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Rituximab and CHOP Induction Therapy for Newly Diagnosed Mantle-Cell Lymphoma: Molecular Complete Responses Are Not Predictive of Progression-Free Survival

From the Departments of Adult Oncology, Biostatistics, and Radiology, Dana-Farber Cancer Institute, and Division of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Address reprint requests to M. Shipp, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: margaret_shipp{at}dfci.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the efficacy of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) induction therapy in patients with newly diagnosed mantle-cell lymphoma (MCL).

PATIENTS AND METHODS: From March 1997 to May 1999, 40 previously untreated patients with stage II through IV MCL were treated with six cycles of rituximab and CHOP chemotherapy in a phase II trial. Pretreatment and interval peripheral-blood (PB) and bone marrow (BM) specimens were also analyzed by polymerase chain reaction (PCR) for tumor-specific BCL-1/immunoglobulin H (IgH) translocations and clonal IgH rearrangements. Study end points included clinical and molecular response rates and long-term progression-free survival (PFS).

RESULTS: Forty-eight percent of patients achieved a complete response (CR)/CR unconfirmed (CRu), and 48% of patients obtained a partial response (PR). However, 28 of the 40 patients have already relapsed or developed progressive disease with a median PFS of 16.6 months. Twenty-five patients had PCR-detectable BCL-1/IgH or clonal IgH products in PB or BM at diagnosis. Nine of the 25 informative patients had no evidence of PCR-detectable disease in PB or BM after rituximab and CHOP therapy. However, patients who achieved molecular remissions in PB or BM had PFS similar to patients without molecular remissions (16.5 v 18.8 months, P = .51).

CONCLUSION: Favorable clinical and molecular response rates associated with rituximab and CHOP chemotherapy do not translate into prolonged PFS in MCL. Nevertheless, rituximab and combination chemotherapy may transiently clear PB or BM of detectable tumor cells, prompting additional consideration of antibody-based in vivo purging in subsequent clinical trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MANTLE-CELL LYMPHOMA (MCL) is a recently characterized entity that accounts for up to 5% of all non-Hodgkin’s lymphomas (NHLs) and 10% of tumors previously identified as low- to intermediate-grade NHLs.^1-3 Most patients with MCL present with advanced-stage disease, which often involves the bone marrow, spleen, and gastrointestinal tract; circulating tumor cells are also common.^2,4-13

Untreated MCL tends to progress rapidly, with most patients requiring therapy within 6 months of diagnosis. However, MCL is responsive to available combination chemotherapy regimens, with reported complete response (CR) rates of 19% to 52%.^{2-4,6-9,14-17} Despite these favorable initial response rates, the median overall survival of patients with MCL is a disappointing 36 to 52 months, with only 8% of patients alive 10 years after diagnosis.^{2-4,6-9,14-16,18-20}

To date, there is no clear evidence that standard-dose chemotherapy regimens result in long-term disease-free survival of patients with MCL. High-dose therapy with autologous stem cell or marrow rescue has been equally disappointing in most series,^21-23 although more optimistic results have been reported in recent trials with short follow-up.^17,24 Analyses of harvested bone marrow or stem cells of patients with MCL indicate the persistence of contaminating residual tumor cells after induction or attempted salvage chemotherapy.^25-27 Taken together, these disappointing data underscore the need to develop additional therapeutic strategies in this disease.

Rituximab (Rituxan; Genentech, San Francisco, CA) is a chimeric murine/human monoclonal antibody that reacts with the cell-surface protein CD20 expressed by normal and malignant mature B cells.^28,29 Immunophenotypic analyses confirm that MCLs are uniformly CD20 positive, expressing high levels of the cell-surface protein.^30-34 Rituximab binds human C1q and initiates both complement-mediated cytolysis and antibody-dependent cellular cytotoxicity of CD20-expressing B cells. In vitro, the antibody has been shown to induce apoptosis and cell sensitivity to cytotoxic agents, including doxorubicin.³⁵ In vivo, rituximab has demonstrated single-agent activity against MCL, with reported responses of approximately 1 year in approximately 30% of newly diagnosed or previously treated patients.^36,37

An open-label, single-arm, phase II study of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) combined with rituximab was recently completed in follicular NHL with impressive overall and CR rates of 95% and 55%, respectively.³⁸ Eight of the patients treated with rituximab and CHOP were also evaluated for minimal residual disease using a polymerase chain reaction (PCR)–based assay of t(11;18); seven of the eight patients achieved a molecular complete response.³⁸ These molecular response data are of particular interest because patients with follicular lymphoma rarely, if ever, achieve a molecular complete responses with CHOP chemotherapy alone. The ability of rituximab in combination with CHOP to induce molecular CRs in this conventionally incurable lymphoid malignancy prompted us to evaluate the treatment regimen in MCL.

MCL is commonly associated with the t(11;14)(q13;q32) translocation, which approximates the immunoglobulin heavy chain (IgH) promoter/enhancer at 14q32 and the BCL-1/cyclin-D1 oncogene at 11q13 and is detectable by PCR in 30% to 50% of tumors.^14,39,40 MCLs are also characterized by unique clonal rearrangements of the immunoglobulin gene. As a consequence, molecular analyses of circulating and bone marrow (BM)–based minimal residual disease in MCL can be performed using PCR-based assays of tumor-specific IgH rearrangements or t(11;14) (q13;q32).^41-43

Here we report the results of a phase II study in which patients with newly diagnosed, previously untreated MCL were treated with the combination of rituximab and CHOP. Study end points included clinical and molecular response rates and long-term progression-free survival (PFS).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Forty previously untreated patients with stage II through IV MCL were enrolled onto the study between March 1997 and May 1999. Patients with physiologic ages between 18 and 65 years were included. Patients were required to have measurable disease, normal renal function (creatinine < 1.5 times the upper limit of normal [UNL]), normal hepatic function (total bilirubin < two times UNL, AST < 2.5 times UNL, alkaline phosphatase < three times UNL), an ejection fraction of greater than 50%, and normal hematologic parameters (hemoglobin > 9 g/dL, absolute neutrophil count [ANC] > 1,500/µL, and platelets > 100,000) unless there was documented BM involvement.

The diagnosis of MCL was confirmed by pathology review at the Brigham and Women’s Hospital or the Massachusetts General Hospital. Additional pretreatment evaluation included chest, abdomen, and pelvic computed tomography scans, gallium scan, and BM biopsy and aspirate.

Treatment Regimen
After informed consent and study enrollment, patients received six cycles of rituximab and CHOP therapy at 21-day intervals. Rituximab was given on day 1 at 375 mg/m², and standard-dose CHOP was given on day 3 (cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m²) (2 mg maximum) and days 3 through 7 (prednisone 100 mg/d for 5 days) of each 21-day cycle.

Patients were required to have an ANC of higher than 1,000/µL and platelet count higher than 90,000/µL to begin their next cycle of therapy unless they had evidence of persistent BM involvement. With persistent BM involvement, patients could be treated on time provided that their ANC was higher than 500/µL and their platelet count was higher than 40,000/µL. If febrile neutropenia occurred or treatment was delayed for a low ANC, granulocyte colony-stimulating factor was administered in future cycles.

Assessment of Toxicity
Toxicity was assessed after each cycle of therapy and at follow-up using standard National Cancer Instiute common toxicity criteria.

Assessment of Clinical Response
Radiographic review of responses was completed by a single study radiologist (M.J.J.) using criteria established by the International Workshop to Standardize Response Criteria for NHL.⁴⁴ CR was defined as the disappearance of all detectable clinical and radiologic evidence of disease and lymphoma-associated laboratory abnormalities. All lymph nodes had to have regressed to normal size (< 1.5 cm in greatest diameter for nodes > 1.5 cm before therapy and < 1 cm for nodes 1.1 to 1.5 cm before therapy).⁴⁴ Previously enlarged spleens had to be nonpalpable, and BMs had to have no morphologic evidence of disease.⁴⁴ CR/unconfirmed CR (CRu) was defined as above with the following exceptions⁴⁴: a lymph node mass greater than 1.5 cm was permitted provided it had regressed by more than 75% in the sum of its perpendicular diameters⁴⁴ and an indeterminate BM with nondiagnostic aggregates was allowed.⁴⁴ However, restaging BMs with suspicious aggregates were defined as partial responses (PRs). PR was defined as a reduction of 50% or greater in the sum of the products of the perpendicular diameters (SPDs) of the largest six measurable lesions, including splenic and hepatic nodules, without the appearance of additional new or enlarging lesions.⁴⁴ Stable disease was defined as less than a PR but not progression.⁴⁴ Objective progression or relapse was defined as a 50% or greater increase in the product of the perpendicular diameters of any measurable lesion or the appearance of new areas of malignant disease.⁴⁴

Assessment of Molecular Response
DNA sample preparation. Peripheral-blood (PB) and BM mononuclear samples were obtained from each patient before the initiation of treatment for PCR analyses of t(11;14) (q13:q32) and clonal IgH rearrangements. Study patients with PCR-detectable BCL-1/IgH translocations or clonal IgH rearrangements (see below) had additional PB and BM samples obtained at specified intervals thereafter for molecular assessment of minimal residual disease.

PCR amplification of BCL-1/JH and clonal IgH rearrangements. PB and BM mononuclear cells were isolated by Ficoll gradient centrifugation (Pharmacia, Uppsala, Sweden) and lysed, and DNA was extracted as previously described⁴⁵ or using the DNA minipreps (Qiagen, Valencia, CA). Before PCR amplification, DNA samples were heated at 96°C for 10 minutes to denature proteinase K and quantified by spectrometry. Well-established precautions were taken to prevent carryover contamination of PCR reactions.⁴⁶ To detect BCL-1/JH rearrangements with a breakpoint within the major translocation cluster region, we used a previously described seminested PCR method.²⁵ Briefly, two sense primers derived from the chromosome 11 sequence just upstream of the breakpoint cluster were used in combination with antisense JH consensus primers. This assay has a level of sensitivity of one tumor cell in 10⁵ normal background cells.²⁵ The BCL-1/JH PCR products from each MCL case were sequenced using an AB 373A DNA sequencer (PE Biosystems, Foster City, CA), and 15 µL of the completed reactions was electrophoresed on 3% agarose gels with ethidium bromide and visualized under ultraviolet light.

To identify MCL-related clonal IgH rearrangements, tumor DNA was PCR amplified using a series of seven VH family framework region one (FR 1) consensus primers and a JH consensus primer, as previously described with minor modifications.⁴³ In brief, PCR amplifications were performed in 100 µL with 1 to 2 µg genomic DNA, 10 µL 10 x PCR buffer II containing 100 mmol/L Tris HC1 (pH 8.3), 500 mmol/L KC1 (PE Biosystems), 10 µL 25 MgCl2 (PE Biosystems), 200 µmol/L each of dATP, dCTP, dTTP, and dGTP, 1.25 units AmpliTaq DNA polymerase (PE Biosystems), and 20 pmols of VH and JH consensus primers. Amplifications were performed on a Perkin Elmer DNA Thermal Cycler 9600 as follows: 94°C for 1 minute, 62°C for 30 seconds, and 72°C for 30 seconds for 30 cycles followed by a 7-minute final extension at 72°C before cooling to 4°C. To increase specificity, hot starts were achieved either by the use of AmpliTaq Gold (PE Biosystems) or the addition of Ampliwax PCR Gem beads (PE Biosystems). As above, aliquots of the PCR reactions were electrophoresed on ethidium bromide–containing agarose gels and visualized under ultraviolet light. Clonal IgH gene rearrangements, predominant single visible bands of 300 to 350 bp, were excised, purified using Wizard PCR preps (Promega, Madison, WI), and sequenced directly as described above. The relevant VH family and JH consensus primers were used as sequencing primers to obtain the sequence information from both strands, and sense and antisense sequences were aligned. VH, DH, JH, and regions of N-nucleotide addition were identified by BLAST Search network service (National Center for Biotechnology Information, Bethesda, MD). Antisense CDRIII region patient allele-specific oligonucleotide primers were designed to have annealing temperatures of approximately 60°C and synthesized by Gibco BRL (Gaithersburg, MD). For MRD detection, seminested PCR reactions were performed initially using the VH and JH consensus primers and then with the VH consensus primer and allele-specific oligonucleotide as previously described.²⁵

In informative patients (patients with PCR-detectable BCL-1/JH or clonal IgH rearrangements in PB or BM at diagnosis), molecular remission was defined as disappearance of PCR-detectable disease in the PB or BM at the first restaging after the completion of therapy.

Statistical Methods
The study was initially designed to have more than 90% power to detect an improvement in the clinical CR rate (CR plus CRu) from 45% to 60% by enrolling 30 patients. It was assumed that approximately 75% of study patients would have a PCR-detectable clonal IgH rearrangement or BCL-1/IgH translocation in PB or BM at diagnosis. However, this estimate proved high, and 10 additional patients were enrolled onto the trial to ensure that adequate numbers of patients were also assessable for molecular response.

PFS, which was defined as the time elapsed from initiation of treatment until progression of disease, date last known alive and free of disease, or date of death without recorded progression, was estimated by the method of Kaplan and Meier; differences in PFS were assessed by the log-rank test. Three patients who obtained PRs with protocol therapy underwent subsequent stem-cell transplants; these patients were censored at the time of transplant. Exact binomial confidence intervals were provided for binary end points.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Between March 1997 and May 1999, 40 patients with newly diagnosed MCL were enrolled onto the study. The median age of protocol patients was 55 years (range, 31 to 69 years) (Table 1). Most patients (35 [88%]) had stage IV disease and documented BM involvement (32 patients [80%]) (Table 1).

Toxicity
Most of the observed toxicities were hematologic in nature and directly attributable to CHOP chemotherapy. Seven patients developed febrile neutropenia and one patient died of neutropenic sepsis 12 days after receiving his first cycle of therapy.

Toxicities likely to be attributable to rituximab included an infusional reaction to the first cycle of the monoclonal antibody in almost 50% of patients. These infusional reactions consisted of fevers, rigors, transient hypotension, and, on rare occasions, stridor or wheezing that necessitated the transient use of oxygen. None of these reactions required hospitalization, and all infusions were subsequently resumed without additional sequelae. Only one patient had an infusional reaction with a subsequent cycle of therapy. One patient who had WBC higher than 200,000 before starting therapy developed a seizure on day 7 of cycle one. A magnetic resonance imaging scan revealed a vascular injury pattern consistent with, but not diagnostic of, intravascular complement activation. The patient subsequently received five additional cycles of rituximab and CHOP without incident. There was one episode of documented Pneumocystis carinii pneumonia and another of suspected Pneumocystis carinii pneumonia that resolved without complications after appropriate therapy.

Overall Responses and Morphologic BM Responses CR/CRu
Thirteen patients achieved a CR and six patients achieved a CRu, for a combined rate of 48% (90% confidence interval [CI], 34% to 62%) (Table 2). Nineteen patients (48%) had partial responses, one patient (3%) had stable disease, and one patient (3%) was unassessable because of early death (Table 2). Of the 32 patients with morphologic evidence of BM involvement at diagnosis, 21 patients (66%; 90% CI, 50% to 79%) obtained a morphologic marrow CR after rituximab and CHOP induction therapy (Table 2).

View larger version (27K): [in this window] [in a new window]   Fig 1. Molecular analyses of MCL in PB or BM of study patients. Patients with PCR-detectable BCL-1/IgH (blue) or clonal IgH (green) rearrangements in PB (top, solid bar) or BM (bottom, open bar) at diagnosis were followed for evidence of molecular remission (. Data are arranged by PCR status after the completion of therapy (vertical double-dotted lines), as follows: (A) PCR negative; (B) PCR mixed; and (C) PCR positive. Clinical progression from CR (red) or PR (yellow) is indicated (). *Three patients with PCR-detectable disease went directly to stem-cell transplant in PR.

At the completion of rituximab and CHOP therapy, nine of the 25 informative patients (36%; 90% CI, 30% to 66%) had no evidence of PCR-detectable disease in paired PB/BM or BM-only specimens (Fig 1A). However, only four of the nine patients in molecular remission had clinical, radiologic, or pathologic CR/CRu to rituximab and CHOP therapy; the remaining five molecular responders achieved only a PR to the induction therapy (Fig 1A). These data suggest that rituximab and CHOP may clear circulating MCL more efficiently than nodal or extranodal disease. However, the PCR-documented PB and BM responses to rituximab and CHOP were also transient in nature. Five of the nine molecular responders were PCR positive in PB or BM at the next determination, and three additional patients relapsed clinically before additional PCR analyses (Fig 1A).

Fifteen of the remaining 16 informative patients had PCR-detectable disease in PB or BM at the completion of rituximab and CHOP therapy (an additional patient underwent immediate stem-cell transplant without restaging PB and BM analyses) (Fig 1, B and C). Seven of these patients had mixed molecular responses (PCR-negative PB and PCR-positive BM, five patients; PCR-positive PB and PCR-negative BM, two patients; Fig 1B), whereas the remaining eight patients had PCR-detectable disease in the BM or both evaluated disease sites (Fig 1C). As indicated, three of the patients with PCR-detectable MCL at the completion of rituximab and CHOP therapy went directly to stem-cell transplant in PR; an additional eight PCR-positive patients have developed clinical evidence of recurrent or progressive disease (Fig 1, B and C).

PFS
Despite the favorable initial response rates to rituximab and CHOP therapy, 28 of the 40 study patients either relapsed or developed progressive disease, with a median PFS of 16.6 months (Fig 2A). There were no significant differences in the PFS for patients who achieved clinical CR, CRu, and PR (18.8, 16.2, and 14.7 months, respectively [P = .23]). Only nine uncensored patients remain alive in remission, with a median follow-up of 25 months (range, 15 to 35 months), and no patients remain in remission longer than 36 months after study entry (Fig 2A). Favorable clinical responses to rituximab and CHOP induction therapy were not associated with prolonged PFS; patients with CR/CRu had PFS that was similar to those who did not achieve CR/CRu (PFS 18.8 v 14.2 months, respectively [data not shown]). Molecular responses to rituximab and CHOP induction therapy were also unassociated with prolonged PFS (Fig 2B). As indicated, patients who achieved molecular remissions in PB or BM (Fig 1A) had PFS that was similar to PFS of patients without evidence of molecular remission (PFS 16.5 v 18.8 months, P = .51, respectively; Fig 2B).

View larger version (14K): [in this window] [in a new window]   Fig 2. PFS of patients with MCL treated with rituximab and CHOP. (A) PFS of all study patients; (B) PFS of study patients according to molecular response at restaging.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Unfortunately, in patients with MCL, the favorable initial response rates associated with rituximab and CHOP therapy do not translate into prolonged PFS. Whereas follicular lymphoma patients with clinical and molecular CRs to rituximab and CHOP have not yet reached the median time to progression with longer than 4 years of follow-up,³⁸ our MCL study patients have progressed at an average of 16.6 months after the initiation of therapy. In addition, the attainment of a molecular CR to rituximab and CHOP is not predictive for PFS in newly diagnosed, previously untreated MCL.

The absence of a correlation between PCR-documented molecular CRs in PB or BM and long-term PFS suggests that rituximab and CHOP may clear circulating MCL more efficiently than nodal or extranodal tumor masses. Consistent with this possibility, five patients with MCL had clinical evidence of persistent tumor at a time when their PB or BM was PCR negative for MCL. These observations are important for two reasons. First, PCR-based analyses of circulating minimal residual disease in MCL and, possibly, other lymphomas, may not be predictive of long-term outcome in patients who are treated with rituximab with or without additional chemotherapy. Second, if rituximab and CHOP transiently clear the PB and BM of detectable tumor cells, such combined-modality therapy may provide in vivo purging and a preferable source of autologous stem cells for subsequent high-dose therapy or immunologic approaches. In fact, many centers are presently conducting trials of in vivo purging with rituximab with or without chemotherapy before autologous stem cell or BM harvest in B-cell lymphomas, including MCL.^47,48 The present study supports additional analysis of such approaches in this disease.

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Submitted June 22, 2001; accepted November 2, 2001.

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