Since its initial recognition in the mid-1970s, this distinct entity has been described with various diagnostic terms, ie, lymphocytic lymphoma of intermediate differentiation by Berard (Berard CW, Dorfman RF. Histopathology of malignant lymphomas. Clin Hematol. 1974;3:39) centrocytic lymphoma by Lennert (Lennert K, Feller AC. Histology of Non-Hodgkin's Lymphomas (Based on the Updated Kiel Classification). Berlin: Springer-Verlag; 1990), and mantle zone lymphoma by Weisenburger^ref. This history reflects the process of identifying the relatively divergent histologic patterns (diffuse, nodular, and mantle zone patterns) of this entity, which may sometimes create diagnostic pitfalls even for expert pathologists. In 1992, Banks et al^ref showed that these differently named lymphomas fell within the same entity and named it mantle cell lymphoma.

Table of contents :

Epidemiology Aetiology Pathogenesis Symptoms & signs Laboratory examinations Differential diagnosis Therapy  Prognosis Web resources

Epidemiology : 5-10% of all NHLs; mainly affects people over 50 years of age (median age of over 60 years), male predominance
Aetiology : ?
Pathogenesis :

• t(11;14)(q13;q32) : this rearrangement at the B-cell lymphoma 1 (BCL1) / cyclin D1 (CCND1) / parathyroid adenoma 1 (PRAD1) locus at 11q13 dysregulates the gene CCND1 following juxtaposition with immunoglobulin heavy chain (IGH) joining (J) region transcriptional enhancers at 14q32 and leading to overexpression of its protein product, cyclin D1, which plays a key role in the control of the cell cycle. Normal B-cells at mantle zone stage down-regulate the expression of BCL1 gene and become resting in cell cycle. However, BCL1 expression from translocated allele with immunoglobulin gene is not down-regulated at the mantle zone stage, preventing cells from entering in resting state, and puts cells in cell cycle, leading to development of MCL


The translocation occur mainly during an attempted primary rearrangement between 1 diversity (D) and 1 J segment of the Ig locus on chromosome 11q13 : the breakpoint on chromosome 11q13 covers a wide range between 15 kb and more than 400 kb distance from the cyclin D1 gene
• major translocation cluster (MTC) (35%) : rearrangements involving this area can be amplified from genomic DNA by PCR using primers directed to the Ig J_H region and to the MTC region.
• mTC1
• mTC2
Cytogenetic and Southern blotting analyses indicate that approximately 50% to 70% of MCL show this specific gene alteration^ref. However, cytogenetic analysis is not always informative because of the low rate of proliferation in lymphoma cells. Interphase FISH techniques^ref can be used to avoid such low proliferative activity, though FISH and genomic analyses are hampered by the large area within the BCL-1 locus in which the rearrangement breakpoint can be located^{ref1, ref2, ref3, ref4} in a series of 35 MCL cases a positivity rate of 97% for FISH compared with 37% by PCR was reported^ref. PCR is the first method of choice in molecular follow-up studies of MCL^{ref1, ref2}. In the bcl1/J_H PCR^- cases, PCR assays targeting VDJ and Kde rearrangements may be used as molecular tools for detecting B-cell monoclonality at diagnosis or during follow-up studies. Cyclin D1 overexpression at the mRNA level can be detected by Northern blotting^{ref1, ref2, ref3} or by reverse transcription-polymerase chain reaction (RT-PCR) (which is directed exclusively to the MTC) analysis and might be a reliable marker for the diagnosis of MCL. However, mRNA is not always obtainable from all patients, and Northern blotting is sometimes complicated by RNA degradation in the specimens. The RT-PCR assay is likely to amplify faint cyclin D1 derived from contaminating nonneoplastic cells, thus necessitating special techniques such as competitive^ref or quantitative PCR^ref, which might make the diagnostic procedure more complicated. As a result, these methods are not convenient for routine diagnostic use. Immunohistochemical detection of cyclin D1 overexpression is particularly important for clinical application because it is simple to use for a far larger number of patients than is possible with mRNA detection. Other investigators have also reported the usefulness of immunohistochemical cyclin D1 detection for the diagnosis of mantle cell lymphomas^{ref1, ref2, ref3}. Immunohistochemical detection of the cyclin D1 protein has been reported to correlate with overexpression of cyclin D1 mRNA^ref.
The D-type cyclin, in combination with CDK4 and CDK6, regulates the cell cycle transition between the G₁ to the S phase, phosphorylating pRB1^ref (Blagosklonny, M.V. & Pardee, A.B. (2002) The restriction point of the cell cycle. In: Cell Cycle Checkpoints (ed. by M.V. Blagosklonny). Landes Bioscience/Eurekah.com, Georgetown, TX, USA). There are 3 types of tissue-specific cyclin D. Myelomocytic and lymphoid cells use D2 and D3, while epithelial and mesenchymal cells mainly use D1. The passage from G₁ to S phase is the most crucial point, after which the cell is irreversibly committed to completing the cycle. During the G₁ phase, extracellular stimuli determine whether the cells undergo DNA replication, followed by the cell replication process or, if they exit the cell cycle, entering the quiescent G₀ phase. Holoenzymes, containing regulatory (cyclin) and catalytic (CDK) subunits, control the passing from one to another cell cycle phase. G₁ progression requires a sustained expression of the D-type cyclins, which, in turn, need a continuous mitogenic stimulation. This determines the effect of exogenous factors on the cell commitment to replication. Cyclin E and CDK2 quickly follow cyclin D/CDK4-6, and act on pRb and on other target proteins that are still unknown. In MCL, cyclin D1 is expressed continuously and independently of exogenous factors, and it replaces cyclins D2 and D3^{ref1, ref2}. Cyclin D1 expression by itself is not sufficient to keep the cells in cycle and transgenic mice that overexpress cyclin D1 in their B cells do not have an increased incidence of lymphoma^{ref1, ref2}. The mitotic index is low in classic MCL, and high in the blastoid variant. In normal cells, 2 classes of inhibitors regulate the cyclin-cdk complexes: the Cip/Kip family and the INK4 family. The Cip/Kip class comprises p21^WAF1/CIP1 (chromosome 6p21.2), p27^KIP1 (12p13) and p57^KIP2 (11p15.5), which inhibit both cyclins D and E. The INK4 family includes p16^INK4A, p15^INK4B (all 9p21), p18^INK4C (1p32) and p19^INK4D (19p13), which selectively inhibit the cyclin D-associated kinases. The gene encoding for p16^INK4A encodes a second protein, p14^ARF, which links the Rb pathway to p53. Expression of p14^ARF is induced by abnormal mitogenic signals induced by overexpression of other proteins such as Myc and E2F1, and it antagonizes the activity of Mdm2, a p53-negative regulator. P53 (17p13.1) acts as a genome guardian. Activated by DNA damages, p53 can stop cell cycle, through p21 activation, to allow DNA repair. If this fails, p53 can trigger the apoptotic process. Besides cyclin D deregulation, other regulatory molecules can be defective in MCL, and can contribute to lymphoma pathogenesis. As many defects are more prevalent among blastic variants, this might explain its higher mitotic index and worse prognosis in comparison with classic MCL. 3 of 7 (43%) blastoids, and only 1 of 21 (5%) classic variants presented loss of p16 expression^ref. Deletion of p16 locus also usually involved the loss of p15^{ref1, ref2}, as well the loss of p14^ARFref. P53 inactivation, as a consequence of deletion or mutations, is more frequent in the blastic variant than in classic type^{ref1, ref2, ref3}. However, as p53 is activated by ATM following DNA damages, and ATM function can be reduced in MCL patients, it is likely that similar to CLL^ref, p53 function might also be reduced due to the loss of ATM. MDM2 can be overexpressed in MCL^ref. Decreased levels of p27 expression, as a result of an enhanced proteasome-mediated degradation of the protein, were shown in > 50% of MCL cases^{ref1, ref2, ref3}. A series of cyclin-dependent kinase inhibitors have been developed and are undergoing preclinical and clinical evaluation as single agents or in combination with chemotherapy^{ref1, ref2} (Shapiro, G.I. (2001) Small molecule inhibitors of cyclin-dependent kinases: preclinical and clinical development. In: Cell Cycle Checkpoints (ed. by M.V. Blagosklonny). Landes Bioscience/Eurekah.com, Georgetown, TX, USA). The deregulation of the cell cycle in MCL and the lack of any adequate conventional treatments make them a possible tool for the treatment of this lymphoma. The increased degradation of p27 protein also suggests a role for proteasome inhibitors^{ref1, ref2}. Among hematolymphoid malignancies, cyclin D1 overexpression resulting from translocational activation has also been recognized in a subset of B-CLL, multiple myeloma, splenic marginal zone lymphoma, and hairy cell leukemia, though the relationship between them remains to be clarified.
• t(11;22)(q13;q11) (less commonly) => BCL1 overexpression^ref
• deletion of chromosome 11q22-23 (20-40%)^{ref1, ref2, ref3, ref4, ref5, ref6}. A similar deletion can be found in B-CLL, a lymphoid neoplasm that shares some genetic similarities with MCL^{ref1, ref2, ref3, ref4, ref5}. 2 distinct minimal deleted regions have been reported in MCL :
• 11q22.2, comprised within the yeast artificial chromosome (YAC) 801e11^ref, which contains the ATM gene. It was shown to be completely inactivated by deletions or mutations in 9 of 12 (75%) MCL patients: in all 7 cases with 11q loss and in 2 of 5 (40%) with normal 11q^ref. In another series, ATM alterations were detected in 12 of 28 (42%)^ref and in 8 of 20 (40%) MCL cases^ref. The ATM gene was first cloned and found to be mutated in patients with ataxia teleangectasia, an autosomal recessive disease characterized by cerebella ataxia, immunodeficiency, increased sensitivity to ionizing radiations and a predisposition to lymphoid tumours. T-cell neoplasms outnumber B-cell tumours in patients with ataxia teleangectasia. A similar pattern can be observed in ATM^-/- knock-out mice^{ref1, ref2, ref3}. ATM is an ubiquitously expressed phosphoprotein, whose main known function is to respond to DNA damage represented by double-strand breaks^{ref1, ref2, ref3, ref4}. Both exogenous (ionizing radiations, chemotherapeutics, chemicals) and endogenous (oxidative damages, replication, programmed rearrangements, meiosis) factors can induce DNA double-strand breaks. ATM signals the presence of double-strand breaks to the cell cycle checkpoints to avoid the cell undergoing division in the presence of important DNA damages. While chk1 and chk2 mediate the arrest at the G₂/M checkpoint, p53 links ATM to the G₁/S checkpoint. As ATM is linked to the repair of DNA double-strand breaks due to programmed rearrangements, its loss is associated with an increased risk of chromosomal translocations during VDJ rearrangement^{ref1, ref2, ref3}. The somatic mutation process also requires double-strand breaks^{ref1, ref2} and it targets not only the VDJ region but other genes as well^{ref1, ref2, ref3, ref4, ref5}. The actual percentage of cases of MCL that bear somatic mutated Igs is still not completely defined. The blastoid variant seems to bear mutated Igs more often than common MCL^{ref1, ref2}, and often has a complex karyotype and a worse prognosis. It might be hypothesized that cases with MCL undergoing somatic mutations with no or reduced ATM function could present a higher risk of chromosome breakages. Of interest, cases with ATM inactivation have a higher number of chromosomal aberrations^ref.
• 11q23.3, covered by YAC 755b11^ref
• various recurrent secondary karyotypic abnormalities, some similar to the ones occurring in B-CLL, have been reported in MCL with a high frequency of the deletions 13q– and 11q–^ref; ^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14} (Dreyling, M.H., Scheubner, M., Maier, M., Hu¨bler, K., German Ott, G. & Hiddemann, W. (2000) Allelotyping of mantle cell lymphoma identifies a new tumor suppressor region on 17p13.3. Blood, 96, 172b; Wlodarska, I., Sestigiani, C., Gasco, M., Willis, T., Bastard, C., Chris De Wolf-Peeters, C., Dyer, M. & Hagemeijer, A. (2000) Identification of a 3 cm commonly deleted region in mantle cell lymphoma with chromosome 1p deletion. Blood, 96, 177b.). ATM gene inactivation was observed in MCL^{ref1, ref2, ref3} and was associated with increased chromosomal imbalances^ref. A gain of genomic material suggests the presence of an oncogene. Conversely, DNA losses can underline the presence of tumour suppressor genes at a particular locus. The vast majority of the targeted genes are still unknown. DNA losses and, even more, gains can involve large DNA regions. Thus it is likely that more than one gene is involved in different MCL cases, according to the size of DNA deletion or losses.
• the above-mentioned P16/P15/P14 and P53 are the strongest candidates for 9p21 and 17p13 respectively. A second gene might be involved with P53, as 2 different minimal deleted regions can be detected^ref.
• the c-MYC oncogene might be the target of 8q22-24 amplification. It is overexpressed in a subset of MCL cases^{ref1, ref2, ref3, ref4}, and 8q24 rearrangements have been reported^{ref1, ref2}. Mouse models showed a strong synergistic transforming effect of overexpressed cyclin D1 and N- and L-MYC^ref.
• BCL2 is highly expressed in MCL. However, the gene does not seem to be amplified at DNA level, even if the 18q21 region, where BCL2 is mapped, is amplified by comparative genomic hybridization (CGH)^ref.
• BCL6, at 3q27, does not play a relevant role in MCL pathogenesis. It is translocated in <5% of cases^{ref1, ref2} and is the target of the Ig somatic mutation process in a low percentage of cases^{ref1, ref2}.
• the polycomb gene BMI-1, on 10p12, is amplified in 4 of 36 (11%) MCL cases^{ref1, ref2}. The polycomb transcriptional repressor genes represent a highly conserved family of proteins, which, by creating heterogeneous multimeric complexes, regulate lymphoid development and contribute to cell cycle regulation^ref. Polycomb targets are the HOX gene clusters, and probably many others, such as the P16^INK4A/P14^ARF locus. 2 groups of polycomb complexes have been identified in humans: BMI-1-containing polycombs and ENX- and EED-containing polycombs. The expression of BMI-1- and EED-containing complexes is mutually exclusive in lymphoid cells^ref. The EED/ENX-1 is expressed in proliferating germinal centroblasts and BMI-1/RING1 in resting mantle cells and in centrocytes. Resting MCL cells express BMI-1/RING-1^{ref1, ref2}. Proliferating MCL cells overexpress only ENX-1 (EZH2, EZH1), not EED, and they do not down-regulate the BMI-1 complex^{ref1, ref2}. Transgenic mice models suggest an oncogenic capacity for BMI-1 and RING1^ref, and EED seems to play an important role in the negative regulation of cell proliferation. Despite apparently normal levels of p16 in MCL cases with BMI-1 amplification^ref, the polycomb pathway appears deeply deregulated in MCL. Down-regulation of P16 and P14, as well as overexpression of BMI-1, were detected by a large gene expression study performed on 101 MCL RNA samples using the Lymphochip microarray^ref. This study also defined 42 genes that are more highly expressed in MCL than in DLBCL, follicular lymphomas or in B-CLL. An index based upon the level of expression of 20 genes involved in cell proliferation is apparently able to discriminate four groups of patients with different overall survival.
• previous observations have already demonstrated that karyotypic complexity has a strong impact on prognosis in MCL^{ref1, ref2}, and the presence of tetraploidy here is probably associated with the blastoid cytology, which usually pursues a more aggressive course^ref.
Regions of genomic DNA gains and losses in mantle cell lymphoma :

		% of cases	known and putative involved genes
amplifications	3q26-27	15–80%
	12q13-14	5–60%
	7p15-22	12–60%
	8q22-24	15–40%	c-MYC
	18q21-22	10–30%
	Xq28	10–30%
	15q22-24	10–25%
	11q25	5–25%
	9q34	15–25%
	10p12-13	5–15%	BMI-1
deletions	13q14-21	40–60%	BCMS
	13q32-34	40–60%
	17p13	15–55%	P53
	11q22-23	20–40%	ATM
	9p21	15–30%	P16, P15, P14
	6q21-27	18–30%
	8p21-22	30%
	1p21-22	25–30%
	10p14-15	15%x

• typical variant : a monotonous proliferation of small- to medium-sized lymphocytes, with irregular (slightly indented) nuclei, condensed chromatin, inconspicuous nucleoli and scant, pale cytoplasm. Low mitotic index. In addition to the malignant cell type, histologically there are 3 different architectural patterns within MCL and these may represent different stages of MCL lymph node infiltration.
• mantle zone pattern : initial infiltration of the mantle-zone surrounding normal germinal centres

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• nodular pattern : resembling pseudofollicles, may be considered a more extensive infiltration; some of the nodules may consist of follicles with reactive germinal centers surrounded by broad expansile mantles of small lymphoid cell^{ref1, ref2}

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• diffuse pattern : loss of the germinal centres due to neoplastic cells; gradual invasion and obliteration of the interfollicular nodular areas by the neoplastic cells, leading to a diffuse pattern of growth. Morphologically, the lymph nodes consist of a monotonous population of atypical small to medium sized lymphocytes with irregular and indented nuclei.
‡
• pleomorphic blastoid (blastic) subtype or variant (BV) / anaplastic centrocytic form of MCL (20%) : t(11;19;14)(q13;q13;q32) [BCL1] and t(8;22)(q24;q11)/CMYC is a rare finding associated with a very poor outcome^ref : the cells are medium-sized lymphocytes, resembling lymphoblasts, with scant cytoplasm, rounded nuclei with finely dispersed chromatin and inconspicuous nucleoli. These BVs are often associated with a higher mitotic rate, a more aggressive clinical course, and an unfavorable natural history.

Histologic progression from a nodular pattern to a diffuse pattern may be evident in repeat biopsy specimens obtained from the same patient, as may progression from the predominantly small lymphocytic forms of MCL to blastic cytology. Some reports suggest that histologic transformation to blastic cytology on re-biopsy can occur in up to 17% of cases, and may be as high as 70% at autopsy. Histologic transformation of MCL to DLBCL, like that seen in patients with FL or B-CLL, is considered a rare event^ref. Distinguishing features of MCL compared to 3 NHL subtypes :

pathology			immunophenotype
FL	small cleaved cell	Grade 1	CD5–, CD23±, CD10+, CD43–
	mixed small cleaved and large cell	Grade 2
	large cell	Grade 3
small lymphocytic lymphoma with plasmacytoid differentiation (SSL-pl)
B-CLL			CD5+, CD23+, CD43+, CD11a+, FMC7–, IgLdim
MCL			CD5+, CD23– (rarely + ref), CD10±, CD43+, cyclinD1+, FMC7+, IgLbright
marginal zone lymphoma (MZL)	MALT		CD5–, CD23–, CD10–, CD43±
	NMZL
	SMZL
splenic lymphoma with villous lymphocytes (SLVL)			CD5–, CD11c±, FMC7+, CD22+, CD24+
hairy cell leukemia (HCL)			CD5–, CD10–, CD25+, CD11c+, CD103+, B-ly-7+

• the most common presentation of MCL is with palpable lymphadenopathy, frequently accompanied by systemic symptoms. MCL is clinically different from SMZL due to the high frequency of peripheral lymphadenopathy, but some example of massive splenomegaly with bone marrow involvement without prominent lymphadenopathy can be observed. Approximately 70% of patients will be stage IV at the time of diagnosis, with frequent bone marrow and peripheral blood involvement
• extranodal :
• gastrointestinal involvement is particularly important to recognize (liver). Patients who present with lymphomatosis polyposis in the large intestine usually have MCL. Patients who present with gastrointestinal tract involvement often have Waldeyer's ring involvement, and vice versa^{ref1, ref2}.
• insect bite-like reaction and true hypersensitivity to mosquito bites : the pathogenesis of the skin eruption may be related to the release of different cytokines that also trigger an IgE elevation and dermal eosinophils. Insect bite-like reaction may appear in patients with MCL. It is important to recognize this entity because it may be the presenting sign of MCL^ref.

• cytomorphology : historically, MCL had been referred to as "lymphocytic lymphoma of intermediate differentiation," because some of the cells had well-rounded nuclei (i.e., small non-cleaved cell lymphomas), while others appeared to have indented or cleaved nuclei like those of small cleaved cell lymphoma. In 1982, Weisenburger^ref and Palutke^ref described a distinctive type of "follicular lymphoma" characterized by the proliferation of atypical small lymphoid cells in the wide mantles around benign germinal centers^ref. Believing this represented the follicular counterpart of diffuse intermediate lymphocytic lymphoma, they coined the term mantle zone lymphoma to describe this entity. In the early 1990s, it became evident there was a subset of diffuse-small cleaved cell lymphomas and small lymphocytic lymphomas that behaved very differently from other diseases with similar morphology. These patients often carried a worse prognosis with a distinctly different natural history. Neoplastic cells are small to medium sized with irregular nuclei, morphologically resembling centrocytes/cleaved follicular center cells, but with less irregular nuclear contours. The bone marrow infiltration can be :
• interstitial
• diffuse
• nodular
• intrasinusoidal component has never been observed (similar to B-CLL, different from SMZL)
• cytogenetics : in the early 1990s, Raffeld and Jaffe^ref and Banks^ref coined the term "mantle cell lymphoma" to describe a subset of small lymphocytic lymphomas that carried a unique translocation that results in the transpositioning of the BCL1 gene (11q13) to a site downstream of the IgH gene promoter (14q32).
• immunophenotype : pan T antigen CD5⁺ (as for B-CLL)10 / CALLA^-11c^-19⁺20^hi22⁺23^{-(exceptionally + ref)}43⁺79a⁺, IgM^lo/hi, IgD^lo/hi, cyclin D1⁺. In addition, a l-light chain restriction predominates, which is different from the typically k-light chain restricted patten commonly seen in other B cell lymphomas^ref
• the rearranged VDJ segment is almost unique for each B-cell clone, and it is therefore a potential marker of clonality in MCL^{ref1, ref2, ref3, ref4, ref5}. PCR analysis with consensus upper primers specific for the highly conserved framework region 3 (FR3A) at the 3'-end of the V_H segment and consensus lower primers to the J_H is the most commonly used. The resulting PCR product has a length of approximately 60–120 bp, and is thus feasible even using DNA samples extracted from paraffin-embedded samples. As MCL Ig genes are not heavily mutated, the rate of false negativity by PCR is low. The peculiarity that MCL more often express the IgL l than the k offers another useful molecular marker of clonality. Igl⁺ B cells often undergo a deletional rearrangement of the IgLk genes, due to a site-specific rearrangement of the k deletion element (kde) with either the recombinant signal sequence (RSS) intron of the constant gene segment (Ck), or with the RSS in the 3'-site of the V segments (Vk)^{ref1, ref2, ref3}. We analysed a series of 12 cases of MCL by PCR, and a monoclonal jde rearrangement was detected in 9 of 10 Igk ⁺ cases^ref. Intron RSS/kde and Vk/k de rearrangements were present in 67% (6/9) and 33% of the cases respectively. The expression of Igs on the cell surface of MCL cells and the absence of ongoing mutation within the cells make them good targets for vaccines. Clinical trials with autologous tumour-derived Ig idiotypes (Kwak, L.W. (2000) Therapeutic vaccines against hematological malignancies. In: Educational Book – Spring 2000 (ed. by M.C. Perry), pp. 349–352. American Society of Clinical Oncology, Alexandria, VA, USA) or with DNA vaccines encoding the tumour IgL and IgH idiotypes (Stevenson, F.K. (1999) Vaccine strategies in indolent lymphomas. In: Hematology – American Society of Hematology Education Program Book, pp. 312–318. American Society of Hematology, Washington) are both running.

• conventional treatment strategies for MCL : because MCL demonstrates some of the poorest long-term survival of all lymphoma subtypes, upfront treatment is typically indicated for most patients, although there appears to exist a small fraction of elderly patients whose MCL can assume a somewhat more indolent course, justifying in these otherwise frail and elderly patients a closely monitored "watch-and-wait" approach. In general, the upfront care of patients with MCL usually revolves around 4 basic questions:
• which combination chemotherapy regimen offers the patient the best chance for a durable remission of their disease?
• is an anthracycline based treatment regimen necessary?
• what are the benefits of high dose chemotherapy in first remission?
• is there a benefit to some consolidation based therapy in the form of either maintenance rituximab or a course of radioimmunotherapy.
To date, while many studies are actively addressing these issues, the jury is largely still adjourned regarding the definitive answers to these questions. Anthracycline-based regimens have become the cornerstone of upfront MCL therapy, despite conflicting evidence regarding the real benefits of the anthracycline component. Complete response rates from 13% to 51% for standard CHOP based chemotherapy have been published in a number of series^{ref1, ref2, ref3, ref4, ref5, ref6}. Only one randomized study to date comparing COP (n = 37) versus CHOP (n = 26) has been reported in MCL^ref. This study could not demonstrate any statistically significant difference between the 2 arms with regard to complete (41% vs 58%) or partial remission (43% vs 31%), median OS (32 vs 37 months), relapse-free survival (10 vs 7 months), rates of relapse (73% vs 67%) or death. Teodorovic et al^ref conducted a small randomized study through the European Organisation for Reseach and Treatment of Cancer (EORTC) from 1985 through 1992. In this study, 64 patients were randomized to one of 4 different regimens, including:
• a cyclophosphamide, doxorubicin, teniposide, prednisone, vincristine, bleomycin regimen
• a modified ProMACE-MOPP regimen
• a CVP (cyclophosphamide, vincristine, prednisone) based regimen
• CVP followed by 1 year of maintenance IFN-a
Although the overall (83% vs 52%) and complete remissions (60% vs 40%) rates were better with the more aggressive regimens in (1) and (2) above, the median survival was 45 months in all arms, with no benefit seen in the maintenance IFN-a arm. The addition of rituximab to different chemotherapy regimens appears to improve overall response, and in select cases, even overall survival, in patients with MCL. For example, integration of rituximab into a purine analog–based treatment in patients with MCL and FL was recently reported by Forstpointner and colleagues, who recently published the results of a large randomized Phase 3 study comparing the regimen of FCM (fludarabine, cyclophosphamide, mitoxantrone) alone versus FCM plus rituximab (R)^ref. Though the study included patients with both MCL and follicular lymphoma (FL), a subset analysis of patients with MCL was performed. The overall response rate (ORR) for all patients on study receiving the R-FCM regimen was 79% (33% CR; 45% PR) compared to 58% for FCM alone (13% CR; 45% PR; P = 0.01), with an overall response rate (ORR) of 58% versus 45% in the subset of patients with MCL, respectively. Interestingly, in FL the PFS was significantly longer in the R-FCM arm (P = 0.0139) while in the MCL patients a significantly longer OS was noted (P = 0.0042), both in favor of the rituximab containing arm. Hence, in this well-balanced randomized study, it appears rituximab favorably benefited patients with MCL receiving FCM. Howard and colleagues also reported on the addition of rituximab to CHOP in patients with newly diagnosed MCL^ref. Of 40 patients enrolled on study, 48% achieved a CR or CRu (CR unconfirmed), while another 48% experienced a PR, which is still in the range of responses seen with CHOP alone. The median PFS was about 16 months; again, not too dramatically different from CHOP alone. Interestingly, though, 9 of 25 patients who achieved molecular remissions (i.e., no evidence of PCR detectable BCL-1/IgH or clonal IgH products) of their disease in peripheral blood or bone marrow had a median PFS that was not statistically different from those patients who did not achieve a molecular remission (18.8 vs 16.5 months; P = 0.51). Collectively, these data appear to suggest some role for the use of rituximab in patients with MCL, though the definitive value of rituximab remains to be clarified in future randomized studies. Recently, the Hyper CVAD regimen has gained a lot of attention in the upfront treatment of MCL, though there are only limited published data on the regimen for this disease^{ref1, ref2, ref3}.
• In one of the earlier reports, Romaguera et al^ref reported on the use of the regimen in 25 patients older than 65 who received HyperCVAD followed by methotrexate/cytarabine, where they reported an overall response rate of 92% and a complete remission rate of 68%. At a median follow up of 17 months, the FFS was 15 months. An update of these data by Romaguera et al (Romaguera J, Cabanillas F, Dang NH, Goy A, Hagemeister FB, Fayad L. Mantle cell lymphoma (MCL)—high rates of complete remission (CR) and prolonged failure-free survival (FFS) with Rituxan-HyperCVAD (R-HCVAD) without stem cell transplant (SCT) [abstract]. Blood. 2001;98:726a) with the addition of rituximab (375 mg/m² preceding each of the first 6 cycles of therapy by 24 hours) reported on 92 patients with a median age of 61. The response rate was nearly 100%, with 91% complete remission, and 3 toxic deaths. For those patients younger than 65, the median FFS at 2 years was 80%, compared to 50% for patients older than 65 years of age.
• Khouri et al^{ref1, ref2} examined the merits of autologous stem cell transplantation following Hyper CVAD–MTX/Ara-C. They reported that at 3 years, the OS and EFS for previously untreated patients was 92% and 72%, respectively. For those patients who were previously treated, the results were much worse, with the OS and EFS being 25% and 17%, respectively. Based on very short follow-up of these studies, the MD Anderson Cancer Center (MDACC) group reported that the addition of rituximab to the HyperCVAD–MTX/Ara-C regimen produced results nearly identical to that seen with a consolidative ASCT^ref (Romaguera J, Cabanillas F, Dang NH, Goy A, Hagemeister FB, Fayad L. Mantle cell lymphoma (MCL)—high rates of complete remission (CR) and prolonged failure-free survival (FFS) with Rituxan-HyperCVAD (R-HCVAD) without stem cell transplant (SCT) [abstract]. Blood. 2001;98:726a). SWOG (Study S0213) is currently conducting a pilot trial of HyperCVAD followed by MTX/Ara-C with rituximab in patients with mantle cell lymphoma with the goal of accruing 50 patients. Clearly, despite what would be considered very aggressive therapy, curative intent may not yet be possible for patients with MCL. For this reason, new strategies which seek to exploit some of the unique biology underlying MCL are warranted.
• rituximab + thalidomide 200 mg/day for 15 days, then 400 mg/day for relapsing MCL : ORR = 81% (CR = 31%)^ref
• HSCT : MCL is most common in 50-70 year old individuals and for this reason transplantation is not a common therapeutic option
• autologous HSCT as part of first-line treatment leads to CR = 76%, a substantial prolongation of disease-free survival but not overall survival, at least in younger patients with MCL^{ref1, ref2, ref3, ref4, ref5}. However, a significant proportion of these patients will ultimately relapse, but prognostic markers allowing individual risk estimation are lacking. Contamination of the autologous stem cell product by lymphoma cells is considered a major reason for recurrence of the disease after ASCT. Antibody-based immunologic purging methods of autologous stem cells fail to produce tumor cell–free stem cell products in most patients with MCL^{ref1, ref2}. The other most relevant factor is the inability to eradicate lymphoma cells in the body by pretransplantation chemotherapy and even by myeloablative radiochemotherapy with subsequent ASCT^{ref1, ref2, ref3}. Sequential quantitative monitoring of residual disease after ASCT is a powerful indicator for treatment outcome in MCL and defines subgroups of patients with a significantly different prognosis^{ref1, ref2}
• allogeneic HSCT : in 6 patients that had a mean of 3 different types of therapy, it was associated with substantial mortality post-transplant from acute toxicity and GVHD. Despite the extensive amount of pretransplant therapy in our patient population, there was no TRM. All patients are alive and in remission a median of 4.3 plus years after transplantation. Survival from the date of diagnosis is a median of 6.5+ years. The results of this series would suggest that in a selected group of patients allogeneic HSCT may be the treatment of choice for lymphomas not curable by standard therapy or autotransplant^ref
• novel agents in development for MCL : over the last several years, there has been an explosion in the number of new drugs being tested in early phase clinical trials. Several of these agents have already shown promising activity in MCL, justifying more detailed advanced phase studies

• proteasome inhibitors: bortezomib : the proteasome is one component of a larger intracellular pathway responsible for the degradation of more than 90% of all cytoplasmic protein, a pathway commonly referred to as the ubiquitin-proteasome pathway. The first step in the degradation of such proteins involves the highly regulated and coordinated cascade of enzymatic reactions that leads to the polyubiquitination of intracellular proteins targeted for degradation. The second major component of the pathway is the proteasome proper. The proteasome itself is composed of two components, one commonly referred to as the 20S proteasome, the second referred to as the 19S regulatory subunit. Collectively, they combine to form the 26S proteasome, which internally houses a number of different proteases responsible for degrading proteins into smaller irrelevant fragments. Many theories abound regarding the potential mechanism through which proteasome inhibition may lead to cell death or cell cycle arrest. One line of evidence has shown that inhibition of the proteasome leads to the accumulation of several cell cycle regulatory proteins, including the cyclins, and cyclin dependent kinase inhibitors p21 and p27^ref. Another potentially important mechanism revolves around the potential direct induction of apoptosis through the modulation of anti- and proapoptotic proteins, namely bax and bik^{ref1, ref2}. To date, the most extensively studied mechanism revolves around the inhibition of NF-kB^ref. Many investigators have demonstrated that inhibitors of the proteasome can block the activation of the transactivating transcription factor NF-kB by inhibiting the degradation of its natural inhibitor, IkB. In normally quiescent cells, NF-kB exists in an inactivated form bound to IkB. In malignant cells, and in cells stimulated or stressed through exposure to various cytokines, cytotoxic drugs, viruses, oxidative triggers, or other mitogenic factors, IkB is phosphorylated by IKK and then ubiquitinated, leading to its eventual degradation, and liberation of active free NF-kB. On the Phase I study of bortezomib in patients with advanced hematologic malignancies, one heavily treated patient with MCL achieved a durable partial remission^ref. Subsequently, at least 3 single agent Phase II studies with significant experiences in MCL have been reported. The first of these was reported by our group at Memorial Sloan-Kettering Cancer Center (MSKCC). Eligible patients had small lymphocytic lymphoma/chronic lymphocytic leukemia, FL, marginal zone lymphoma, or MCL. All patients were treated with 1.5 mg/m² on the typical day 1, 4, 8 and 11 schedule. Based on an update of the original data set^ref, over 11 evaluable patients with MCL had been treated, with 6 of them achieving major partial remissions, and 5 achieving stable disease. Of the patients that achieved a PR, the shortest duration of that response has been 6 months, and the longest duration has been over 19 months. The latter patient has since gone on to receive 3 courses of therapy, now with over 27 months of disease-free survival, despite only a 6 month duration of response to CHOP followed by rituximab. A second study, recently reported by Goy et al from the MDACC (Goy A, Younes A, McLaughlin P, et al. Update on a phase (ph) 2 study of bortezomib in patients (pts) with relapsed or refractory indolent or aggressive non-Hodgkin’s lymphomas (NHL) [abstract]. Proc ASCO. 2004;23:#6581), designed exactly the same as the MSKCC study except for a broader set of inclusion criteria for the types of NHL allowed, recently reported on 29 evaluable patients with MCL, 12 of whom achieved a major response to bortezomib (41% response rate). Interestingly, 6 of these patients had achieved a CR, 6 achieved a PR, and 6 attained stable disease. Though the followup in both studies is short, the median duration of response thus far in the MDACC study is about 6 months, in what would be considered a very heavily treated population of patients. In addition to these studies, another smaller study being conducted by the National Cancer Institute of Canada (NCIC) in patients with MCL recently reported on their results (Assouline S, Belch, A., Sehn, L., et al. A phase II study of bortezomib in patients with mantle cell lymphoma [abstract]. Blood. 2003;102:#3358). As of the most recent report on these data, 13 of 17 patients were evaluable for response. The NCIC study differed from the ones reported by MSKCC and MDACC in that they employed a lower dose of bortezomib (1.3 mg/m²). Partial responses were seen in 38% of patients, with one of these patients achieving a complete remission of all nodal and non-nodal based disease, though their bone marrow response was not fully evaluated (hence one CRu). Of those patients achieving a PR, the median time to response was about 2 cycles, with a duration of remission that ranged from 2.4 to 6.7 months (as of this report, and with unclear period of follow-up, the median duration of response had not been attained). Presently, based on the encouraging results from these Phase II studies, a large industry sponsored multicenter study evaluating the time to progression and overall response rate for MCL patients receiving bortezomib is underway.
• thalidomide-based treatments : thalidomide, originally developed as a sedative in the 1950s, was found to have marked teratogenic properties when administered to pregnant women, which eventually led to the widespread restriction of its use. Most recently, the drug has been resurrected based on its promising activity in both multiple myeloma and in combination with clarithromycin and dexamethasone in Waldenström’s macroglobulinemia^ref. Thalidomide is an immunomodulatory agent whose exact mechanism of action in both liquid and solid tumors remains to be clarified. In general though, it is known to have a number of pleotrophic effects on cells, ranging from anti-angiogenic to anti-inflammatory effects, presumably by altering cytokine production. One of the properties that may explain its efficacy in multiple myeloma revolves around its potential to modify the stromal environment in the bone marrow, leading to a perturbation in the signaling pathways responsible for plasma cell survival. Damaj et al^ref published a case report on 2 patients with very heavily pretreated MCL who achieved major durable partial remissions on thalidomide, which in both cases was maintained for over a year on the maintenance therapy. Recently, Kaufmann et al (Kaufmann H, Raderer M, Woehrer S, et al. Anti-tumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma. Blood. 2004) conducted a Phase II study of rituximab (R; 375 mg/m² IV weekly times four weekly doses) given concomitantly with thalidomide (T; 200 mg by mouth daily, with a incremental dose increases to 400 mg on day 15). The therapy was administered until progression or relapse. Remarkably, 13 patients (81%) experienced an objective response, with 5 complete responders (31%). The median PFS was 20.4 months, and the estimated 3-year survival was 75%. In those patients attaining a response, the PFS after R+T was longer than that achieved with the preceding chemotherapy. Overall the regimen was well tolerated, and the major adverse effects included 2 thromboembolic events and one grade 4 neutropenia. Based on the anticancer properties of thalidomide, a significant research effort has been dedicated to the generation of new small molecules are that are structurally similar though functionally distinct from thalidomide. These novel molecules, known as IMiDs, are orally bioavailable compounds with a safety profile that so far seems more favorable compared to thalidomide. One of these compounds, Revlimid, has now completed Phase I/II evaluation in multiple myeloma. These studies have demonstrated that Revlimid is not associated with the same spectrum of toxicities associated with thalidomide (sedation, thromboembolic events, constipation, neuropathy) and has produced significant reductions in paraproteins in most myeloma patients. Many studies are now underway to evaluate the activity of Revlimid in combination with rituximab in patients with lymphoma (Cancer and Leukemia Group B; CALGB). Clearly, the IMiDS are a class of molecules that warrant further attention in patients with MCL, especially in combination with other active agents like rituximab, traditional chemotherapy programs, and possibly bortezomib.
• flavopiridol : one promising agent in development which may make perfect sense in targeting a disease characterized by gross dysregulation of a cyclin, is the use of flavopiridol. Flavopiridol is a large multicyclic compound originally derived from a plant indigenous to India known as Dysoxylum binectariferum. Flavopiridol is a pan cyclin-dependent kinase (cdk) inhibitor that binds directly to the ATP-binding site at nanomolar concentration of most cyclin-dependent kinases^ref. It is a potent inhibitor of the Cyclin D1, D2, D3-cdk4/6 complex, the Cyclin E/cdk2 complex, the Cylin B/cdk1 complex, and the Cyclin A/cdk 1 complex. As such, it has been found to be a potent inducer of apoptosis when used with traditional chemotherapy drugs in a schedule dependent manner^{ref1, ref2}. Recently, Kouroukis et al^ref published their experience with a Phase II study of flavopiridol in 30 patients with MCL, of whom 11 had no prior therapy. The response rate was about 11% (3 of 28 patients), with a median duration of response of only about 3 months (range 3 to 13 months). While these data suggested only modest activity, it is clear from the solid tumor experience to date that the merit of flavopiridol may not exist in its single agent use, but rather when combined rationally, and in a schedule dependent manner, with other chemotherapeutic agents with known single agent-activity^{ref1, ref2}
• pixantrone (BBR 2778): anthracyclines are among the most active drugs in the treatment of aggressive large cell lymphoma. These compounds however, are often associated with cardiotoxicity, especially when used in high cumulative doses. In preclinical models pixantrone, a novel aza-anthracenedione, was shown to have greater cytotoxicity against P388 and L1210 leukemia cell lines compared to mitoxantrone and doxorubicin, and an in vivo murine model^{ref1, ref2}. These studies reported a more favorable therapeutic index with less cardiotoxicity. Recently, a very small Phase II experience in lymphoma was published on 33 patients with either DLBCL (n = 24), MCL (n = 7), and 2 patients with transformed lymphoma^ref. The overall response rate in this heavily treated population of patients was 27%. Of the 7 patients with MCL, one patient achieved a CR that was durable for over 15 months. 5 of the 7 patients experienced a transient tumor reduction of more than 50%, which was unfortunately not durable. While pixantrone may have some suggestion of activity in MCL, its most promising venue for development may reside in the treatment of aggressive lymphomas and MCL. Within this context, it is becoming clear that understanding the levels of certain biochemical determinants, such as glutathione-S-transferase p (GST-p) and topoisomerase II (topoII), for example, may help predict the patients and subtypes of disease more or less likely to respond. Recent reports have shown that topoII correlated very strongly with OS in patients with MCL^ref. Patients with low topoII expression (i.e., 0–10%) had a median OS of 49 months, while those patients with levels > 10% had a median survival of only 17 months. A multivariate Cox regression analysis revealed the expression of topoII as the most important prognostic factor in MCL (P < 0.001), superior to the IPI. In addition, Bennaceur-Griscelli et al reported that the level of GST- expression in MCL was significantly higher that that typically seen in DLCL-B or FL^ref. Interestingly, GST-p is located at 11q13 and is co-amplified with the cyclin D1 gene in the same amplicon, which may account for some of the intrinsic chemotherapy resistance in MCL. Given that pixantrone produces its cytotoxic effects through the inhibition of topoisomerase II, by inducing double-strand breaks and intercalating into DNA, interpreting these results in the context of these molecular markers may afford new opportunities to tailor some of these new drugs to an individual’s particular subtype of MCL.
• m-TOR inhibitors: the phosphoprotein kinase, TOR (target of rapamycin) is an important downstream component in the PI3K/Akt pathway, playing an important role in the regulation of protein translation. Following mitogenic stimulation, activation of these kinases led to the proliferation of both T and B cells. In fact, increased PI3K activity in transgenic mice induces a T cell lymphoproliferative disorder that leads to the early development of T cell lymphoma^{ref1, ref2, ref3}. Constitutive activation of the Akt pathway has been described in many cell lines, including multiple myeloma. The importance of this pathway may be an extremely important determinant in explaining the sensitivity of to the rapamycin analogs against T and B cells. Recently, Witzig et al reported on the results of a single-agent Phase II study of the rapamycin analog CCI-779 in previously treated patients with MCL^ref. They treated the patients with 250 mg IV on days 1, 8, 15 and 22 every 4 weeks. Based on an interim evaluation of the results reported at ASH 2003, 18 eligible patients had been registered, with an overall response rate of 44%, including 1 CR (7 PR). Though the study is still ongoing, the scientific rationale coupled with the preclinical and now clinical data suggest that this target warrants further investigation.

• IPI score : only occasional patients who present with a high IPI score surviving 5 years and 50% of patients with a low IPI score surviving 5 years
• BV has a much worse prognosis than the classic form, with a median survival of < 2 years
• cyclin D1⁺ MCL group, which comprises the majority of MCLs and pursues an aggressive clinical course, should be demarcated from the cyclin D1^- group, which has a remarkably favorable prognosis^ref. 85% of MCL show positive nuclear staining for cyclin D1, while the remaining 15% are negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1⁺ and ^- groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1⁺ group showed a higher age distribution, larger cell size, higher mitotic index, more frequent gastrointestinal involvement (P = .05), higher international prognostic index score, and lower p27^KIP1 expression. Of particular interest is that cyclin D1⁺ MCL showed significantly worse survival than cyclin D1^- lymphoma (5-year survival: 30% versus 86%), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1⁺ and ^- groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL^ref.
• 17p/p53 overexpressions^{ref1, ref2, ref3}
• INK4a/ARF deletions^{ref1, ref2, ref3}
• complex karyotypes or tetraploid chromosome clones were associated with aggressive variants of MCL^{ref1, ref2}

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