Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies

29

Hodgkin Lymphoma

Gisa Schun*

Jame Abraham

Marcel P. Devetten

*Section of Hematology/Oncology, West Virginia University, Morgantown, West Virginia

Section of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia

Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska

EPIDEMIOLOGY

Hodgkin lymphoma (HL) is among the most common malignancies of young adults. It constitutes approximately 1% of all malignancies and 18% of all lymphomas, and, in the United States, 3 of every 100,000 people develop this condition. In Europe and North America, there is a bimodal age distribution, with an increasing frequency between the second and third decades, and a second peak in the seventh decade.

ETIOLOGY AND RISK FACTORS

  • The etiology of HL is unclear and may be multifactorial.
  • Same-sex siblings of patients with HL have a ten times higher risk of developing HL than siblings of a different sex. This association may be caused by genetic factors and/or environmental factors.
  • Approximately 40% to 50% of the cases of “classic” HL have clonal integration of Epstein–Barr virus (EBV) in the Reed–Sternberg (RS) cells.
  • Smoking has recently been linked to HL.

PATHOLOGY

HL is a neoplastic disorder of the lymphoid system, usually arising from B lymphocytes. Typically, a small number of scattered giant neoplastic cells (RS cells) are surrounded by an inflammatory background.

Reed–Sternberg Cells or Variants

  • The RS cell is a lymphoid cell, and in most of the cases studied, it is a clonal B cell.
  • Cytologically, the RS cell is a multinucleated giant cell with large eosinophilic inclusion-like nucleoli, with a thick, well-defined nuclear membrane and pale-staining chromatin.
  • The classic RS cell has two mirror-image nuclei, which are often described as “owl's eyes.”
  • A background of lymphocytes, eosinophils, and histiocytes is usually present (see Fig. 29.1).
 

FIG. 29.1. A: Diagnostic Reed–Sternberg cell, seen in classic types of Hodgkin lymphomas (mixed cellularity, nodular sclerosis, lymphocyte depletion). B: Variants of Reed–Sternberg cells seen in nodular lymphocyte-predominant Hodgkin lymphomas: popcorn cells or L and H cells (lymphocytic or histiocytic predominance). Reed–Sternberg cells of the classic type generally are not seen in a nodular lymphocyte-predominant Hodgkin lymphoma.

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Histopathologic Classification

In 1994, the International Lymphoma Study Group introduced a classification incorporating immunologic and molecular data as part of a Revised European–American Lymphoma classification (REAL) for HL, which replaced the older Rye classification. The REAL classification was incorporated in the classification of the World Health Organization (WHO) in 2001 (see Table 29.1).

TABLE 29.1. Classification systems

REAL Classification, 1994

Rye Classification, 1965

REAL, Revised European–American Lymphoma.

Lymphocyte predominance Classic Hodgkin lymphoma

Lymphocyte predominance, nodular

Lymphocyte predominance, diffuse (most cases)

Lymphocyte-rich classic HL

Lymphocyte predominance, nodular (some cases)

Nodular sclerosis (NSHL)

Nodular sclerosis (NSHL)

Mixed cellularity (MCHL)

Mixed cellularity (MCHL)

Lymphocyte depletion

Lymphocyte depletion

The REAL/WHO classification recognizes two distinct diseases with distinguishing histopathologic features and immunophenotypes:

  1. Classic Hodgkin Lymphoma (CHL)
  2. Lymphocyte-predominant Hodgkin Lymphoma (LPHL).

Features and immunophenotypes of classic HL and LPHL are described in Table 29.2.

TABLE 29.2. Features and immunophenotypes of Hodgkin lymphomas

Cells/Antigen

Classic HL

Lymphocyte-predominant HL

HL, Hodgkin lymphoma.

Diagnostic RS cells

Always present

Rare to absent

Lymphocytes (background)

T > B cells

B > T cells

CD30 (Ki-1)

Usually positive

Often positive

CD15 (Leu M1)

Usually positive

Negative

CD45 (LCA)

Usually negative

Positive

CD20 (L26)

Usually negative

Positive

EBV

40%–50% positive

Usually negative

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CLINICAL FEATURES

  • More than 80% of patients present with cervical lymph node enlargement, and more than 50% have mediastinal adenopathy.
  • Lymph nodes are usually nontender, firm, and rubbery.
  • Constitutional symptoms (“B” symptoms):
  • Unexplained fever (temperature, >38°C)
  • Drenching night sweats
  • Unexplained weight loss (>10% of body weight, more than 6 months before the diagnosis)
  • Other symptoms are important to note but are not considered “B” symptoms: fatigue, weakness, anorexia, alcohol-induced nodal pain, and pruritus.

Staging [Ann Arbor/American Joint Committee for Cancer (AJCC) and Cotswold] is outlined in Table 29.3.

TABLE 29.3. Staging

Stage I

Involvement of single lymph node region or lymphoid structure (spleen, thymus, Waldeyer ring), or involvement of a single extralymphatic site (IE)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm (II), which may be accompanied by localized contiguous involvement of an extralymphatic organ or site (IIE). The number of anatomic sites may be indicated by numeric subscript

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIE+S)

Stage IV

Disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

Each stage is divided into A and B categories: B for those with defined systemic symptoms, and A for those without

X

A mass >10 cm or a mediastinal mass larger than one third of the thoracic diameter

E

Involvement of a single extranodal site contiguous to a known nodal site

CS

Clinical staging

PS

Pathologic staging

Pretreatment Evaluation

  1. Excisional biopsy of an enlarged lymph node: evaluation of the specimen by a hematopathologist, including immunophenotyping. Generally, needle biopsies are insufficient for a proper diagnosis.
  2. History with attention to B symptoms.
  3. Complete physical examination and documentation of measurable disease.
  4. Laboratory tests include:
  • Complete blood count (CBC), erythrocyte sedimentation rate (ESR)
  • Biochemical tests of liver function, renal function, and serum uric acid, lactate dehydrogenase (LDH), serum albumin.

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  1. Radiologic studies:
  • Chest radiograph and computerized tomography (CT) scan of the chest, abdomen, and pelvis are used for evaluation. CT scan of the neck is useful, particularly if the neck or upper chest is involved.
  • Baseline gallium scans or positron emission tomography (PET) scans can be useful. PET scan is increasingly favored for staging because of evidence of higher sensitivity and accuracy, particularly in the spleen.
  • Bone scan or radiographs are used if bone pain or tenderness is present.
  1. Bone marrow biopsy of at least one posterior iliac crest for those with abnormal CBC or clinical stage IIB, III, or IV.

Staging laparotomy and splenectomy were done routinely in the past for patients with early stage disease above the diaphragm and for whom definitive radiation treatment was considered. Now, with newer radiologic testing such as PET scans, it is rarely used.

Unfavorable Prognostic Features

The most important unfavorable prognostic features are advanced stage, B symptoms, and presence of bulky disease.

  1. Advanced stage (IIIB and IV)
  2. Presence of B symptoms (i.e., fever, weight loss, and drenching night sweats)
  3. Bulky disease defined as >10-cm diameter, particularly in the mediastinum (more than one third of chest diameter)
  4. Extranodal involvement (liver, spleen, and bone marrow)
  5. Patients older than 40 years
  6. Increased ESR (B symptoms + ESR >30, or no B symptoms and ESR >70)
  7. Histology

o   Unfavorable: mixed cellularity and lymphocyte depletion

o   Favorable: lymphocyte-predominant and nodular sclerosis

  1. Low serum albumin.

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MANAGEMENT OF NEWLY DIAGNOSED HODGKIN LYMPHOMA

HL is treated with a curative intent. In view of the high cure rates, studies have increasingly addressed long-term toxicities to define best treatment strategies. Treatment selection is therefore not only influenced by stage and unfavorable prognostic factors but also by toxicity.

Risk Stratification and PROGNOSIS

Two major risk groups are distinguished, early and advanced disease:

  1. Stages I and II without B symptoms or bulky disease are considered “favorable early stage” and are at low risk for recurrence. Cure rate is greater than 90%.
  2. Stage IIB and stages I to IIB with bulk are variably considered “early” or “advanced” by different study groups. Most U.S. groups treat them as “unfavorable early disease.” Cure rate is greater than 80%.
  3. Stages III and IV are considered “advanced stage” and are at significant risk for recurrence. Cure rate is about 60% to 70%.

Other criteria might be included to subdivide the two major risk groups further to avoid under- or overtreatment of patients with early stage disease.

For example, the Canada Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) separate early stage Hodgkin Disease HD into:

Low risk: includes nodular lymphocyte-predominant Hodgkin disease (NLPHD) and nodular sclerosing histology, affects individuals younger than 40 years, ESR is less than 50, and three or less disease-site regions are involved.

High risk: includes all other diseases in stages I to II, excluding bulky disease >10 cm.

Radiation Treatment

Radiation is the most effective single therapeutic modality for HL. In general, the management of HL with radiation therapy consists of treating regions of known disease (“involved field”). An “extended field” treats unaffected adjacent nodal groups in addition to the involved regions (see Table 29.4).

TABLE 29.4. Radiation guidelines

Tumoricidal dose

40–45 By at the rate of 10 Gy/wk

Clinically negative nodal regions

35 Gy

Consolidation (after chemotherapy)

15–20 Gy

Radiation covering extended fields is used to three major fields, known as the mantle, paraaortic, and pelvic or inverted-Y fields (see Fig. 29.2).

 

FIG. 29.2. Radiation therapy fields used in treating Hodgkin disease (A, B, C, and D). When the fields shown in C and D are combined, this is commonly called total nodal irradiation (TNI). (From Haskell CM. Cancer Treatment. 4th ed. Philadelphia: WB Saunders, 1995:965, with permission.)

The usual dose of radiation is 25 to 30 Gy to uninvolved areas and 35 to 44 Gy to the involved field. Radiation doses can be lower when used in conjunction with chemotherapy

  • Radiation therapy alone is reserved for early stages of HL without unfavorable prognostic features.
  • In patients with advanced disease, radiation contributes to disease-free survival shown for bulky disease and nodular sclerosis histology, but whether it prolongs overall survival is not evident. Adding long-term toxicity with radiation remains a concern because of the high cure rate even in advanced disease.
  • When choosing modalities, one should consider the higher risk of young women (younger than 27 years old) for breast cancer and the higher risk of lung cancer in smokers as late toxicity from radiation to the chest.
  • Patients who relapse after treatment with radiation therapy alone are frequently salvaged successfully with combination chemotherapy.

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Chemotherapy

The first “curative regimen” was mechlorethamine, Oncovin, procarbazine, prednisone (MOPP), which resulted in a 70% complete remission in patients with stage III and stage IV

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cancer. Subsequently, many regimens have been developed, including MOPP variants, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) and its variants, and hybrids of MOPP/ABVD.

Choosing between MOPP, ABVD, and MOPP/ABVD

In a randomized study, the Cancer and Leukemia Group B (CALGB) showed ABVD and MOPP/ABVD to be superior to MOPP alone in terms of remission, freedom from progression, and survival. At 10 years, the risk of developing treatment-related leukemia with the MOPP regimen is 2% to 3%, whereas it is 0.7% with ABVD. Infertility rates are much lower with ABVD than with MOPP (see Table 29.5).

TABLE 29.5. Cancer and Leukemia Group B study comparing combination treatments

Regimen

Complete response rate (%)

Survival rate (%)

MOPP, mechlorethamine, Oncovin, procarbazine, and prednisone; ABVD, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine.

MOPP

67

64

ABVD

82

72

MOPP/ABVD

83

73

A recent randomized intergroup trial demonstrated that MOPP/ABV is associated with a greater incidence of acute toxicity, myelodysplasia (MDS), and leukemia than ABVD is, with no difference in failure-free survival or overall survival at 5 years. ABVD should be considered the standard regimen for treatment of advanced HD (see Table 29.6).

TABLE 29.6. Commonly used treatment regimens

ABVD

Doxorubicin, 25 mg/m2/dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 50 mg/m2)

Bleomycin, 10 units/m2/dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 20 units/m2)

Vinblastine, 6 mg/m2/dose i.v. push for two doses, d 1 and 15 (total dose/cycle, 12 mg/m2)

Dacarbazine, 375 mg/m2/dose i.v. infusion for two doses, d 1 and 15 (total dose/cycle, 750 mg/m2)

Treatment cycle repeats every 28 d

MOPP

Mechlorethamine, 6 mg/m2/dose i.v. push for two doses, d 1 and 8 (total dose/cycle, 12 mg/m2)

Vincristine, 1.4 mg/m2/dose i.v. push for two doses, d 1 and 8 (total dose/cycle, 2.8 mg/m2)

Procarbazine, 100 mg/m2/d PO for 14 doses, d 1–14 (total dose/cycle, 1,400 mg/m2)

Prednisone, 40 mg/m2/d PO for 14 doses, d 1–14 (cycles 1 and 14 only) (total dose/cycle, 560 mg/m2)

Treatment cycle repeats every 28 d

Alternating MOPP/ABVD

Alternate MOPP and ABVD cycles by 28 d

MOPP/ABV hybrid

Mechlorethamine, 6 mg/m2 i.v. push d 1 (total dose/cycle, 6 mg/m2)

Vincristine, 1.4 mg/m2 i.v. push d 1 (total dose/cycle, 1.4 mg/m2; maximal dose, 2 mg)

Procarbazine, 100 mg/m2/d PO for 7 doses, d 1–7 (total dose/cycle, 700 mg/m2)

Prednisone, 40 mg/m2/d PO for 14 doses, d 1–14 (total dose/cycle, 560 mg/m2)

Doxorubicin, 25 mg/m2 i.v. push d 8 (total dose/cycle, 25 mg/m2)

Hydrocortisone, 100 mg i.v. d 8, before bleomycin (total dose/cycle, 100 mg)

Bleomycin, 10 units/m2 i.v. push d 8 (total dose/cycle, 10 units/m2)

Vinblastine, 6 mg/m2 i.v. push d 8 (total dose/cycle, 6 mg/m2)

Treatment cycle repeats every 28 d

Stanford V

Mustard, 6 mg/m2 i.v. wk 1, 5, 9

Vincristine, 1.4 mg/m2 i.v. wk 2, 4, 6, 8, 10, 12 (maximal dose, 2 mg)

Prednisone, 40 mg/m2/d PO every other d wk 1–9, taper

Doxorubicin, 25 mg/m2 i.v. wk, 1, 3, 5, 7, 9, 11

Bleomycin, 5 units/m2 i.v. wk 2, 4, 6, 8, 10, 12

Vinblastine, 6 mg/m2 i.v. wk, 1, 3, 5, 7, 9, 11

VP-16 60 mg/m2 i.v. × 2 wk 3, 7, 11

1. The maximum dose of vincristine is 2 mg

2. All drugs are administered on d 1, except for VP-16, which is given on d 1 and 2

3. Taper prednisone by 10 mg of the total dose q.o.d. (every other day) on wk 10 and 11

4. Reduce the dose of vinblastine to 4 mg/m2 if on wk 9 and 11 for patients over the age of 50 yr old

5. Reduce the dose of vincristine to 1 mg on wk 10 and 12 for patients over the age of 50 yr

6. If mustard is not available, a substitution with 650 mg/m2 of cyclophosphamide can be made on wk 1, 5, 9

7. Patients will receive total of 12 wk of treatment.

Combined Modality Treatment

A meta-analysis of 23 trials of patients with early stage HD showed that the 10-year rate of freedom from relapse was higher with combined modality therapy than with radiation, but survival rates were not significantly different.

Primary Treatment Options

  1. Favorable early disease
  2. Two to four cycles ABVD with involved field radiation to follow
  3. Extended field radiation alone.
  4. Unfavorable early disease
  5. Four to six cycles ABVD with involved or extended field radiation. One European randomized trial showed no difference in freedom from treatment failure or overall survival when extended field radiation was replaced by involved field radiation (30 Gy to field, 10 Gy to bulk).
  6. Advanced disease
  7. ABVD for six to eight cycles is the current standard. Treatment is usually continued two cycles after resolution of disease by imaging studies.
  8. Addition of involved field radiation is usually considered, particularly for bulky disease. Recent evidence from a randomized trial suggests there may be no need to add radiation, if a complete response can be achieved with combination chemotherapy.
  9. Stanford V is an effective regimen with shorter treatment duration (3 months) and is currently undergoing randomized comparison with ABVD-based treatment in intergroup trial E2496.

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  1. Lymphocyte-predominant Hodgkin lymphoma: This subtype has the propensity to cause multiple relapses even up to 15 years.
  2. Early stages of LPHL without risk factors are treated with radiation alone.
  3. Advanced stages are rare at diagnosis and carry a poor prognosis. They are treated like nodular sclerosing histology.
  4. Phase II trials show single-agent activity of rituximab for the usually CD20-positive LPHL. It is possibly effective in the chemotherapy-refractory setting, although the effect is of short duration. The use of rituximab has to be considered investigational and affected patients should be referred for trials because of the rarity of the disease.

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High-dose Therapy and Autologous Stem Cell Transplantation

High-dose therapy with autologous transplant has no defined role for consolidation in the treatment programs for newly diagnosed unfavorable-risk HL that respond to standard chemotherapy. One randomized trial from the United Kingdom demonstrated no advantage in patients with highly unfavorable prognosis in achieving complete response with the European regimen PVACE-BOP.

Evaluation of Treatment Response with Positron Emission Tomography

PET is a new tool in managing patients with lymphomas. A negative PET scan at completion of therapy indicates a favorable prognosis. Persistently positive PET scans at the end of chemotherapy seem to have a high sensitivity for predicting subsequent relapse and need close follow-up; however, some of those patients may remain in prolonged remission. More prospective studies are needed to define the usefulness and limitations of PET scans more precisely.

TREATMENT OF RELAPSED HODGKIN LYMPHOMA

In general, relapsed HL is still curable.

Relapses usually occur within 2 to 3 years after primary therapy. There are currently no clear parameters to predict the 15% to 20% of patients who will progress during treatment or relapse early. Patients with relapse within 1 year of primary treatment or with a second relapse have a survival of less than 20% at 5 years. For successful choice of management, one should consider the following:

  1. Sites of relapse (i.e., prior radiated area, single or multiple nodes, extranodal, bulky).
  2. Details of previous treatment.

If the relapse is due to inadequate initial treatment, retreatment with chemotherapy or radiation is considered.

Relapse after primary radiation is best managed with chemotherapy.

  1. Achievement and duration of first remission:

Early relapse (<1 year) or persistent disease after primary therapy with adequate numbers of cycles of combination chemotherapy should be treated with salvage chemotherapy followed by autologous stem cell transplantation with curative intent.

Late relapse (particularly with favorable features: no B symptoms, long disease-free interval, no bulk, disease confined to lymph nodes, best only one site) has a chance for cure with salvage chemotherapy (and radiation if applicable). But consolidation with autologous stem cell transplantation should always be considered. Chemosensitive relapse treated with transplantation has the best prognosis.

  1. Primary refractory HL is associated with a poor overall survival. However, some (15% to 20%) patients experience prolonged disease-free survival (DFS) after high-dose chemotherapy with autologous stem cell transplantation.

SALVAGE CHEMOTHERAPY REGIMENS

Non–Anthracycline-containing Regimens

  1. ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)
  2. ICE (ifosfamide, carboplatin, and etoposide)
  3. EIP (etoposide, ifosfamide, and cisplatin)
  4. DHAP (dexamethasone, high-dose cytarabine, and cisplatin)
  5. MINE [mitoguazone (500 mg per m2on days 1 and 5), ifosfamide (1,500 mg/m2per day from day 1 to day 5), vinorelbine (15 mg per m2 on days 1 and 5), and etoposide (150 mg/m2/day from day 1 to day 3) for two 28-day cycles]

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Anthracycline-containing Regimens

EVA (etoposide, vincristine, and doxorubicin)

ASHAP (doxorubicin, cisplatin, high-dose cytarabine, and methylprednisolone)

Prognostic Factors in Relapse (Stanford Study)

  1. 10-year DFS worsens with disease stage at the time of initial radiation:
  • Stage IA, 88%.
  • Stages IIA and IIIA, 58%.
  • Stage IV or B symptoms, 34%.
  1. 10-year DFS depends on histology
  • LPHL and Nodular Sclerosis Hodgkin Lymphoma (NSHL), 67%.
  • Mixed Cellular Hodgkin Lymphoma (MCHL) and LPHL, 44%

Palliative Treatments

  1. Investigational treatment
  2. Radiation treatment
  3. Sequential single-agent chemotherapy

Gemcitabine emerges as new active agent in refractory HL

  1. Steroids

COMPLICATIONS OF THERAPY

Radiation THERAPY

Early Complications

  • Mantle field radiation: mouth dryness, pharyngitis, cough, and dermatitis
  • Subdiaphragmatic radiation: anorexia, nausea, and diarrhea
  • Myelosuppression

Late Complications of Radiation for Hodgkin Lymphoma

  • Hypothyroidism
  • Pericarditis and pneumonitis
  • Lhermitte sign: Six to 12 weeks after the treatment, 15% of the patients receiving mantle radiation may experience electric shock sensation radiating down the back of the legs when their head is flexed. This sensation may be caused by the transient demyelinization of the spinal cord, and it usually resolves spontaneously.
  • Coronary artery disease (CAD): Increased risk in patients who receive cardiac radiation. Patients should be monitored and evaluated for other risk factors for CAD.

SECONDARY NEOPLASM

Secondary neoplasms arise 20 years after radiation treatment in 75% of cases in the radiation field at a rate of 20% to 25%. Studies raise the possibility that splenic field radiation and splenectomy increase the risk of treatment-related cancer.

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  • Lung cancer:
  • Twofold to eightfold increase in lung cancer is observed more than 5 years after the radiation treatment and persists through the second decade.
  • The increase in lung cancer occurs mostly in smokers, who should be encouraged to stop smoking.
  • Breast cancer:
  • The increase in breast cancer is inversely proportional to the age at radiation treatment. The relative risk (RR) is 136 if the patient is younger than 15 years. RR is 19 for age group 15 to 24 years and is 7 for age group 24 to 29 years.
  • Women irradiated before age 30 years are at high risk.
  • Average interval between radiation and diagnosis of breast cancer is 15 years.
  • Breast examination should be part of follow-up for women at risk.
  • Routine mammography should begin about 8 years after completion of the radiation.
  • Thyroid cancer
  • Stomach and esophageal cancer
  • Sarcomas

Chemotherapy

Early Complications

  • Nausea and vomiting
  • Alopecia
  • Myelosuppression
  • Infection
  • Pneumonitis (bleomycin)

Late Complications

Long-term follow-up for chemotherapy has not been documented beyond 15 years and is therefore not yet comparable with long-term data for radiation toxicity.

  • Sterility
  • High risk with MOPP-based regimens
  • ABVD has a very low risk for permanent amenorrhea in women younger than 25 years. Male fertility returns to normal in most patients.
  • Neuropathy (primarily with vincristine)
  • Cardiomyopathy (doxorubicin)
  • Pulmonary fibrosis (bleomycin)
  • Secondary leukemia (MOPP ± radiation

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