Non-Hodgkin’s Lymphoma Introduction and Historical Background

5.1 Introduction . . . 85

5.2 The Early Era, Pre-1970 . . . 86

5.3 The Latter Era, Post-1970s . . . 86

References . . . 88

5.1 Introduction

Th e history of advances in our understanding and man- agement of non-Hodgkin’s lymphoma (NHL) in the last half of the twentieth century is arguably one of the modern success stories of pediatric oncology. Advances in classifi cation, staging, treatment, and supportive care have transformed a once invariably fatal disease into one of the most curable of pediatric cancers.

Progress in the fi eld coincided with the introduc- tion in the 1960s of combination chemotherapy and combined modality treatments and paralleled advanc- es in the management of childhood acute lymphoblas- tic leukemia (ALL) and Hodgkin lymphoma. Th e pathologic classifi cation has shift ed in the meantime from mere morphologic observations and vague ter- minology (lymphosarcoma or reticulum cell sarcoma) to a sophisticated understanding of tumor origins, stratifi ed according to T- and B-cell lineage, recogniz- ing a number of distinctive lymphoid neoplasms, as- sociated with characteristic immunophenotypic, ge- netic, and clinical features.

Particularly gratifying has been the unprecedented level of cooperation and communication between in- vestigators from around the world which has facilitat- ed the extraordinary progress achieved. Th is historical overview of progress in the fi eld of pediatric NHL will attempt to provide a chronology of the advances.

Burkitt’s lymphoma, a discrete clinical and geographic entity common among children in both endemic and nonendemic areas, was fi rst described in 1958 and oc- cupies a very important place in the history of lym- phoma, but is discussed in detail elsewhere in this book and will not be covered in this chapter.

Sharon B. Murphy

Non-Hodgkin’s Lymphoma

Introduction and Historical Background

Contents

5.2 The Early Era, Pre-1970

Writing in 1960 in the fi rst really comprehensive pedi- atric oncology textbook, Harold Dargeon, then Chief of the Pediatric Service at Memorial Hospital in New York City, lamented the lack of a satisfactory classifi ca- tion of lymphoid tumors and noted the frequent con- fusion with and/or evolution to leukemia. He recog- nized that separation of patients with lymphosarcoma in whom leukemia subsequently developed, «aka» leu- kosarcoma, from those in whom it did not may be challenged as arbitrary since, had the latter cases sim- ply lived longer, leukemia might have developed (Dar- geon 1960). Th is nosologic confusion was perpetuated by many investigators, resulting in continuing confu- sion regarding “leukemic transformation of lympho- sarcoma” and the even more puzzling “lymphoma-leu- kemia syndrome” or “lymphomatous ALL”. Dargeon presciently observed that “great opportunities for con- fusion among clinicians are aff orded”, noting the terms used to designate the disease are of more than academ- ic interest but would impact estimates of incidence, management, and prognosis. However, in those early days, it hardly mattered, since the results were consis- tently discouraging, with most children dying within weeks to months. Occasional long-term survivors who presented with localized disease were noted, however, following surgery, irradiation, and treatment with the single agents then available, such as Coley’s toxin or nitrogen mustard. Reporting the results of 69 children with lymphosarcoma seen at Memorial from 1928 to 1953, Dargeon and his co-authors (Rosenberg et al.

1958) observed that 17.4% survived fi ve years or more and noted that this “not infrequent long-term survival should plant seeds of optimism in the physicians re- sponsible for the treatment of these children”.

Contemporary experiences of many other pioneer- ing pediatric oncologists echoed the same general ex- perience with lymphosarcoma in childhood, painting a picture of a generally fatal disease, with a high inci- dence (around 30%) of leukemic transformation, and a small number (about 10%) of long-term survivors, most of whom presented with localized disease. Jones and Klingberg (1963) summarized their experience with 43 cases of lymphosarcoma seen at St. Louis Chil- dren’s Hospital between 1945 and 1960 and reviewed

data from several similar series of cases reported from other institutions, noting that only 50% of cases were alive at the end of six months, and only 9% survived fi ve years. Jenkin and Sonley (1969) summarized their experience with 121 NHL cases seen at the Hospital for Sick Children in Toronto from 1930 to 1965. Th e end result was that 14/121 (12%) were cured, and 12 of these 14 long-term survivors had grossly complete surgical excision of a primary gastrointestinal tumor followed by wide-fi eld whole abdominal irradiation, highlighting the curability of this favorable subgroup of abdominal primaries. Th is favorable outcome was in marked contrast to other NHL cases treated with irradiation in whom responses were limited to three or four weeks because of disease appearing at other sites.

By the end of the 1960s, irradiation was fi rmly estab- lished as a modality essential for the cure of Hodgkin’s disease. Glatstein, Donaldson, Kaplan, and colleagues at Stanford attempted to directly apply their approach so successful in pediatric Hodgkin’s disease to the treat- ment of NHL in children (Glatstein et al. 1974). Th ey reported the outcome of a series of children treated from 1961 to 1971, attempting to eradicate all known disease with high-dose radiation therapy (minimum 3500 rad) to all involved or extended fi elds. In a series of 25 confi rmed pediatric NHL cases who presented with Ann Arbor stage I, II, or III disease (excluding stage IV patients), they reported ten of the 25 survived more than two years, half of whom had stage I disease, with the majority who failed relapsing outside the irradiated fi eld at extra nodal sites, particularly bone marrow. Th ey concluded that chemotherapy as well as irradiation was essential for the management of children with NHL. In- vestigators at St. Jude Children Research Hospital, led by Donald Pinkel, also recommended that local radio- therapy be combined with multiple-agent chemothera- py, based on their favorable experience with apparently curing six out of eight children with localized lympho- sarcoma with this approach (Aur et al. 1971).

5.3 The Latter Era, Post-1970s

Th e experience of the Toronto, Stanford, and St. Jude

groups in apparently curing half or more of favorable

localized cases of pediatric NHL with irradiation led to

its fi rm establishment as a modality considered essen- tial in the treatment armamentarium for NHL. Results of controlled trials which assessed the contribution of irradiation to the overall success of combined modali- ty treatment regimens for NHL were much later in coming, the result being that, for the next two to three decades, children with NHL routinely received both radiation and multidrug chemotherapy. Such ap- proaches resulted in dramatic improvements in end results of therapy, compared to historical controls treated less aggressively, but produced signifi cant acute toxicity and serious sequelae among survivors. In the fi rst controlled trial of the role of radiotherapy in child- hood NHL in 1975−1978, I conducted a stage-strati- fi ed and randomized trial of the effi cacy of adding in- volved fi eld radiotherapy to multiple drugs during induction for patients with a poor prognosis (stage III−IV) and found no benefi t of radiation whatsoever (Murphy and Hustu 1980). Th is fi nding led to a series of controlled trials by the Pediatric Oncology Group (POG), conducted over more than a decade, random- izing radiotherapy while treating children with local- ized (stage I−II) disease with a chemotherapy regimen of reduced intensity and short duration (Link et al.

1990). Results conclusively demonstrated that radio- therapy could safely be omitted. Present-day regimens for childhood NHL no longer include radiotherapy.

Th e most striking improvements in end-results of treatment for all stages of NHL in children came about in the late 1970s and early 1980s from the systematic and widespread application of successful multidrug antileukemia regimens for the treatment of children with lymphoma, generally (and in hindsight unfortu- nately) combined with irradiation to involved fi elds or sites of bulk disease.

In addition to the pioneering eff orts at St. Jude in adapting Total Th erapy leukemia regimens for lym- phoma treatment, Norma Wollner and her colleagues at Memorial produced great excitement in the fi eld by their reports of striking success with adaptation of the L

leukemia regimen for lymphomas, dubbing the pro- tocol LSA-L

. Th e LSA-L

protocol was developed in 1971 and was essentially identical to the L

regimen used at Memorial for the treatment of ALL, with the addition of a single large dose of cyclophosphamide at the onset of therapy plus individualized radiation

treatment in a substantial proportion of patients to ar- eas of bulky tumor. In her initial report, Wollner re- ported results signifi cantly superior to historical con- trols, i.e., 76% two-year disease-free survival in a series of 43 patients, almost half of whom had stage IV dis- ease, many of whom would have conventionally been considered to have leukemia (Wollner et al. 1976). Th is experience from Memorial provided the fi rst convinc- ing demonstration that intensive combination chemo- therapy had substantially altered the previously poor prognosis for childhood NHL.

Th is reported success led directly to a large random- ized trial by the members of the Children’s Cancer Study Group, conducted from 1977 to 1979, compar- ing the ten-drug LSA-L

regimen to a four-drug regi- men (COMP), adapted from the earlier work of Ziegler, combining high-dose cyclophosphamide with a varia- tion of moderate-dose methotrexate, originally pio- neered by Djerassi and piloted by Meadows (Anderson et al. 1983). Both regimens incorporated irradiation to sites of bulk disease and prophylactic treatment of the central nervous system with repeated intrathecal injec- tions of methotrexate. Th e results of this large trial were important in confi rming the powerful prognostic im- portance of stage and in highlighting the infl uence of histologic subtype of NHL on the likelihood of success for patients with nonlocalized presentations of disease.

Th is trial provided the fi rst clear evidence that chemo- therapy strategies for diff erent histologic subsets of NHL must be selective. While both treatments were ef- fective in curing over 80% of children with localized disease, the LSA

-L

regimen was more eff ective for nonlocalized lymphoblastic lymphomas than COMP (76% vs 26%, respectively). Th e outcome of patients presenting with nonlocalized nonlymphoblastic dis- ease was superior when treated with COMP (57% vs 28%), though neither regimen was particularly eff ec- tive when there was initial involvement of the marrow or central nervous system. (Anderson et al. 1983).

Concurrently from 1976 to 1979, members of the

Pediatric Division of the Southwest Oncology Group

(which later became the Pediatric Oncology Group)

conducted a nonrandomized trial of modifi ed LSA

-L

therapy for childhood NHL, excluding Burkitt’s, and

confi rmed the eff ectiveness of the regimen in curing

the majority of patients (Sullivan et al. 1985). Pediatric

Oncology Group investigators subsequently conducted a randomized study (POG 7905) comparing LSA

L

with the ACOP

regimen, but discontinued the ran- domization due to the emerging evidence of inferiority of the LSA

L

regimen for nonlymphoblastic histolo- gy. Th e results with the ACOP

regimen confi rmed the previously reported importance of stage and provided important evidence of a diff erence in outcome between small noncleaved cell and large cell types of nonlym- phoblastic lymphomas (Hvizdala et al. 1991). Results of this pivotal trial for POG cemented a stage- and his- tology/phenotype-specifi c stratifi cation strategy for the subsequent generation of POG NHL trials.

Meantime, national clinical trials groups in Ger- many (BFM) and France (SFOP) were developing the early trials which laid the groundwork for their highly successful modern protocols for childhood NHL. Th e results of BFM Study 1975/81 for NHL, conducted in parallel and with treatments similar to their ALL study, confi rmed the prognostic importance of stage and his- tology/immunophenotype (Müller-Weihrich et al.

1982) and led to the design of subsequent stratifi ed tri- als, separating “B” from “non-B” types of disease. In the successor trial, NHL-BFM81, a new treatment reg- imen was introduced for patients with B-cell lympho- mas (small noncleaved and diff use large-cell), while non-B NHL (mainly T-cell lymphoblastic) were treat- ed as ALL, and treatment duration was adapted to risk, i.e., stage. Th is strategy was further refi ned in NHL- BFM-83 and -86, leading to outstanding overall event- free survival (80%) for all NHL subtypes (Reiter et al.

1995). French investigators, meanwhile, led by Cathe- rine Patte of the Institut Gustave-Roussy in Villejuif, built upon a pulsed COPAD protocol, adding high doses of methotrexate and cytosine arabrinoside plus a

“mini”- BACT regimen which had proved useful to sal- vage relapsed patients, thus devising LMB 0281, a pro- tocol specifi cally designed for B-cell NHL and B-ALL (Patte et al. 1986). Th us was launched the highly suc- cessful series of LMB protocols, culminating in the stunning achievement of 91% failure-free survival re- ported for LMB-89 (Patte et al. 1997). Th is success triggered the international randomized FAB (French American-British) Cooperative Study of B-NHL and B-ALL.

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