (C)	Hydroxyurea & Interferon alfa-2a	Inferior OS

Chemotherapy

• Hydroxyurea (Hydrea) by the following weight-based criteria:
  • 70 kg or less: 1500 mg/day PO
  • More than 70 kg: 2000 mg/day PO

Continued indefinitely

Dose and schedule modifications

• Physicians were "free to adjust the dose" to achieve leukocyte counts between 5 to 20 x 10⁹/L, "preferably in the lower part of this range"

References

1. MI400: Tura S, Baccarani M, Zuffa E, Russo D, Fanin R, Zaccaria A, Fiacchini M; Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994 Mar 24;330(12):820-5. link to original article PubMed
2. Allan NC, Richards SM, Shepherd PC; UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. Lancet. 1995 Jun 3;345(8962):1392-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. CML-Study II: Hehlmann R, Berger U, Pfirrmann M, Hochhaus A, Metzgeroth G, Maywald O, Hasford J, Reiter A, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Griesshammer M, Nerl C, Kuse R, Tobler A, Eimermacher H, Tichelli A, Aul C, Wilhelm M, Fischer JT, Perker M, Scheid C, Schenk M, Weiss J, Meier CR, Kremers S, Labedzki L, Schmeiser T, Lohrmann HP, Heimpel H; German CML Study Group. Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea. Leukemia. 2003 Aug;17(8):1529-37. link to original article PubMed

Hydroxyurea & Interferon alfa-2a

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hehlmann et al. 2003 (CML-Study II)	1991-1994	Phase 3 (E-esc)	Hydroxyurea	Superior OS
Hehlmann et al. 2007 (CML-Study III)	1995-2001	Phase 3 (E-de-esc)	Allo HSCT (no specific conditioning regimen)	Seems to have superior OS (primary endpoint)
Gratwohl et al. 2015 (CML-Study IIIA)	1997-2004	Phase 3 (C)	Allo HSCT (no specific conditioning regimen)	Did not meet primary endpoint of OS

Note: One of the few regimens compared in large RCTs against allogeneic HSCT.

Chemotherapy

• Hydroxyurea (Hydrea)

Immunotherapy

• Interferon alfa-2a (Roferon-A)

References

1. CML-Study II: Hehlmann R, Berger U, Pfirrmann M, Hochhaus A, Metzgeroth G, Maywald O, Hasford J, Reiter A, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Griesshammer M, Nerl C, Kuse R, Tobler A, Eimermacher H, Tichelli A, Aul C, Wilhelm M, Fischer JT, Perker M, Scheid C, Schenk M, Weiss J, Meier CR, Kremers S, Labedzki L, Schmeiser T, Lohrmann HP, Heimpel H; German CML Study Group. Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea. Leukemia. 2003 Aug;17(8):1529-37. link to original article PubMed
2. CML-Study III: Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, Kolb HJ, Lahaye T, Maywald O, Reiter A, Hossfeld DK, Huber C, Löffler H, Pralle H, Queisser W, Tobler A, Nerl C, Solenthaler M, Goebeler ME, Griesshammer M, Fischer T, Kremers S, Eimermacher H, Pfreundschuh M, Hirschmann WD, Lechner K, Wassmann B, Falge C, Kirchner HH, Gratwohl A. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007 Jun 1;109(11):4686-92. Epub 2007 Feb 22. link to original article does not contain dosing details PubMed NCT00002771
3. CML-Study IIIA: Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, Nerl C, Scheid C, Spiekermann K, Mayer J, Sayer HG, Falge C, Bunjes D, Döhner H, Ganser A, Schmidt-Wolf I, Schwerdtfeger R, Baurmann H, Kuse R, Schmitz N, Wehmeier A, Fischer JT, Ho AD, Wilhelm M, Goebeler ME, Lindemann HW, Bormann M, Hertenstein B, Schlimok G, Baerlocher GM, Aul C, Pfreundschuh M, Fabian M, Staib P, Edinger M, Schatz M, Fauser A, Arnold R, Kindler T, Wulf G, Rosselet A, Hellmann A, Schäfer E, Prümmer O, Schenk M, Hasford J, Heimpel H, Hossfeld DK, Kolb HJ, Büsche G, Haferlach C, Schnittger S, Müller MC, Reiter A, Berger U, Saußele S, Hochhaus A, Hehlmann R; SAKK; German CML Study Group. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016 Mar;30(3):562-9. Epub 2015 Oct 14. link to original article does not contain dosing details link to PMC article PubMed NCT00025402

Interferon alfa monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hehlmann et al. 1994	1983-1991	Phase 3 (E-switch-ooc)	1. Busulfan	Superior OS
			2. Hydrea	Did not meet primary endpoint of OS

Note: This article does not specify the exact type of interferon alfa.

Immunotherapy

• Interferon alfa

Continued indefinitely

References

1. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queisser W, Löffler H, Hochhaus A, Heinze B, Georgii A, Bartram CR, Griesshammer M, Bergmann L, Essers U, Falge C, Queisser U, Meyer P, Schmitz N, Eimermacher H, Walther F, Fett W, Kleeberg UR, Kabisch A, Nerl C, Zimmermann R, Meuret G, Tichelli A, Kanz L, Tigges FJ, Schmid L, Brockhaus W, Tobler A, Reiter A, Perker M, Emmerich B, Verpoort K, Zankovich R, Wussow PV, Prummer O, Thiele J, Buhr T, Carbonell F, Ansari H; German CML Study Group. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood. 1994 Dec 15;84(12):4064-77. link to original article PubMed

Chronic phase, relapsed or refractory

Busulfan monotherapy

Regimen

Study	Dates of enrollment	Evidence
Schilling & Meyer 1956	Not reported	Non-randomized, fewer than 20 pts
Unugur et al. 1957	1953-10 to 1956-01	Non-randomized

Chemotherapy

• Busulfan (Myleran)

References

1. Schilling RF, Meyer OO. Treatment of chronic granulocytic leukemia with 1, 4-dimethanesulfonyloxybutane (Myleran). N Engl J Med. 1956 May 24;254(21):986-9. link to original article PubMed
2. Unugur A, Schulman E, Dameshek W. Treatment of chronic granulocytic leukemia with Myleran. N Engl J Med. 1957 Apr 18;256(16):727-34. link to original article PubMed

Interferon alfa-2b & DLI

DLI: Donor Lymphocyte Infusion

Regimen

Study	Dates of enrollment	Evidence
Porter et al. 1994	Not reported	Non-randomized, fewer than 20 pts

Note: Patients had relapsed after allogeneic HSCT

Immunotherapy

• Interferon alfa-2b (Intron-A)
• DLI

References

1. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994 Jan 13;330(2):100-6. link to original article PubMed

Blast crisis

Hydroxyurea & Plicamycin

Regimen

Study	Dates of enrollment	Evidence
Koller & Miller 1986	Not reported	Pilot, fewer than 20 pts (RT)

Chemotherapy

• Hydroxyurea (Hydrea) by the following laboratory-based criteria:
  • WBC count more than 100 x 10⁹/L: 4000 mg/day PO
  • WBC count more than 75 x 10⁹/L up to 100 x 10⁹/L: 3000 mg/day PO
  • WBC count more than 50 x 10⁹/L up to 75 x 10⁹/L: 2000 mg/day PO
  • WBC count more than 30 x 10⁹/L up to 50 x 10⁹/L: 1500 mg/day PO
  • WBC count more than 15 x 10⁹/L up to 30 x 10⁹/L: 1000 mg/day PO
  • WBC count more than 7.5 x 10⁹/L up to 15 x 10⁹/L: 500 mg/day PO
• Plicamycin (Mithracin) 25 mcg/kg IV over 2 to 4 hours once per day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27

21-day course

References

1. Koller CA, Miller DM. Preliminary observations on the therapy of the myeloid blast phase of chronic granulocytic leukemia with plicamycin and hydroxyurea. N Engl J Med. 1986 Dec 4;315(23):1433-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Vincristine & Prednisone

Regimen

Study	Dates of enrollment	Evidence
Marks et al. 1978	Not reported	Non-randomized

Chemotherapy

• Vincristine (Oncovin) 2 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 7

7-day cycles

References

1. Marks SM, Baltimore D, McCaffrey R. Terminal transferase as a predictor of initial responsiveness to vincristine and prednisone in blastic chronic myelogenous leukemia: a co-operative study. N Engl J Med. 1978 Apr 13;298(15):812-4. link to original article dosing details in manuscript have been reviewed by our editors PubMed