Exhibit 2002 Page 001
`
`Pharmacyclics LLC - Ex. 2002
`Coalition for Affordable Drugs IV LLC v. Pharmacyclics LLC
`Case IPR2015-01076
`
`

`

`American Cancer Society
`
`Atlas of
`Clinical Oncology
`
`Editors
`
`GLENN D. STEELE JR, MD
`
`Geisinger Health System
`
`THEODORE L. PHILLIPS, MD
`
`University of California
`
`BRUCE A. CHABNER, MD
`
`Harvard Medical School
`
`Managing Editor
`
`TED S. GANSLER, MD, MBA
`
`Director of Health Content, American Cancer Society
`
`Exhibit 2002 Page 002
`
`Exhibit 2002 Page 002
`
`

`

`American Cancer Society
`Atlas of
`Clinical Oncology
`
`Malignant
`Lymphomas
`
`Michael L. Grossbard, MD
`
`Associate Professor of Clinical Medicine
`
`Columbia University College of Physicians and Surgeons
`Chief, Hematology/Oncology
`St. Luke’s—Ro0seve1t Hospital Center
`and Beth Israel Medical Center
`
`New York, New York
`
`2002
`
`BC Decker Inc
`
`Hamilton - London
`
`Exhibit 2002 Page 003
`
`Exhibit 2002 Page 003
`
`

`

`
`
`BC Decker Inc
`
`20 Hughson Street South
`PO. Box 620, LCD 1
`Hamilton, Ontario L8N 3K7
`Tel: 905-522-7017; 1-800-568-7281
`Fax: 905-522-7839; 1-888-311-4987
`
`E-mail: info@bcdecker.com
`Website: www.bcdecker.com
`
`© 2002 American Cancer Society
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by
`any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher.
`
`02 03 0405 /UTP/9876 5 4 3 21
`
`ISBN 1—55009—152-2
`Printed in Canada
`Cover figure (top left) courtesy of Dr. Treseler, from Chapter 20, The Pathology of Hodgkin’s Disease.
`Cover figure (top right) courtesy of Drs. Foss and Demierre, from Chapter 15, Cutaneous T-Cell Lymphoma.
`Cover figure (bottom) courtesy of Drs. Khushalani and Czuczman, from Chapter 3, Molecular Biology of Non—Hodgkir1’s Lymphomas.
`
`Sales and Distribution
`
`United States
`BC Decker Inc
`PO. Box 785
`
`Lewiston, NY 14092-0785
`Tel: 905-522-7017; 1-800-568-7281
`Fax: 905-522-7839; 1-888-311-4987
`E-mail: info@bcdecker.com
`Website: www.bcdecker.com
`
`Canada
`BC Decker Inc
`
`20 Hughson Street South
`PO. Box 620, LCD 1
`Hamilton, Ontario L8N 3K7
`Tel: 905-522-7017; 1-800-568-7281
`Fax: 905-522-7839; 1-888-311-4987
`E-mail: info@bcdecker.com
`Website: www.bcdecker.com
`
`Foreign Rights
`John Scott & Company
`International Publishers’ Agency
`PO. Box 878
`
`Kimberton, PA 19442
`Tel: 610-827-1640
`Fax: 610-827-1671
`
`E-mail: jsco@voicenet.com
`
`UK, Europe, Scandinavia,
`Middle East
`Elsevier Science
`
`Customer Service Department
`Foots Cray High Street
`Sidcup, Kent
`DA14 SHR UK
`Tel: 44 208 308 5760
`Fax: 44 181 308 5702
`
`E-mail: cservice@harcourt.com
`
`Australia, New Zealand
`Elsevier Science Australia
`
`Customer Service Department
`STM Division
`
`Locked Bag 16
`St. Peters, New South Wales, 2044
`Australia
`Tel: 61 02 9517-8999
`Fax: 61 02 9517-2249
`
`E-mail: stmp@harcourt.com.au
`Website: wvvw.harcourt.com.au
`
`Japan
`Igaku-Shoin Ltd.
`Foreign Publications Department
`3-24-17 Hongo
`Bunkyo-ku, Tokyo, Japan 113-8719
`Tel: 81 3 3817 5680
`Fax: 81 3 3815 6776
`
`E-mail: fd@igaku-shoin.co.jp
`
`Singapore, Malaysia, Thailand,
`Philippines, Indonesia, Vietnam,
`Pacific Rim, Korea
`Elsevier Science Asia
`583 Orchard Road
`
`#09/01, Forum
`Singapore 238884
`Tel: 65-737-3593
`Fax: 65-753-2145
`
`Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and
`drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly
`change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes rec-
`ommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs.
`
`‘B<h|b|t 20'O‘2'Page'OT54
`
`Exhibit 2002 Page 004
`
`

`

`GROSSBARD
`
`MALIGNANT LYMPHOMAS
`
`ATLAS OF CLINICAL ONCOLOGY
`
`Over the past decade, the incidence of non-Hodgkin’s lymphoma has been rising. At the same time, the benefits of
`extensive research in tumor immunology and molecular biology have radically altered our understanding of lymphoma
`biology. New therapeutic agents have advanced rapidly from the laboratory to the bedside.
`
`In Malignant Lymphomas, Dr. Grossbard has assembled an expert group of 48 colleagues to address the disease group
`by type—-indoient B-cell
`lymphoma, diffuse large cell
`lymphomas, Burkitt’s/high-grade non-Hodgkin’s lymphoma
`«was well as the key therapies of chemotherapy, monoclonal antibody, radiation, vaccine, hematopoietic stem cell
`transplants, and more.
`
`This volume on lymphoma is designed to summarize current knowledge on the pathology, epidemiology, molecular
`biology, presentation, and management of patients with both non-Hodgkin’s lymphoma and Hodgkin’s disease. It is
`an essential reference not only for the specialist in lymphoma but also for the general oncologist and all those who
`manage these diseases on a daily basis.
`
`' Covers screening and diagnosis
`
`° Presents contemporary data designed to stimulate further discussion and research
`-
`includes contributions representing medical, surgical, and radiation oncology and related disciplines
`° More than 200 color clinical photographs, photomicrographs, karyotypes, radiographs, tables, and algorithms illus-
`trate the manifestation of the disease
`
`-
`
`lmages from the CD-ROM can be downloaded for lectures and presentations
`
`6 CD-ROM Inside.
`
`Malignant Lymphomas comes complete with its own CD-ROM.The disk includes the complete text and illustrations
`contained within the book in fully searchable PDF files.
`
`BC Decker Inc is committed to providing medical and health care professionals with high quality electronic publications
`that complement traditional information and learning methods.
`
`PO. BOX 620, LCD l
`Hamilton,ON L8N 3K7
`Canada
`800-568-728 l
`
`; 905-522-70 l 7
`
`Fax: 888-3| l-4987; 905-522-7839
`
`E-mail: info@bcdecker.com
`Web: www.bcdecker.com
`
`P.O. BOX 785
`Lewiston, NY |4092-0785
`U.S.A.
`
`[SEN 1_55009_152_2
`
`Malignant Lymphomas, Atlas of Clinical Oncology
`
`lSBN l-55009-l52-2
`
`Exhibit 2002 Page 005
`
`

`

`9
`
`Mantle Cell Lymphoma
`
`ORION HOWARD, MD
`
`OVERVIEW AND HISTORY
`
`Mantle cell lymphoma (MCL) is a recently character-
`ized subtype of non-Hodgkin’s lymphoma (NHL) that
`occupies its own category in the Revised European
`American Lymphoma (REAL) and World Health
`Organization (WHO) NHL classifications. The dis-
`ease now recognized as MCL was previously admixed
`within a variety of heterogeneous NHL entities. In the
`past, MCL was incorporated within centrocytic lym-
`phoma (Kiel classification), diffuse poorly differenti-
`ated lymphocytic lymphoma (Rappaport Classifica-
`tion), and follicular center cell lymphoma, small
`cleaved diffuse type (Lukes-Collins Classification).
`In the Working Formulation (WF), most cases of
`MCL fell into WF category E, diffuse small cleaved
`cell lymphoma. Other names previously used for what
`was to become MCL included intermediate lympho-
`cytic lymphoma and mantle zone lymphoma.
`The diagnosis and treatment of mantle cell lym-
`phoma is currently an area of intensive investigation.
`This interest stems from the observation that mantle
`cell lymphoma appears to be incurable with standard
`therapeutic techniques and also has an aggressive
`natural history that places it on par with the more
`aggressive forms of NHL. This is obviously of clin-
`ical concern and is relatively unique within the
`realm of NHL.
`From a biologic standpoint, MCL also is unique
`in that it tends to uniformly overexpress the cell
`cycle regulatory protein cyclin D1, the result of the
`t(11;14) translocation involving bcl-1. This makes
`MCL a disease with a unique molecular feature that
`may be a target for diagnostic and therapeutic inter-
`
`vention. This chapter reviews the pathology, biology,
`presentation, and treatment of patients with MCL.
`
`EPIDEMIOLOGY
`
`Mantle cell lymphoma accounts for 3 to 5 percent of
`all NHL diagnosed using modern methodology1 and
`10 percent of NHL previously identified as WF cate-
`gory A–E.2 Two recent reviews of NHL cases in
`Japan3 and India4 showed that MCL made up 2.8 per-
`cent and 3.4 percent of all NHL diagnosed in those
`countries, respectively, using the WHO classification.
`This makes MCL as common as other unique NHL
`entities such as marginal zone lymphoma. On the
`basis of the unique immunophenotypic and cytoge-
`netic signature of MCL, discussed below, the diagno-
`sis of MCL is being made with greater accuracy and
`frequency so the true incidence of MCL may increase
`as familiarity with its diagnosis disseminates.
`Patients with mantle cell lymphoma tend to be
`older, with an average age of 61 to 68 years, and
`have a strong male predominance (2:1 to 4:1). There
`are no known risk factors associated with an ele-
`vated risk of developing MCL. It does not appear to
`be more common in human immunodeficiency
`virus–infected individuals.
`
`PATHOLOGY
`
`Mantle cell lymphoma previously has been referred
`to as lymphocytic lymphoma of intermediate differ-
`entiation, and some of the initial pathologic descrip-
`tions of MCL were given for this entity.5 Mantle cell
`lymphoma cells have been described as monotonous
`
`135
`
`Exhibit 2002 Page 006
`
`

`

`136 MALIGNANT LYMPHOMAS
`
`relatively small lymphoid cells with enlarged,
`grooved nuclei, coarse chromatin, small nucleoli,
`scant cytoplasm, and few larger admixed cells (Fig-
`ures 9–1 and 9–2C).6 Circulating MCL cells tend to
`be small (7 to 10 mu) with slightly folded nuclei.7
`The growth patterns of MCL have been exten-
`sively described and include a mantle zone pattern,
`a nodular pattern, a diffuse pattern, and a blastoid
`variant (Figures 9–2 and 9–3). Some studies have
`suggested a survival advantage to the mantle zone
`pattern8 and nodular pattern,9 and others have sug-
`gested a distinct survival disadvantage to the blas-
`toid variant at diagnosis or a transformation to the
`blastoid variant during the course of the illness.10
`The blastoid transformation is detected in up to 32
`percent of patients during life and up to 70 percent
`at autopsy,10 suggesting that most patients progress
`through the blastoid variant prior to death. This may
`suggest that the blastoid variant is more a factor
`related to the time since diagnosis than a distinct
`pathologic subtype, similar to the Richter’s transfor-
`mation seen in chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL).
`Bone marrow involvement is predominantly
`intertrabecular with both nodules and interstitial
`infiltrates. Paratrabecular and diffuse involvement is
`seen somewhat less commonly. Since there is a con-
`siderable pattern of bone marrow involvement over-
`
`lap between MCL, CLL, and follicular lymphoma,
`bone marrow morphology is not a useful differential
`diagnostic tool.7,11
`
`BIOLOGY
`
`Cell of Origin
`
`Pregerminal center B cells have nonmutated (nonre-
`arranged) VH (heavy chain variable region) genes,
`whereas germinal center and postgerminal center B
`cells have mutated (rearranged) VH genes. A study
`of six MCL patients looked at somatic mutations in
`the VH region and showed that the VH regions in
`MCL are not rearranged, consistent with a pregermi-
`nal center cell of origin.12 Since CLL also arises
`from a pregerminal center origin, these two entities
`may have similarities that need to be distinguished
`by an experienced hematopathologist using
`immunophenotyping and/or molecular analysis. A
`recent study demonstrated that the blastic variant of
`MCL often had mutated VH regions, suggesting both
`a postgerminal center origin13 and that the blastic
`variant may arise from a different ontogeny.
`
`Immunophenotype
`
`The MCL cells tend to be CD20+, CD5+, and
`CD23–, and lack CD10 (Figure 9–4).14,15 The cells
`
`Figure 9–1. Morphology of mantle cell lymphoma—lymph node aspirate.
`
`Exhibit 2002 Page 007
`
`

`

`Mantle Cell Lymphoma
`
`137
`
`A
`
`C
`
`B
`
`D
`
`Figure 9–2. Mantle cell lymphoma. A, Mantle zone variant. B, Nodular variant. C, Diffuse type. D, Blastic variant.
`
`Figure 9–3. Mantle cell lymphoma—a comparison of the typical and blastic morphology.
`
`Exhibit 2002 Page 008
`
`

`

`138 MALIGNANT LYMPHOMAS
`
`also tend to be CD43+.14 Immunophenotyping for
`CD23 by either immunohistochemistry or flow
`cytometry is able to distinguish reliably between
`CLL/SLL (CD23+) and MCL (CD23–).16–19 This dis-
`tinction usually is retained even in large cell or blas-
`toid transformations from SLL/CLL and MCL,
`respectively.20 Since CLL/SLL and MCL both share a
`pregerminal center origin, and both are CD20, CD5,
`and CD43 positive, CD23 is an important marker to
`
`help distinguish these entities. Circulating MCL cells,
`particularly those of the blastoid variant, may be dif-
`ficult to distinguish morphologically from other blast-
`like cells (eg, acute lymphoblastic leukemia). In these
`cases, immunophenotyping becomes particularly
`important.21 Mantle cell lymphoma has been reported
`to occasionally co-express CD8.22
`Immunostaining for cyclin D1 (Figure 9–5) has
`proven to be sensitive and specific for MCL,23,24
`
`A
`
`C
`
`B
`
`D
`
`Figure 9–4. Mantle cell immunohistochemistry. A, CD10–. B, CD5+. C, CD20+. D, CD3–.
`
`Exhibit 2002 Page 009
`
`

`

`Mantle Cell Lymphoma
`
`139
`
`with cyclin D1 being expressed in 72 percent of
`cases of MCL diagnosed in the bone marrow25 and
`76 to 92 percent diagnosed in nodal biopsies.14,26,27
`In the former study, only 1 of 18 cases of SLL/CLL
`and 1 of 5 cases of hairy cell leukemia stained pos-
`itive for cyclin D1, and, in the latter studies, none of
`the other NHLs stained positively. Cyclin D1
`expression by immunohistochemistry has been
`directly correlated with bcl-1/PRAD-1 messenger
`ribonucleic acid (mRNA) expression.28 Recently,
`cyclin D1 expression assessment by flow cytometry
`has been reported.29 Studies have suggested that
`MCL patients with positive cyclin D1 staining have
`a significantly worse outcome than do MCL
`patients with negative cyclin D1 staining,30–32 sug-
`gesting that the production of cyclin D1 may be
`essential to the disease process. This also raises the
`possibility that cyclin D1–negative MCL may be a
`separate disease entity.
`Twenty-six MCL patients were studied for
`cyclin D1 and D3 expression;33 23 of 26 showed
`cyclin D1 nuclear staining in the MCL cells,
`whereas germinal centers were negative for cyclin
`D1. In contrast, germinal centers stained positive for
`cyclin D3, and MCL cells did not. Other B-cell
`NHLs tended to demonstrate a germinal center pat-
`tern of expression, with the majority staining positive
`for cyclin D3 and negative for cyclin D1. This may
`
`suggest that the t(11;14) conveys an up-regulation of
`cyclin D1 and a down-regulation of cyclin D3. Inter-
`estingly, the same investigators demonstrated that
`the degree of cyclin-D1 staining did not correlate
`with the S phase fraction of the MCLs.
`
`Cytogenetics and Molecular Genetics
`
`Mantle cell lymphoma is characterized by a unique
`chromosomal
`translocation,
`t(11;14)(q13;q32),
`which occurs at or near the major translocation clus-
`ter. This translocation involves the PRAD-1/bcl-1
`gene and results in the overexpression of the cell
`cycle regulatory protein cyclin D1. Cyclin D1 is
`known to form a complex with CDK4, which then
`phosphorylates and inactivates the retinoblastoma
`protein and therefore represents a possible mecha-
`nism of tumorigenesis (Figure 9–6).
`This bcl-1 translocation is an excellent target for
`polymerase chain reaction (PCR) detection tech-
`niques, which have high sensitivity and specificity for
`MCL.34,35 Detection rates for bcl-1 translocations by
`PCR are approximately 20 to 50 percent36–39 and may
`be somewhat lower in formalin-fixed paraffin-
`embedded tissue.40,41 Rates for detection of unique
`immunoglobulin (Ig) rearrangements in the same sam-
`ples are 92 to 100 percent.37,40 Since peripheral blood
`involvement is quite common in MCL, bcl-1 and/or
`
`Figure 9–5. Cyclin D1 immunostaining in mantle cell lymphoma.
`
`Exhibit 2002 Page 010
`
`

`

`140 MALIGNANT LYMPHOMAS
`
`Figure 9–6. Representation of the cell cycle alterations in mantle cell lymphoma. ©Virginia Ferrante 2000. Repro-
`duced with the kind permission of Ferrante Medical Media, Darien, CT. http://www.indexedvisuals.com/ferrante.html.
`
`unique Ig rearrangements are attractive targets for
`diagnosis based on peripheral blood involvement.42
`Northern blot analysis of cyclin D1 gene overex-
`pression has been found to be highly sensitive and
`specific for MCL,43–45 as has Western blot analysis.46
`Cyclin D1 mRNA also can be detected by PCR and
`has been detected in 23 of 24 samples of MCL.41
`Unfortunately, cyclin D1 mRNA detection was not as
`specific as that reported for cyclin D1 immunostain-
`ing, with many cases of non-MCL NHL also being
`positive. An assay comparing the ratio of mRNA
`expression for cyclin D1 to that of β2-microglobulin
`was significantly more specific for MCL.41 In situ
`hybridization (ISH) also may be a more specific tech-
`nique for the detection of cyclin D1 mRNA,47 but test-
`ing of this technique in larger numbers of patients is
`necessary. Other investigators report additional tech-
`niques for rapid, sensitive, and specific detection of
`cyclin D1 overexpression using small samples of
`peripheral blood.48 Fluorescence in situ hybridization
`(FISH) may be able to demonstrate the t(11;14) in
`almost all cases of MCL diagnosed by morphologic
`and immunologic criteria.49–51 This technique demon-
`
`strates that the bcl-1 breakpoints are widely scattered,
`demonstrating why the t(11;14) has been so difficult
`to detect by other modalities.
`Cyclin D1 overexpression alone is not sufficient
`for tumorigenesis in experimental models of MCL.
`This suggests that other tumor suppressor deletions
`may be present and/or involved in the pathogenesis
`of MCL. One study found that, in addition to
`t(11;14), CDKN2/p16 and Rb were both deleted in 41
`percent of MCL cases.52 The same investigators
`demonstrated that CDKN2/p16 deletion was associ-
`ated with an increased proliferation index but not a
`blastoid transformation. Rb deletions were not inde-
`pendently associated with proliferation index or
`transformation. Loss of p53, p15, p16, and p18 all
`have been associated with the development of a clin-
`ically aggressive course in MCL, with a higher rate
`of extranodal disease and blastoid transforma-
`tion,53,54 as well as a variant termed the “large cell
`variant” of MCL.55 Loss of expression of
`p21Waf1/p16INK4a and deletions of p16INK4a have also
`been associated with an aggressive (blastoid) clini-
`cal variant of MCL and are independent of p53
`
`Exhibit 2002 Page 011
`
`

`

`mutations/loss.56 The blastoid variant tends to have
`elevated tetraploid chromosome numbers, mitotic
`rates, proliferation indexes, and p53 overexpression
`when compared with MCL in general.57 Three stud-
`ies have documented a substantial rate of p53 muta-
`tions in aggressive variants of MCL,58–60 although
`other studies have failed to show a relationship
`between the proliferative index and the presence of
`either bcl-1 translocations or p53 mutations.61
`Other chromosomal abnormalities seen in MCL
`include gains at 3q, 8q, and 15q, as well as losses at
`13q, 1p, 6q, 9p, and 11q.62,63 The number of gains
`and losses tended to correlate with the presence of a
`blastoid transformation. Recent studies have sug-
`gested that deletions of 11q were found in many
`cases of MCL and involved the ATM gene, possibly
`supporting the role of ATM as a tumor suppressor
`gene in MCL.64–66 Other investigators have shown a
`unique chromosomal deletion at 6q25 and a unique
`amplification at 3q28q29, suggesting a possible
`tumor suppressor and oncogene at these loci, respec-
`tively, that may be involved in the pathogenesis of
`MCL.67 Bcl-6 rearrangements have been reported in
`MCL, but the significance of this has not been eval-
`uated,68 and the bcl-6 rearrangements appear to be
`quite rare,69 as would be expected with a pregermi-
`nal center origin. Bax mutations do not appear to be
`responsible for resistance to apoptosis in MCL.70
`Recent studies have suggested that certain
`patients whose MCL expresses the mucosal homing
`receptor integrin α4β7 have a significantly higher
`rate of gastrointestinal involvement than those with
`MCL who do not express α4β7.71 The prognostic sig-
`nificance of this has not been studied.
`Other recent studies have shown that MCL cells
`have a high level of CD40 expression and low
`expression of Fas.72 This may help explain the resis-
`tance to apoptosis seen in MCL. Human CD40 lig-
`and alone can stimulate MCL cells in culture,73,74
`and this stimulation can be enhanced by interleukin-
`10 (IL-10).74 CD44, a glycoprotein homing receptor,
`has been shown to be involved in B-cell trafficking
`and may be responsible for disease dissemination in
`NHL. Investigators have looked at both MCL and
`CLL/SLL with regard to CD44 expression.14 Both
`CLL/SLL and MCL express CD44, although the
`rate of expression is higher in MCL (75%) than in
`
`Mantle Cell Lymphoma
`
`141
`
`CLL/SLL (37%). In addition, CD44 intensity was
`much higher in MCL than in CLL/SLL. Despite
`these findings, CD44 expression/intensity did not
`correlate with the likelihood of peripheral blood
`involvement in MCL.
`Studies of Ki-67 proliferative index and topoiso-
`merase II-α expression were evaluated by immuno-
`histochemistry in MCL.75 The percentage of Ki-67
`and topoisomerase II-α-positive cells correlated
`with overall survival, with shorter survival in
`patients with greater than 10 percent expression of
`either marker.
`
`DIFFERENTIAL DIAGNOSIS
`
`The diagnosis of MCL must be determined by an
`experienced hematopathologist. Mantle cell lym-
`phoma can appear morphologically similar to
`CLL/SLL, follicular lymphoma, and marginal zone
`lymphoma. The blastic/aggressive variants can
`appear similar to large cell lymphoma or even acute
`lymphoblastic leukemia (Figure 9–7). Thus, an accu-
`rate diagnosis usually requires a combination of
`morphology, immunohistochemistry, flow cytome-
`try, and molecular techniques. Given the appropriate
`morphology, the combination of CD20 and CD5
`co-expression with the absence of CD23 expression
`is highly suggestive of MCL. Confirmation can usu-
`ally be obtained by finding evidence of cyclin D1
`overexpression by immunohistochemistry or evi-
`dence of a bcl-1/t(11;14) translocation by cytogenet-
`ics, PCR, or FISH.
`
`Clinical Presentation
`
`Patients with MCL tend to present with advanced-
`stage disease and a high rate of extranodal dis-
`ease.1,76–84 In a series of 121 MCL patients, the rate
`of stage IV disease was 87 percent; of bone marrow
`involvement, 79 percent; of peripheral blood
`involvement, 36 percent; and of gastrointestinal (GI)
`involvement, 18 percent.84 Other investigators have
`found even higher rates of bone marrow and periph-
`eral blood involvement, with the rate of bone mar-
`row involvement in some series approaching 90 per-
`cent.11 Some studies have found peripheral blood
`involvement to be quite common, and it may occur
`
`Exhibit 2002 Page 012
`
`

`

`142 MALIGNANT LYMPHOMAS
`
`Figure 9–7. Blastic mantle cell lymphoma on bone marrow aspirate mimicking ALL.
`
`in the majority of patients at some point during their
`disease.11,79 The high rate of peripheral blood
`involvement in MCL may mimic CLL and needs to
`be considered when evaluating a patient with a pro-
`found lymphocytosis. Splenomegaly occurs com-
`monly in MCL, and splenomegaly in the absence of
`lymphadenopathy is not an uncommon presentation
`of MCL.81,85 In fact, spontaneous splenic rupture has
`been reported as a rare sequela of the massive
`splenomegaly often seen in this disease.86 Mantle
`cell lymphoma also has a distinct predilection for
`the GI tract, and it likely is responsible for the
`majority of cases of multiple lymphomatous polypo-
`sis,87–89 although follicular lymphoma is thought to
`be the etiology of a minority of cases.87
`Central nervous system (CNS) involvement is
`rare in MCL, occurring in one series in 4 of 94 (4%)
`of patients during the course of their illness, gener-
`ally as a late complication and almost always associ-
`ated with a leukemic disease phase.90 Transformation
`to the blastoid variant of MCL may carry a slightly
`increased risk of producing CNS disease, but no
`prognostic variables at diagnosis were predictive of
`the later development of CNS disease. All CNS dis-
`ease was present as lymphomatous meningitis, and 2
`of the 4 patients also had parenchymal brain disease.
`Life expectancy after CNS diagnosis was less than 2
`months. A smaller series of 22 patients found a rate
`
`of CNS involvement of 22 percent at some point dur-
`ing the disease course.91 The average time to onset of
`CNS symptoms in this series was 18 months from
`diagnosis, and the course of patients with CNS dis-
`ease also was rapidly downhill.
`
`NATURAL HISTORY
`
`Mantle cell lymphoma occupies a somewhat unique
`and notorious niche between the indolent (low-
`grade) and aggressive (intermediate-grade) NHLs.
`Previously, MCL was considered an indolent NHL,
`based upon its morphologic appearance and com-
`mon confusion with other indolent NHL entities.
`However, a review of survival curves from the Kiel
`Classification reveals the poor survival associated
`with centrocytic lymphoma, most cases of which are
`now recognized as MCL. When these curves are
`reviewed, it is apparent that the historic average sur-
`vival of MCL patients is on the order of 2 to 3 years
`from diagnosis, less than half the average survival
`seen in the other indolent NHL entities. For this rea-
`son, MCL is now usually considered an aggressive
`or intermediate-grade NHL.
`Unfortunately, the categorization of MCL as an
`aggressive NHL does not appropriately reflect its
`relative resistance to therapy. Whereas most aggres-
`sive NHL is at least potentially curable with multi-
`
`Exhibit 2002 Page 013
`
`

`

`agent (anthracycline-based) chemotherapy, MCL
`does not appear to be curable with current standard
`therapies. This leads to the description of MCL as
`having the worst properties of both the indolent and
`aggressive NHLs. That is, it has the natural history
`and average survival of the aggressive NHLs and yet
`the resistance to therapy and incurability of the indo-
`lent NHLs. The average survivals of patients with
`MCL in various series are presented in Table 9–1.
`
`PROGNOSTIC FACTORS
`
`Factors associated with an improved prognosis in
`some MCL series include age less than 65 years,
`good performance status (PS), limited-stage disease,
`normal lactate dehydrogenase, normal β2-micro-
`globulin, and a low-risk international prognostic
`index (IPI) score.9,10,77–80 One study suggested that
`patients with low-risk disease by the IPI have a much
`better prognosis, with an average overall survival
`(OS) of 93 months.76 Other investigators have con-
`firmed the validity of the IPI as a predictive model in
`MCL.9,93 Poor prognostic factors in many series
`include blastoid transformation, high mitotic rate, B
`symptoms, splenomegaly, and low albumin.9,10,79
`Peripheral blood involvement also has been shown to
`be a poor prognostic factor.78,83 Bone marrow
`involvement is quite common and does not appear to
`be a negative prognostic sign in most series.
`One of the largest prognostic series of MCL
`patients showed young age, good PS, stage I–II dis-
`ease, fewer than two extranodal sites of disease,
`absence of spleen involvement, absence of peripheral
`blood involvement, normal lactate dehydrogenase,
`normal β2-microglobulin, and hemoglobin greater
`than 12 to be associated with a better prognosis.84 In
`multivariate analysis, only age, PS, hemoglobin, and
`peripheral blood involvement retained significance.
`
`TREATMENT
`
`Indications
`
`Because MCL is not considered curable with stan-
`dard techniques, many oncologists believe that
`observation of asymptomatic patients is appropriate,
`similar to the approach in CLL/SLL and follicular
`
`Mantle Cell Lymphoma
`
`143
`
`lymphoma. Other oncologists believe that aggres-
`sive approaches may improve the outcome of some
`patients with MCL and that early investigational or
`high-dose intervention is appropriate. This section
`discusses some of the standard, investigational, and
`high-dose approaches to the treatment of MCL.
`
`Chemotherapy
`
`Complete remission (CR) rates with multiagent
`chemotherapy in MCL have been reported to range
`from 19 to 52 percent.1,76,77,79–81,93 In a large number
`of MCL series, the time to progression after a CR
`ranges from 18 to 44 months, and the median OS
`ranges from 36 to 52 months.1,10,76–81,84,93 There is no
`clear benefit to anthracycline-containing regimens
`except perhaps in a distinct low-risk subset of
`patients.9,76,77,81,94–96
`A large retrospective series of MCL patients
`grouped patients according to whether their disease
`had been categorized as low grade or intermediate/
`high grade in the WF.97 The 29 MCL patients cate-
`gorized as intermediate/high grade had received
`either CHVmP/BV (cyclophosphamide, doxoru-
`bicin, teniposide, and prednisone, with bleomycin
`and vincristine) or ProMACE-MOPP (cyclophos-
`phamide, doxorubicin, etoposide, methotrexate,
`mechlorethamine, vincristine, procarbazine, and
`prednisone), and the 35 MCL patients categorized as
`low grade had received CVP (cyclophosphamide,
`vincristine, and prednisone) followed by either
`
`Table 9–1. AVERAGE SURVIVAL OF PATIENTS WITH MCL
`
`Author (Ref. No.)
`
`No. of Patients
`
`Avg. Surv. (mo)
`
`Velders (1)
`Fisher (2)
`Weisenburger (9)
`Norton (10)
`Chim (76)
`Zucca (77)
`Argatoff (78)
`Bosch (79)
`Oinonen (80)
`Bertini (81)
`Hiddemann (82)
`Samaha (84)
`Callea (92)
`Vandenberghe (94)
`Zucca (95)
`Totals
`
`41
`45
`68
`66
`20
`65
`80
`59
`94
`27
`45
`121
`34
`65
`26
`856
`
`31.5
`28
`38
`36
`52
`42
`43
`49
`41
`43
`28
`38
`41
`57
`33
`40.2 (avg)
`
`Exhibit 2002 Page 014
`
`

`

`144 MALIGNANT LYMPHOMAS
`
`observation or interferon. When compared with
`other intermediate-/high-grade NHLs, the MCL
`patients in the intermediate-/high-grade group had
`similar response rates and OS but a shorter duration
`of responses and progression-free survivals. When
`compared with other low-grade NHLs, the MCL
`patients in the low-grade group had much shorter
`OS, despite similar response rates, duration of
`responses, and progression-free survivals. This sug-
`gests that MCL has the incurability of the low-grade
`NHLs but the natural history of the intermediate/
`high-grade NHLs. Other investigators also have
`found similarities between the OS of MCL and other
`intermediate-/high-grade NHLs.92
`One of the most comprehensive series of MCL
`treatment and response data can be found in the
`review of the stage III–IV patients with WF A–E
`disease that were treated with CHOP (cyclophos-
`phamide, doxorubicin, vincristine, and prednisone)
`on Southwestern Oncology Group protocols.2 This
`review showed that MCL made up approximately 10
`percent of advanced-stage disease in WFormulation
`classes A–E. The failure-free and OS of the MCL
`patients was significantly shorter compared with
`that of non-MCL patients in WF categories A–E.
`Another study compared MCL and follicular lym-
`phoma randomized to COP (cyclophosphamide,
`vincristine, prednisone) versus PM (prednimustine
`and mitoxantrone) followed by observation versus
`maintenance interferon.82 There were 45 MCL and
`165 follicular NHL patients in this study. Patients
`with MCL had a lower response rate (69% versus
`88%), shorter event-free survival (8 months versus
`24 months), and shorter OS (28 months versus 77
`months) than follicular lymphoma patients. In this
`study, a subgroup of MCL patients who achieved a
`minimal disease state to initial chemotherapy did
`have a 60 percent 5-year survival.
`Fludarabine has been studied in previously
`untreated MCL.98 The response rate in MCL was 41
`percent, with few complete responses and a time to
`progression that was significantly shorter than that
`seen in follicular lymphoma or CLL. A study of flu-
`darabine in previously treated MCL patients99
`showed a response rate of 33 percent, with no com-
`plete responses and a time to progression of only 4
`to 8 months. Other studies of fludarabine in MCL
`
`have shown similar response rates,100 including one
`that suggested a better response rate, including three
`CRs, in patients with the mantle zone pathologic
`variant of MCL.101 Other purine analogues such as
`cladribine have been studied alone102 and in combi-
`nation with mitoxantrone and have shown reason-
`able response rates but few long-term remissions.
`Induction therapy with more aggressive regimens
`has been studied. Investigators at the M. D. Ander-
`son Cancer Center have treated MCL patients with
`Hyper-CVAD and M-A (escalated cyclophos-
`phamide, vincristine, doxorubicin, and dexametha-
`sone, and alternating with MTX and high-dose
`cytarabine).103 The response rate to the Hyper-
`CVAD/M-A induction was 94 percent, with 38 per-
`cent CRs. Disease-free survival (DFS) following
`Hyper-CVAD/M-A alone was difficult to assess as
`the majority of patients in the largest series went on
`to receive subsequent bone marrow transplantation
`(BMT) (discussed below). Better data for the role of
`aggressive chem