Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial

doi:10.1182/blood-2002-08-2644Prepublished online February 13, 2003;

Yasodha Natkunam, Nancy L Bartlett and Sandra J HorningBradley C Ekstrand, Jennifer B Lucas, Steven M Horwitz, Zhen Fan, Sheila Breslin, Richard T Hoppe, Phase II TrialRituximab in Lymphocyte Predominant Hodgkin's Disease: Results of a

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RITUXIMAB IN LYMPHOCYTE PREDOMINANT HODGKIN’S DISEASE: RESULTS OF A PHASE II TRIAL

Bradley C. Ekstrand1, Jennifer B. Lucas1, Steven M. Horwitz1, Zhen Fan2, Sheila Breslin1, Richard T. Hoppe3, Yasodha Natkunam2,

Nancy L. Bartlett4, and Sandra J. Horning1

Departments of Medicine (Oncology)1, Pathology2, and Radiation Oncology3, Stanford University School of Medicine, Stanford, CA; and

Department of Medicine (Oncology)4, Washington University, St. Louis, MO.

Scientific heading: Clinical observations, interventions, and therapeutic trials

Running Title: Rituximab in LPHD

Word Counts: Abstract: 239 words; Article: 3052 words

Financial Support: supported by a grant from Genentech and by National Institutes of Health grant R01-CA56060

Correspondence: Sandra J. Horning, MDDivision of OncologyStanford University1000 Welch Road, Suite 202Palo Alto, CA 94304Tel: 650-725-6456Fax: [email protected]

Copyright (c) 2003 American Society of Hematology

Blood First Edition Paper, prepublished online February 13, 2003; DOI 10.1182/blood-2002-08-2644 For personal use only. by guest on June 1, 2013. bloodjournal.hematologylibrary.orgFrom



1

ABSTRACT

Lymphocyte predominant Hodgkin’s disease (LPHD) is a unique clinical entity characterized

by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The

malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late

effects than standard therapy. In this phase II trial, 22 patients with CD20+ LPHD received four

weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for HD while

12 patients had untreated disease. All 22 patients responded to rituximab (OR 100%) with CR in

9 (41%), CRu in 1 (5%) and PR in 12 (54%). Acute treatment-related adverse events were

minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median

freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3

had recurrent LPHD while 2 patients had transformation to large cell non-Hodgkin’s lymphoma

(LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR

seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of

22 LPHD patients with minimal acute toxicity; however, based on the relatively short response

duration seen in our trial and the concerns about transformation, rituximab should be considered

investigational treatment for LPHD. Further clinical trials are warranted to determine the

optimal dosing schedule of rituximab, the potential for combination treatment, and the possible

relationship of rituximab treatment to the development of LCL.

Email: [email protected]




2

INTRODUCTION

Lymphocyte predominant Hodgkin’s disease (LPHD) has long been recognized as the

subtype of Hodgkin’s disease (HD) with the most favorable prognosis. Typical patients are

males in the third or fourth decade of life who present with asymptomatic lymphadenopathy,

usually limited to cervical, axillary, or inguinal regions. The disease is generally indolent, with

slowly progressive lymphadenopathy that is often present for years prior to diagnosis.1

Pathologically, LPHD is characterized by the presence of atypical large cells known as

lymphocytic and/or histiocytic (L&H) cells or “popcorn” cells due to the unique appearance of

their nuclei.2 L&H cells reside within a characteristic cellular background composed mostly of

small B-lymphocytes with fewer numbers of T cells. Recent advances in immunophenotyping

and molecular genetics have confirmed that LPHD represents a B-cell neoplasm likely derived

from a germinal center precursor cell.3 L&H cells express the B-cell marker CD20 and lack

expression of CD15 and CD30, the markers characteristic of classical HD.1 This unique

immunophenotype constitutes an integral component of the definition of LPHD in the current

WHO classification.4

On average, fewer than 400 patients are diagnosed with LPHD each year in the United

States.5 Therefore, our understanding of the clinical features of this subtype has generally

evolved from retrospective reviews of cases seen at single institutions.6 Unfortunately, these

studies differ in patient populations, pathological criteria for the diagnosis of LPHD, and

approaches to treatment. The European Task Force on Lymphoma (ETFL) project on LPHD

sought to address this problem by retrospectively evaluating a large group of patients previously

diagnosed with LPHD using the pathological requirements of the WHO classification. The

results of this study form the basis of our current knowledge of the pathologic and clinical




3

features of LPHD and its response to standard Hodgkin’s disease treatment.7,8 The ETFL found

that treatment of LPHD with radiotherapy and/or chemotherapy using standard Hodgkin’s

disease protocols can lead to a complete response (CR) in greater than 95% of patients.8

However, two observations suggest that this approach may not represent the optimal

treatment for patients with LPHD. First, both radiotherapy and chemotherapy are associated

with significant late toxic effects, including secondary malignancies.9 In the ETFL study at least

as many patients died of secondary malignancies as did from LPHD itself.8 Second, despite the

high initial CR rate, these patients tend to relapse continuously over time, with relapses often

occurring greater than 10 years after initial therapy. A plateau in the failure-free survival (FFS)

curve at 10-20 years has only been observed in retrospective single institution studies that have

remarkably long follow-up.10,11 Fortunately, most relapses are not life threatening, and overall

survival is excellent, exceeding 90 percent at 10 years in most published studies.6

Therefore, current LPHD research aims to identify alternative treatment approaches that

possess significant activity but less toxicity. Because L&H cells express CD20, the anti-CD20

antibody rituximab has naturally emerged as a potential treatment option for patients with LPHD.

Two individual case reports have documented complete remission of advanced, recurrent and

chemotherapy-refractory LPHD after 4 weekly doses of rituximab.12,13 In order to formally

define the overall response rate and response duration of this approach, we performed a phase II

trial of rituximab in patients with either newly-diagnosed or recurrent LPHD. Here, we describe

the results of rituximab treatment in 22 patients.




4

METHODS

Patients

In 1999 we opened a phase II trial for LPHD patients at Stanford University and Washington

University. The diagnosis was confirmed by institutional pathologists according to morphologic

features and immunohistochemistry with the CD20+, CD15-, CD30- profile. We included

patients with either untreated or previously treated LPHD. Patients were eligible if they were

between the ages of 3 and 70 and had an ECOG performance status of 0-2. Patients were

required to have measurable disease, with at least one lymph node mass measuring ≥ 1.0 cm in

largest dimension, or quantifiable extranodal disease. Adequate end-organ function was required

as follows: absolute neutrophil count of > 1500, platelet count > 50,000, serum creatinine of <

1.5 times the upper limit of normal, and alkaline phophatase, bilirubin, AST, and ALT all less

than 2 times the upper limit of normal. All patients gave written informed consent. The protocol

was approved by the human subjects review board at each of the participating institutions.

Patients were excluded if they had any of the following: radiotherapy or chemotherapy

within the previous 4 weeks, prior monoclonal antibody treatment, major surgery within the

previous 4 weeks, current use of systemic glucocorticoids, or any other previous malignancy

other than cured carcinoma in situ of the cervix or basal cell carcinoma of the skin. Women had

to be of non-childbearing potential or using adequate contraception with a negative pregnancy

test at study entry. We also excluded patients with serious non-malignant disease, such as

congestive heart failure or active, uncontrolled bacterial, viral, or fungal infections.




5

All patients were evaluated at most 4 weeks prior to initiating treatment with routine medical

history, physical examination, baseline laboratory tests, and baseline computed tomography (CT)

scans of the neck, chest, abdomen, and pelvis to identify all sites of measurable disease.

Treatment and evaluation

Treatment consisted of rituximab (Rituxan, IDEC pharmaceuticals) given as an intravenous

infusion of 375 mg/m2 weekly for four consecutive weeks. Patients were premedicated 30

minutes prior to treatment with oral doses of acetaminophen 650 mg and diphenhydramine 25

mg. Premedication with glucocorticoids was prohibited. Patients were seen in follow up at 1

month after the fourth dose of antibody and then again at 3, 6, 12, 15, 18, and 24 months. At

each of these visits history, physical exam, and determination of CBC and serum chemistries

were obtained. Repeat CT scans of the neck, chest, abdomen, and pelvis were required at 3, 6,

12, 18, and 24 months after the fourth dose of rituximab. Patients with bone marrow

involvement prior to rituximab were required to have a bone marrow biopsy to confirm a

complete response.

Data management and statistics

The primary outcome measure was overall response rate. Response to treatment was

determined on post-treatment CT scans using the criteria of the National Cancer Institute (NCI)

Workshop.14 Freedom from progression (FFP) was calculated starting with the date of the first

rituximab treatment. FFP estimations were performed with the Kaplan-Meier method using

Statview 5.0 (SAS Institute, Carey, North Carolina). Toxicity was measured using the NCI

Common Toxicity Criteria.




6

A Simon 2-stage optimal trial design was employed.15 It was assumed that rituximab would

be of no further interest if the true overall response rate is 20% or lower, and of interest if the

true response rate is 40% or greater. For rejection of the null hypothesis, 12 responses were

required among a total of 43 patients targeted for enrollment. We terminated the study after 22

patients because the response rate was 100%, indicating that rituximab was of sufficient interest

for further study.

RESULTS

Patient characteristics

From March 1999 to April 2002, 22 patients with either recurrent or untreated LPHD met the

enrollment criteria and agreed to participate. Nineteen patients were treated at Stanford

University and 3 were treated at Washington University. The characteristics of the cohort are

summarized in Table 1. Generally, involved regions were characterized by the presence of

several distinctly abnormal lymph nodes that individually had little bulk. The largest lymph

node in each patient ranged from 1.5 to 5.5 cm. Only two patients had nodes greater than 5 cm

in maximum diameter.

Ten patients had been previously treated for Hodgkin’s disease as outlined in Table 1. The

median time from original diagnosis of Hodgkin’s disease in the relapsed patients was 11.9 years

(range 1 – 33), and the median length of the most recent remission was 9 years (range 0.4 – 27).

Twelve patients had untreated disease, with staging shown in Table 1. The median time from

diagnosis to the start of treatment in these patients was 3 months (range 1.8 – 7.5).




7

Toxicity

All 22 patients received the planned treatment on schedule and without dose modification.

Rituximab treatment was well tolerated, and toxicity was limited to mild infusion related

reactions that were expected. No grade III or IV toxicity was seen, and no patient required

hospitalization. Hematologic toxicity was limited to one instance each of leukopenia,

thrombocytopenia, and anemia, all grade 1.

Initial response to treatment

All 22 patients were evaluable for response. As demonstrated in Table 2, the overall

response rate to rituximab was 100 percent. Nine patients (41%) achieved a CR, 1 patient (5%)

achieved an unconfirmed complete response (CRu), and 12 patients (54%) achieved a partial

response (PR). Each patient’s best response was seen within 3 months after treatment. Patients

with relapsed disease had responses similar to untreated patients. We noted that patients with

larger lymph nodes, transdiaphragmatic disease, and > 2 nodal regions involved were generally

less likely to achieve a CR (Table 2). However, these associations were not statistically

significant (all p > 0.1 by Chi squared test), likely due to the limited number of patients in our

study.

Response duration

The responses we observed were in general short-lived. With a median follow up of 13

months (range 3 – 32), 9 patients have relapsed a median of 9 months after start of treatment

(range 6 – 14). The characteristics of these patients are shown in Table 3. Eight patients

relapsed exclusively at sites previously involved with LPHD. We found that the quality of the




8

response to rituximab correlated with relapse. At the time of the analysis, only 2 of 10 patients

who attained a CR or CRu had relapsed compared with 7 of 12 patients who had a PR (p =

0.0686 by Chi-squared test).

Figure 1 shows the estimated freedom from progression (FFP) in all 22 patients. No relapses

were seen before 6 months. The estimated probability of progressive disease at 10.2 months was

52% (± standard error of 13%). While the number of patients enrolled makes subgroup analysis

hazardous, patient age, sex, disease extent, and previous treatment did not appear to correlate

with the probability of relapse. However, the quality of response to rituximab (CR/CRu vs. PR)

was a significant predictor of relapse (p = 0.0027 by log-rank test). There have been no deaths,

yielding an overall survival of 100%.

Pathological analysis of relapsed disease

Of the 9 patients who relapsed, 5 underwent re-biopsy to assess the status of their disease.

The characteristics of relapsed patients and the results of these biopsies are summarized in Table

3. Three patients were found to have recurrent LPHD. However, specimens from two other

patients demonstrated evidence of transformation to large cell non-Hodgkin’s lymphomas

(LCL). The subtypes were found to be T-cell rich B-cell lymphoma (TCR-BCL) in patient 1 and

diffuse large B-cell lymphoma (DLBCL) in patient 9.

To better understand the potential effect of rituximab treatment on the transformation

process, we performed a dedicated pathological review of the initial biopsy and subsequent LCL

in these two cases. The initial biopsies of both patient 1 and patient 9 showed features typical of

LPHD characterized by a nodular lymphocytic proliferation containing scattered large atypical

CD20+ cells against a small lymphocytic background (Figure 2, A, B, E, F). The biopsy of




9

progressive disease in patient 9 demonstrated sheets of CD20+ large atypical cells without

significant nodularity, a typical finding in DLBCL (Figure 2, C). Areas rich in T cells (Figure 2,

D) were rare and did not warrant the diagnosis of TCR-BCL. The LCL that developed in patient

1 contained numerous small T-cells in the background of scattered large neoplastic B-cells, a

pattern typical of TCR-BCL (Figure 2, G&H).

Management of progressive disease

The management of disease progression depended largely on the results of rebiopsy, if

performed (see Table 3). The three patients with recurrent LPHD were re-treated with rituximab.

One patient had a CR one month after retreatment. A second patient had stable disease 4.5

months after treatment. The third patient had stable disease for 16.5 months but then progressed.

A total of 4 patients have been observed for periods ranging from 2 –19 months. These patients

remain asymptomatic from their disease and are doing well.

The patient with diffuse large B-cell lymphoma (patient 9) received 4 weekly infusions of

rituximab followed by CHOP. Interestingly, a positron emission tomography scan that was

positive at relapse became negative after rituximab was given but prior to beginning CHOP. The

patient achieved a complete remission and is currently free of both LPHD and large cell

lymphoma. The patient with TCR-BCL (patient 1) had advanced disease involving the bone

marrow and was started on CHOP chemotherapy. At of the time of this analysis he had received

4 cycles and was in complete remission, including a negative bone marrow biopsy.




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DISCUSSION

We report here the results of a phase II trial of rituximab in patients with either untreated or

recurrent LPHD. We have found that rituximab has high initial activity, with an overall response

rate of 100 percent. Patients who had relapsed after standard chemo- or radiotherapy had

responses similar to those who had not been previously treated. Rituximab appeared to be less

effective in patients with greater disease bulk or more widespread disease at baseline. However,

despite the high initial response rate, we found the duration of response to be relatively short.

With a median follow up of 13 months, a total of 9 patients had relapsed. The estimated

probability of relapse reached 50 percent by ten months after the start of treatment. Not

surprisingly, we found that patients who achieved a PR were at significantly higher risk for

relapse than those who attained a CR. Treatment with rituximab was well tolerated, with toxicity

limited to transient infusion reactions.

The initial response rate we observed is essentially identical to that seen in a phase II trial

performed by the German Hodgkin’s Lymphoma Study Group (GHSG)16. These investigators

studied a heterogeneous group of patients with recurrent CD20+ disease, consisting of 10 patients

with LPHD, 2 patients with lymphocyte-rich classical HD, and 2 patients with HD that had

transformed to TCR-BCL. At the time of their most recent analysis, OR was 100% with 7 CR

and 5 PR in 12 assessable patients; 9 of 12 patients were in remission 10 to 26 months after

treatment.16 Differences in eligibility criteria and other patient characteristics may underlie the

variable response durations seen in the two trials. The GHSG study was limited to patients with

relapsed disease and included 4 patients who were not classified as LPHD. The patients in our

study, particularly untreated patients, tended to have more advanced disease than typical LPHD.




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Nearly half of the untreated patients were stage III, and overall 10 patients had three or more

nodal sites of disease. Of note, in the ETFL only 20% of patients were stage III or IV.8

In our study, two of the patients with recurrent disease after rituximab treatment were found

on rebiopsy to have transformed to a large cell lymphoma. The occurrence of these 2 cases

within a cohort of 22 patients, when compared to the 2.9% incidence of NHL in the ETFL

study,1 raises concern that rituximab might facilitate transformation. Our cases showed

morphologic and immunophenotypic patterns similar to those of transformed LCL in the absence

of rituximab therapy.17 We found that in both cases the initial LPHD lesions showed an

increased number of extranodular L&H cells, the presence of which has been observed to

correlate with recurrence as well as progression to LCL (Fan et al., manuscript in preparation).

This observation suggested a high risk for transformation in these patients, before rituximab was

given. It is also possible that rituximab created a pathological artifact by depleting the

background B-cell population, leaving a predominance of T-cells and histiocytes. In support of

this view, rituximab treatment has been shown to increase the ratio of T cells to B cells in lymph

nodes affected by low-grade NHL.18

The optimal treatment for patients with LPHD remains uncertain. Radiotherapy for early

stage patients and chemotherapy or combined modality treatment for advanced stage patients

continue to represent the standard of care. Based on the relatively short response duration seen

in our trial and the concerns about transformation, rituximab should be considered an

investigational agent in LPHD. The high initial activity seen in our trial, along with the observed

benefit of re-treatment for relapsed patients, suggests that perhaps alternative dosing schedules or

combination therapy with other treatment modalities might increase response duration. With a

disease as rare as LPHD, the optimal treatment approach can only be defined by cooperative




12

efforts between community and academic physicians in prospective clinical trials. We therefore

gratefully acknowledge referrals to our current study.

ACKNOWLEDGEMENTS

The authors would like to thank the following physicians for referral of patients for this

study: James Heckman, Alan Yuen, Peter Sayre, Joseph Szumawski, Tony Reid, Carol Portlock,

Daniel Wong, Brian Lewis, Beverly McLeod, Lawrence Strieff, James Wong, Barbara Beach,

Peter Wong, Thierry Jahan, Charlotte Kim, George Selby, Sidney Crain, Richard Robinson, Alex

Denes, and Shabir Safdar.

REFERENCES

1. Diehl V, Franklin J, Sextro M, Mauch PM. Clinical presentation and treatment of

lymphocyte predominance Hodgkin’s disease. In: Mauch PM, Armitage JO, Diehl V et al.

Hodgkin’s Disease. Philadelphia, PA: Lippincott Williams & Williams; 1999:563-582.

2. Harris NL. Hodgkin’s lymphomas: classification, diagnosis, and grading. Semin Hematol.

1999;36:220-232.

3. Chan WC. Cellular origin of nodular lymphocyte-predominant Hodgkin’s lymphoma:

immunophenotypic and molecular studies. Semin Hematol. 1999;36:242-252.

4. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of

neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical

advisory committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol.

1999;17:3835-3849.




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5. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin.

2002;52:23-47.

6. Ekstrand BC, Horning SJ. Lymphocyte predominant Hodgkin’s disease. Curr Oncol Rep.

2002;4:424-433.

7. Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on

Lymphoma project on lymphocyte-predominance Hodgkin’s disease: histologic and

immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a

nodular growth pattern and abundant lymphocytes. Blood. 2000;96:1889-1899.

8. Diehl V, Sextro M, Franklin J, et al. Clinical presentation, course, and prognostic factors in

lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s

disease: report from the European Task Force on Lymphoma project on lymphocyte-

predominant Hodgkin’s disease. J Clin Oncol. 1999;17:776-783.

9. Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term

survivors of Hodgkin’s disease: a population-based evaluation over 25 years. J Clin Oncol.

2002;20:3484-3494.

10. Regula DP, Hoppe RT, Weiss LM: Nodular and diffuse types of lymphocyte

predominance Hodgkin’s disease. N Engl J Med. 1988;318:214-219.

11. Bodis S, Kraus MD, Pinkus G, et al. Clinical presentation and outcome in lymphocyte-

predominant Hodgkin’s disease. J Clin Oncol. 1997;15:3060-3066.

12. Kielholz U, Szelenya H, Siehl J, et al. Rapid regression of chemotherapy refractory

lymphocyte predominant Hodgkin’s disease after administration of rituximab (anti CD20

monoclonal antibody) and interleukin-2. Leuk Lymphoma. 1999;35:641-642.




14

13. Lush RJ, Jones SG, Haynes AP. Advanced-stage, chemorefractory lymphocyte-

predominant Hodgkin’s disease: long-term follow-up of allografting and monoclonal

antibody therapy. Br J Haematol. 2001;114:734-735.

14. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to

standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol. 1999;17:1244-

1253.

15. Simon R. Design and analysis of clinical trials. In: DeVita VT, Hellman S, Rosenberg SA,

eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams

& Williams; 2001:521-538.

16. Schulz H, Rehwald U, Reiser M, Diehl V, Engert A. The monoclonal antibody rituximab

is well tolerated and extremely effective in the treatment of relapsed CD20-positive

Hodgkin’s lymphoma—an update [abstract]. Ann Oncol. 2002;13(Suppl 2):63a.

17. Natkunam Y, Stanton TS, Warnke RA, Horning SJ. Durable remission in recurent T-cell-

rich B-cell lymphoma with the anti-CD20 antibody rituximab. Clin Lymphoma. 2001;2:1-

3.

18. Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating

single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients

with recurrent B-cell lymphoma. Blood. 1994;84:2457-2466.




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Table 1: Characteristics of 22 patients with LPHD

CharacteristicRelapsedn = 10

Untreatedn = 12

Male:female 8:2 8:4

Median Age (range) 44 (29 – 61) 45 (18 – 63)

Stage/Relapse StageIIIIII

343

435

B symptoms 0 2

Number of lymph node regions involved

1-2 3-4 > 4

532

741

Relapse history1st relapse2nd relapse4th relapse

631

n.a.

Prior treatmentRadiotherapy

IFRegional*STLI

ChemotherapyMOPPABVDMOPP/ABVDCHOP

232

3221

n.a.

*Mantle (1 pt), Mini-mantle (1 pt), Inverted-Y (1 pt)Abbreviations: IF, involved field; STLI, subtotal lymphoid irradiation; MOPP, mechlorethamine, vincristine, procarbazine, prednisone; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; n.a., not applicable.




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Table 2: Results of treatment

Characteristic CR CRu PR

All Patients 9 1 12

Untreated patients 4 0 8

Relapsed patients 5 1 4

Stage/RestageIIIIII

522

010

246

Number of lymph node regions involved

1-2 3-4 > 4

630

100

543

Largest lymph node size 1.5 – 2.0 cm2.1 – 4.0 cm 4.1 – 5.5 cm

360

001

075

Abbreviations: CR, complete response; CRu, unconfirmed complete response; PR, partial response




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Table 3: Summary of the 9 patients who relapsed after rituximab treatment

Patient Age SexStage/

Restage

Initial response to rituximab

FFP(mos)

Histology at progression Treatment Response

Not previously treated

1 60 M IIIA PR 10 TCR-BCL CHOP responding

2 23 M IIIA PR 9 LPHD Rituximab SD (4.5 mos.)

3 38 F IA PR 6 n.d. Observation n.a.

4 45 M IA PR 10 n.d. Observation n.a.

5 32 M IIIA PR 7.5 LPHD Rituximab SD (16.5 mos.)†

6 46 F IIIA CR 14 n.d. Observation n.a.

Previously treated

7 51 M IIIA CR 12 n.d. Observation n.a.

8 25 M IIA PR 7.5 LPHD Rituximab CR (11 mos.)

9 29 M IIA PR 8.5 DLBCL Rituximab followed by

CHOP

CR (12 mos.)

† progressive disease at 16.5 months

Abbreviations: FFP, freedom from progression; n.d., not done; n.a., not applicable; LPHD, lymphocyte predominant Hodgkin’s disease; TCR-BCL, T cell- rich B cell lymphoma; DLBCL, diffuse large B cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; SD, stable disease; CR, complete response




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Figure 1: Freedom from progression

0

.2

.4

.6

.8

1

estim

ated

sur

viva

l

0 5 10 15 20 25 30 35

months




19




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FIGURE LEGENDS

Figure 1: Freedom from progression in the entire cohort.

Figure 2: Photomicrographs of LPHD and subsequent transformation.

Shown are representative H&E stains (A, C, E, G) and CD20 immunohistochemistry (B, D, F,

H) from patient 9 (A-D) and patient 1 (E-H). A. H&E of initial biopsy of patient 9 showing

nodular proliferation of lymphocytes. B. CD20 stain of initial biopsy highlights large nodules of

B-cells containing scattered large B-cells, characteristic of NLPHD. C. H&E stain of post-

rituximab biopsy at low power showing sheets of large atypical lymphocytes, diagnostic of

DLBCL. D. CD20 stain from C highlights a focal area in which the large CD20+ B cells are

surrounded by negatively stained T cells. E. H&E stain of initial biopsy from patient 1 showing

LPHD with vague nodularity. F. Anti-CD20 antibody stain from highlights loose nodular

aggregates of B-lymphocytes. Scattered large CD20 positive cells (L&H cells) are present

within and outside the B-cell nodules. G. H&E section of post-rituximab transformation to

TCR-BCL showing diffuse proliferation of lymphocytes. CD20 stain of DLBCL (H)

demonstrates scattered CD20 positive large cells with loss of nodularity. The large neoplastic

cells are set against a background of T-cells.




Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial

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