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`JOURNAL OF CLINICAL ONCOLOGY
`
`E D I T O R I A L
`
`Mantle Cell Lymphoma: At Last, Some Hope for
`Successful Innovative Treatment Strategies
`
`Richard I. Fisher, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY
`
`While it is quite unusual for totally new types of cancer to
`develop, it is not unusual for new and distinct forms of cancer
`to be recognized among what were previously thought to be
`well-defined homogeneous diseases. Such is the case with
`mantle cell lymphoma (MCL). Originally recognized in Eu-
`rope and subsequently called many different names, the uni-
`fying term MCL was proposed by an international consensus
`conference in 1992.1 Morphology alone was not sufficient to
`accurately separate these cases from other “small round cell”
`lymphomas. However, morphology plus an immunopheno-
`type consisting of CD20⫹, CD22⫹, IgM⫹, IgD⫹, and
`CD5⫹, as well as either detection of the characteristic chromo-
`somal translocation t(11;14) or overexpression of the resultant
`gene product cyclin D1, result in an accurate diagnosis.2 Fur-
`thermore, the previously unrecognized entity of MCL was not
`rare and actually represented 6% of all non-Hodgkin’s lym-
`phomas. A retrospective review of 375 patients enrolled on
`Southwest Oncology Group (SWOG) indolent lymphoma
`clinical trials demonstrated that these cases did not have an
`indolent course: the median progression-free survival follow-
`ing initial treatment was only 20 months, the median survival
`was only 36 months, and no patients were cured of their
`disease.3 A subsequent review of 524 patients treated on 12
`different clinical trials revealed amazing uniformity in the
`treatment results.4 Thus, in comparison with the indolent lym-
`phomas, which were incurable but had a median survival of 7
`to 10 years, and the aggressive lymphomas, which could be cured
`in 40% to 50% of all cases, patients with MCL could be viewed as
`havingtheworstprognosisofallformsoflymphoma.Thatmanu-
`scriptconcludedthatpatientswithMCL“arecandidatesforinno-
`vative (and hopefully more successful) therapy.”3
`Clinical trials conducted in the intervening years have
`generally yielded disappointing results. Although there is no
`established standard of care for patients with MCL, combina-
`tion chemotherapy with CHOP (cyclophosphamide, doxoru-
`bicin, vincristine, and prednisone) remained the most
`
`commonly used initial treatment, especially in the United
`States. There still remains some controversy over the value of
`doxorubicin. Fludarabine-based regimens are also utilized. Af-
`ter rituximab was shown to have an approximately 30% re-
`sponse rate in patients with relapsed MCL,5 Howard et al6
`conducted a phase II study of CHOP plus rituximab (R-
`CHOP) in untreated patients. Although they did note an in-
`creased complete remission rate compared with historical
`controls,
`there did not seem to be any difference in
`progression-free or overall survival. Hiddeman et al7 recently
`reported the initial results of a relatively small randomized trial
`in untreated MCL comparing CHOP and R-CHOP. Although
`there seemed to be some improvement in time to treatment
`failure from the addition of rituximab, the magnitude of the
`benefit was not great. The study also had a second randomiza-
`tion to interferon maintenance therapy or autologous stem-
`cell transplantation; those aspects of the study have not yet
`been analyzed. The only published trial that reported greatly
`improved results in MCL was a single-institution study by The
`M.D. Anderson Cancer Center group, with relatively short
`follow-up, utilizing HyperCVAD (fractionated cyclophos-
`phamide, doxorubicin, vincristine, dexamethasone) with or
`without stem-cell transplantation.8 However, allogeneic trans-
`plantation is not an option for most patients with MCL be-
`cause of their median age of 60 years; the vast majority of
`patients who undergo autologous stem-cell transplantation
`will relapse. Subsequently, the same group reported that the
`addition of rituximab to the HyperCVAD regimen eliminated
`the need for stem-cell transplantation. A national phase II trial
`of that same regimen is currently being conducted by SWOG.
`Thus, it is clear that new therapeutic approaches for the
`treatment of patients with MCL need to be developed. A series
`of new agents, including bortezomib, thalidomide, flavopiri-
`dol, pixantrone, m-TOR inhibitors, and others, has shown
`some initial activity in pretreated patients. In this issue of the
`Journal, O’Connor et al9 and Goy et al,10 report the results of
`
`Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp 657-658
`DOI: 10.1200/JCO.2005.10.980
`
`657
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`Downloaded from ascopubs.org by 134.174.157.156 on March 29, 2018 from 134.174.157.156
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`IPR2018-00685
`Celgene Ex. 2005, Page 1
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`

`

`Richard I. Fisher
`
`two separate phase II clinical trials conducted in relapsed or
`refractory indolent non-Hodgkin’s lymphoma with the novel
`proteasome inhibitor bortezomib. While it is beyond the scope
`of this Editorial to review in detail the ubiquitin-proteasome
`pathway, there is ample preclinical evidence to support trials of
`proteasome inhibition in hematologic malignancies, and par-
`ticularly in indolent lymphomas. Both studies used a dose of
`1.5 mg/m2, which is higher than the 1.3-mg/m2 dose currently
`recommended in multiple myeloma. However, the schedule of
`administration remains the same in all studies: twice-weekly
`intravenous injections administered during the first 2 weeks of
`a 3-week cycle. The median number of prior therapies ex-
`ceeded three in both studies. Although bortezomib is clearly
`active in follicular lymphoma, the results in follicular lym-
`phoma differ somewhat between the two studies and will need
`to be better defined in larger trials. In addition, there are many
`more active agents for patients with follicular lymphoma.
`However, the results in MCL patients are remarkably consis-
`tent and quite exciting. Five of the 10 assessable MCL patients
`in the O’Connor study achieved objective responses (50%; one
`complete response [CR], four partial response [PR]). Re-
`sponse durations were 6, 6⫹, 7⫹, 9⫹, and 19 months. The last
`patient has been re-treated and achieved a second PR that
`continues at 4 additional months. Of the 29 assessable MCL
`patients who were treated on the Goy et al study, there were six
`CR and six PR, for an objective response rate of 41% (95% CI,
`24% to 61%). The median time to progression for MCL has
`not been reached, and an estimated 80% are still in response at
`6 months, with a median follow-up of 9.3 months. In general,
`both studies report reasonably tolerable toxicity profiles, sim-
`ilar to those seen in patients with multiple myeloma. The
`National Cancer Institute of Canada is also conducting a phase
`II study of bortezomib in MCL using the 1.3-mg/m2 dose.11
`They initially reported an overall response rate of 39%.11 Thus,
`three separate phase II studies report an overall response rate of
`40% to 50%, with durations of response in the two published
`studies exceeding 6 months in heavily pretreated patients with
`MCL. This author is currently leading a large, multicenter,
`industry-sponsored phase II trial of bortezomib at a dose of 1.3
`mg/m2 to accurately define clinical benefit for patients with
`relapsed or refractory MCL. In an initial attempt to combine
`bortezomib with combination chemotherapy, the National
`Cancer Institute is conducting a phase I/II study of bort-
`ezomib combined with dose-adjusted EPOCH (etoposide,
`prednisone, vincristine, cyclophosphamide, doxorubicin)
`chemotherapy in relapsed or refractory diffuse large B-cell
`lymphoma. Preliminary results suggested that gastrointestinal
`toxicity, but not neurotoxicity, might be increased compared
`with historical controls; the authors concluded that bort-
`ezomib can be given with combination chemotherapy at full
`dose without significant overlapping toxicity.12 However, to
`date, there was only one PR among 13 enrolled patients with
`diffuse large B-cell lymphoma. Currently, studies of bort-
`ezomib in combination with chemoimmunotherapy are being
`conducted in untreated patients with MCL. Until the value of
`
`adding bortezomib to the treatment of patients with MCL is
`fully evaluated, these patients should continue to be en-
`tered on clinical trials, which offer the best hope for
`changing the prognosis of patients with MCL.
`
`■ ■ ■
`
`Author’s Disclosures of Potential
`Conflicts of Interest
`The following author or their immediate family members
`have indicated a financial interest. No conflict exists for drugs
`or devices used in a study if they are not being evaluated as part
`of the investigation. Consultant/Advisory Role: Richard I.
`Fisher, Genentech, IDEC, Millennium Pharmaceuticals. Hon-
`oraria: Richard I. Fisher, Genentech, IDEC, Millennium Phar-
`maceuticals. For a detailed description of these categories, or
`for more information about ASCO’s conflict of interest policy,
`please refer to the Author Disclosure Declaration and the “Dis-
`closures of Potential Conflicts of Interest” section of Informa-
`tion for Contributors found in the front of every issue.
`
`© 2005 by American Society of Clinical Oncology
`
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`
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`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 134.174.157.156 on March 29, 2018 from 134.174.157.156
`
`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`IPR2018-00685
`Celgene Ex. 2005, Page 2
`
`