淋巴瘤教案高雄榮民總醫院 藥劑部

Speaker ：方柔壹 藥師100.11.26

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OutlineOutline教案學習目標 教案設計的注意事項

◦在設計教案之前◦疾病治療 - 建議參考資料

教案設計與問題討論 (SOAP)

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教案學習目標教案學習目標了解淋巴瘤的藥物治療

◦了解藥物相關問題：適當的藥物治療、治療中的注意事項及藥物不良反應

◦治療目標的達成：設立治療目標、確保病患依順性

學習以 SOAP 格式建立完整的合理用藥評估◦了解病患案例報告 (case presentation) 之結構及順序

◦說明 SOAP 之格式組成及擷取治療準則所需資訊

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教案設計的注意事項教案設計的注意事項◦在設計教案之前

依對象設計教案難易 Burkitt’s Lymphoma 的表現、診斷 確定教案的問題發生在疾病初期還是治療中

◦疾病治療 - 建議參考資料 臨床指引 (clinical practical guideline)

NCCN practice guideline American Society of Clinical Oncology /ASCO

- Journal of clinical oncology European Society for Medical Oncology / ESMO

– Annals of Oncology

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教案設計與問題討論教案設計與問題討論(SOAP)(SOAP)

什麼是淋巴瘤 ?

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Textbook & Uptodate

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Normal lymph nodes are usually less than 1 cm in diameter and tend to be larger in adolescence than later in life. Lymph nodes are often palpable in the inguinal region in healthy people.

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Disease associated with lymphadenopathy

1. Infectious disease

Viral

Bacterial

Fungal

Chlamydial

2. Immunologic disease

Rheumatoid arthritis

Mixed connective tissue disease

Systemic lupus erythematosus

Drug hypersensitivity

Primary biliary cirrhosis

3. Malignant disease

Hematologic – leukemia, hodgkin’s disease, non-hodgkin’s lymphoma

Metastatic

4. Endocrine disease hyperthyrodism

5. Other disorders

Sarcoidosis

Severe hypertriglyceridemia

Inflammatory pseudotumor of lymph node

Disease associated with lymphadenopathy

1. Infectious disease

Viral

Bacterial

Fungal

Chlamydial

2. Immunologic disease

Rheumatoid arthritis

Mixed connective tissue disease

Systemic lupus erythematosus

Drug hypersensitivity

Primary biliary cirrhosis

3. Malignant disease

Hematologic – leukemia, hodgkin’s disease, non-hodgkin’s lymphoma

Metastatic

4. Endocrine disease hyperthyrodism

5. Other disorders

Sarcoidosis

Severe hypertriglyceridemia

Inflammatory pseudotumor of lymph node

Aggressive lymphomas commonly present acutely or subacutely with a rapidly growing mass, systemic B symptoms, and/or elevated levels of serum LDH and uric acid

B symptoms Fever (BT > 38℃)Night sweatsWeight loss (loss > 10% weight within 6 months)

These cancers arise from cells of the immune system at different stages of differentiation, resulting in a wide range of 　 morphologic, immunologic, and clinical　findings.

Lymphomas －Ｔ umors of the immune system.

Malignancies　of　lymphoid　cells

8HARRISON’S_Hematology and Oncology textbook, 17th ed

The WHO classification takes into account morphologic, clinical, immunologic, and genetic formation and attempts to divide non-Hodgkin's lymphomas and other lymphoid malignancies into clinical/pathologic entities that have clinical and therapeutic relevance.

9HARRISON’S_Hematology and Oncology textbook, 17th ed

Relative frequency of lymphoid malignancies

10HARRISON’S_Hematology and Oncology textbook, 17th ed

97 年度 Non-Hodgkin’s Lymphoma 佔整年度癌症死亡率 1941 ÷ 38913 ≒ 5 ％

衛生署統計資料 _ 臺灣地區惡性淋巴瘤申報發生人數

11衛生署健康局癌症組

A number of environmental factors have been implicated in the occurrence of non-Hodgkin’s lymphoma, including infectious　agents, chemical　exposures, and medical　treatments. Several studies have demonstrated an association between exposure to agricultural chemicals and an increaseed incidence in non-Hodgkin’s lymphoma.

12HARRISON’S_Hematology and Oncology textbook, 17th ed

Burkitt’s Lymphoma morphology and immunophenotyping

1. The neoplastic cells are homogenous, small to medium-sized B cells with frequent mitotic figures, a morphologic correlate of high growth fraction. Reactive macrophages are scattered through the tumor, and their pale cytoplasm in a background of blue-staining tumor cells give the tumor a so-called starry sky appearance.

2. The classical immunophenotype of BL is IgM+/CD10+/CD20+/ BCL2-/BCL6+ and TdT (-), with the Ki-67proliferation index > 95%. The chromosomal translocation t(8;14)(q24;q32) or one of its variants t(8;22) or t(2;8).

13HARRISON’S_Hematology and Oncology textbook, 17th ed

Three distinct clinical forms of Burkitt's lymphoma are recognized; endemic, sporadic, and immunodeficiency associated.

Endemic and sporadic Burkitt's lymphomas occur frequently in children in Africa, and the sporadic form in Western countries. Immunodeficiency-associated Burkitt's lymphoma is seen in patients with HIV infection.

BL present with peripheral lymphadenopathy or an intraabdominal mass. The disease is rapidly progressive and has a propensity to metastasize to the CNS. Initial evaluation should always include an examination of cerebral spinal fluid to rule out metastasis.

Characteristics of Burkitt’s Lymphoma

14HARRISON’S_Hematology and Oncology textbook, 17th ed

案例討論 (Non-Hodgkin’s Lymphoma)

Burkitt’s lymphoma

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Case　PresentationName ：蔡 @@ Age ： 38y/o

Sex ：♀ Occupation ： military personnel

Marital Status ： Married Ht / Wt ： 156cm / 51kg

Chief Complaint ：Progressive left upper neck mass for 2

months

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＜ Present illness ＞ One month prior to admission, she noticed there was an enlarging mass at left upper neck area. The mass was about 4×4 cm, fixed, firm, non-tender, and slightly movable. Fine needle biopsy was done but showed no malignancy at 802 Hospital. Then she sought help at our ENT OPD, admission for biopsy was done and showed unclassified lymphoma. Whole bone scan and sonogram of upper abdomen showed no malignancy.

＜ Past History ＞ No diabetes, No HTN, No asthma, no liver disease, No CV D’z, No renal D’z

Case　Presentation

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＜ Personal History ＞ Gravida ： 2 Drug/Food allergy ： Nil Cigarette smoking ： Nil

Para ： 2Alcohol drinking ： NilBetel nut ： Nil

＜ Review of Systems ＞ General condition ： no body weight loss, no fatigue, no fever

Skin ： no rash, no pruritus, no nodule

Head ： no dizziness /　Eyes ： no blurred vision, diplopia

Ears ： no hearing impairment

/ Nose ： no smell disturbance

Throat ： no oral ulcer, no sore throat

Respiratory system ： no dyspnea, no cough

Case　Presentation

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＜ Physical Examination ＞ Ht / Wt ： 156cm / 51kg Vital sign ： BP_105/64mmHg ， PR_62/min ， RR_18/min ， BT_36.3℃ General appearance ： conscious level ： GCS E:4 V:5 M:6 Total:15 HEENT ： Head_no tenderness ， Ears_no vertigo ， Eyes_noraml corneal reflex ， Nose_no epitaxis ， Throat_no exudates Neck ： mass lesion over L’t upper neck Heart ： No murmur / Extremities ： freely movable

Case　Presentation

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Case　Presentation

Case　PresentationLabs　and　Diagnostic　Tests

6/16 CT face + neck

Presence of a large confluent nodal mass with central necrosis, measured about 4.2cm in maximal diameter, in left carotid space of upper neck. Nodal metastasis should be first considered. Suggest biopsy.

6/17 Surgical pathology

Nasopharynx, biopsy- - Nasopharyngeal tissue with prominent lymphoid follicles and inflammatory cell infiltration. There is no evidence of malignancy in the sections examined.

Tongue base, biopsy- - Tongue tissue with dense chronic inflammatory cell infiltration.

Esophagus, panendoscopic biopsy- - Normal esophageal mucosa with mild acute inflammatory cell infiltration.

Pyriform sinus, left, biopsy– Normal squamous mucosa with acute inflammatory cell infiltration.

Soft tissue, neck, left, punch biopsy– Dense small lymphoid cells aggregate in soft tissue. The immunostains show mixed CD10(+) and CD20(+) in lymphoid cells

Tonsil, left, biopsy– Tonsillar tissue with increased cellularity of lymphoid tissue and formation of many follicles.

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Labs　and　Diagnostic　Tests6/17 Frozen section-- soft tissue, neck, left

Pathological diagnosis ： 1) B cell lymphoma, classifiable with features Burkitt’s lymphoma. 2) Favor malignant

The normal architecture is effected by diffuse infiltration of small lymphoid cells with starry-sky background. The tumor cells are positive for the CD20 and CD10, and negative for Bcl 2. The Ki-67 proliferation index is >95%.

Case　Presentation

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2011/07/03 Admitted for staging and possible re-biopsy of lymphoma

7/6 Surgical pathology – Soft tissue, neck, left upper, incisional biopsy

B-cell lymphoma, classifiable, with features Burkitt’s lymphoma. The normal architecture is effaced infiltration of small lymphoid cells with starry-sky background.

Case　Presentation

Diagnosis Burkitt’s lymphoma

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Problem list

Current medical problem

Goal of therapy Measureable endpoint

Burkitt’s　　　　Lymphoma

Symptom control- Response rate

Prophylaxis metastasis to CNS

Nodular size decreased No CNS

involement

Current Drug-Related Problem

Subjective　and　ObjectiveProblem　(subjective　and　objective) Current

medication

S: She　complains　of　progressive　left　upper　neck　mass　for　2　months

No diabetes, No HTN, No asthma, no liver disease, No CV D’z,No renal D’z

No medical record

Review of Systems : General condition ： no body weight loss, no fatigue,no fever, no rash, no pruritus, no nodule, no dizziness, no blurred vision, diplopia, no hearing impairment, no smell disturbance, no oral ulcer, no sore throat, no dyspnea, no cough

Personal History : Married with 2 children. She is a military personnelNo Tobacco, Betel nut or alcohol smoking

Drug/Food allergy : NKDA

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Current Drug-Related Problem

Subjective　and　ObjectiveProblem　(subjective　and　objective) Current

medication

O:156cm / 51kg, BSA 1.49, BP_105/64mmHg ， PR_62/min ， RR_18/min ， BT_36.3℃General appearance ： conscious level ： GCS E:4 V:5 M:6, Total:15HEENT ： Head_no tenderness, Ears_no vertigo, Eyes_normal corneal reflex, Nose_no epitaxis, Throat_no exudatesNeck ： mass lesion over L’t upper neck Heart ： No murmur / Extremities ： freely movable

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Current Drug-Related Problem

Subjective　and　Objective　　　　　　　　　　　　　(Continued)

Problem　(subjective　and　objective) Current medication

O:

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Current Drug-Related Problem

AssessmentEtiology (/risk factors)

Evidence need for therapy evaluation (current/ recommended therapy)

Burkitt’s Lymphoma

Risk Factor : Infectious agents

(-) Chemical

exposure (-) Medical

treatment (-)

Treatment for Burkitt’s lymphoma- The best drug therapy option for

this patient is ：

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Treatment for Burkitt’s　Lymphoma

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Those patients with all of the following features were regarded as low risk : (i) normal LDH level; (ii) WHO performance status of 0 or 1; (iii) Ann Arbor stage I–II; and (iv) no tumor mass ≥10cm. All remaining patients were considered high risk.

LDH 191 U/L PS 1 Stage Ia The mass was about 4×4

cm

Low risk Burkitt’s Lymphoma31

Treatment for Burkitt’s　Lymphoma

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Original　CODOX-M　regimen-- Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate

Epirubicin 60mg/m2

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CNS prophylaxisIntrathecal Ara-C &

MTX

Modified CODOX-M Regimen

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High dose MTX : decreased from 6,720 mg/m2 to 3,000 mg/m2, reduce toxicity while maintaining adequate CNS penetration

Endoxan was changed from 800 mg/m2 day 1 followed by 200 mg/m2 days 2–5 to 800 mg/m2 days 1 and 2 to reduce myelosuppression

IT Ara-C was reduced from 70 mg to 50 mg to reduce the incidence of neurotoxicity

Modified Magrath Regimens for Adults with Burkitt’s and Burkitt-Like Lymphomas: Preserved Efficacy with

Decreased Toxicity

There were a total of 16 relapses (20%). Fewer relapses were observed among

rituximab-treated patients compared with patients treated with chemotherapy alone (3 vs. 13, P=0.01).

40 p’t received rituximab + C/T

(R-CODOX-M/R-IVAC)

VS. 40 p’t treated with C/T

alone.

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Renal function GFR 10 ～ 50 mL/min- 50% of the usual dose given at the

normal interval GFR < 10 mL/min - avoided GFR > 50 mL/min – No adjustment

Liver function Bilirubin is < 3.0 mg/dL & SGOT< 180IU - 100% of the dose

may be administered. Bilirubin 3.1 ～ 5.0 mg/dL or SGOT >180 IU -75% of the

dose Bilirubin > 5.0 mg/dL –omitted

Micromedex

Methotrexate　dosage　adjustment

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High dose Methotrexate therapy, patient should be given leucovorin to prevent myelosuppression toxicity.

Leucovorin commenced 24 h after starting MTX infusion and continued until the serum MTX level <5 × 10–8 M

Alkalinization of the urine in patients receiving high-dose methotrexate therapy has also been shown to be effective in preventing nephrotoxicity and attentuating the myelosuppression.

Methotrexate related medical problem

Complication _ Tumor lysis syndrome (TLS)

It typically occurs in patients with lymphoproliferative malignancies, most commonly observed following chemotherapy for high-grade lymphoproliferative malignancies such as acute lymphocytic leukemia and Burkitt’s lymphoma, who are exposed to chemotherapy, radiation, or corticosteroids, but can occur spontaneously in the absence of treatment.

Release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.

Renal failure impairment Catabolism of the nucleic acids to uric acid leads

to hyperuricemia

Hyperphosphatemia with calcium phosphate deposition in the renal tubules

The best management of TLS is preventionHydration 5% dextrose +1/4 normal saline or

normal saline 2 ～ 3 L/m2/day

Urine alkalinization

use of sodium bicarbonate & keep urine PH >7

Allopurinol 100 mg/m2 Q8H (max 800 mg/day)initiated 24 to 48 hours before the start of induction chemotherapy. It is continued for up to three to seven days afterward

Rasburicase 0.15 ～ 0.2 mg/kg once daily for 5 days

Complication _ Tumor lysis syndrome (TLS) Certain intrinsic tumor-related high risk factors

High tumor cell proliferation rate Chemosensitivity of the malignancy Large tumor burden, as manifested by -bulky >10

cm -WBC >50,000 /ul -LDH >2× ULN

Current Drug-Related Problem

AssessmentEtiology (/risk factors)

Evidence need for therapy evaluation (current/ recommended therapy)

Burkitt’s　lymphoma

Risk factory of NHL

infectious agents (-)

chemical exposures (-)

medical treatments (-)

Treatment　for　Burkitt’s　LymphomaRituximab + (Original/Modified) CODOX-M regimen

repeated 2 weeks cycle, total 3-4 cycles

*Rescue high dose MTX toxicity : Leucovorin initial

dose 10mg/m2 every 3-6 hrs after 24hs MTX infusion

started. *Prevent tumor lysis syndrome : - Allopurinol (100mg/m2 every 8 hrs, max

800mg/d) is generally initiated 24 to 48 hours

before the start of induction chemotherapy - Hydration – normal saline 2-3L/m2/day - Urine alkalinization–concomitant with

Sodium bicarbonate, keep urine PH > 7

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Current Drug-Related Problem

PlanRecommended drug treatment, drug to be revised, further test

Goal and monitoring parameters

Patient education

1. Rituximab + original CODOX-M regimen, repeated 2 weeks cycle, total 4 cycles

R + modified CODOX-M repeated 2 weeks cycle, total 4 cycles

2. Leucovorin, initial 15mg IV Q3H, subsequently dose adjust by MTX level

3. Alkalinization with NaHCO3 7% 40cc IV Q6H & hydration with N/S 3000cc followed by MTX

4. Prophylaxis for tumor lysis syndrome Allopurinol 100mg PO TID beginning 2-3 days prior to chemotherapy and continued for 10-14 days

1. Therapeutic Drug monitor-MTX serum level ≦ 0.05-0.1uM

2. Closed monitor liver & renal

function

3. Keep urine PH > 7 4. Keep ANC>1000 G-CSF continued until neutropenia resolved.

5. Monitor of serum potassium,

uric acid, phosphorous, calcium & LDH

6. F/U bone marrow aspiration

7. Evaluation response CR, PR, SD or PD

1. 化療後免疫力降低，容易造成Neutropenia & Infection - 避免使用生食

2. Elevated liver enzyme was noticed after C/T, suspected MTX-related避免食用具肝毒性食物

例如：酒類，花生、玉米 .. 等含黃麴毒素食品

3. 黏膜受損 – Nystatin 漱口水

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Liver impairment / Toxicity

Response criteria for lymphoma

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(complete remission)

(partial remission)

Reference1. Hematol Oncol 2010; 28: 53–56

2. Annals of Oncology 21 (Supplement 5): v172–v174, 2010

3. Blood. 2010; 116(12):2040-2045

4. American Society of Hematology, 2009, The 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue

5. J Clin Oncol 29:1835-1843

6. 衛生署健康局癌症組7. Uptodate

8. Micromedex

9. NCCN Clinical Practice Guidelines in Oncology

10. HARRISON’S_Hematology and Oncology textbook, 17th ed

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Rituximab需經事前審查核准後使用限用於•復發或對化學療效有抗性之低惡度 B細胞非何杰金氏淋巴瘤。•併用 CHOP或其他化學療法，用於 CD20抗原陽性之 B瀰漫性大細胞非何杰 金氏淋巴瘤之病患。•併用 CVP化學療法，用於未經治療之和緩性（組織型態為濾泡型） B細胞 非何杰金氏淋巴瘤的病人。•用於做為濾泡性淋巴瘤患者對誘導療法產生反應之後的維持治療用藥。 限用八劑，每三個月使用一劑，最多不超過二年。

In the current issue of Haematologica, as well as in other series, the outcome of these patients is dismal irrespective of standard R-CHOP or intensified treatment including bone marrow transplantation. 17 While in elderly patients, who actually form the majority of this group, this may be sufficient grounds to refrain from aggressive treatment, this policy may not be acceptable for younger and fit patients. In these patients, treatment with BL regimens may therefore be preferred over standard R-CHOP, which will certainly not be sufficient to control the disease.

Haematologica, 2009; 94(7), p894

Lymphomas fall into one of two major categories: Hodgkin's lymphoma (HL, previously called Hodgkin's disease) and all other lymphomas (non-Hodgkin's lymphomas or NHLs).

These two types occur in the same places, may be associated with the same symptoms, and often have similar appearance on physical examination. However, they are readily distinguishable via microscopic examination.

Hodgkin's disease develops from a specific abnormal B lymphocyte lineage. NHL may derive from either abnormal B or T cells and are distinguished by unique genetic markers.

There are five subtypes of Hodgkin's disease and about 30 subtypes of non-Hodgkin's lymphoma.

Because there are so many different subtypes of lymphoma, the classification of lymphomas is complicated (it includes both the microscopic appearance as well as genetic and molecular markers).

Many of the NHL subtypes look similar, but they are functionally quite different and respond to different therapies with different probabilities of cure. HL subtypes are microscopically distinct, and typing is based upon the microscopic differences as well as extent of disease.