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56-year-old man with chronic anemia for one year	true	Hsieh-Ting Lin	true	3	main	[■](#table-of-contents)

58-year-old Man with Nasal Bleeding for Six Months

林協霆醫師，和信治癌中心醫院

Hsieh-Ting Lin, [email protected]

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淋例盡致 CLL，WM 病例挑戰賽

Patient Infomation

58-year-old man

Past medical history

Gastroesophageal Reflux Disease,2021
Herniation of Inter-Vertebral Disc (HIVD) at FEMH
No Current Medication(s)

Lifestyle Risk Factors

Tobacco: 0.4 pack(s) per day for 15 year(s), quit for 15 year(s)
Alcohol consumption: 600 ml (beer) 2 times a week, for 15 year(s), quit for 2 year(s)
Betel nut: 1# per day for 15 year(s), quit for 15 year(s)
No illicit drugs

* Far Eastern Memorial Hospital

Social history

Occupation: Telecom Operator
Language: Mandarin
Care giver: self,Spouse

Family history

Father: Deceased, age 50
Mother: Alive, age 84
Marital Status: Married
- Spouse: Age 50, residing together
Children:
- 1: Female, age 24 (from previous marriage)
Caregiver: Self, Spouse

History of Present Illness

2020, Initial Presentation

2020-01
- persistent hiccups
- 1-2 episodes of spontaneous severe nosebleeds monthly,
  - not triggered by trauma or nasal irritation.
2020-05
- CGH^*^ ENT
- HB: 7.7 mg/dL
- AG reverse
- further workup:
  - IgM: ==9650 mg/dL==
  - Free kappa: Elevated.
  - Bone Marrow Biopsy: Evidence of B-cell lymphoid involvement.
  - Lost to follow-up
2021-03
- Sudden hearing loss in the right ear upon waking
- Dx at SKH^**^:
  - MRI: ==Right ear stroke==
- Hyperbaric oxygen therapy was recommended but hearing did not improve.

* Cathay General Hospital ** Shin Kong Wu Ho-Su Memorial Hospital

2021,2022, HB 6.9, 2nd Bone Marrow Biospy

2021-12
- Visited CGMH^*^ GI department for hiccups and GERD symptoms.
- CBC results: HB: 6.9.
- BMBx findings:
  - Involvement by B-cell lymphoid neoplasm with plasmacytic differentiation.
  - Suspected Waldenström macroglobulinemia.
- Pertinent negatives:
  - No significant hepatosplenomegaly identified.
  - No gastrointestinal bleeding or obstruction.
2022-01-14
- Presented to KFSYSCC^**^.
- Diagnosis:
  - Waldenström macroglobulinemia confirmed.

No Fatigue, Fever, Weight loss, Night sweats, Numbness in the hands or feet, Swollen lymph nodes, Easy bruising, Bleeding nose or gums, Headache, Shortness of breath, Changes in vision,

* Chang Gung Memorial Hospital, 基隆 ** Koo Foundation Sun Yat-Sen Cancer Center

Diagnostic Workup

Dimopoulos MA, Kastritis E. How I treat waldenström macroglobulinemia. Blood. 2019;134(23):2022-2035. doi:10.1182/blood.2019000725

Physical examination

:::half

Measurement	Value
Height	165.3 cm
Weight	52.7 kg
Temperature	36 ℃
Blood Pressure	109/63 mmHg
Pulse	92 bpm
Respiration Rate	16 /min

Appears well-nourished and alert, No distress
Skin:
- 📍Pallor, No petechiae, ecchymoses, or skin lesions
Head, Eyes, Ears, Nose, and Throat (HEENT):
- 📍Pale conjunctiva, No scleral icterus
- Ears, Nose, Throat: no abnormalities

:::split

Neck:
- No lymphadenopathy
- No thyroid enlargement or tenderness
Respiratory:
- Normal breath sounds bilaterally
- No wheezes, rales, or rhonchi
Cardiovascular:
- Normal S1, S2; no murmurs, rubs, or gallops
- Capillary refill < 2 seconds
- No jugular venous distention
Abdomen:
- Non-tender, no hepatosplenomegaly
- Bowel sounds present and normal

:::

(continued)

:::half

Musculoskeletal:
- No bony tenderness
- Normal range of motion
- No joint swelling or deformities
Neurological:
- Cranial nerves II–XII intact
- except right CN VIII hearing impaired
Lymphatic:
- No palpable lymphadenopathy

:::split

Extremities:
- No cyanosis, clubbing, or edema, no Raynaud phenomenon
- Nails without spooning (no koilonychia)
- No livedo reticularis
No signs of infection or fever

:::

Initial Laboratory Workup

NCCN Guidelines Version 1.2025 Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma

CBC,DC, platelet count, `2022-01-14`

:::half

Test	Value	Unit	Reference Range
HGB	7.4	g/dL	13.5 - 17.5 (male)
MCV	88.1	fL	80 - 100
PLT	443.0	x10^3/uL	150 - 450
W.B.C	7.70	x10^3/uL	4.0 - 11.0
SEG	70.2	%	50 - 70
MONO	3.1	%	2 - 10
EO	0.0	%	0 - 5
BASO	0.1	%	0 - 1
LYMPH	26.6	%	20 - 40

Severe anemia, normal MCV, elevated platelets, and normal WBC with a high-normal neutrophil count

:::split

Test	Value	Unit	Reference Range
Prothrombin time	14.8	seconds	11.0 - 13.5
PT (control)	10.3	seconds	N/A
INR	1.41		0.8 - 1.2
APTT	46.4	seconds	25 - 35
APTT (control)	28.1	seconds	N/A
aPTT Pool Control	33.0	seconds	N/A
Fibrinogen	404.8	mg/dL	200 - 400
Indirect Coomb's test	Negative		Negative
Direct Coomb's test	Negative		Negative

:::

Comprehensive Metabolic Panel, `2022-01-14`

Test	Value	Unit	Reference Range
Glucose (random)	137	mg/dL	70 - 140
BUN	14.0	mg/dL	7 - 20
Creatinine	1.18	mg/dL	0.6 - 1.3 (male) / 0.5 - 1.1 (female)
eGFR	68	mL/min/1.73^2	>90
Uric acid	9.4	mg/dL	3.4 - 7.0 (male) / 2.4 - 6.0 (female)
AST / GOT	12	U/L	10 - 40
ALT / GPT	7	U/L	7 - 56
Bilirubin Total	0.08	mg/dL	0.1 - 1.2
LDH	145	U/L	120 - 230
Na	141	mmol/L	135 - 145
K	4.9	mmol/L	3.5 - 5.0
Ca	12.5	mg/dL	8.6 - 10.2

Serum quantitative immunoglobulins, `2022-01-14`

:::half

Test	Value	Unit	Reference Range
Total protein	12.53	g/dL	6.0 - 8.3
Albumin	3.11	g/dL	3.5 - 5.0
Globulin	9.4	g/dL	2.3 - 3.5
A/G Ratio	0.3		1.0 - 2.1
Kappa light chain	199.15	mg/L	3.3 - 19.4
Lambda light chain	14.08	mg/L	5.7 - 26.3
Free kappa/lambda ratio	14.144		0.26 - 1.65
IgA (Nephelometry)	108.0	mg/dL	70 - 400
IgG (Nephelometry)	901.0	mg/dL	700 - 1600
IgM (Nephelometry)	8588.0	mg/dL	40 - 230

:::split

Test	Value	Unit	Reference Range
Haptoglobin	319.0	mg/dL	30 - 200
Cold hemoagglutinin	1:4x		<1:16
Cryoglobulin	Positive		Negative

Hyperproteinemia and Dysproteinemia: Elevated total protein, high globulin, low albumin, and abnormal A/G ratio (0.3)
Monoclonal Protein Abnormality: Extremely high IgM and abnormal free kappa/lambda ratio point to monoclonal gammopathy
Hemolysis and Cold Agglutination: Elevated haptoglobin, positive cryoglobulins, and low-titer cold agglutinins (1:4)

:::

Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) `2022-01-22`

Rt. bone marrow aspirate and biopsy

dated 2020-06-12 from CGH^*^

* Cathay General Hospital

Cellularity: Up to 90%
Marrow Infiltration By small lymphoid cells
- Diffuse, Paratrabecular pattern
Immunohistochemistry
- Small lymphoid cells Positive for CD20
- With plasmacytic differentiation: Plasma cells Positive for CD138, Kapp Light Chain
Diagnosis
- Lymphoplasmacytic lymphoma is favored

CD20 (+), CD23 (-)

- POSITIVE
- NEGATIVE

CD3 (-), CD5 (-)

- NEGATIVE
- NEGATIVE

Kappa light chain (+) , Lambda light chain (-)

- POSITIVE
- NEGATIVE

CD138: positive, in the plasmacytic cells

- POSITIVE

Ki-67: estimated <5%

Diagnosis: Waldenström Macroglobulinemia

IgM monoclonal gammopathy
Bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells
Diffuse, interstitial, or nodular pattern of bone marrow infiltration

Revised IPSS Waldenström Macroglobulinemia Scoring

2 points: Intermediate (3-year WM related death rate 14%; 10 y-OS 37%)
3 poinst: High risk (3-year WM related death rate 38%; 10 y-OS 19%)

Indications to start therapy

Note

Hyperviscosity, Anemia (Hb<10)

Dimopoulos MA, Kastritis E. How I treat waldenström macroglobulinemia. Blood. 2019;134(23):2022-2035. doi:10.1182/blood.2019000725

Treatment Course

Management of WM: choice of therapy in previously untreated patients

Dimopoulos MA, Kastritis E. How I treat waldenström macroglobulinemia. Blood. 2019;134(23):2022-2035. doi:10.1182/blood.2019000725

2022/02/11 ~ 2022/02/12

R-COP^*^
- Rituximab 375 mg/m2, Cyclophosphamide 800 mg/m2 , Vincristine 1.4, Prednisolone 40 mg/m2 x 5 days
- Serum IgM: 8588.0 to 6409.0

Ioakimidis L, Patterson C, Soumerai J, Manning R, Sheehy P, Treon S. Comparative Outcomes Following CP-R, CVP-R and CHOP-R in Patients with Waldenstrom’s Macroglobulinemia. Blood. 2008;112(11):2011-2011. doi:10.1182/blood.V112.11.2011.2011

Warning

AEs after 1# R-COP: myalgia, peripheral dysesthesia, and abdomen discomfort and constipation

Blood, 112(11), 2011–2011. "comparable response characteristics among CP-R, CVP-R, or CHOP-R though a trend for attainment of more CR/nCR in CVP-R and CHOP-R"

2022/03/04 ~

2022-03-04 ~ 2022-04-15
- Chlorambucil 2mg daily plus prednisolone 25mg BID for 4 cycles between 01-13 to 04-15^*^
- Serum IgM: 6409 to 4961
2022-05-01 ~ 2022-05-07
- Headache and N/V
- CT of Head: Subarachnoid hemorrhage 🩸, mainly in the interpeducular and the left ambient cistern

Note

Single-agent Chlorambucil: Effective in 70–80% of non-fit patients but slow response, not ideal for rapid disease control.

Kyle RA, 2000	Fludarabine	Chlorambucil	P-value
Duration of Response (months)	38.5	21.3	0.0024
Median PFS (months)	37.8	27.1	≤0.015
Median OS (months)	Not reached	69.8	≤0.015 (CI: 61.6–79.8)

* Kyle RA, Greipp PR, Gertz MA, Witzig TE, Lust JA, Lacy MQ et al. Waldenstrom’s macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 2000; 108: 737–742.

2022-05-01 ~ 2022-05-07 Subarachnoid hemorrhage

● 2022-05-01: transfer the patient to CHGH^*^ NICU ● 2022-05-04: Patient discharge from NICU and return to our general ward

- Brain CT on 2022-05-01
- Brain MRI on 2022-05-06

*Cheng Hsin General Hospital

2022/09/19 ~

2022-05-15 ~ 2022-08-15
- Chlorambucil 2mg daily plus prednisolone 25mg BID for another 4 cycles
- Serum IgM: 4961 to 3634.0
2022-09-19 ~ 2024-12-27
- Start zanubrutinib (compassionate use)
  - 160mg BID
- Serum IgM: 3634 to 353

Response

IWWM-11 RESPONSE CRITERIA FOR ASSESSMENT OF DISEASE RESPONSE IN WM/LPL

NCCN Guidelines Version 1.2025 Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma

Serum IgM Level Over Time (mg/dL)

2022/01/14: 8588.0 | 2024/11/29: 433.0 👉Very good partial response (VGPR)

SPEP and IFE at different time points

CBC, `2024-06-28` to `2024-11-29`,recent 6 months

Date	2024-06-28	2024-07-26	2024-08-30	2024-09-27	2024-10-25	2024-11-29
HGB	11.7	13.4	12.1	12.8	13.0	13.1
MCV	88.9	88.0	87.3	87.8	87.0	87.9
PLT	279.0	311.0	292.0	298.0	291.0	340.0
W.B.C	10.02	8.35	7.51	8.59	8.40	11.33
SEG	56.4	60.3	64.3	64.2	60.9	70.0
MONO	6.8	6.0	7.6	4.5	6.0	5.6
EO	2.7	2.3	2.8	2.9	2.5	1.6
BASO	1.1	1.1	0.9	0.7	0.8	0.7
LYMPH	33.0	30.3	24.4	27.7	29.8	22.1

Note

The patient continues to take Zanubrutinib and attends regular follow-up appointments monthly.

「如果沒有這顆藥，再來一次腦出血我可能就走了」by Patient 💬

Discussion

If we could time travel

Treatment Landscape of Waldenström Macroglobulinemia

Modified from: Mayo Clinic Consensus for Newly Diagnosed Waldenström Macroglobulinemia (WM). Hb indicates hemoglobin; IgM, immunoglobulin M; MGUS, monoclonal gammopathy of undetermined significance; RCD, rituximab, cyclophosphamide, and dexamethasone. (https://www.msmart.org/wm-treatment-guidelines)

ASPEN trial: Zanubrutinib vs Ibrutinib in WM

Phase III, RCT

:::half

:::split

:::

Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

Result

ASPEN: Best Overall Response and PFS by Investigator Assessment

Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

Final Outcome, update in 2023

Dimopoulos MA, Opat S, D’Sa S, et al. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;41(33):5099-5106. doi:10.1200/JCO.22.02830

PFS, OS

:::half

:::split

:::

AEs

Dimopoulos MA, Opat S, D’Sa S, et al. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;41(33):5099-5106. doi:10.1200/JCO.22.02830

Thank You 🙏 🫰

58-year-old Man with Nasal Bleeding for Six Months

Let’s Take Some Questions 🤔 🙋

Supplement

Syndromes seen with hyperviscosity

Acute hyperviscosity: syndromes and management

Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018;132(13):1379-1385. doi:10.1182/blood-2018-06-846816

How about ASPEN cohort 2, i.e. MYD88 WT

Impact of mutated CXCR4 on BTKi activity for ibrutinib and zanubrutinib in WM

Treon SP, Sarosiek S, Castillo JJ. How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia. Blood. 2024;143(17):1702-1712. doi:10.1182/blood.2022017235

Genomic-based treatment algorithm

patients with symptomatic, treatment-naïve WM

Treon SP, Sarosiek S, Castillo JJ. How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia. Blood. 2024;143(17):1702-1712. doi:10.1182/blood.2022017235

[[TOC]]

htlin222/WM.md

58-year-old Man with Nasal Bleeding for Six Months

林協霆醫師，和信治癌中心醫院

Patient Infomation

58-year-old man

Past medical history

Lifestyle Risk Factors

Social history

Family history

History of Present Illness

2020, Initial Presentation

2021,2022, HB 6.9, 2nd Bone Marrow Biospy

Diagnostic Workup

Physical examination

Initial Laboratory Workup

CBC,DC, platelet count, 2022-01-14

Comprehensive Metabolic Panel, 2022-01-14

Serum quantitative immunoglobulins, 2022-01-14

Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) 2022-01-22

Rt. bone marrow aspirate and biopsy

CD20 (+), CD23 (-)

CD3 (-), CD5 (-)

Kappa light chain (+) , Lambda light chain (-)

CD138: positive, in the plasmacytic cells

Ki-67: estimated <5%

Diagnosis: Waldenström Macroglobulinemia

Revised IPSS Waldenström Macroglobulinemia Scoring

Indications to start therapy

Treatment Course

Management of WM: choice of therapy in previously untreated patients

2022/02/11 ~ 2022/02/12

2022/03/04 ~

2022-05-01 ~ 2022-05-07 Subarachnoid hemorrhage

2022/09/19 ~

Response

IWWM-11 RESPONSE CRITERIA FOR ASSESSMENT OF DISEASE RESPONSE IN WM/LPL

Serum IgM Level Over Time (mg/dL)

SPEP and IFE at different time points

CBC, 2024-06-28 to 2024-11-29,recent 6 months

Discussion

If we could time travel

Treatment Landscape of Waldenström Macroglobulinemia

ASPEN trial: Zanubrutinib vs Ibrutinib in WM

Result

ASPEN: Best Overall Response and PFS by Investigator Assessment

Final Outcome, update in 2023

PFS, OS

AEs

Thank You 🙏 🫰

58-year-old Man with Nasal Bleeding for Six Months

Let’s Take Some Questions 🤔 🙋

Supplement

Syndromes seen with hyperviscosity

Acute hyperviscosity: syndromes and management

How about ASPEN cohort 2, i.e. MYD88 WT

Impact of mutated CXCR4 on BTKi activity for ibrutinib and zanubrutinib in WM

Genomic-based treatment algorithm

Table of Contents

CBC,DC, platelet count, `2022-01-14`

Comprehensive Metabolic Panel, `2022-01-14`

Serum quantitative immunoglobulins, `2022-01-14`

Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE) `2022-01-22`

CBC, `2024-06-28` to `2024-11-29`,recent 6 months