Waldenström macroglobulinemia

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Untreated

BDR

BDR: Bortezomib, Dexamethasone, Rituximab

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

Level of Evidence: 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 per day on days 1, 4, 8, 11
• Dexamethasone (Decadron) 40 mg IV once per day on days 1, 4, 8, 11
• Rituximab (Rituxan) 375 mg/m2 IV once on day 11

"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.

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."

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. doi: 10.1200/JCO.2008.20.4677. Epub 2009 Jun 8. link to original article contains verified protocol PubMed

Bortezomib & Rituximab

Regimen, Ghobrial et al. 2010

Level of Evidence: Phase II

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

28-day cycles x up to 6 cycles

Supportive medications:

• "Antiviral prophylaxis was recommended in all patients prior to initiation of therapy and for 3 months after completion of the six 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. doi: 10.1002/ajh.21788. link to original article contains verified protocol PubMed

Chlorambucil (Leukeran)

Regimen, Leblond et al. 2013

Level of Evidence: Phase III

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

28-day cycles x up to 12 cycles

Supportive medications:

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

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

Level of Evidence: Phase II

• Cladribine (Leustatin) 0.1 mg/kg SC once daily 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

Fludarabine (Fludara)

Regimen

Level of Evidence: Phase III

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

28-day cycles x up to 6 cycles

Supportive medications:

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

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. doi:10.1200/JCO.2012.44.7920. Epub 2012 Dec 10. link to original article contains verified protocol PubMed

Relapsed/refractory

Bortezomib & Rituximab

Regimen, Ghobrial et al. 2010

Level of Evidence: Phase II

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

28-day cycles x up to 6 cycles

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."

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. doi: 10.1200/JCO.2009.25.3237. Epub 2010 Feb 8. link to original article contains verified protocol PubMed

BR

BR: Bendamustine, Rituximab

Regimen, Rummel et al. 2005

Level of Evidence: 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 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

Level of Evidence: Phase II

• Cladribine (Leustatin) 0.1 mg/kg SC once daily 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

Level of Evidence: Phase II

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

28-day cycles, given until progression or unacceptable toxicity

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.

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. doi:10.1200/JCO.2009.24.0994. Epub 2010 Feb 8. link to original article contains verified protocol PubMed

Panobinostat

Regimen, Ghobrial et al. 2013

Level of Evidence: Phase II

• Panobinostat (LBH589) 30 mg PO 3 days per week (Mondays, Wednesdays, and Fridays)

28-day cycles, given until progression of disease

References

1. Ghobrial IM, Campigotto F, Murphy TJ, Boswell EN, Banwait R, Azab F, Chuma S, Kunsman J, Donovan A, Masood F, Warren D, Rodig S, Anderson KC, Richardson PG, Weller E, Matous J. Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenstrom macroglobulinemia. Blood. 2013 Feb 21;121(8):1296-303. doi:10.1182/blood-2012-06-439307. Epub 2013 Jan 3. link to original article contains verified protocol PubMed