Waldenström macroglobulinemia

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Untreated

BDR

BDR: Bortezomib, Dexamethasone, Rituximab

Regimen #1, Treon et al. 2009 (WMCTG 05-180)

Phase II

Treon et al. 2009 did not clearly indicate the schedule for bortezomib, but it is inferred that this is what was meant.

• Bortezomib (Velcade) 1.3 mg/m2 IV once on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg IV once on days 1, 4, 8, 11
• Rituximab (Rituxan) 375 mg/m2 IV once on day 11

Supportive medications:

• Valacyclovir (Valtrex) 1 g PO once per day or Acyclovir (Zovirax) 400 mg PO twice per day recommended for shingles prophylaxis
• "The use of diphenhydramine, acetaminophen and, at the treating physician's discretion, corticosteroids and/or ranitidine or cimetidine was permitted for rituximab infusion prophylaxis. Granulocyte colony-stimulating factor, erythropoietin, and transfusions of packed RBCs or platelets were permitted to support patient's counts during therapy."
• "The prophylactic use of plasmapheresis was recommended for patients demonstrating an IgM level of ≥ 5,000 mg/dL before the administration of rituximab, given the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity."

"four continuous cycles of BDR followed by a 12-week pause and then four additional cycles of BDR spaced 12 weeks apart" in hopes of reducing the incidence of peripheral neuropathy. The length of the initial cycles was not specified in the paper.

Regimen #2, Dimopoulos et al. 2013

Phase II

• Bortezomib (Velcade) 1.3 mg/m2 IV once on days 1, 4, 8, 11

21-day cycle, followed by:

• Bortezomib (Velcade) 1.6 mg/m2 IV once per week on days 1, 8, 15, 22
• Dexamethasone (Decadron) 40 mg IV once per week on days 1, 8, 15, 22, cycles 2 and 5 only
• Rituximab (Rituxan) 375 mg/m2 IV once per week on days 1, 8, 15, 22, cycles 2 and 5 only

Supportive medications:

• Acetaminophen (Tylenol) 1000 mg PO once prior to Rituximab (Rituxan) infusions
• Diphenhydramine (Benadryl) 50 mg IV once prior to Rituximab (Rituxan) infusions
  • Valacyclovir (Valtrex) dose not specified or Acyclovir (Zovirax) dose not specified mandated for VZV prophylaxis

21-day cycle x 4 cycles (5 cycles, overall)

References

1. Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, Willen M, Matous J, Mattern J 2nd, Diener JG, Keogh GP, Myers TJ, Boral A, Birner A, Esseltine DL, Ghobrial IM. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009 Aug 10;27(23):3830-5. Epub 2009 Jun 8. link to original article contains verified protocol PubMed content property of HemOnc.org
2. Dimopoulos MA, García-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Kastritis E, Sonneveld P. Primary therapy of Waldenstrom's macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone and rituximab (BDR): long term results of a phase II study of the European Myeloma Network (EMN). Blood. 2013 Sep 4. [Epub ahead of print] link to original article contains verified protocol PubMed

Bortezomib & Rituximab

Regimen, Ghobrial et al. 2010

Phase II

• Bortezomib (Velcade) 1.6 mg/m2 IV once per week on days 1, 8, 15
• Rituximab (Rituxan) 375 mg/m2 IV once per week on days 1, 8, 15, 22 of cycles 1 and 4 only

Supportive medications:

• "Antiviral prophylaxis was recommended in all patients prior to initiation of therapy and for 3 months after completion of the six cycles."

28-day cycles x up to 6 cycles

References

1. Ghobrial IM, Xie W, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Poon T, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am J Hematol. 2010 Sep;85(9):670-4. link to original article contains verified protocol PubMed

Chlorambucil (Leukeran)

Regimen, Leblond et al. 2012 (WM1)

Phase III

• Chlorambucil (Leukeran) 8 mg/m2 (6 mg/m2 if older than 75 years old) PO once per day on days 1 to 10

Supportive medications:

• Recommended PCP prophylaxis with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day
  • Pentamidine (Nebupent) 300 mg inhaled once per month

28-day cycles x up to 12 cycles

References

1. Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article contains verified protocol PubMed

Cladribine & Rituximab

Regimen, Laszlo et al. 2010

Phase II

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

Monthly cycles x 4 cycles

References

1. Laszlo D, Andreola G, Rigacci L, Fabbri A, Rabascio C, Mancuso P, Pruneri G, Radice D, Pinto A, Frigeri F, Calabrese L, Billio A, Bertolini F, Martinelli G. Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol. 2010 May 1;28(13):2233-8. Epub 2010 Apr 5. link to original article contains verified protocol PubMed

Dexamethasone, Rituximab, Cyclophosphamide (DRC)

Regimen, Dimopoulos et al 2007

Phase II

Note: The body text of Dimopoulos et al 2007 said that the regimen is given for "six courses," whereas the abstract says that it is given for 6 months."

• Dexamethasone (Decadron) 20 mg IV once on day 1, given first
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given after dexamethasone
• Cyclophosphamide (Cytoxan) 100 mg/m2 PO BID on days 1 to 5 (total dose per cycle: 1,000 mg/m2)

21-day cycles x 6 cycles

References

1. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, Repoussis P, Symeonidis A, Delimpasi S, Katodritou E, Vervessou E, Michali E, Pouli A, Gika D, Vassou A, Terpos E, Anagnostopoulos N, Economopoulos T, Pangalis G. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007 Aug 1;25(22):3344-9. link to original article contains verified protocol PubMed

Fludarabine (Fludara)

Regimen, Leblond et al. 2012 (WM1)

Phase III

• Fludarabine (Fludara) 40 mg/m2 (30 mg/m2 if older than 75 years old) PO once per day on days 1 to 5

Supportive medications:

• Recommended PCP prophylaxis with one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim SS) 1 tablet PO once per day
  • Pentamidine (Nebupent) 300 mg inhaled once per month
• Herpes zoster prophylaxis with one of the following:
  • Valacyclovir (Valtrex) 500 mg PO once per day
  • Acyclovir (Zovirax) 200 to 400 mg PO BID

28-day cycles x up to 6 cycles

References

1. Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013 Jan 20;31(3):301-7. Epub 2012 Dec 10. link to original article contains verified protocol PubMed

Relapsed/refractory

Bortezomib & Rituximab

Regimen, Ghobrial et al. 2010

Phase II

• Bortezomib (Velcade) 1.6 mg/m2 IV once per week on days 1, 8, 15
• Rituximab (Rituxan) 375 mg/m2 IV once per week on days 1, 8, 15, 22 of cycles 1 and 4 only

Supportive medications:

• "At the time of initiation of the study, the incidence of herpes zoster reactivation with bortezomib in WM was not well documented; therefore, antiviral prophylaxis was not mandated."

28-day cycles x up to 6 cycles

References

1. Ghobrial IM, Hong F, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1422-8. Epub 2010 Feb 8. link to original article contains verified protocol PubMed

BR

BR: Bendamustine, Rituximab

Regimen, Rummel et al. 2005

Phase II, <20 patients reported

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

Cycle 1 is started 7 days after the first dose of rituximab:

• Bendamustine (Treanda) 90 mg/m2 IV over 30 minutes once per day on days 1 & 2 of cycles 1 to 4
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycles 1 to 5

28-day cycles x 5 cycles

References

1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article contains protocol PubMed

Cladribine & Rituximab

Regimen, Laszlo et al. 2010

Phase II

• Cladribine (Leustatin) 0.1 mg/kg SC once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

Monthly cycles x 4 cycles

References

1. Laszlo D, Andreola G, Rigacci L, Fabbri A, Rabascio C, Mancuso P, Pruneri G, Radice D, Pinto A, Frigeri F, Calabrese L, Billio A, Bertolini F, Martinelli G. Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol. 2010 May 1;28(13):2233-8. Epub 2010 Apr 5. link to original article contains verified protocol PubMed

Everolimus

Regimen, Ghobrial et al. 2010

Phase II

• Everolimus (Afinitor) 10 mg PO once per day while fasting

Supportive medications:

• WBC growth factors per physician discretion if neutropenia occurred, but it was not to be used prophylactically in order to maintain dosing.
• Erythropoietin for anemia allowed per physician discretion.

28-day cycles, given until progression or unacceptable toxicity

References

1. Ghobrial IM, Gertz M, Laplant B, Camoriano J, Hayman S, Lacy M, Chuma S, Harris B, Leduc R, Rourke M, Ansell SM, Deangelo D, Dispenzieri A, Bergsagel L, Reeder C, Anderson KC, Richardson PG, Treon SP, Witzig TE. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1408-14. Epub 2010 Feb 8. link to original article contains verified protocol PubMed

Ibrutinib (Imbruvica)

Regimen, Treon et al. 2013

Phase II

• Ibrutinib (Imbruvica) 420 mg PO once per day for 2 years or until progresson or unacceptable toxicity.

References

1. Treon SP, Tripsas CK, Yang G, et al: A prospective multicenter study of the Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenstrom’s macroglobulinemia. 2013 ASH Annual Meeting link to abstract

Idelalisib (Zydelig)

Regimen, Gopal et al. 2014 (DELTA)

Phase II

• Idelalisib (Zydelig) 150 mg PO BID

Continued until progression, death, or unacceptable toxicity

References

1. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. N Engl J Med. 2014 Jan 22. link to original article contains verified protocol PubMed