Waldenström's macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is an indolent subtype of B-cell non-Hodgkin lymphoma.1,2 WM is characterized by malignant B-cells that overproduce the abnormal monoclonal protein known as immunoglobulin (Ig) M or macroglobulin.2
As malignant B-cells grow in the bone marrow, they crowd out healthy erythrocytes, white cells, and platelets, and disrupt normal hematopoiesis.2 As such, fatigue and bruising are common among patients with WM.2 WM most often involves the blood and bone marrow at the time of diagnosis, but can metastasize to the lymph nodes, liver, or spleen, as well as to the gastrointestinal system and the lungs.2
WM is a rare condition, representing approximately 2% of all hematologic malignancies.2 In the United States, 6 new cases per 1 million individuals are diagnosed annually, translating to approximately 1500 patients annually.2 Older white men are at a relatively increased risk for WM.2
WM is staged based on the patient's risk status using the WM International Prognostic Scoring System.3 Overall, 5 adverse covariates have been identified, including3:
- Age >65 years
- Hemoglobin level ≥11.5 g/dL
- Platelet count ≤100,000/mm3
- β2-microglobulin level >3 mg/L
- Serum IgM level >7.0 g/dL.
Patients at low risk are aged <65 years and have 0 or 1 adverse covariates.3 Patients at intermediate risk are aged >65 years and have 2 adverse covariates. High-risk patients have more than 2 adverse covariates.3 According to the American Cancer Society, the 5-year overall survival rate for patients with high-risk WM is 36%, with a median survival of 3.5 years.4
Similar to other indolent lymphomas, active surveillance or watchful waiting is an appropriate approach for patients with WM who are asymptomatic.2 Initiation of treatment is recommended when patients report ≥1 of the symptoms of WM, including recurrent fever; night sweats; fatigue associated with anemia (hemoglobin ≤10 g/dL); thrombocytopenia (<100 g/L), or weight loss; severe peripheral neuropathy resulting from the abnormal IgM protein; impaired kidney function as a result of the abnormal IgM protein; and systemic amyloidosis with organ damage related to the IgM protein.2
Therapeutic options for patients with WM who warrant treatment include chemotherapy agents (ie, bendamustine); purine nucleoside analogs (ie, fludarabine); monoclonal antibodies (ie, rituximab, alemtuzumab); corticosteroids; immunomodulatory agents (ie, thalidomide); and proteasome inhibitors (ie, bortezomib).2 However, none of these therapies has been approved by the US Food and Drug Administration (FDA) for WM.2 Additional treatment with ≥1 of these agents, or with high-dose chemotherapy followed by autologous stem-cell transplantation can be considered upon disease progression or disease relapse.2,5
Recently, significant progress has been made in the identification of genetic abnormalities associated with WM.3,6,7 Gene sequencing has revealed a prevalent mutation in the MYD88 gene, as well as multiple mutations in the CXCR4 gene in patients with WM.3,6,7 A somatic mutation known as MYD88L265P is known to fuel cancer-cell growth by activating the nuclear factor κB through 2 distinct pathways-(1) Bruton's tyrosine kinase and (2) interleukin-1 receptor associated kinases, IRAK1 and IRAK4.8 It is expected that the discovery of WM-specific mutations will facilitate the evaluation of agents that target these mutations and/or their downstream effects and improve clinical outcomes.3,6-8
Ibrutinib First Drug Approved for Waldenström's Macroglobulinemia
On January 29, 2015, the FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with WM. Ibrutinib became the first drug to receive approval for the treatment of patients with WM.9 This is the fourth indication for ibrutinib in the United States.
The FDA's approval of ibrutinib for WM was based on a phase 2 multicenter study of 63 patients with previously treated WM.3,9,10 During the initial data analysis, 62% of patients with relapsed WM had responded to ibrutinib therapy.10
Richard Pazdur, MD, Director of the FDA's Office of Hematology and Oncology Products, commented, "Today's approval highlights the importance of development of drugs for supplemental indications. Continued research has discovered new uses of Imbruvica."9
In 2013, ibrutinib received accelerated approval for the treatment of patients with mantle-cell lymphoma who had received at least 1 previous therapy.10 In 2014, ibrutinib was approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who received at least 1 previous regimen, and for patients with CLL with the 17p deletion.10
And on March 4, 2016, the FDA approved a new indication for ibrutinib as first-line treatment of patients with CLL, regardless of any previous treatment.11 This is the first FDA approval for a chemotherapy-free option as first-line treatment for patients with CLL. The approval was based on updated data showing 84% reduction in disease progression or death with ibrutinib compared with chlorambucil.11
Ibrutinib is the first FDA-approved drug designed to target Bruton's tyrosine kinase, a protein necessary for the growth and the survival of B-cells.12
Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.10 As an irreversible covalent inhibitor, ibrutinib continues to inhibit Bruton's tyrosine kinase even after the drug is metabolized.13 Preclinical studies have demonstrated that ibrutinib prevents the activation of downstream pathways affected by Bruton's tyrosine kinase, inhibits cell proliferation, and promotes apoptosis of cancer cells.14
Dosing and Administration
In patients with WM, the recommended dose and schedule for ibrutinib is 420 mg (three 140-mg capsules) taken orally once daily.10
Ibrutinib should be administered at the same time each day, and should be swallowed whole with water. The oral capsules should not be opened, broken, or chewed.10
Pivotal Clinical Trial
The clinical utility of ibrutinib for the treatment of patients with WM was demonstrated in a prospective, phase 2, open-label, multicenter clinical trial of 63 patients with WM whose disease had relapsed after ≥1 therapies.3,10
In this study, ibrutinib 420 mg was given orally once daily until disease progression or until unacceptable toxicity.10 The study's primary objective was overall response rate, defined as the sum of minor responses (≥25% reduction in serum IgM levels), partial responses (≥50% reduction in serum IgM levels), very good partial responses (≥90% reduction in serum IgM levels), and complete responses (100% reduction in serum IgM levels).3,10 Responses were evaluated by an Independent Review Committee using criteria adopted from the International Workshop on Waldenström's Macroglobulinemia.10,15
All 63 patients had relapsed WM and an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients' median age was 63 years (range, 44-86 years).10 The majority of patients were male (76%) and white (95%).10 The median time since diagnosis of WM was 74 months.10 All patients received a median of 2 previous therapies for WM (range, 1-11 therapies).10 At baseline, the patients' serum IgM levels ranged from 0.7 g/dL to 8.4 g/dL (median, 3.5 g/dL).10
Efficacy Results
At the time of the initial analysis (at median duration of therapy of 11.7 months), the overall response rate was 62% (Table 1).10 The duration of response ranged from ≥2.8 months to ≥18.8 months. The median duration of response was not reached at the time of the FDA's approval of ibrutinib for WM.10
A subsequent analysis of the phase 2 clinical trial of ibrutinib in WM included a long-term follow-up of the 63 patients with WM: after treatment with ibrutinib for a median duration of 19.1 months (range, 0.5-29.7 months), the overall response rate for all patients was 91%.3
The researchers noted that the presence of specific MYD88 and CXCR4 mutations affected the responses to ibrutinib; an overall response rate of 100% was observed in the genomic subgroup characterized as MYD88L265P CXCR4wild-type. Improvements in the overall response rate were reported in all genomic subgroups after more than 6 cycles of ibrutinib therapy, with more pronounced improvements observed in patients in the MYD88L265P CXCR4WHIM subgroup.3
Adverse Events
At the time of the initial data analysis of the clinical trial, adverse reactions in ≥20% of patients taking ibrutinib included neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue (Table 2).10 Grade 3 or 4 events included neutropenia (19%), thrombocytopenia (13%), anemia (8%), pneumonia (6%), and skin infections (2%; Table 2).
Discontinuation of ibrutinib because of adverse events occurred in 6% of patients. Dose reductions secondary to adverse events were required in 11% of patients.10
Hypersensitivity reactions, including anaphylactic shock (fatal), urticaria, and angioedema, have been reported after the FDA approval of ibrutinib for WM. It is not known whether these reactions were drug-related.10
Ibrutinib has no contraindications.10
Drug Interactions
Because ibrutinib is metabolized primarily by the cytochrome (CY) P450 enzyme 3A, it should not be coadministered with strong or moderate CYP3A inhibitors or with strong CYP3A inducers.10
Ibrutinib therapy may need to be interrupted during use of strong short-term CYP3A inhibitors. The concomitant use of strong long-term CYP3A inhibitors with ibrutinib should be avoided.10
Warnings and Precautions
Hemorrhage. Patients taking ibrutinib have experienced fatal bleeding events. Grade ≥3 bleeding, including subdural hematoma, gastrointestinal bleeding, hematuria, and postprocedural hemorrhage, have been reported in up to 6% of patients taking ibrutinib.10 Bruising, petechiae, and other bleeding events (any grade) have been noted in approximately 50% of patients using ibrutinib.10 Ibrutinib may increase the bleeding risk in patients who require antiplatelet or anticoagulant therapies. Ibrutinib may need to be stopped for 3 to 7 days before and after surgery, depending on the risk for bleeding.10
Infections. Fatal and nonfatal infections, including progressive multifocal leukoencephalopathy, have occurred with ibrutinib. Monitor ibrutinib recipients for fever and infections.10
Cytopenias. Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia, were reported with ibrutinib. Patients should undergo monthly complete blood cell counts while taking ibrutinib.10
Atrial fibrillation. Atrial fibrillation (AF) and atrial flutter have occurred in 6% to 9% of patients taking ibrutinib, particularly those with cardiac risk factors, acute infections, and a history of AF. Patients should be periodically monitored for AF. If arrhythmic symptoms or new-onset dyspnea are observed, an electrocardiogram should be performed. If AF persists, the risks and benefits of ibrutinib dose modification or discontinuation should be considered.10
Second primary malignancies. Patients who received ibrutinib have developed second cancers, including nonmelanoma skin cancer (4%-11%) and other carcinomas (1%-3%).10
Tumor lysis syndrome. Patients who received ibrutinib have experienced tumor lysis syndrome. Clinicians should closely monitor patients, particularly those at risk based on their tumor burden.10
Embryo-fetal toxicity. Based on animal studies, ibrutinib can cause fetal harm when used in pregnancy.10
Use in Specific Populations
Pregnant women. Based on animal data, ibrutinib can cause fetal harm when administered to a pregnant woman; women should be advised to avoid becoming pregnant while taking ibrutinib.10
Nursing mothers. Ibrutinib has not been studied in nursing mothers. Nursing mothers should discontinue nursing or discontinue ibrutinib therapy, taking into account the importance of ibrutinib to the mother.10
Pediatric patients. The safety and efficacy of ibrutinib in pediatric patients have not been established.10
Geriatric patients. Overall, 59% of patients with WM who were enrolled in the clinical trial of ibrutinib were aged ≥65 years. No differences in the efficacy of ibrutinib were observed between older and younger patients.10 Elderly patients were more likely than younger patients to have cardiac adverse events and infections.10
Renal impairment. Ibrutinib exposure is not affected in patients whose creatinine clearance exceeds 25 mL/min. Patients with severe renal impairment or patients on dialysis have not been studied.10
Hepatic impairment. Because ibrutinib exposure increases in patients with liver failure, it is not recommended for patients with moderate or severe hepatic impairment. Patients should be monitored for liver toxicity, with dose reduction as needed.10
Females of reproductive potential. Women should avoid becoming pregnant while taking ibrutinib.10
Plasmapheresis. Patients with WM may require plasmapheresis before and during treatment with ibrutinib to manage hyperviscosity. No modification of ibrutinib dosing is required.10
Conclusion
Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is the first medication approved in the United States for the treatment of patients with WM, an indolent lymphoma characterized by genetic mutations that alter cancer-cell growth through Bruton's tyrosine kinase and other signaling pathways. A phase 2 clinical trial that documented a 62% overall response rate at the initial data analysis, and a 91% overall response rate after a longer follow-up period. In addition, this once-daily oral agent has demonstrated acceptable toxicity in patients with WM, with cytopenias and diarrhea reported as the most common adverse reactions. Because ibrutinib has a favorable therapeutic index, its use alone and in combination with other agents for the treatment of patients with WM and other hematologic malignancies is currently being explored. Examples include a randomized, placebo-controlled study of ibrutinib combined with rituximab in patients with WM; the combination of ibrutinib with obinutuzumab in patients with previously untreated CLL; and the combination of ibrutinib with bendamustine and rituximab in patients with newly diagnosed mantle-cell lymphoma.16
References
1. American Cancer Society. What is Waldenstrom macroglobulinemia? Revised January 28, 2015. www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-w-m. Accessed November 24, 2015.
2. Leukemia & Lymphoma Society. Waldenström macroglobulinemia facts. No. 20. Revised January 2012. www.lls.org/sites/default/files/file_assets/waldenstrom macroglobulinemia.pdf. Accessed November 24, 2015.
3. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372:1430-1440.
4. American Cancer Society. Survival rates for Waldenstrom macroglobulinemia. Revised January 28, 2015. www.cancer.org/cancer/waldenstrommacroglobulinemia/detailedguide/waldenstrom-macroglobulinemia-survival-rates. Accessed November 24, 2015.
5. Oza A, Rajkumar SV. Waldenstrom macroglobulinemia: prognosis and management. Blood Cancer J. 2015;5:e296.
6. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012;367:826-833.
7. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637-1646.
8. Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122:1222-1232.
9. US Food and Drug Administration. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma: first drug approved to treat Waldenström's macroglobulinemia. Press release. January 29, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. Accessed November 29, 2015.
10. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; Horsham, PA: Janssen Biotech, Inc; March 2016.
11. PR Newswire. IMBRUVICA (ibrutinib) approved by U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. Press release. March 4, 2016. www.prnewswire.com/news-releases/imbruvica-ibrutinib-approved-by-us-fda-for-the-first-line-treatment-of-chronic-lymphocytic-leukemia-300231107.html. Accessed March 7, 2016.
12. Lymphoma Research Foundation. Breakthrough therapy ibrutinib effective in CLL and MCL lymphomas. August 2013. www.lymphoma.org/site/pp.asp? c=bkLTKaOQLmK8E&b=8756085. Accessed November 28, 2015.
13. Woyach J. BTK inhibition and the mechanism of action of ibrutinib. Targeted Oncology. August 20, 2013. www.targetedonc.com/videos/Dr-Woyach-on- BTK-Inhibition-and-the-Mechanism-of-Action-of-Ibrutinib. Accessed November 28, 2015.
14. Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59.
15. Anderson KC, Alsina M, Bensinger W, et al; for the NCCN (National Comprehensive Cancer Network). Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2012;10:1211-1219.
16. ClinicalTrials.gov. Ibrutinib. Search results. http://clinicaltrials.gov/ct2/results?term=ibrutinib+&Search=Search. Accessed November 28, 2015.