relapse patterns in burkitt's...

[CANCER RESEARCH 32, 1267-1272, June 1972]

Relapse Patterns in Burkitt's Lymphoma1

John L. Ziegler,2 Avrum Z. Bluming, ' Leroy Pass,4 and Richard H. Morrow, Jr.5

Lymphoma Treatment Center, Department of Surgery, Makerere University Medical School, Kampala, Uganda

SUMMARY

The clinical course of 130 patients with Burkitt's lymphoma

was reviewed. Death occurred soon after treatment in 18(14%), and failure to respond to chemotherapy was observedin 5 (4%). One hundred seven patients achieved completeremissions, among whom 84 were followed for at least 1 year,or until relapse. Tumor relapse was observed to be of twodistinct types. Early relapse was characterized by recurrenttumor growth in the same site as the original tumor andoccurred within 10 weeks of initial therapy. Patients withearly relapse tended to have generalized disease on admission,responded poorly to subsequent treatment, and had a poorprognosis. Late relapse occurred beyond the 10-week intervalfrom initial therapy and usually appeared in previouslyuninvolved anatomical sites. Responses to subsequentchemotherapy were excellent, and the prognosis was good.The pattern of relapse appeared to be independent of theaggressiveness of the initial chemotherapeutic regime. Drugresistance, immunoresistance, and/or host immune failure arepostulated to explain the emergence of early relapse. Althoughimmunological mechanisms may be operative in thepathogenesis of late relapse, reinduction of tumor remains apossibility.

INTRODUCTION

Burkitt's lymphoma has attracted world-wide attention

because of its response to chemotherapy, the evidence ofantitumor immunity in the host, and the epidemiological andimmunological data implicating a viral cause (3, 4, 13). Thehigh "apparent cure" rate has stimulated trials of intensive

chemotherapy in the hope of effecting a total tumor-cell kill(25). However, despite intensive chemotherapeutic efforts incenters where the tumor is endemic, a proportion of patients

1Supported by Contract PH 43-67-1343 from the National Cancer

Institute, Bethesda, Md.2Director, Uganda Cancer Institute, Department of Surgery,

Makerere University Medical School, Kampala, Uganda (SeniorInvestigator, Medicine Branch, National Cancer Institute, Bethesda,Md.).

3Formerly Director, Lymphoma Treatment Center. Present address:

Department of Medicine, Columbia College of Physicians and Surgeons,New York, N. Y.

4Formerly Scientific Advisor, Lymphoma Treatment Center. Present

address: Department of Medicine, University of Washington, Seattle,Wash.

'Formerly Senior Lecturer, Department of Preventive Medicine,Makerere University Medical School, Kampala, Uganda. Presentaddress: Harvard School of Public Health, Boston, Mass.

Received November 30, 1971; accepted March 'I, 1972.

with Burkitt's lymphoma continue to relapse and die (6, 25).

This paper reports an analysis of tumor relapse in 84 patientswith Burkitt's lymphoma in an attempt to ascertain any

predictive features present on admission and to investigatepossible pathogenetic mechanisms. The results reveal 2 distinctpatterns of relapse, early and late, which are separable on thebasis of the initial duration of remission. Analysis of theclinical and immunological features of patients in these 2groups yields evidence for a different pathogenesis in eachgroup and provides new insight into the treatment,immunology, and etiology of Burkitt's lymphoma.

MATERIALS AND METHODS

Patients. In the 4-year period between July 1967 and July1971, a total of 130 untreated patients with histologicallyconfirmed Burkitt's lymphoma were admitted to the

Lymphoma Treatment Center in Kampala, Uganda. Allpatients were uniformly evaluated and clinically stagedaccording to the anatomical sites of their tumors on admission(Table 1) (25). Following the staging procedures, patients wererandomized by stage for chemotherapeutic trials designed tocompare either 2 different schedules of the same drug or acombination of agents with intensive single-agent therapy. Asinitial treatment, all patients received i.v. cyclophosphamide,40 mg/kg in a single dose. The subsequent drug regimens, theircode names, and the chronology of the trials are detailed inTable 2.

Patients who presented with or who developed malignantcells in the cerebrospinal fluid were treated with intrathecalchemotherapy, with the use of methotrexate or cytosinearabinoside in various doses and schedules (22).

The response to treatment and the clinical course of allpatients were reviewed. The duration of initial remission wasdefined as the interval between the 1st dose ofcyclophosphamide and the 1st appearance of tumor relapse.ER6 was defined as occurring within 10 weeks of the 1st doseof chemotherapy, while LR took place beyond the 10-weekinterval. This arbitrary interval was chosen because it clearlydelineated 2 different prognostic groups, which could also bedistinguished by a number of clinical and immunologicalfeatures. With respect to relapse, the anatomical site, responseto therapy, and relationship to presenting clinical stage andtreatment regimen were analyzed.

6The abbreviations used are: ER, early relapse (occurring within 10

weeks of initial therapy); LR, late relapse (occurring beyond 10 weeksof initial therapy; SR, sustained remission (of 1 year or longer); TRIKE,a sequential chemotherapeutic regimen consisting of cyclophosphamide, vincristine, methotrexate, and cytosine arabinoside (for details,see Table 2).

JUNE 1972 1267

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Ziegler, Bluming, Pass and Morrow

Table 1Clinical staging ofBurkitt's lymphoma

Stage Site of disease

I Single facial tumorII 2 or more facial tumors

III Intrathoracic, intraabdominal, or osseous tumor (excludingfacial bones)

IV Tumor cells in the cerebrospinal fluid and/or bone marrow

Immunological and kinetic data from a number of patients,reported in detail elsewhere, were reanalyzed in the presentreport to discern any relationship to the relapse pattern. Theseanalyses investigated (a) immunoglobulin levels, with the useof a gel diffusion technique (24); (b) primary and establisheddelayed hypersensitivity responses, with the use ofdinitrochlorobenzene and a battery of bacterial, viral, andfungal skin test antigens (1, 7, 24); (c) cutaneous sensitivityreactions to extracts of both autologous tumor cells andcontrol autologous normal peripheral lymphocytesadministered intradermally during the 1st 2 to 4 weeks ofremission (1, 7); and (d) tumor kinetics, performed in vitroand in vivo with tritiated thymidine, designed to estimate thepotential doubling time and the growth fraction of the tumorcell population (12).

RESULTS

Eighteen of 130 patients (14%) died within the 1st 2 weeksfollowing therapy. Most had rapid tumor regression butsuccumbed to complications such as respiratory obstruction,renal failure, bone marrow failure with sepsis, postoperativecomplications, widespread tumor, or unknown causes. Allpatients in this category were either Stage III (8 patients) orStage IV (10 patients) with large, disseminated tumors.

Only 5 of the 112 surviving patients (4%) failed to respondor responded only transiently to a variety of chemotherapeuticagents. All 5 patients had widespread tumors (Stage III-IV),and they died at 9, 11, 22, 27, and 38 weeks from treatment,respectively.

Of the remaining 107 patients who entered completeremission, 84 were followed for at least 1 year, or untilrelapse. (The remaining 23 are still on therapy or have not yetrelapsed within a 1-year period of observation.) Twenty-fourpatients (29%) who relapsed within 10 weeks of initialtreatment (ER) had a median remission duration of 8 weeks(range, 2 to 10 weeks). Twenty-seven patients (32%) whorelapsed beyond 10 weeks after initial treatment (LR) had amedian remission duration of 26 weeks (range, 14 to 88weeks). The remaining 33 (39%) had SR's of 1 year or longer.

Table 3 shows the anatomical site of relapse in the 2 relapsegroups. Seventeen of 24 patients with ER developed recurrenttumor masses in the site of the original tumors, while only 1developed tumor in a previously uninvolved site. The moststriking feature in the ER group, however, was the highfrequency of central nervous system involvement noted in atotal of 20 of 24 patients (83%), manifest as cranial orperipheral neuropathy, and/or the appearance of malignantcells in the cerebrospinal fluid. In 6 patients with ER, central

Table 2Chemotherapy ofBurkitt's lymphoma at the Lymphoma

Treatment Center, J967 to 1971

Drug dose, route, andduration of trial Schedule

Trial I (July 1967-August 1969)All stages

CTX," 40 mg/kg, i.v.vs.

CTX, 40 mg/kg, i.v.Trial II (August 1969-June 1971)

Stage MICTX, 40 mg/kg, i.v.

Single dose

6 doses at 2-3-week intervals

6 doses at 2-3-week intervals

CTX, VCR/MTX, and ara-Cseparated by 2-3-week intervals,given for 2 complete cycles

Repeated at 2-3-week intervalsuntil remission (usually only1-2 doses required)

Stage III-IVCTX, 40 mg/kg, i.v.

vs.TRIKE

CTX, 40 mg/kg, i.v., thenVCR, 1.4 mg/sq m, i.V.,

Day 1,MTX, 15 mg/sq m, p.o.,

Days 1-4, thenara-C, 250 mg/sq m, daily in

3-day infusionRelapse

CTX (as above), in multiple doses if initial therapy was limited to1 or 2 doses

BIKE (VCR/MTX, and ara-C, as above), for patients relapsing onmultiple dose CTX, or

Daunomycin, 40 mg/sq m, i.v. daily for 3 days for patients resistant toCTX, VCR/MTX, and ara-C

0 The abbreviations used are: CTX, cyclophosphamide; VCR,vincristine; MTX, methotrexate; ara-C, cytosine arabinoside.

Table 3Anatomical site of tumor relapse

Relapse type

Relapse site Early Late

Same as original(with CNSÂ°involvement)

Previously uninvolved(with CNS involvement)

CNS involvement alone

17(14)

(0)

(0)

20(3)

24 27

Â°CNS, central nervous system.

nervous system manifestations were the only clinical evidenceof relapse. Central nervous system involvement alone is treatedas a special category and is not tabulated as a site differentfrom primary disease. In contrast, only 5 of 27 patients withLR developed tumor masses in the site of the original tumor,whereas 20 had tumor relapse in previously uninvolved sites.The difference is significant at the 5% level by x2 analysis.

Only 5 of 27 patients with LR had central nervous systeminvolvement, which was the only manifestation of relapse in 2patients.

Of the 84 patients achieving remission, 24 developed ER,leaving 60 patients at risk of developing LR. Only 3 (13%) of

1268 CANCER RESEARCH VOL. 32



Relapse in Burkitt's Lymphoma

the patients with localized tumors developed ER. Theremaining 21 ER patients (34%) had generalized (Stage III-IV)disease on admission. Of the remaining 60 patients who didnot develop ER, 6 of 20 patients (33%) with localized (StageHI) and 21 of 40 patients (52%) with generalized (StageIII-IV) disease developed LR. Thus, patients with generalizeddisease on admission are more likely to relapse (p < 0.05, byX2 analysis), but the type of relapse cannot be predicted by

the initial tumor stage.Table 4 shows the effect of the initial treatment regimen on

the outcome (ER, LR, or SR) of the 84 patients achievingcomplete remissions. No differences were observed in thefrequency of ER, LR, or SR among the patients treated witheither a single dose of cyclophosphamide, multiple doses ofcyclophosphamide, or TRIKE. Although the number ofpatients treated with the TRIKE regimen is still small, itappears that initial chemotherapy, whether minimal oraggressive, has little effect on the clinical course once asubstantial remission has been induced.

The responses to chemotherapy of relapsing Burkitt's

lymphoma are summarized in Table 5. Although completeresponses were reinduced (in 12 of the 23 treated patientswith ER) either the same agents (8 patients) or agentsdifferent from those originally used (4 patients), the tendencyin this group was toward transient, partial responses,recurrence of tumor, and ultimate drug resistance.

In contrast to the generally poor response to therapyexhibited by patients with ER, 24 of 26 patients with LR whowere treated in relapse had complete tumor regression,showing sensitivity either to the same drugs used initially (12patients) or to agents that were not used previously (12patients). The 2 patients who failed to respond to chemotherapy died. Subsequent relapse occurred in 6 of the 24

Table 4Initial treatment and clinical course

QinicalcourseTreatmentCTX"

(singledose)CTX(multipledose)TRIKE

(multiple dose)No.174215ER6135LR8163SR13137

84 24 27 33

0 The abbreviation used is: CTX, cyclophosphamide.

Table 5Response of patients in relapse to subsequent chemotherapy

Response

ER (23) LR (26)

Treatment regimen CRÂ° PR/NR CR PR/NR

Same as initial treatmentDifferent agents847 412 121 1

Total 12 11 24

a The abbreviations used are: CR, complete response; PR/NR, partial

or no response.

successfully retreated patients. In 3 patients, this relapseoccurred more than 10 weeks following secondary therapy,appeared in previously uninvolved sites, and again respondedcompletely to chemotherapy with sustained remissions oflonger than 1 year. The 3 remaining patients developedrecurrent tumors soon after retreatment, failed to respond totherapy, and diedâ€”acourse similar to patients with ER. One

patient in the LR group was not treated. He is of interest inthat he presented with Stage II disease involving the mandibleand scalp and had a complete remission following a single doseof cyclophosphamide. Eighty-eight weeks later, he developedtumor in the skin, bone, lung, and lymph nodes and died witha postmortem diagnosis of reticulum cell sarcoma. Review ofthe initial biopsy (mandible) confirmed Burkitt's lymphoma.

Chart 1 shows an actuarial analysis of survival in patientswith ER or LR. Nineteen of 24 patients with ER have died.Three patients are living with disease at 28, 41, and 65 weeksfrom initial treatment; 2 patients are free of disease at 88 and96 weeks from treatment and may be long-term survivors. Theestimated survival at 156 weeks (3 years) from therapy,however, is 0%. In contrast, only 6 of 27 patients with LRhave died, and the estimated survival at 156 weeks is 72%.

In an effort to discover features present either on admissionor early in the patients' course which might predict the

outcome of an individual patient (particularly, the poorprognosis ER group), data from certain immunological tests,performed on most of these patients, were reviewed (1, 7, 24).

Immunoglobulin levels were performed on admission sera of35 patients, of whom there were 9 patients with ER, 12patients with LR, and 14 patients with SR. No significantdifferences were observed in either IgG, IgA, or IgM levelsbetween these 3 groups.

Delayed hypersensitivity reactions to a variety of recallantigens (mumps, tuberculin, candidin, or streptokinase-streptodornase), dinitrochlorobenzene, autologous tumorextract, and autologous normal lymphocyte extract wereevaluated in many patients in previously described studies ofnonspecific and tumor-specific cellular immunity (1, 7, 24).Reactivity to at least 1 recall antigen was noted in 6 of 18

100

n

f 40

LateRelapse(Remission-10leeks)n-27

t

l

EjrlyRelapse(Remission<10leeks)nÂ«24

40 80 120 160 200 240 280IEEKSFROM Â»mil

Chart 1. A comparison of survival in patients with Burkitt's

lymphoma, with ER and LR.

JUNE 1972 1269



Ziegler, Bluming, Fass,and Morrow

patients with ER and 5 of 18 patients with LR, but was notedin 15 of 21 patients with SR. Thus, patients destined torelapse appear less responsive than patients in SR with respectto established delayed hypersensitivity reactions to recallantigens (p < 0.01 by \2 analysis). Reactivity todinitrochlorobenzene was present in 4 of 6 patients with ER, lof 3 patients with LR, and 8 of 9 patients with SR. Positive,tumor-specific, cellular immune reactions (i.e., autologoustumor extract-positive, autologous lymphocyte extract-negative), observed only during clinical remission, were notedin 0 of 9 patients with ER, 10 of 16 patients with LR, and 6of 12 patients with SR.

Kinetic studies of Burkitt lymphoma ceils in 13 patientsinvestigated before treatment revealed a potential doublingtime of 24 hr (12). Tumor samples taken at the time of relapsein 3 patients with LR and 1 patient with ER had tumorcell-doubling times of 19, 31, 37, and 19 hi, respectively,values well within the range observed in untreated patients. Inthe patient with ER, serial tumor samples (admission andrelapse) yielded nearly identical doubling times.

No correlation was detected between the relapse type andage, sex, weight on admission, or histological and cytologicalfeatures of the original tumor biopsy.

DISCUSSION

Although complete response after initial treatment is therule in Burkitt's lymphoma, a proportion of the patients

relapse and die. In a neoplasm that is potentially curable, it isof obvious value to be able to identify patients who are at riskof relapse, in order to design appropriate therapy. The presentstudy has shown that the nature of relapse is not homogeneousin Burkitt's lymphoma and has identified 2 distinct patterns of

relapse, separable by the duration of initial remission. ERoccurred within the 1st 10 weeks of therapy in 29% of thepatients, and LR occurred well beyond the 10-week interval(median: 26 weeks from therapy) in 32%. These 2 relapsepatterns were otherwise distinguishable by several clinical andimmunological features.

In a previous report from this Center (25), tumor relapsewas found in 1 of 11 (9.1%) patients with localized (Stage I-II)tumors, and 13 of 26 (50$>)patients with generalized (StageIII-IV) tumors. In the present study, the frequency wasincreased to 9 of 23 (39%) and 42 of 61 (69%) patients withlocalized and generalized tumors, respectively. The increasedfrequency of relapse is attributable to longer follow-up and tothe exclusion of patients in complete remission who werefollowed for less than 1 year after initial treatment.

The pathogenesis of ER may involve several mechanisms.The timing, site, and kinetic features of relapse point toregrowth of the original tumor. Inadequate initial chemotherapy is the first possibility to consider. This is a possibleexplanation in at least 1 of the 6 patients with ER who weretreated with single doses of cyclophosphamide; that patientresponded with a sustained remission of 96+ weeks followingreinstitution of cyclophosphamide in multiple doses. Theremaining 5 patients, however, had only brief remissionsfollowing cyclophosphamide retreatment, and 4 relapsed after1 or 2 additional doses with apparent cyclophosphamide-

resistant tumors. All other patients with ER relapsed duringtreatment with an intensive chemotherapeutic regimen (eithermultiple-dose cyclophosphamide or TRIKE). Inadequateinitial therapy is thus an unlikely cause of ER in the majorityof patients. Drug resistance may explain the emergence of ERin those patients who relapsed while on treatment or whofailed to respond to the same therapy that was used initially.

Alteration of immunological features of the tumor or of thehost may contribute to the development of ER. Sincechemotherapy kills only a proportion of tumor cells,immunological mechanisms may be invoked to explain whysome patients with Burkitt's lymphoma never relapse.Evidence for the participation of host-immune defenses inreducing the number of residual tumor cells followingchemotherapy has been recently reviewed (13). Escape oftumor cells from immunological control may occur through avariety of mechanisms (10, 19, 21). For example, theproduction of "blocking" antibodies may be responsible in

part for protecting tumor cells from immunological attack(10). In support of this, Klein (13) has reported heavy IgG"coating" of tumor cells taken from patients in relapse. This

phenomenon is irreversible and appears to herald a poorprognosis. Other possibilities to explain tumor "escape,"

which are yet to be tested, include weak or absent tumorantigenicity, antigenic modulation, or immunological tolerance(1,7,19).

Alternatively (or in addition), failure of host immunemechanisms may contribute to the emergence of ER. Thisexplanation is supported by the tendency toward impaireddelayed hypersensitivity reactions to both recall andtumor-specific antigens. Reactivity to primary sensitization todinitrochlorobenzene, however, seems unimpaired (24),although reports on this aspect are conflicting (20). Possiblemechanisms to explain this immunological unresponsivenessinclude immunosuppression by chemotherapy, malaria, or thepresence of a large tumor (16, 20). Further support forweakened host immunity in the pathogenesis of ER comesfrom the clinical observation of a high frequency ofgeneralized disease and central nervous system involvement inthese patients. Although it is not clear whether the relationship between advanced, widespread tumor and impairedimmune mechanisms is "cause" or "effect" (20, 24), the

association of defective host immunity and the developmentand progression of tumors are well documented (15, 19, 21).In addition, the blood-brain barrier provides both animmunological and pharmacological sanctuary which may leadto the frequent appearance of central nervous system relapseas the first and occasionally the only sign of recurrent tumorin these patients (23).The pathogenesis of LR in Burkitt's lymphoma is probably

associated with mechanisms different from those described forER. It is possible that the original tumor cell population,having been substantially reduced by chemotherapy, is held incheck by immunological mechanisms for a period of time.Late relapse may then occur as the result of interruption inimmunological surveillance, with tumor cell escape (13, 14,19, 21). In support of this hypothesis is the consistentlyobserved conversion of autologous tumor extract reactivityeither preceding or concurrent with clinical relapse in patientswith LR (1, 7). Other workers have noted a decline in




Relapse in Burkit t's Lymphoma

circulating antibodies reacting with Burkitt's tumor cell

membranes preceding a LR in a Kenyan child (14). This childfailed to respond to subsequent therapy, and her tumor cellsbecame progressively coated with IgG. Another Kenyan childwith LR was reported to have the majority of relapsing cells inthe tetraploid range (5). It is possible that cells of thiskaryotype have a selective growth advantage whenimmunological mechanisms are operative.

Another explanation for LR is an alteration of tumor cellkinetics. Slowly replicating cells may be held in check untilsome unknown factor, leading to rapid cellular proliferation,allows escape from effective immunological surveillance. Wehave observed in a small number of patients, however, that thepotential doubling time is similar in relapsing tumors frompatients with LR and ER and in tumors from patients oninitial presentation (12). In addition,/Â« vivo experiments haveshown that virtually all tumor cells participate in theproliferative pool (12). Nevertheless, the possibility thatdormant or slowly replicating tumor cells are present cannotbe ruled out.

The occurrence of LR may also be accounted for byreinduction of tumor by the original oncogenic agent. Insupport of this suggestion is the observation that the clinicalbehavior in patients with LR is identical to that of patientswho present with Burkitt's lymphoma for the first time. A

relationship has also been observed between the occurrence ofLR and persistent elevation of antibody titers to Epstein-Barrvirus-induced "early antigen" (11). (A detailed analysis of the

relationship between antibody titers to Epstein-Barrvirus-induced antigens and the clinical course of Burkitt's

lymphoma will be the subject of another report.) In furthersupport of tumor reinduction is the observation that some LRtumors are of a genetic constitition that is different from thatof the original tumor. Karyotypes tend to hyperploidy (5),and the glucose 6-phosphate dehydrogenase phenotype in aheterozygous (AB) female revealed 2 separate clones in apresenting abdominal tumor (B) and in a subsequent parotidtumor (A).7 Two patients who appear to have had ER, on theother hand, are reported to have glucose 6-phosphatedehydrogenase phenotypes identical to that of the originaltumor (8).

From a therapeutic standpoint, the prognosis of patientswith Burkitt's lymphoma appears to be independent of the

aggressiveness of the initial chemotherapeutic regimen. This isreminiscent of Burkitt's earlier premise that minimal treatmentof Burkitt's lymphoma should be adequate therapy (2).

Although intensive repetitive chemotherapy in mice withLI 210 leukemia may produce a total cell kill and cure thedisease (18), this approach does not appear to be applicable inBurkitt's lymphoma, although the tumor cells are initially very

sensitive to cytotoxic agents.Drug resistance, immunoresistance, and host-immune failure

appear to play a role in the pathogenesis of ER. These ERpatients might well benefit from the early institution ofspecific or nonspecific immunotherapy similar to the programused in acute leukemia in some centers (17). Such a trial iscurrently under way in Kampala. Whether immunological

7G. Klein and P. J. Fialkow, personal communication.

mechanisms are important in the occurrence of LR is notclear, but as these patients tend to do well, immunotherapymay not be indicated.

ACKNOWLEDGMENTS

The authors wish to thank Professor S. K. Kyalwazi, Mr. D. Bhana,and Mr. W. Carswell of the Department of Surgery for performing thebiopsies in our patients, and Dr. A. C. Templeton of the Department ofPathology for reviewing the histological and cytological material. Dr. C.L. Vogel provided advice on the preparation of the manuscript, and Mr.Peter Smith assisted in the statistical analysis of the data. Professor O.H. Iversen collaborated on the kinetic studies of Burkitt's lymphoma,

and Dr. Paul P. Carbone advised on chemotherapy.

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1972;32:1267-1272. Cancer Res John L. Ziegler, Avrum Z. Bluming, Leroy Fass, et al. Relapse Patterns in Burkitt's Lymphoma

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