Waldenstrom's Macroglobulinemia/ Lymphoplasmacytic Lymphoma Treatment Regimens

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WALDENSTROM MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA TREATMENT REGIMENS

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma cancer treatment regimens are only provided to supplement the latest treatment strategies.

These Cancer Treatment Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

(Revised 6/2016)

© 2016 by Haymarket Media, Inc.

Systemic Therapy for Waldenstrom Macroglobulinemia

Note: All recommendations are Category 2A unless otherwise indicated.

Primary Therapy—Non-Stem Cell Toxic1

REGIMEN

DOSING

Bortezomib ± rituximab2a,b,c,d

Days 1, 8, and 15: Bortezomib 1.6mg/m2 IV, ±

Days 1, 8, 15, and 22 on cycles 1 and 4: Rituximab 375mg/m2 IV.

Repeat every 28 days for 6 cycles.

Bortezomib + dexamethasone3c,d

Days 1, 4, 8, and 11: Bortezomib 1.3mg/m2 IV

Days 1, 4, 8, and 11: Dexamethasone 40mg IV.

Repeat for 4 consecutive cycles as induction therapy and follow with 4 maintenance cycles, each given 3 months apart.

Bortezomib + dexamethasone + rituximab3,4a,b,c,d

Days 1, 4, 8, and 11: Bortezomib 1.3mg/m2 IV

Day 11: Rituximab 375mg/m2 IV

Days 1, 4, 8, and 11: Dexamethasone 40mg IV.

Repeat for 4 consecutive cycles as induction therapy and follow with 4 maintenance cycles, each given 3 months apart.

CaRD (Carfilzomib + rituximab + dexamethasone)5,6a,c,e

Induction:

Days 1, 2, 8, 9, 15, and 16: Carfilzomib 20mg/m2 20-minute IV infusion (cycle 1), then 36mg/m2 30-minute IV infusion (cycles 2–6)

Days 1, 2, 8, and 9: Dexamethasone 20mg IV

Days 2 and 9: Rituximab 375mg/m2

Maintenance:

Days 1, 2, 8, 9, 15, and 16: Carfilzomib 36mg/m2 IV

Days 1 and 2: Dexamethasone 20mg IV

Day 2: Rituximab 375mg/m2.

Repeat every 21 days for 6 induction cycles, then 8 weeks later, begin maintenance every 8 weeks for 8 cycles.

Cyclophosphamide + doxorubicin + vincristine + prednisone + rituximab7,8a,d,f

Day 1: Cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV + vincristine 1.4mg/m2 (max 2mg) IV + rituximab 375mg/m2 IV

Days 1–5: Prednisone 100mg orally.

Repeat every 3 weeks for 6 cycles.

Ibrutinib9g

Ibrutinib 420mg orally once daily.

Continue treatment until disease progression or unacceptable toxicity.

Rituximab10a

Day 1: Rituximab 375mg/m2 IV.

Repeat every 7 days for 4 weeks.

Rituximab + cyclophosphamide + prednisone11a

Day 1: Rituximab 375mg/m2 IV + cyclophosphamide 1,000mg/m2 IV

Days 1–5: Prednisone 100mg orally.

Repeat every 21 days for 6 cycles.

Rituximab + cyclophosphamide + dexamethasone12,13a

Day 1: Dexamethasone 20mg IV followed by rituximab 375mg/m2 IV

Days 1–5: Cyclophosphamide 100mg/m2 orally twice daily.

Repeat every 21 days for 6 months.

Thalidomide ± rituximab14a,d

Weeks 1 and 2: Thalidomide 200mg orally daily

Weeks 3–52: Thalidomide 400mg orally daily

Weeks 2–5 and 13–16: Rituximab 375mg/m2 IV once weekly for a total of 8 infusions.

Primary Therapy—Possible Stem Cell Toxicity and/or Risk of Transformation (or unknown)1

Bendamustine ± rituximab15a

Days 1–2: Bendamustine 90mg/m2 IV, ±

Day 1: Rituximab 375mg/m2 IV.

Repeat every 4 weeks for 4 cycles.

Cladribine ± rituximab16a,c,h,i

Days 1–5: Cladribine 0.1mg/kg subcutaneous injection, ±

Day 1: Rituximab 375mg/m2 IV.

Repeat every 4 weeks for 4 cycles.

Chlorambucil17g,h

Days 1–7: Chlorambucil 0.1mg/kg orally daily OR 0.3mg/kg orally daily.

Repeat every 6 weeks.

Fludarabine ± rituximab18a,c,h,i

Weeks 5, 9, 13, 19, 23, and 27: Fludarabine 25mg/m2 IV daily for 5 days, ±

Weeks 1–4, 17, 18, 30, and 31: Rituximab 375mg/m2 IV per week.

Fludarabine + cyclophosphamide + rituximab19a,c,h,i

Day 1: Rituximab 375mg/m2 IV

Days 2–4: Fludarabine 25mg/m2 IV + cyclophosphamide 250mg/m2 IV.

Repeat every 28 days for a maximum of 6 cycles.

Previously Treated WM/LPL—Non-Stem Cell Toxic1

Alemtuzumab20

Alemtuzumab doses gradually escalated over 1 week (3, 10, and 30 mg), followed by 36 additional treatment-phase infusions at 30-mg IV 3 times weekly for 12 weeks.

Bortezomib ± rituximab21a,b,c,d

Days 1, 8, and 15: Bortezomib 1.6mg/m2 IV, ±

Days 1, 8, 15, and 22 on cycles 1 and 4: Rituximab 375mg/m2 IV.

Repeat every 28 days for 6 cycles.

Bortezomib + dexamethasone22c,d

Days 1, 4, 8, and 11: Bortezomib 1.0 or 1.3mg/m2

If disease progression after 2 cycles of stable disease or after first 4 cycles of bortezomib:

Dexamethasone 20mg orally on the day of and the day after each bortezomib dose.

Bortezomib + dexamethasone + rituximab3a,b,c,d

Days 1, 4, 8, and 11: Bortezomib 1.3mg/m2 IV + dexamethasone 40mg IV.

Day 11: Rituximab 375mg/m2 IV.

Repeat for 4 consecutive cycles as induction therapy and follow with 4 maintenance cycles, each given 3 months apart.

Cyclophosphamide + doxorubicin + vincristine + prednisone + rituximab7,8a,d,f

Day 1: Cyclophosphamide 750mg/m2 IV + doxorubicin 50mg/m2 IV + vincristine 1.4mg/m2 (max 2mg) IV + rituximab 375mg/m2 IV

Days 1–5: Prednisone 100mg orally.

Repeat every 3 weeks for 6 cycles.

Everolimus23

Everolimus 10mg orally daily for 4 weeks (1 cycle).

Repeat until disease progression or unacceptable drug toxicity.

Ibrutinib9,24

Ibrutinib 420mg orally daily for 2 years or until disease progression or unacceptable drug toxicity.

Ofatumumab (for rituximab-intolerant individuals)25a,j

Week 1: Ofatumumab 300mg IV

Weeks 2–4: Ofatumumab 1,000mg IV.

OR

Week 1: Ofatumumab 300mg IV

Weeks 2–5: Ofatumumab 2,000mg IV.

Rituximab10a

Day 1: Rituximab 375mg/m2 IV.

Repeat every 7 days for 4 weeks.

Rituximab + cyclophosphamide + prednisone11a

Day 1: Rituximab 375mg/m2 IV + cyclophosphamide 1,000mg/m2 IV

Days 1–5: Prednisone 100mg orally.

Repeat every 21 days for 6 cycles.

Rituximab + cyclophosphamide + dexamethasone13a

Days 1–5: Cyclophosphamide 100mg/m2 orally twice daily

Day 1: Dexamethasone 20mg IV followed by rituximab 375mg/m2 IV.

Repeat every 21 days for 6 months.

Thalidomide ± rituximab14a,d

Weeks 1 and 2: Thalidomide 200mg orally daily

Weeks 3–52: Thalidomide 400mg orally daily, ±

Weeks 2–5 and 13–16: Rituximab 375mg/m2 IV once weekly for a total of 8 infusions.

Previously Treated WM/LPL—Possible Stem Cell Toxicity and/or Risk of Transformation (or unknown)1

Bendamustine ± rituximab26a

Days 1–2: Bendamustine 90mg/m2 IV, ±

Day 1 or 2: Rituximab 375mg/m2 IV.

Repeat every 4 weeks for 5 cycles.

Cladribine ± rituximab11a,c,h,i

Days 1–5: Cladribine 0.1mg/kg subcutaneous injection, ±

Day 1: Rituximab 375mg/m2 IV.

Repeat every 4 weeks for 4 cycles.

Chlorambucil17h,i

Days 1–7: Chlorambucil 0.1mg/kg orally daily OR 0.3mg/kg orally daily.

Repeat every 6 weeks.

Fludarabine ± rituximab18a,c,h,i

Weeks 5, 9, 13, 19, 23, and 27: Fludarabine 25mg/m2 IV daily for 5 days, ±

Weeks 1–4, 17, 18, 30, and 31: Rituximab 375mg/m2 IV per week.

Fludarabine + cyclophosphamide + rituximab19a,c,h,i

Day 1: Rituximab 375mg/m2 IV

Days 2–4: Fludarabine 25mg/m2 IV + cyclophosphamide 250mg/m2 IV.

Repeat every 28 days for a maximum of 6 cycles.

Previously Treated WM/LPL—Stem Cell Transplant1

High-dose therapy with stem cell rescue27

Treatment varied depending on local protocols.

Allogeneic stem cell transplant (myeloablative or non-myeloablative)28k

Preferably undertaken in the context of a clinical trial.

a In patients with symptomatic hyperviscosity, plasmapheresis should first be performed. Plasmapheresis should also be considered before treatment with rituximab or ofatumumab in patients with asymptomatic Waldenström's macroglobulinemia and an IgM ≥4,000mg/dL to avoid aggravation of serum viscosity on the basis of rituximab-related IgM flare. Rituximab or ofatumumab may also be held in patients with elevated serum IgM levels for initial treatment cycles.

b Consider particularly for patients presenting with symptomatic hyperviscosity, or in whom rapid IgM reduction is required.

c Herpes zoster prophylaxis should be considered for patients receiving these regimens.

d These regimens are associated with treatment-related neuropathy and should be avoided in patients with disease-related neuropathy.

e Serial serum IgA and IgG levels should be carefully monitored as these patients can be depleted with carfilzomib therapy

f Vincristine is associated with a high risk of peripheral neuropathy in patients with Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma. Consider alternative regimens without vincristine (eg, cyclophosphamide, dexamethasone, rituximab), if cyclophosphamide-based therapy is being considered.

g Lower overall responses and absence of major responses have been observed in patients with MYD88 wild-type mutations.

h May be associated with disease transformation and/or development of myelodysplastic syndrome /acute myeloid leukemia in patients with Waldenström's macroglobulinemia.

i Avoid in patients who are potential autologous stem cell transplant candidates.

j Ofatumumab may be used for rituximab-intolerant individuals as a single agent or in combination therapy.

k Should ideally be undertaken in the context of a clinical trial.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines®) for Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma. V2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf. Accessed March 2, 2016.

2. Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am J Hematol. 2010;85(9):670–674.

3. Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström's Macroglobulinemia. J Clin Oncol. 2009;27(1):120–126.

4. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab. WMCTG clinical trial 05-180. J Clin Oncol. 2009;27(23):3830–3835.

5. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment recommendations for patients with Waldenström's macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124(9):1404–1411.

6. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood. 2014;124(4):503–510.

7. Treon SP, Hunter Z, Barnagan AR. CHOP plus rituximab therapy in Waldenström's macroglobulinemia. Clin Lymphoma. 2005;5(4):273–277.

8. Buske C, Hoster E, Dreyling M, et al. The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treat failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia. 2009;23(1):153–161.

9. Imbruvica (ibrutinib) [package insert]. Sunnyvale, CA: Pharmacyclics, Inc.; 2015.

10. Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol. 2002;20(9):2327–2333.

11. Ioakimidis L, Patterson CJ, Hunter ZR, et al. Comparative outcomes following CP-R, CVP-R, and CHOP-R in Waldenström's macroglobulinemia. Clin Lymphoma Myeloma. 2009;9(1):62–66.

12. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25(22):3344–3349.

13. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al. Primary treatment of Waldenström's macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25(22):3344–3349.

14. Treon SP, Soumerai JD, Branagan AR, et al. Thalidomide and rituximab in Waldenström macroglobulinemia. Blood. 2008; 112(12):4452–4457.

15. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol. 2009;27(9):1492-1501. Erratum in: J Clin Oncol. 2009;27(17):2892.

16. Laszlo D, Andreola G, Rigacci L, et al. 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;28(13):2233–2238.

17. Kyle RA, Greipp PR, Gertz MA, et al. Waldenström's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol. 2000;108(4): 737–742.

18. Treon SP, Branagan AR, Ioakimidis L, et al. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009;113(16):3673–3678.

19. Tedeschi A, Benevolo G, Varettoni M, et al. Fludarabine plus cyclophosphamide and rituximab in Waldenström macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer. 2012;118(2):434–443.

20. Treon SP, Soumerai JD, Hunter ZR, et al. Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab. Blood. 2011;118(2):276–281.

21. Ghobrial IM, Hong F, Padmanabhan S, et al. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenström macroglobulinemia. J Clin Oncol. 2010;28(8):1422–1428.

22. Jagannath S, Richardson PG, Barlogie B, et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006;91(7):929–934.

23. Ghobrial IM, Gertz M, Laplant B, et al. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenström macroglobulinemia. J Clin Oncol. 2010;28(8):1408–1414.

24. Treon S, Tripsas C, Yang G, et al. A prospective, multicenter, study of the Bruton's tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenström's macroglobulinemia [abstract]. Hematol Oncol. 2013;31 (Suppl 1):119:067.

25. Furman RR, Eradat H, Switzky JC, et al. A phase II trial of ofatumumab in subjects with Waldenström's macroglobulinemia [abstract]. Blood. 2010;116:Abstract 1795

26. Treon SP, Hanzis C, Tripsas C, et al. Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011;11(1):133–135.

27. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenström macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010;28(13):2227–2232.

28. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem-cell transplantation in patients with Waldenström macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010;28(33):4926–4934.


Hematologic Cancer Drug Monographs

Leukemias, Lymphomas, And Other Hematologic Cancers

ADCETRIS ALKERAN ALKERAN FOR INJECTION
ARRANON ARZERRA BELEODAQ
BENDEKA BEXXAR BICNU
BLEOMYCIN BLINCYTO BOSULIF
BUSULFEX CAMPATH CERUBIDINE
CLADRIBINE CLOLAR CYCLOPHOSPHAMIDE
CYTARABINE CYTOXAN INJECTION DACOGEN
DARZALEX DEPOCYT DOXIL
DOXORUBICIN HCL DOXORUBICIN HCL SOLUTION DTIC-DOME
EMPLICITI ERWINAZE EVOMELA
FARYDAK FLUDARA FOLOTYN
GAZYVA GLEEVEC GLEOSTINE
HYDREA ICLUSIG IDAMYCIN
IDAMYCIN PFS IMBRUVICA INTRON A
INTRON A SOLN ISTODAX JAKAFI
KEYTRUDA KYPROLIS LEUKERAN
MARQIBO MATULANE METHOTREXATE FOR INJECTION
METHOTREXATE INJECTION MITOXANTRONE HCL MUSTARGEN
MYLERAN NINLARO ONCASPAR
ONTAK OPDIVO PAMIDRONATE DISODIUM INJECTION
PENTOSTATIN POMALYST PURINETHOL
PURIXAN REVLIMID RITUXAN
SPRYCEL SYNRIBO TABLOID
TARGRETIN TARGRETIN GEL TASIGNA
THALOMID TREANDA TREXALL
TRISENOX UVADEX VALCHLOR
VELCADE VENCLEXTA VESANOID
VIDAZA VINBLASTINE FOR INJECTION VINBLASTINE INJECTION
VINCASAR PFS VUMON ZEVALIN
ZOLINZA ZOMETA ZYDELIG

Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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