Chemotherapy of Hodgkin Lymphoma

Anne Hudson Blaes

Bruce A. Peterson

In the four decades since the introduction of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) by DeVita and coworkers,¹ significant advances have been made in enhancing efficacy and ameliorating the adverse effects of chemotherapy in Hodgkin lymphoma. Multidrug chemotherapy is now firmly established as the basis for curative treatment in patients with advanced-stage disease, and its role has been expanded to include its use in those with localized disease as well. In 2010, there were nearly 8,500 new cases of Hodgkin lymphoma diagnosed in the United States and approximately 1,300 deaths.² This translates into an annual age-standardized incidence rate of 2.8 per 100,000 and a death rate of approximately 0.4 per 100,000, down from 1.8 before the introduction of MOPP. It is increasingly clear, however, that many survivors of Hodgkin lymphoma experience late effects from their treatment, including second malignancies, cardiovascular and pulmonary disease, endocrine dysfunction, infertility and a compromised quality of life.³^,⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹ They are often more likely to die of second cancers or cardiopulmonary disease than of Hodgkin lymphoma, itself.¹²^,¹³ Today there are nearly 165,000 people alive in the United States with a history of Hodgkin lymphoma, underscoring the success of current treatment and the necessity of advancing therapeutic strategies that remain effective but have minimal adverse late effects.

BACKGROUND

In most developed countries, the incidence of Hodgkin lymphoma is bimodal by age, with an early peak seen in young adults and, later, a continuous rise after the age of 50 or 60 years. In less developed countries, the early peak is usually not apparent. These patterns reflect varying risk factors, etiologies, and host and tumor biology that contribute to important differences in the behavior of Hodgkin lymphoma in younger and older patients. Differences are also apparent by geographical region and socioeconomic groups, affecting both incidence and mortality rates. Internationally, there are nearly 70,000 new cases annually with wide variations in incidence ranging from similar to those in the United States to over 5.0 per 100,000.¹⁴^,¹⁵ New evidence related to the molecular biology¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹ and etiology of Hodgkin lymphoma, such as heredity, Epstein-Barr virus (EBV), timing of oral exposure to the microbiome, and the nature of Th1 or Th2 responses, is beginning to support a consistent theoretical framework for the pathogenesis of Hodgkin lymphoma,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³² but a detailed discussion is beyond the scope of the chapter.

The malignant cells in classical Hodgkin lymphoma (cHL) (Table 41-1) are called “Hodgkin” or “Reed-Sternberg” (H-RS) cells, depending on whether mononucleated or multinucleated.³³ In nodular lymphocyte predominant Hodgkin lymphoma, the characteristic malignant cell is referred to as the “lymphocyte predominant” (LP) cell.³³ Although the origin of malignant cells in Hodgkin lymphoma eluded investigators for many years, it is now apparent that H-RS cells most commonly derive from crippled germinal center B-cells that have engaged in an immune response but in which apoptosis has been blocked.²¹^,²⁹^,³³^,³⁴^,³⁵^,³⁶ The relative rarity of H-RS cells, which aberrantly express antigens and are admixed with large numbers of normal cells that are, themselves, perturbed by heightened cytokine stimulation, made this identification especially difficult. LP cells are transformed germinal center B-cells. They have ongoing IgV mutations and express common B-cell antigens such as CD20.¹⁶^,³²^,³⁷

The different histologic subtypes of Hodgkin lymphoma³³ are associated with distinct clinical patterns (Table 41-1). Nodular lymphocyte predominant Hodgkin lymphoma tends to present in peripheral nodes as early-stage disease. It tends to be indolent and responds very well to treatment, but may relapse quite late and, occasionally, transforms into diffuse large B-cell non-Hodgkin lymphoma.³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ Nodular sclerosis cHL, the most common subtype in young patients, shows a female preponderance and is primarily nodal in distribution, frequently involving the mediastinum. Mixed cellularity cHL, in contrast, occurs in a slightly older, predominantly male population and more likely at an advanced stage, often in the abdomen. Lymphocyte-depleted cHL, the subtype characteristic of the older patient, is frequently associated with B-symptoms
and is rarely localized.³³^,⁴⁸ Lymphocyte-rich cHL must be distinguished from the nodular lymphocyte predominant subtype.³³^,⁴¹^,⁴⁹ It is seen in patients who are somewhat older but who often have limited stage disease that spares the mediastinum. Response to therapy and prognosis are excellent, and late relapses, such as in nodular lymphocyte predominant Hodgkin lymphoma, are infrequent. Although histopathologic subtype is a factor in determining outcome, therapeutic approach and prognosis, with some exceptions, depend primarily on stage.

Table 41-1 World Health Organization Classification of Hodgkin Lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma cHL
	Nodular sclerosis cHL
	Mixed cellularity cHL
	Lymphocyte-rich cHL
	Lymphocyte-depleted cHL
From Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2008.

Recognition of clinical stages extends back to 1902 when Dorothy Reed⁵⁰ distinguished between “first” and “second” stages of Hodgkin lymphoma. Her stages were not truly anatomical, but she recognized the tendency for spread to occur to “neighboring glands,” which is the foundation of modern staging. Surgical mapping of disease patterns during the era of staging laparotomy contributed to the understanding of patterns of spread and the refinement of stage-driven treatment.⁵¹^,⁵² Now, however, contemporary imaging techniques and the use of at least some chemotherapy in almost every patient make laparotomy rarely necessary. Clinical staging is sufficiently precise to permit selection of a therapeutic plan for most patients.

The emergence of ¹⁸ F-fluorodeoxyglucose positron emission tomography (FDG-PET) immensely improved the accuracy of staging and is now routinely included with CT scanning in the initial evaluation. FDG-PET more accurately delineates active disease sites, including those not identified or misidentified by CT scan, alone. Sequential FDG-PET scans have also become crucial in the assessment of response. The functional information provided by FDG-PET is critical to confirming persistent disease, especially in masses that remain after therapy.⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ Also, the rapidity of response as assessed by FDG-PET provides prognostic information. The resolution of abnormal hypermetabolic activity on an interim FDG-PET scan after only two or three⁵⁶^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶² cycles of chemotherapy is independently associated with excellent progression-free and overall survival, whereas persistently positive scans at these early reassessments are associated with a high rate of relapse even if the scan is negative after completing all therapy. Early restaging FDG-PET scans are increasingly being incorporated into clinical trials to make real-time management decisions in hopes they will improve patient outcomes and minimize acute and late toxicities by eliminating exposure to unnecessary treatments.

Table 41-2 The Ann Arbor Staging Classification with Cotswold Modification⁶³^,⁶⁴

Stage I

Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring)

Stage II

Involvement of two or more lymph node regions or structures on the same side of the diaphragm

Stage III

Involvement of lymph node regions or structures on both sides of the diaphragm

III₁: with or without splenic, hilar, celiac, or portal nodes

III₂: with para-aortic, iliac, mesenteric nodes

Stage IV

Diffuse or disseminated involvement of one or more extranodal site(s)

Special Designations

A No fevers, night sweats, or weight loss

B Fever (>38°C)

Drenching night sweats

Weight loss (>10% body weight over 6 mo)

E Focal involvement of a single extranodal site contiguous or proximal to known nodal site in stages I—III

X Suffix to designate bulky disease as greater than one-third widening of the mediastinum or >10 cm maximum dimension of nodal mass

S Subscript to designate splenic involvement

The number of anatomical regions involved should be indicated by a subscript (e.g., II₃)

Staging should be identified as clinical stage (CS) or pathologic stage (PS)

Staging of Hodgkin lymphoma is currently based upon the 1989 Cotswolds modification⁶³ of the original Ann Arbor staging system⁶⁴ (Table 41-2). Clinical stage, more than any other factor, determines treatment selection and by delineating the
initial sites of involvement provides the baseline for subsequent assessments of response. Standardized staging also permits comparisons of results across clinical trials.

Other clinical and laboratory findings may supplement the histopathologic subtype and clinical stage, helping to identify favorable or unfavorable subsets of patients who might benefit from the use of either less therapy or more.⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷² Some factors, such as age and gender, define the host while others reflect biologic characteristics of the malignancy or the host’s response to it. These include serum levels of lactate dehydrogenase, β₂-microglobulin, albumin, alkaline phosphatase, hemoglobin, erythrocyte sedimentation rate, tumor bulk, and the location or number of disease sites. In addition, studies of the malignant cell and its microenvironment using comparative genomic hybridization, gene-expression profiling, and immunohistochemistry, among other techniques are beginning to provide prognostic information as well as important biologic insights.¹⁷^,¹⁸^,⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹

With rare exceptions, such as tumor bulk, single prognostic factors are insufficient to substantially alter initial treatment strategies for individual patients. However, aggregate prognostic factors do assist in assessing prognosis and selecting uniform subsets of patients for clinical studies. The International Prognostic Score (IPS), derived from an analysis of 4,695 patients with advanced Hodgkin lymphoma by the German Hodgkin Study Group (GHSG), is the most commonly used supplemental prognostic tool.⁶⁶ All of the patients received “state-of-the-art” therapy and also had sufficient follow-up so that long-term outcomes could be adequately judged. Seven factors were identified, each with a similarly small, but definite effect on prognosis, freedom from progression (FFP) and overall survival (Table 41-3). The IPS is the sum of factors present in a given patient. It predicted 5-year survival rates ranging from 90% when either 0 to 1 factors were present to 59% with 4 to 7. A relatively small number, however, were included in this highrisk group. FFP was 74% at 5 years in those with 0 to 2 factors, but only 55% in patients who had 3 to 7. The identification of a large group of newly diagnosed patients who have an extremely poor outcome continues to be elusive. Another scoring system, based on time to first relapse, clinical stage, and anemia at relapse, has been developed by the GHSG for use in relapsed patients.⁸⁰ However, there has been less uniformity in adopting this tool in clinical trials. It may be that newer, more sophisticated tests will do a better job of assessing prognosis in Hodgkin lymphoma. For example, higher numbers of tumor-associated macrophages were recently reported to more strongly correlate with shortened survival than the IPS.⁷⁷

Table 41-3
International Prognostic Score for Advanced Hodgkin Lymphoma

Prognostic Factors
Serum albumin	<4 g/dl
Hemoglobin	< 10 g/dl
Gender	Male
Stage	IV
Age	≥45 y
Leukocytes	≥ 15,000 per ml
Lymphocytes	<600 per ml and/or 8% of total leukocyte count

Number of Factors	Percentage of Patients (%)	Freedom from Progression at 5 y (%)	Survival at 5 y (%)
0	7	84	89
1	22	77	90
2	29	67	81
3	23	60	78
4	12	51	61
≥5	7	42	56
From Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. N Engl J Med. 1998;339(21):1506-1514.

CHEMOTHERAPY OF HODGKIN LYMPHOMA

Although radiation had been established in the 1930s as potentially curative for patients with localized Hodgkin lymphoma,⁸¹^,⁸² no approach was successful when the disease had spread beyond the confines of practical radiation fields.
Hodgkin lymphoma was sensitive to some of the first chemotherapeutic agents identified beginning in the 1940s.⁸³^,⁸⁴^,⁸⁵ However, not until the introduction of the four-drug combination called “MOPP” in 1970 were complete remissions (CR) obtained with any regularity in the setting of widespread disease.¹ In the subsequent four decades, other drug combinations have been developed that match or surpass the efficacy of MOPP while, at the same time, ameliorating both acute and late toxicities. The success of multiagent chemotherapy, especially its curative potential in advanced stages, has led to the inclusion of chemotherapy in therapeutic strategies for almost all patients with localized disease as well.

MOPP and MOPP Variants

Alkylating agents, most notably mechlorethamine, were among the first to induce responses in Hodgkin lymphoma as well as in other hematologic malignancies.⁸³^,⁸⁴ Other drugs of that era were also added to the list of active single agents.⁸⁵^,⁸⁶ However, although these drugs could induce tumor regression, durable responses were rare.

Lacher and Durant combined chlorambucil with vinblastine in the 1960s⁸⁷ leading to the subsequent development of four-drug regimens, including MOPP¹^,⁸⁸^,⁸⁹^,⁹⁰ (see Table 41-4 for details of selected chemotherapeutic regimens). The four drugs in MOPP, each active, but with different toxicities and mechanisms of action, could be combined without substantial dose reductions. In the first 43 patients, DeVita et al.¹ reported a high CR rate and, significantly, that some patients were still in remission beyond 4 years. As a result of this unprecedented success, MOPP was quickly adopted for patients with advanced disease. The activity of MOPP was confirmed by an 84% CR rate in an expanded series treated at the National Cancer Institute, and just more than one-half were alive at 10 years.⁹¹^,⁹²

Table 41-4 Selected Chemotherapeutic Regimens for Hodgkin Lymphoma

Drug	Dose	Route	Schedule
MOPP¹
Mechlorethamine	6 mg/m²	IV	Days 1 and 8
Vincristine	1.4 mg/m²	IV	Days 1 and 8
Procarbazine	100 mg/m²	PO	Days 1-14
Prednisone	40 mg/m²	PO	Days 1-14
Repeated every 28 d for at least six cycles
Vincristine—maximum dose 2 mg
ChlVPP¹⁰⁴
Chlorambucil	6 mg/m²	PO	Days 1-14
Vinblastine	6 mg/m²	IV	Days 1 and 8
Procarbazine	100 mg/m²	PO	Days 1-14
Prednisone	40 mg	PO	Days 1-14
Repeated every 28 d for 6-10 cycles
Chlorambucil—maximum dose 10 mg/d
Vinblastine—maximum dose 10 mg
ABVD¹¹⁰
Doxorubicin	25 mg/m²	IV	Days 1 and 15
Bleomycin	10 U/m²	IV	Days 1 and 15
Vinblastine	6 mg/m²	IV	Days 1 and 15
Dacarbazine	375 mg/m²	IV	Days 1 and 15
Repeated every 28 d for at least six cycles
MOPP/ABVD—Alternating¹²⁴
Mechlorethamine	6 mg/m²	IV	Days 1 and 8
Vincristine	1.4 mg/m²	IV	Days 1 and 8
Procarbazine	100 mg/m²	PO	Days 1-14
Prednisone	40 mg/m²	PO	Days 1-14
Doxorubicin	25 mg/m²	IV	Days 1 and 15
Bleomycin	10 U/m²	IV	Days 1 and 15
Vinblastine	6 mg/m²	IV	Days 1 and 15
Dacarbazine	375 mg/m²	IV	Days 1 and 15
MOPP and ABVD are alternated every other month for 12 mo
Vincristine—maximum dose 2 mg
MOPP-ABV Hybrid¹¹⁸
Mechlorethamine	6 mg/m²	IV	Day 1
Vincristine	1.4 mg/m²	IV	Day 1
Procarbazine	100 mg/m²	PO	Days 1-7
Prednisone	40 mg/m²	PO	Days 1-14
Doxorubicin	35 mg/m²	IV	Day 8
Vinblastine	6 mg/m²	IV	Day 8
Bleomycin	10 U/m²	IV	Day 8
Repeated every 28 d for six to eight cycles
Vincristine—maximum dose 2 mg
COPP/ABVD—Alternating^141,143,144
Cyclophosphamide	650 mg/m²	IV	Days 1 and 8
Vincristine	1.4 mg/m²	IV	Days 1 and 8
Procarbazine	100 mg/m²	PO	Days 1-14
Prednisone	40 mg/m²	PO	Days 1-14
Doxorubicin	25 mg/m²	IV	Days 1 and 15
Bleomycin	10 U/m²	IV	Days 1 and 15
Vinblastine	6 mg/m²	IV	Days 1 and 15
Dacarbazine	375 mg/m²	IV	Days 1 and 15
COPP and ABVD are alternated every other month for 8 mo
Vincristine—maximum dose 2 mg
BEACOPP—Baseline JCO^143,144
Bleomycin	10 U/m²	IV	Day 8
Etoposide	100 mg/m²	IV	Days 1-3
Doxorubicin	25 mg/m²	IV	Day 1
Cyclophosphamide	650 mg/m²	IV	Day 1
Vincristine	1.4 mg/m²	IV	Day 8
Procarbazine	100 mg/m²	PO	Days 1-7
Prednisone	40 mg/m²	PO	Days 1-14
Repeated every 3 wk for eight cycles
Vincristine—maximum dose 2 mg
Consolidation radiation therapy
BEACOPP—Escalated^142,144
Bleomycin	10 U/m²	IV	Day 8
Etoposide	200 mg/m²	IV	Days 1-3
Doxorubicin	35 mg/m²	IV	Day 1
Cyclophosphamide	1,200 mg/m²	IV	Day 1
Vincristine	1.4 mg/m²	IV	Day 8
Procarbazine	100 mg/m²	PO	Days 1-7
Prednisone	40 mg/m²	PO	Days 1-14
G-CSF Day 8 to recovery of leukocytes (> 1,000 per ml × 3 d)
Repeated every 3 wk for eight cycles
Vincristine—maximum dose 2 mg
Consolidation radiation therapy
Stanford V¹⁵²
Doxorubicin	25 mg/m²	IV	Days 1 and 15
Vinblastine	6 mg/m²	IV	Days 1 and 15
Mechlorethamine	6 mg/m²	IV	Day 1
Vincristine	1.4 mg/m²	IV	Days 8 and 22
Bleomycin	5 U/m²	IV	Days 8 and 22
Etoposide	60 mg/m²	IV	Days 15 and 16
Prednisone	40 mg/m²	PO	Every other day
Repeated every 28 d—total three cycles
Vincristine—maximum dose 2 mg
Vinblastine reduced to 4 mg/m² and vincristine to 1 mg/m² during cycle 3 for patients ≥50 y
Prednisone tapered in 10 mg decrements every other day beginning week 10
Consolidation radiation therapy

All four drugs contribute to the cumulative impact of MOPP.⁹³^,⁹⁴^,⁹⁵ Attempts to improve upon it through minor modifications, including the substitution of nitrosoureas,⁹⁶ cyclophosphamide,⁹⁷ or both⁹⁸ for mechlorethamine and vinblastine for vincristine⁹⁹^,¹⁰⁰ have not dramatically altered outcomes. However, these substitutions may reduce the acute toxicities of MOPP, such as severe nausea and vomiting, myelosuppression, and neurotoxicity. In fact, the neurotoxicity of the original dose of vincristine in MOPP led to “capping” individual doses at 2 mg,¹⁰¹ a change widely adopted, but not without controversy.⁹²^,¹⁰²^,¹⁰³ Similarly, the replacement of vincristine by vinblastine reduces neurotoxicity.⁹⁷^,⁹⁹^,¹⁰⁰ Cyclophosphamide in place of mechlorethamine results in less nausea and vomiting,⁹⁷ a major concern before the era of modern antiemetics. Thus, cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP)⁹⁷ and mechlorethamine, vinblastine, procarbazine, and prednisone (MVPP)⁹⁹^,¹⁰⁰ are both considered alternatives to MOPP. However, azospermia, premature ovarian failure, acute myeloid leukemia or MDS (AML/MDS) subsequently emerged as serious late effects. With the availability of other more effective and less toxic options, MOPP is now largely reserved for special circumstances.

One MOPP variant, however, appears to retain efficacy while simultaneously reducing acute toxicities and has advantages in special circumstances. Chlorambucil, vinblastine, procarbazine, and prednisolone (or prednisone) (ChlVPP)¹⁰⁴ is easy to administer because it contains three oral agents of relatively low toxicity. In a series of 284 patients, the CR rate with Ch1VPP was 85%, and long-term results were also similar to those expected from MOPP.¹⁰⁵^,¹⁰⁶ Others have also found Ch1VPP effective and with a high degree of patient acceptance. ¹⁰⁷^,¹⁰⁸^,¹⁰⁹ The acute side effects are far less common. Although never directly compared with MOPP, ChlVPP is a useful alternative when it is necessary to avoid certain toxicities, such as cardiopulmonary injury or severe myelosuppression, associated with other regimens.

ABVD

Five years after the publication of MOPP,¹ Bonadonna et al.¹¹⁰ introduced the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). These drugs were chosen because each was potentially non-cross-resistant with those in MOPP. ABVD was initially proposed as an alternative to MOPP, for use in combinations with MOPP, or for use in MOPP failures. The original report compared ABVD with MOPP in only 45 patients. Response rates as well as response durations were comparable, but the toxicity of ABVD appeared somewhat less. Furthermore, ABVD was effective in some patients after failure with MOPP. The extended experience in Milan confirmed this impression of ABVD¹¹¹^,¹¹² and subsequent studies have established its role in frontline treatment.¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶

Prospective Trials of MOPP, ABVD, and Variants

It was not long before both MOPP and ABVD were, themselves, combined in multiple permutations. Investigators in Milan alternated cycles of ABVD with MOPP (MOPP-ABVD).¹¹⁵^,¹¹⁷ Another variation “hybridized” the first half of the standard MOPP program to that of ABVD but excluded dacarbazine (MOPP-ABV hybrid).¹¹⁸ Several other “hybridized” regimens were also created.¹¹⁶^,¹¹⁹^,¹²⁰^,¹²¹ Many of these were of sufficient interest to evaluate in large-scale randomized clinical trials. A series of related phase III studies involving approximately 2,300 patients with advanced Hodgkin lymphoma was conducted among the cooperative groups of North America sequentially assessing the relative merits of the parent programs, MOPP and ABVD, as well as derivative combinations.¹¹³^,¹¹⁴^,¹²²^,¹²³ Other trials conducted in Europe, totaling nearly 700 patients, undertook similar comparisons.¹¹²^,¹¹⁶^,¹²⁴^,¹²⁵ Together, these trials established the role of ABVD (Table 41-5).

The first in the North American series conducted by the Cancer and Leukemia Group B (CALGB) randomized 400 patients to 6 to 8 cycles of MOPP or ABVD, or to 12 cycles of MOPP alternating with ABVD (MOPP-ABVD), as originally described.¹¹³ ABVD, alone or in MOPP-ABVD, resulted in higher CR rates than MOPP alone as well as improved failure-free survival at 5 years. Survival was also better in those who received ABVD or MOPP-ABVD, but differences when compared with MOPP were not statistically significant. After 18 years of follow-up, the relative results, including overall survival, remain unchanged.¹²⁶ MOPP was not only less effective, it was also more toxic, especially with regard to nausea and vomiting, serious myelosuppression, infections, neuropathy, and alopecia. The myelosuppression after each MOPP cycle required greater dose reductions in the subsequent cycle, whether followed by another MOPP or by ABVD. Two cases of AML/MDS were reported, one each with MOPP and MOPP-ABVD. Although not demonstrably superior in terms of survival, the two regimens containing ABVD provided better disease control and less toxicity than MOPP. This study did not identify meaningful differences between ABVD and MOPP-ABVD.

The second in this series was a comparison of the MOPP-ABV hybrid to the sequence of MOPP, alone, administered for six to eight cycles followed in complete responders by three cycles of ABVD.¹²³ This design was intended to test the Goldie-Coldman hypothesis,¹²⁷ which suggests that the initial use of a large number of effective drugs in full dose is preferable to the use of a more limited number of drugs. In this trial, CR rates, 8-year failure-free survival, and 8-year overall survival were better with the hybrid program, supporting the Goldie-Coldman model. The hybrid was associated with more severe neutropenia and pulmonary reactions, but the sequential regimen was associated with more cases of AML/MDS, likely reflecting greater exposure to an alkylating agent in the unalleviated use of MOPP for six to eight cycles. The hybrid, however, has also been associated with a significant incidence of AML/MDS.¹¹⁴

Thus, initial treatment with ABVD, alternating MOPP-ABVD, or the MOPP-ABV hybrid is better than MOPP when used alone¹¹³^,¹²⁴^,¹²⁵^,¹²⁶ or when the use of ABVD is delayed.¹²³ To determine whether and how MOPP and ABVD are combined is important, the National Cancer Institute of Canada (NCI-C) compared the MOPP-ABV hybrid with MOPP-ABVD in 301 patients.¹²² Responding patients received a total of eight cycles of therapy, and adjuvant radiation could be administered. There were no significant differences between treatments in CR, failure-free survival, or overall survival. Although toxicities were generally comparable, there was more stomatitis and febrile neutropenia, including four infectious deaths, with the hybrid. A similar study from Italy with a slightly different hybrid (one-half course of MOPP plus one-half course of ABVD [MA-MA hybrid]) compared with alternating MOPP-ABVD came to similar conclusions,¹¹⁶ namely, that the efficacy of such combinations is not affected by these modest changes. However, the value of even retaining the MOPP component in these variants was largely unexplored.¹¹³^,¹²⁶

In the final trial of this series, the possibility of eliminating the MOPP component altogether was assessed by comparing ABVD alone directly to the MOPP-ABV hybrid.¹¹⁴ In this intergroup study of 856 patients, CR rates, failure-free survival, and overall survival were similar. However, again there was significantly greater toxicity, pulmonary, hematologic, and infectious, as well as a greater number of treatment-related deaths with the hybrid. Of special note, accrual was closed just short of the original goal of 900 subjects because of AML/MDS occurring in those receiving MOPP-ABV. After a median follow-up of 6 years, 11 cases of AML/MDS were observed in patients randomized to MOPP-ABV and none in those receiving only ABVD.

The cumulative evidence from these studies in North America and Europe led to the widespread adoption of ABVD as the treatment of choice for advanced Hodgkin lymphoma. ABVD was more active than MOPP and the equal of the merged regimens. Thus, toxicity became the deciding factor. The acute toxicities with MOPP and MOPP-containing combinations were greater than those with ABVD.¹¹³^,¹¹⁴ However, certain toxicities, such as cardiotoxicity with doxorubicin and pulmonary toxicity with bleomycin, are observed in the ABVD-containing programs. It appears that 2% to 6% of patients will have clinically significant pulmonary toxicity from bleomycin and deaths occasionally result, mostly in
those older than 55 years.¹¹³^,¹¹⁴^,¹²²^,¹²³^,¹²⁸ Cardiotoxicity from doxorubicin appears to be rare but may be underreported because evidence for it is not often systematically sought after treatment.¹²⁹ Overall, acute toxic deaths occurred in approximately 2% to 3% of patients with infectious deaths occurring most commonly after MOPP, or combinations that predominantly use MOPP, and pulmonary deaths after the use of bleomycin.

Table 41-5 Randomized Trials of MOPP, ABVD, and MOPP-ABVD Variants in Advanced Hodgkin Lymphoma

First Author	Treatment^a	Number of Patients	Complete Response	Failure-free Survival	Overall Survival
Santoro et al.¹²⁴	MOPP × 12 cycles¹’	43	74%	36% at 8 y	62% at 8 y
Bonadonnaetal.¹¹²	MOPP/ABVD × 12 cycles^b	45	89% P =.14	65% at 8 y P < <.005	76% at 8 y P = .ll
Canellos et al.^113,126	MOPP × 6-8 cycles	123	67%	32% at 18 y	42% at 18 y
	ABVD × 6-8 cycles	115	82%	43% at 18 y	50% at 18 y
	MOPP/ABVD × 12 cycles^b	123	83% P =.006	40% at 18 y P = .05	43% at 18 y P = .31
Somers et al.¹²⁵	MOPP × 8 cycles^b	96	57%	43% at 6 y	57% at 6 y
	MOPP (2)/ABVD (2) × 8 cycles^b	96	59%	60% at 6 y P =.013	65% at 6 y P =.013
Glick et al.¹²³	MOPP-ABV × 6-12 cycles	347	83%	64% at 8 y	77% at 8 y
	MOPP × 6-8 → ABVD × 3 cycles	344	75% P = .02	54% at 8 y P =.01	69% at 8 y P = .06
Connors et al.¹²²	MOPP-ABV × 8-12 cycles^b	153	80%	71% at 5 y	81% at 5 y
	MOPP/ABVD × 8-12 cycles^b	148	76%	67% at 5 y P = .87	83% at 5 y P = .74
Vivianietal.¹¹⁶	MOPP/ABVD × 6-8 cycles^b	211	91%	67% at 10 y	74% at 10 y
	MA/MA × 6-8 cycles^b	204	89% P = ns	69% at 10 y P = ns	72% at 10 y P = ns
Duggan et al.¹¹⁴	MOPP-ABV × 6-10 cycles	419	80%	66% at 5 y	81% at 5 y
	ABVD × 6-10 cycles	433	76% P =.16	63% at 5 y P =.42	82% at 5 y P = .82
^aSee Table 41-4 for details of treatment programs. Number at end of each regimen refers to total number of cycles. ^bConsolidation radiation therapy.

In survivors of Hodgkin lymphoma, the relative risk of AML/MDS is increased nearly 35-fold compared with the general population.¹³⁰ In these trials with follow-up ranging from 3 to 9 years, approximately 1% to 2.6% of patients treated with MOPP as part of their initial chemotherapy developed AML/MDS.¹¹³^,¹¹⁴^,¹²²^,¹²³ Others have also reported that those who receive MOPP have the highest incidence and that risk is related to cumulative dose.¹³⁰^,¹³¹ However, there have been no cases reported on these studies so far in those randomized and treated only with ABVD.¹¹³^,¹¹⁴ A very low risk of AML/MDS after ABVD is supported by other reports as well,¹³²^,¹³³ and since the wider use of ABVD, the incidence of AML/MDS in patients treated for Hodgkin lymphoma has decreased.¹³⁰

None of these large studies directly address the impact of therapy on reproductive function, but other studies with MOPP, ABVD, and various combinations¹³⁴^,¹³⁵^,¹³⁶^,¹³⁷^,¹³⁸ show that persistent azoospermia, amenorrhea, and infertility are almost universal after standard MOPP, intermediate in patients treated
with regimens in which exposure to MOPP is diluted by combining it with elements of ABVD, and uncommon after ABVD. After treatment with ABVD, of those trying to conceive, the cumulative incidence of pregnancy is comparable to controls.¹³⁹ As more patients are living longer, the prospect of these late effects must be considered in the choice of initial therapies.

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