New developments in the management of Waldenström macroglobulinemia

Figures & data

Table 1 Genotypic–phenotypic association in WM

Clinical Characteristics	MYD88^L265PCXCR4^WT	MYD88^L265PCXCR4^WHIM/FS	MYD88^L265PCXCR4^WHIM/NS	MYD88^WTCXCR4^WT
IgM	↑↑	↑↑	↑↑↑↑	↑
BM infiltration	↑↑↑	↑↑	↑↑↑↑	↑
Sensitivity to BTK inhibitors	↑↑↑	↑↑	↑	↓
Incidence (%)	~60	27–40*	27–40*	<10

Notes: This table is a relative semiquantitative representation of the frequency of disease characteristics with various genetic mutations.

* Frameshift (FS) and nonsense (NS) mutations are almost equally divided among WM patients with CXCR4 somatic mutations.

Abbreviations: BM, bone marrow; BTK, Bruton’s tyrosine kinase; IgM, immunoglobulin M; WM, Waldenström macroglobulinemia.

Table 2 Disease characteristics of WM

Parameter	Clinical characteristics
Features attributable to tumor infiltration	Constitutional symptoms: recurrent fever, night sweats, weight loss, and fatigue Cytopenias due to BM infiltration Organomegaly Lymphadenopathy
Features attributable to monoclonal immunoglobulin	Hyperviscosity that may present as oro-nasal bleeding, blurred vision, headache, dizziness, vertigo, ataxia, peripheral neuropathy, altered sensorium, and encephalopathy^Citation87 Deposition of IgM as amorphous material in heart, kidney, and gastrointestinal tract causing amyloidosis or IgM infiltrative disease Coombs’ positive autoimmune cold hemolytic anemia and cryoglobulinemia^Citation88,Citation89 Neuropathy due to IgM directed against myelin-associated glycoprotein or other neural components^Citation90

Abbreviations: BM, bone marrow; IgM, immunoglobulin M; WM, Waldenström macroglobulinemia.

Table 3 Disease prognosis based on IPSS

Prognostic factors	Cutoffs at which the factor is considered adverse at the time of initiation of treatment
Age	≥65 years
Hemoglobin	≤11.5 g/dL
Platelets	≤100×10^9/L
β2-Microglobulin	>3 mg/L
Serum monoclonal IgM	>7 g/dL
Risk stratification	Criteria	5-Year survival (%)
Low	≤1 adverse variable (except age)	87
Intermediate	2 adverse variables or age >65 years	68
High	>2 adverse variables	36

Abbreviations: IgM, immunoglobulin M; IPSS, International Prognostic Symptom Score.

Table 4 Treatment indications for symptomatic patients

Clinical indications	Laboratory indications
Signs and symptoms associated with hyperviscosity	Hemoglobin <10 g/dL
Moderate to severe peripheral neuropathy	Platelet count <100×10^9/dL
AL amyloidosis	Hemolytic anemia
Symptomatic cryoglobulinemia
Constitutional symptoms, Raynaud’s phenomenon, and arthralgia
Bulky or symptomatic lymphadenopathy
Symptomatic organomegaly

Abbreviation: AL, amyloid light-chain.

Table 5 Various regimens with rituximab in WM

Regimen	Schedule	Responses	TTP/PFS
Rituximab monotherapy – standard dosing^Citation27–Citation29	375 mg/m^2 ×4 weekly doses	ORR: 30–60%; VGPR/CR: 0–5%	DOR: 8–11 months
Rituximab monotherapy – extended schedule^Citation27–Citation29	375 mg/m^2 ×4 weekly doses (weeks 1–4) + repeat 4 weekly doses (weeks 12–16)	ORR: 35–45%; VGPR/CR: 5–10%	DOR: 16–29 months
Ofatumumab monotherapy^Citation38	300 mg for weeks 1 to 2–4 with either standard dose: 1 g/week or high dose: 2 g/week in patients with minor response/stable disease – week 16: 300 mg → 2 g/week ×4 weeks (weeks 17–20)	ORR: 59%; major response: 35%
Rituximab + alkylator (DRC)^Citation40	Dexamethasone 20 mg IV → rituximab 375 mg/m^2 IV on D1 and cyclophosphamide 100 mg/m^2 orally bid on D1–5 (total dose, 1,000 mg/m^2) every 21 days × 6 cycles	ORR: 83%; major response: 74%	Median PFS: 35 months
Rituximab + alkylator (bendamustine)^Citation42	90 mg/m^2 bendamustine D1/D2; 375 mg/m^2 rituximab on D1 repeated every 4 weeks × 6 cycles	ORR: 95%	PFS: 69.5 months
Rituximab + proteosome inhibitor (bortezomib – BDR)^Citation50	Bortezomib – 1.3 mg/m^2 IV – D1,4,8,11; dexamethasone – 40 mg IV – D1,4,8,11; rituximab – 375 mg/m^2 IV – D11 every 21 days × 4 cycles of induction and 4 cycles from 3 months as maintenance	ORR: 96%; major responses: 83%	Median PFS: 66 months
Rituximab + proteosome inhibitor (carfilzomib – CaRD)^Citation52	Carfilzomib (20 mg/m^2 – cycle: 1, 36 mg/m^2 – cycles: 2–6); rituximab (375 mg/m^2, D2,9); dexamethasone (20 mg, D1,2,8,9) every 21 days × 6 cycles	CR: 87%; VGPR: 36%	Median PFS: >16 months
Rituximab + IMiD^Citation60	Rituximab (375 mg/m^2, weekly on weeks 2–5 and 13–16) and len 25 mg for 21/28 days	ORR: 50% (abrupt decrease in Hgb in 88% of patients)	Median TTP: 17.1 months
Rituximab + mTOR inhibitor + bortezomib^Citation63	Everolimus – 10 mg PO daily; bortezomib 1.6 mg/m^2 IV D1, 8, 15 for 28 days/cycle × six cycles; rituximab 375 mg/m^2 IV D1,8,15,22 – cycles 1 and 4 only	ORR: 89%	Median PFS: 21 months

Abbreviations: BDR, bortezomib dexamethasone rituximab; CaRD, carfilzomib, rituximab and dexamethasone; CR, complete response; D, dexamethasone; DOR, duration of response; DRC, dexamethasone and rituximab in combination with cyclophosphamide; Hgb, hemoglobin; IMiD, immunomodulatory drug; IV, intravenous; Len, lenalidomide; mTOR, mechanistic target of rapamycin; ORR, overall response rate; PFS, progression-free survival; PO, oral; TTP, time to progression; VGPR, very good partial response; WM, Waldenström macroglobulinemia.

Table 6 Aide memoirs on ibrutinib

Pharmacokinetics	Dose modifications	Interactions
• A BTK inhibitor • t1/2 – 2–3 h • Oral bioavailability – good • Peak plasma levels – 1–2 h • Clearance – liver metabolism by CYP3A • Elimination t1/2 – 4–6 h	• Renal modification  • No modification required  • Monitor toxicities • Hepatic modification based on Child–Pugh classification  • Class A – ↓ to once daily  • Classes B and C – avoid usage	• CYP3A inducers – ↓ plasma level  • Antiepileptics: carbamazepine and phenytoin  • Antitubercular: rifampin  • St John’s wort • CYP3A inhibitors – ↑ plasma level  • Antivirals (protease inhibitors)  • Antifungals (azoles)  • Macrolides • Food interactions: avoid  • Seville orange  • Starfruit  • Grapefruit juice
Special category of population	Dosage	Side effects
• Pregnancy – avoid pregnancy for 1 month after cessation of therapy • Males – avoid fathering for 1 month after cessation of therapy • Breast feeding – not studied; decision based on the risk–benefit ratio for the mother’s health vis-à-vis exposure to newborn • Surgery – withhold 3–7 days before and after surgery depending on the bleeding risk involved with the surgery	• Capsule strength – 140 mg • Dose – three tablets per day • Timing with regard to food intake – no bearing on the bioavailability • Missed dosing – to take capsule as soon as the patient remembers in the same day; no additional dosing on subsequent day recommended for missed doses	• Bleeding  • Platelet dysfunction  • Aggravation of avWD secondary • Atrial fibrillation, hyper/hypotension • Headache and dizziness • Cytopenias • Infections • Gastrointestinal disturbances • Fatigue, musculoskeletal pain, and arthralgias

Abbreviations: avWD, acquired von Willebrand’s disease; BTK, Bruton’s tyrosine kinase.

Table 7 Studies using ibrutinib monotherapy in WM

Reference	Type of study	Sample size	Disease setting	Outcome
Advani et al^Citation91	Phase I	4a	RR	75% achieved response and continued to have response at 4 years^Citation92
Treon et al^Citation68	Phase II	63	RR	ORR – 95% OS – 95% at 2 years PFS – 69% at 2 years
Dimopoulos et al,^Citation69 iNNOVATE™	Phase III	31	Refractory to last rituximab containing therapy	ORR – 90% OS – 92% at 18 months PFS – 86% at 18 months

Note:

a Out of total 56 patients of CLL/NHL.

Abbreviations: CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RR, relapsed and/or refractory; WM, Waldenström macroglobulinemia.

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