883
`
`The Role of Fludarabine in the Treatment of Follicular
`and Mantle Cell Lymphoma
`
`Georg Lenz, M.D.
`Wolfgang Hiddemann, M.D., Ph.D.
`Martin Dreyling, M.D., Ph.D.
`
`Department of Internal Medicine III, Grosshadern
`Hospital, Ludwig-Maximilians University, Munich,
`Germany.
`
`Address for reprints: Georg Lenz, M.D., Depart-
`ment of Internal Medicine III, University Hospital
`Grosshadern, Ludwig-Maximilians University, Mar-
`chioninistrasse 15, 81377 Munich, Germany; Fax:
`(011) 49 89 7095 5550; E-mail: georg.lenz@
`med3.med.uni-muenchen.de
`
`Received April 14, 2004; revision received June 8,
`2004; accepted June 8, 2004.
`
`Advanced-stage follicular lymphoma (FL) and mantle cell lymphoma (MCL) can-
`not be cured using conventional chemotherapy. Fludarabine, the most widely used
`purine analog, exhibits a particularly high level of activity against small lympho-
`cytic lymphoma and chronic lymphocytic leukemia (CLL). Numerous studies have
`investigated the efficacy of fludarabine as a single agent or in combination with
`other cytostatic compounds in the treatment of FL and MCL. Hematologic toxicity
`is the most commonly observed adverse event in patients treated with fludarabine,
`but serious infectious complications are relatively rare. Fludarabine monotherapy
`has proven to be particularly effective in the treatment of FL; however, complete
`responses (CRs) are observed in only approximately 20 – 40% of all cases. In
`contrast, combinations containing fludarabine and anthracyclines or alkylating
`agents have yielded superior response rates and longer periods of progression-free
`survival (PFS), and the addition of the anti-CD20 antibody rituximab appears to
`yield even better results. In a randomized trial, an immunochemotherapy regimen
`consisting of a fludarabine-containing combination and rituximab resulted in
`superior remission and survival rates compared with the fludarabine-containing
`combination alone. In summary, fludarabine has proven to be a safe and effective
`agent in the treatment of indolent lymphoma. In particular, combinations con-
`taining fludarabine, anthracyclines and/or alkylating agents, and rituximab have
`yielded remarkable CR and PFS rates. Consequently, current research efforts have
`focused on the use of fludarabine-containing combinations in the first-line
`treatment of FL and MCL. Cancer 2004;101:883–93.
`© 2004 American Cancer Society.
`
`KEYWORDS: fludarabine, follicular lymphoma, mantle cell lymphoma, chemother-
`apy, immunochemotherapy, rituximab.
`
`Introduction
`
`Follicular lymphoma (FL) is the second most common non-
`
`Hodgkin lymphoma (NHL), accounting for 20 –30% of all cases of
`NHL.1 FL typically follows an indolent clinical course and is associ-
`ated with a median survival of 7–10 years.2 Only in certain cases of
`Ann Arbor Stage I or II, FL can be cured using radiotherapy; however,
`approximately 80% of all patients have Stage III or IV FL at presen-
`tation. For these patients, conventional chemotherapy is not curative,
`nor does it substantially prolong overall survival (OS).2
`Unlike FL, mantle cell lymphoma (MCL) accounts for only 5–10%
`of all cases of lymphoma.3,4 MCL, which is characterized by an ag-
`gressive clinical course and a median survival duration of only 3 years,
`is the lymphoma subtype associated with the poorest long-term out-
`come.5 Consequently, treatment should be administered immediately
`after diagnosis, although conventional chemotherapy is not curative.6
`
`© 2004 American Cancer Society
`DOI 10.1002/cncr.20483
`Published online 27 July 2004 in Wiley InterScience (www.interscience.wiley.com).
`
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`884
`
`CANCER September 1, 2004 / Volume 101 / Number 5
`
`Recently, the progression-free survival (PFS) of pa-
`tients with MCL was found to be significantly im-
`proved by high-dose therapy followed by autologous
`stem cell transplantation.7 Similarly, very encouraging
`results have been obtained using aggressive regimens
`(e.g., hyperfractionated cyclophosphamide, vincris-
`tine, doxorubicin, and dexamethasone) as induction
`chemotherapy or for patients for whom autologous
`stem cell transplantation is not possible.8,9 Nonethe-
`less, even after receiving such dose-intensified regi-
`mens, the majority of patients will eventually experi-
`ence recurrence. Thus, novel therapeutic approaches
`and chemotherapeutic agents developed with the goal
`of improving clinical outcome for patients with FL and
`MCL are urgently needed.
`Fludarabine, an antimetabolite that inhibits DNA
`synthesis, currently is the most widely used purine
`analog. This agent has exhibited high levels of efficacy
`in the treatment of chronic lymphocytic leukemia
`(CLL) and Waldenstrom macroglobulinemia, and in
`combination with cytosine arabinoside, it has also
`been effective in the treatment of acute myeloid leu-
`kemia (AML).10 –12 Various studies have also investi-
`gated the use of fludarabine to treat FL and MCL. The
`purpose of the current review was to summarize the
`existing body of knowledge regarding the clinical ac-
`tivity of and the toxicities associated with fludarabine
`in the treatment of these two malignancies. Special
`attention has been given to recently established im-
`munochemotherapy regimens in which fludarabine is
`used in combination with the monoclonal anti-CD20
`antibody rituximab.
`Mechanism of Action
`is converted to the free
`Fludarabine, a prodrug,
`nucleoside
`9-beta-D-arabinosyl-2-fluoroadenine,
`which enters the cells and accumulates as the 5⬘-
`triphosphorylated compound 9-beta-D-arabinosyl-
`2-fluoroadenosine triphosphate (F-ara-ATP). F-ara-
`ATP inhibits ribonucleotide reductase, as well as
`DNA ligase and DNA primase. In addition, F-ara-
`ATP is incorporated into DNA, with this incorpo-
`ration resulting in the repression of further DNA
`polymerization. In cell lines, the incorporation of
`F-ara-ATP into RNA and the subsequent inhibition
`of transcription has also been demonstrated.13
`Fludarabine has also been used in combination
`with other chemotherapeutic agents. In patients with
`indolent lymphoma, the combination of fludarabine
`and cyclophosphamide, an alkylating agent that in-
`duces DNA damage, resulted in increased treatment
`efficacy,14 which may have been attributable to the
`inhibition of interstrand DNA crosslink removal by
`fludarabine.15 Similarly, synergy between fludarabine
`
`and the anti-CD20 antibody rituximab has been dem-
`onstrated in vitro. Rituximab acts primarily by stimu-
`lating antibody-dependent as well as complement-
`dependent cytotoxicity.16,17 Fludarabine is capable of
`down-regulating the complement
`inhibitor CD55,
`which is partially responsible for the decreased activ-
`ity of rituximab in therapy-resistant NHL. Thus, flu-
`darabine and rituximab exert synergistic effects, lead-
`ing to increased response rates.18
`
`Toxicity
`The toxicity of single-agent fludarabine is considered
`to be moderate. In a number of nonrandomized Phase
`II studies, the most commonly observed adverse effect
`was myelosuppression leading to neutropenia, throm-
`bocytopenia, and anemia. In a recent randomized
`trial, Hagenbeek et al.19 compared fludarabine with
`cyclophosphamide, vincristine, and prednisone (CVP)
`in patients with newly diagnosed indolent lymphoma
`and found that granulocytopenia and thrombocytope-
`nia were significantly more common in the fludara-
`bine arm (28% vs. 12% and 8% vs. 1%, respectively).
`This observation has been confirmed in various other
`studies; in those studies, 0 – 4% of all patients receiving
`fludarabine experienced severe anemia, 0 – 8% experi-
`enced thrombocytopenia (incidence rate in previously
`treated patients, 11–13%), and 11– 41% experienced
`neutropenia (incidence rate in previously treated pa-
`tients, 11–21%).20 –23 Nonetheless, the duration of my-
`elosuppression is short, and blood cell support is only
`rarely required.24 Immunomodulation due to an al-
`tered CD4-to-CD8 ratio and changes in the T cell
`repertoire has also been observed following fludara-
`bine therapy.25,26 Thus, infectious events occur rela-
`tively frequently in patients receiving fludarabine.
`Klasa et al.,27 who compared fludarabine with CVP in
`patients with recurrent
`low-grade lymphoma, re-
`ported that 36% of patients in the fludarabine arm
`developed infectious complications, with 11% experi-
`encing World Health Organization Grade 3 or 4 infec-
`tion.
`Nonhematologic toxicities are uncommon and are
`generally mild in patients receiving fludarabine. Nau-
`sea and emesis are observed in approximately 20 –30%
`of such patients. Neurologic side effects, alopecia, and
`cardiac, pulmonary, and renal toxicities are also rela-
`tively rare.22,24,27
`Chemotherapy combinations containing fludara-
`bine and alkylating agents or anthracyclines are gen-
`erally well tolerated. Various Phase II studies have
`demonstrated the feasibility of such combinations,
`with myelosuppression being identified as the most
`serious toxic event in those studies (Table 1).28 –31 In a
`study conducted by Velasquez et al.,32 patients with
`
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`TABLE 1
`Grade 3/4 Hematologic Toxicity in Patients Receiving Fludarabine-Containing Regimens
`
`Study
`
`Regimen
`
`No. of
`patients
`
`Disease
`status
`
`Anemia (%)
`
`Thrombocytopenia
`(%)
`
`Neutropenia
`(%)
`
`Fludarabine in FL and MCL/Lenz et al.
`
`885
`
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1; prednisone 40 mg per day ⫻ 5
`Fludarabine 20 mg/m2 per day ⫻ 5; cyclophosphamide
`600 mg/m2 per day ⫻ 1
`Fludarabine 20–25 mg/m2 per day ⫻ 3;
`cyclophosphamide 600 mg/m2 per day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1; dexamethasone 20 mg per day
`⫻ 5
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide
`200 mg/m2 per day ⫻ 3; mitoxantrone 6 mg/m2 per
`day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide
`300 mg/m2 per day ⫻ 3; mitoxantrone 10 mg/m2
`per day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide
`200 mg/m2 per day ⫻ 3; mitoxantrone 8 mg/m2 per
`day ⫻ 1
`
`30
`
`43
`
`30
`
`73
`
`78
`
`53
`
`54
`
`57
`
`Recurrent
`
`n.a.
`
`Untreated
`
`Untreated or
`recurrent
`Untreated
`
`Untreated
`
`Untreated
`
`9
`
`36
`
`n.a.
`
`4
`
`n.a.
`
`Untreated
`
`25a
`
`Recurrent
`
`5
`
`0
`
`2
`
`37
`
`12
`
`8
`
`0.5
`
`27a
`
`11
`
`17
`
`40
`
`50
`
`81
`
`35
`
`7
`
`42b
`
`41
`
`Zinzani et al., 199764
`
`Flinn et al., 200045
`
`Cohen et al., 200128
`
`Tsimberidou et al., 200237
`
`Velasquez et al., 200332
`
`Montoto et al., 200263
`
`Spriano et al., 200239
`
`Dreyling et al., 200352
`
`n.a.: not available.
`a Grade 1–3.
`b Leukopenia.
`
`previously untreated advanced-stage, low-grade NHL
`received a combination of fludarabine and mitox-
`antrone. Fifteen percent of those patients developed
`Grade III neutropenia, and 19% developed Grade IV
`neutropenia. In contrast, fever was observed in only 18
`of 78 patients (23%) in that study.
`Immunosuppression due to prolonged T lympho-
`cytopenia is another major side effect associated with
`fludarabine-containing regimens. Accordingly, the re-
`activation of latent Epstein–Barr virus (EBV) infections
`as well as EBV-positive lymphoproliferative disorders
`has been observed.33,34 The addition of corticosteroids
`to fludarabine-containing regimens significantly in-
`creases the risk of opportunistic infection and there-
`fore should be avoided.35 McLaughlin et al.36 observed
`that a significant number of patients developed op-
`portunistic infections, including Pneumocystis carinii
`pneumonia, herpes zoster virus infection, and various
`mycobacterial infections, after receiving an FND reg-
`imen (fludarabine 25 mg/m2 daily for 3 days, mitox-
`antrone 10 mg/m2 per day for 1 day, and dexametha-
`sone 20 mg per day for 5 days). In another trial
`conducted at the M. D. Anderson Cancer Center
`(Houston, TX), 2 of 73 patients developed P. carinii
`pneumonia after receiving FND.37 Thus, although ran-
`domized trials confirming the superiority of prophy-
`lactic antibiotics have not been performed, all patients
`
`receiving fludarabine and concomitant steroid ther-
`apy should also receive trimethoprim sulfamethox-
`azole as a prophylactic measure against P. carinii
`pneumonia.38
`The incidence of toxic side effects depends heavily
`on chemotherapy dose levels, with slight increases
`resulting in significant increases in the incidence of
`Grade 3/4 hematologic toxicity.39 This finding was
`confirmed by Hochster et al.,40 who conducted a
`Phase I trial involving previously untreated patients
`with low-grade lymphoma. In that study, the admin-
`istered cyclophosphamide dose was increased from
`600 mg/m2 to 1000 mg/m2 (Day 1), and fludarabine
`was administered at a dose of 20 mg/m2 (Days 1–5).
`Treatment cycles initially were repeated every 21 days,
`but due to the observation of Grade 4 hematologic
`toxicity in 50% of all patients, these cycles eventually
`were extended to 28 days. In addition, prophylaxis for
`P. carinii pneumonia and herpes zoster infection were
`required. Nineteen percent of all patients developed
`Grade 3 or 4 interstitial pneumonia, and 11% of pa-
`tients developed other infectious toxicities (Grade 4
`fungal sepsis, lobar pneumonia, and venous port in-
`fection in 1 case each). These data confirm that in-
`creasing the doses of chemotherapeutic agents in flu-
`darabine-containing regimens significantly increases
`the risk of infectious complications. Thus, when rela-
`
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`886
`
`CANCER September 1, 2004 / Volume 101 / Number 5
`
`tively dose-intense regimens are used, prophylactic
`growth factor support and P. carinii prophylaxis are
`strongly recommended.
`Reviews of various trials have suggested that her-
`pes simplex and herpes zoster infections occur rather
`frequently during and after fludarabine-based chemo-
`therapy in patients with CLL.41,42 In contrast, the in-
`cidence of these infections has not been investigated
`in large series of patients with FL or MCL. Thus, at
`present, it is unclear as to whether a subgroup of
`patients with FL or MCL and high-risk characteristics
`(e.g., depressed CD4 counts) might benefit from pro-
`phylaxis involving acyclovir or valganciclovir; this is-
`sue warrants attention in future studies.
`One major side effect of fludarabine in patients
`with CLL is autoimmune hemolysis43,44; however, this
`phenomenon has not been described in larger studies
`involving patients with FL or MCL. This finding sug-
`gests that autoimmune hemolysis is not related exclu-
`sively to fludarabine use but might also depend on the
`subtype of lymphoproliferative disease being treated.
`Another controversial issue involves stem cell mo-
`bilization following the administration of fludarabine-
`containing chemotherapy. Flinn et al.45 did not ob-
`serve reduced stem cell mobilization after
`the
`administration of several cycles of a combined regi-
`men containing fludarabine and cyclophosphamide,
`whereas other studies have reported that stem cell
`harvesting is significantly impaired following fludara-
`bine-containing chemotherapy.46 – 48 Thus, the issue of
`stem cell mobilization in this setting has not been fully
`resolved.
`A recent analysis performed by Morrison et al.49
`revealed another potential adverse effect associated
`with fludarabine. In patients with CLL, those investi-
`gators observed an increased incidence of secondary
`myelodysplastic syndromes (t-MDS) following treat-
`ment with fludarabine (either alone or in combination
`with chlorambucil). In contrast, Cheson et al.50 did not
`detect a significant increase in the incidence of sec-
`ondary malignancies. The incidence of secondary ma-
`lignancies has not been described in larger series of
`patients with FL or MCL; to date, only individual case
`reports of t-MDS following fludarabine use have been
`published.51 Thus, it currently is unclear as to whether
`patients with malignant lymphoma have an increased
`risk of developing secondary neoplasia following
`treatment with fludarabine.
`The use of fludarabine-containing combinations
`in conjunction with rituximab has proven to be feasi-
`ble in various studies.52–56 Hematologic toxicity is the
`primary side effect associated with such treatment,
`whereas nonhematologic toxicity is rare. In a study
`conducted by Cohen et al.,56 patients were treated
`
`with the FCR chemotherapy regimen (4 – 6 cycles of
`fludarabine 25 mg/m2 per day for 3 days, cyclophos-
`phamide 250 mg/m2 per day for 3 days, and rituximab
`375 mg/m2 weekly); hematologic toxicity was noted in
`30% of all patients, with 6% of patients developing
`Grade 3 or 4 neutropenia. It is noteworthy that despite
`the expectation of immunosuppression due to the
`elimination of the B cell compartment and changes in
`the T cell repertoire, only 1 of 33 patients (3%) in that
`study developed neutropenic fever. The addition of
`rituximab to fludarabine-containing regimens leads to
`myelosuppression in a larger number of cases. Byrd et
`al. found that patients with CLL who were treated with
`fludarabine and rituximab experienced significantly
`more hematologic toxicity (especially Grade 3/4 neu-
`tropenia) compared with patients who did not receive
`rituximab.57 This finding was confirmed in a recent
`trial conducted by McLaughlin et al.,58 in which pa-
`tients receiving a combined immunochemotherapy
`regimen (rituximab, fludarabine, mitoxantrone, and
`dexamethasone) experienced neutropenia slightly
`more frequently compared with patients in the che-
`motherapy-only arm (27% vs. 16%). Similarly, in a
`randomized trial conducted by Dreyling et al.,52 lym-
`phocytopenia was significantly more common among
`patients receiving rituximab, fludarabine, cyclophos-
`phamide, and mitoxantrone compared with patients
`in the chemotherapy-only arm.
`In summary, the use of fludarabine as a single
`agent or in combination with other cytostatic drugs or
`the anti-CD20 antibody rituximab is feasible. None-
`theless, hematologic toxicities must be closely moni-
`tored, especially following the administration of com-
`bination regimens,
`so
`that
`therapy-associated
`infections can be prevented.
`
`Efficacy of Fludarabine
`Fludarabine as a single agent
`Various Phase II studies have investigated the efficacy
`of fludarabine as a single agent in the treatment of
`previously untreated FL. Fludarabine exhibits a high
`level of efficacy in this setting, with overall response
`rates of approximately 60 –70% and complete remis-
`sion (CR) rates of approximately 30% (Table 2).21,59
`Encouraging data regarding PFS have also been ob-
`tained; Coiffier et al.59 reported a 2-year PFS rate of
`49% in patients receiving fludarabine monotherapy. In
`a randomized trial, Hagenbeek et al.19 compared flu-
`darabine with CVP in patients with low-grade NHL
`and found that the overall response rate associated
`with fludarabine use was significantly higher (68% vs.
`51% [P ⫽ 0.001]; CR rate, 38% vs. 15%); however, the
`observed median time to progression did not differ
`significantly between the two treatment arms (21
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`Fludarabine in FL and MCL/Lenz et al.
`
`887
`
`TABLE 2
`Efficacy of Fludarabine as a Single Agenta in Patients with Follicular
`Lymphoma
`
`TABLE 3
`Efficacy of Fludarabine as a Single Agenta in Patients with Mantle
`Cell Lymphoma
`
`Study
`
`No. of
`patients
`
`Disease status
`
`CR/OR
`(%)
`
`Median PFS
`(mos)
`
`Study
`
`No. of
`patients
`
`Disease status
`
`CR/OR (%)
`
`Whelan et al., 199173
`Redman et al., 199223
`Solal-Celigny et al., 199621
`Coiffier et al., 199959
`Zinzani et al., 200024
`Hagenbeek et al., 200119
`
`23
`28
`54
`61
`60
`n.a.
`
`Recurrent
`Recurrent
`Untreated
`Untreated
`Untreated
`Untreated
`
`22/48
`n.a./68
`37/65
`33/59
`60/87
`38/68
`
`n.a.
`n.a.
`13.6
`49%b
`n.a.
`21
`
`CR: complete remission; OR: overall response; PFS: progression-free survival; n.a.: not available.
`a Fludarabine 25 mg/m2 per day for 5 days.
`b Two-year progression-free survival rate.
`
`months vs. 15 months [P ⫽ 0.24]), and the median OS
`had not yet been reached at the time of that report. In
`patients with recurrent or refractory disease, although
`fludarabine remains an active chemotherapeutic
`agent, response rates generally are lower. In this set-
`ting, overall response rates of 40 – 65% and noteworthy
`OS rates have been obtained in a number of Phase II
`studies.20,32,37,60 In a recent Phase III trial, Klasa et al.27
`found that the response rate associated with fludara-
`bine and the response rate associated with CVP were
`similar (64% vs. 52% [P ⫽ 0.72]); unlike Hagenbeek et
`al.,19 however, those investigators reported that the
`median PFS was significantly longer in the fludarabine
`arm (11 months vs. 9.1 months [P ⫽ 0.03]), although
`there was no detectable difference between the two
`treatment arms in terms of median OS.
`In summary, fludarabine is effective in the treat-
`ment of FL, and it is particularly active when used as
`first-line therapy. Furthermore, fludarabine may be
`especially useful for patients who are ineligible for
`more aggressive therapeutic approaches, such as
`high-dose chemotherapy followed by autologous stem
`cell transplantation.
`Fludarabine monotherapy possesses moderate ef-
`ficacy in patients with MCL. For the most part, the
`utility of fludarabine as first-line therapy in this setting
`has been investigated only in small Phase II stud-
`ies.22,24,61 Reported overall response rates have been
`relatively low (40 –50%), with accompanying CR rates
`ranging from 20% to 30% (Table 3). Remission periods
`tended to be short, ranging from 4 to 8 months.61 In
`patients with recurrent or refractory disease, re-
`sponses to fludarabine monotherapy are even less
`favorable.20 Thus, fludarabine monotherapy possesses
`limited activity against MCL and should be adminis-
`tered only to heavily pretreated patients when other
`therapeutic options are not available.
`
`Decaudin et al., 199861
`Foran et al., 199922
`Zinzani et al., 200024
`
`15
`17
`11
`
`Untreated or recurrent
`Untreated
`Untreated
`
`0/33
`29/41
`27/73
`
`CR: complete remission; OR: overall response.
`a Fludarabine 25 mg/m2 per day for 5 days.
`
`Fludarabine-containing regimens
`Based on the finding of synergistic effects in vitro,
`fludarabine has been combined with other chemo-
`therapeutic agents, particularly anthracyclines (e.g.,
`mitoxantrone or idarubicin) and alkylating agents
`(e.g., cyclophosphamide). In various studies, fludara-
`bine-containing combinations have yielded encourag-
`ing results in the first-line treatment of FL. In a re-
`cently published Phase II study, Velasquez et al.32
`evaluated the FM regimen (fludarabine 25 mg/m2 per
`day for 3 days and mitoxantrone 10 mg/m2 per day for
`1 day) in 78 evaluable patients with low-grade lym-
`phoma; an overall response rate of 94% and a CR rate
`of 44% were reported in that study (median follow-up,
`5.5 years). Those investigators reported a 4-year PFS
`rate of 38% and a 4-year OS rate of 88%. These results
`confirmed the findings of previous studies in which
`similarly high response rates were reported (Table
`4).31,53 Likewise, in various small, nonrandomized tri-
`als, high overall response rates have been yielded by
`the combination of fludarabine and cyclophospha-
`mide (FC). In a study conducted by Flinn et al.,45 FC
`(fludarabine 20 mg/m2 per day for 5 days and cyclo-
`phosphamide 600 mg/m2 per day for 1 day) resulted in
`an overall response rate of 90%.
`The addition of dexamethasone to either FC or
`FM did not significantly improve response rates or PFS
`rates.29,37,60 In a number of studies, an FCM regimen
`(fludarabine 25 mg/m2 per day for 3 days, cyclophos-
`phamide 200 –300 mg/m2 per day for 3 days, and mi-
`toxantrone 6 – 8 mg/m2 per day for 1 day) yielded
`noteworthy results.39,52,62,63 Montoto et al.63 reported
`an overall response rate of 95% (CR rate, 75%); in
`addition, 69% of all patients in that study achieved
`molecular remission, and the 1.5-year failure-free sur-
`vival rate was 90%. These results were confirmed by
`Spriano et al.,39 who reported the occurrence of mo-
`lecular remission in 74% of all patients. In contrast, in
`the only randomized trial to compare single-agent
`fludarabine with a fludarabine-containing combina-
`tion, Zinzani et al.24 found that fludarabine mono-
`
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`CANCER September 1, 2004 / Volume 101 / Number 5
`
`TABLE 4
`Efficacy of Fludarabine-Containing Combinations in Patients with Follicular Lymphoma
`
`Study
`
`Regimen
`
`No. of
`patients
`
`Disease
`status
`
`CR/OR
`(%)
`
`Median duration of
`CR (mos)
`
`McLaughlin et al., 199636
`
`Zinzani et al., 199764
`
`Zinzani et al., 200024
`
`Flinn et al., 200045
`
`Crawley et al., 200029
`
`Montoto et al., 200263
`
`Spriano et al., 200239
`
`Velasquez et al., 200332
`
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1; dexamethasone 20 mg per day
`⫻ 5
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1; prednisone 40 mg per day ⫻ 5
`Fludarabine 25 mg/m2 per day ⫻ 3; idarubicin 12 mg/
`m2 per day ⫻ 1
`Fludarabine 20 mg/m2 per day ⫻ 5; cyclophosphamide
`600 mg/m2 per day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1; dexamethasone 20 mg per day
`⫻ 5
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide
`200 mg/m2 per day ⫻ 3; mitoxantrone 6 mg/m2 per
`day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide
`300 mg/m2 per day ⫻ 3; mitoxantrone 10 mg/m2
`per day ⫻ 1
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10
`mg/m2 per day ⫻ 1
`
`33
`
`30
`
`43
`
`20
`
`54
`
`53
`
`54
`
`78
`
`CR: complete remission; OR: overall response; OS: overall survival; n.a.: not available.
`a Median overall survival duration.
`b Overall survival rate at 33 months.
`c Overall survival rate at 3 years.
`d Overall survival rate at 4 years.
`
`Recurrent
`
`45/94
`
`Recurrent
`
`Untreated
`
`Untreated
`
`Untreated or
`recurrent
`
`23/83
`
`40/84
`
`60/90
`
`20/69
`
`21
`
`18
`
`n.a.
`
`n.a.
`
`n.a.
`
`Untreated
`
`75/95
`
`n.a.
`
`Untreated
`
`61/91
`
`n.a.
`
`Untreated
`
`44/94
`
`n.a.
`
`OS
`
`34 mosa
`
`67%b
`
`n.a.
`
`n.a.
`
`n.a.
`
`n.a.
`
`91%c
`
`88%d
`
`therapy and FLU-ID (fludarabine 25 mg/m2 per day
`for 3 days and idarubicin 12 mg/m2 per day for 1 day)
`yielded comparable response rates (87% vs. 84%);
`however, after a median follow-up period of 36
`months, the PFS rate was significantly higher in the
`FLU-ID arm (P ⫽ 0.006), a finding that suggests that
`patients receiving the combination regimen experi-
`enced higher-quality responses (Table 4).
`The response rates associated with fludarabine-
`containing regimens are slightly lower for patients
`with recurrent FL.30,31,36,62,64 In a randomized trial
`conducted by the German Low-Grade Lymphoma
`Study Group (GLSG), Dreyling et al.52 compared the
`FCM regimen with combined immunochemotherapy
`(FCM plus rituximab) in patients with recurrent or
`refractory low-grade NHL;
`the chemotherapy-only
`regimen resulted in an overall response rate of 70%
`and a CR rate of 23%.
`Thus, in patients with FL, fludarabine-containing
`regimens that include anthracyclines and/or alkylat-
`ing agents are highly effective as first-line therapy as
`well as in the treatment of recurrent or refractory
`disease. Various trials have reported that fludarabine-
`containing combinations (relative to single-agent flu-
`darabine) can improve CR rates from 20 – 40% to 40 –
`
`60% and overall response rates from 60 –70% to 80 –
`90%. In addition, a randomized trial conducted by
`Zinzani et al.24 confirmed the finding of a superior PFS
`rate in patients receiving FLU-ID chemotherapy com-
`pared with patients receiving single-agent fludara-
`bine. Thus, we can conclude that fludarabine-contain-
`ing combinations, rather than fludarabine alone,
`should be administered to patients with FL. To date,
`however, no randomized trial has compared the vari-
`ous fludarabine-combinations with each other. Be-
`cause remission rates associated with the various
`combinations containing alkylating agents or anthra-
`cyclines appear to be comparable to each other, reg-
`imens (e.g., FC, FM, or FCM) can be selected for use
`on the basis of individual clinical experience.
`A number of small studies have investigated the
`efficacy of fludarabine-containing combinations in
`patients with MCL (Table 5).24,28,31,45 In previously
`untreated patients, the FLU-ID regimen yielded an
`overall response rate of 61%.24 Similarly, an overall
`response rate of 80% was observed in previously un-
`treated patients who received the FC regimen.45 In
`another study, FC was found to be active against
`newly diagnosed disease, as well as recurrent and
`refractory disease.28 In that study, previously un-
`
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`

`Fludarabine in FL and MCL/Lenz et al.
`
`889
`
`TABLE 5
`Efficacy of Fludarabine-Containing Combinations in Patients with Mantle Cell Lymphoma
`
`Study
`
`Regimen
`
`McLaughlin et al., 199636
`
`Zinzani et al., 200024
`Flinn et al., 200045
`Cohen et al., 200128
`
`Seymour et al., 200274
`
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10 mg/m2 per day ⫻ 1;
`dexamethasone 20 mg per day ⫻ 5
`Fludarabine 25 mg/m2 per day ⫻ 3; idarubicin 12 mg/m2 per day ⫻ 1
`Fludarabine 20 mg/m2 per day ⫻ 5; cyclophosphamide 600 mg/m2 per day ⫻ 1
`Fludarabine 20–25 mg/m2 per day ⫻ 3; cyclophosphamide 600 mg/m2 per day ⫻ 1
`
`Fludarabine 30 mg/m2 per day ⫻ 2; cisplatin 25 mg/m2 per day ⫻ 4; cytosine
`arabinoside 500 mg/m2 per day ⫻ 2
`
`CR: complete remission; OR: overall response.
`
`No. of
`patients
`
`5
`
`18
`10
`30
`
`8
`
`Disease
`status
`
`Recurrent
`
`Untreated
`Untreated
`Untreated or
`recurrent
`Recurrent
`
`CR/OR
`(%)
`
`20/80
`
`33/61
`40/80
`30/63
`
`88
`
`TABLE 6
`Fludarabine-Containing Chemotherapy plus Rituximab in Patients with Follicular Lymphoma or Mantle Cell Lymphoma
`
`Study
`
`Regimen
`
`No. of
`patients
`
`Disease status
`
`Cohen et al., 200256
`
`Vitolo et al., 200254
`
`Sacchi et al., 200255
`
`Fludarabine 25 mg/m2 per day ⫻ 3; cyclophosphamide 250 mg/m2 per day ⫻
`3; rituximab 375 mg/m2 per day (4 cycles)
`Fludarabine 25 mg/m2 per day ⫻ 3; mitoxantrone 10 mg/m2 per day ⫻ 1;
`dexamethasone 20 mg per day ⫻ 3; rituximab 375 mg/m2 per day (4 cycles)
`Fludarabine 30 mg/m2 per day ⫻ 3; cyclophosphamide 300 mg/m2 per day ⫻
`3; rituximab 375 mg/m2 per day ⫻ 1
`
`33
`
`36
`
`52
`
`Untreated
`
`Untreated
`
`Recurrent
`
`CR/OR
`(%)
`
`85/88
`
`90/95
`
`65/82
`
`OS rate
`(%)
`
`89a
`
`n.a.
`
`n.a.
`
`CR: complete remission; OR: overall response; OS: overall survival; n.a.: not available.
`a Two-year overall survival rate.
`
`treated patients had an overall response rate of 100%
`(CR rate, 70%; PR rate, 30%) and a median PFS of 28.1
`months; however, the efficacy of the FC regimen ap-
`peared to be limited in previously treated patients. In
`another recent trial, an overall response rate of 46%
`was achieved using the FCM regimen, although no
`CRs were documented in that trial.52 In summary,
`fludarabine-containing combinations that include ei-
`ther anthracyclines or alkylating agents are efficient in
`the first-line treatment of MCL; however, it currently is
`unclear as to whether improved remission rates will
`lead to prolonged survival for patients with MCL.
`
`Combinations involving fludarabine and rituximab
`Monoclonal antibodies represent one of the most
`promising options for the treatment of B-cell lym-
`phoma. In patients with FL, the anti-CD20 antibody
`rituximab yielded impressive overall response rates
`(approximately 50 – 60%).65– 68 Because in vitro data
`suggest that combined immunochemotherapy regi-
`mens may exert synergistic effects, various Phase II
`studies have investigated the efficacy of fludarabine-
`containing combinations administered in conjunction
`with rituximab. To date, such studies have produced
`
`encouraging results (Table 6).53,54,56,69 For example,
`Cohen et al.56 investigated the activity of the FCR
`regimen in previously untreated patients with FL and
`found an overall response rate of 88% (CR rate, 85%),
`a disease-free survival rate of 63.4%, and an OS rate of
`89.2% after 2 years. Similar data were reported by
`Vitolo et al.,54 who investigated responses to an FND
`combination (fludarabine 25 mg/m2 per day for 3
`days, mitoxantrone 10 mg/m2 per day for 1 day, and
`dexamethasone 20 mg per day for 3 days) adminis-
`tered in conjunction with rituximab (375 mg/m2). In
`that trial, an overall response rate of ⬎ 90% and a
`recurrence rate of only 9% were observed after a me-
`dian follow-up period of 18 months.
`Sacchi et al.55 investigated the efficacy of FCR in
`52 patients with recurrent FL; the median number of
`chemotherapy regimens previously received by those
`52 patients was 1.7 (range, 1– 4). An intent-to-treat
`analysis revealed that the overall response rate among
`those patients was 82% (CR rate, 65%). Another note-
`worthy finding was that molecular remission occurred
`in 58% of all patients who underwent molecular mon-
`itoring. Finally,
`in a recent randomized trial con-
`ducted by the GLSG,52 a combined immunochemo-
`
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`

`890
`
`CANCER September 1, 2004 / Volume 101 / Number 5
`
`TABLE 7
`Comparison of Combined Immunochemotherapy (R-FCM) with
`Chemotherapy Alone (FCM) in Patients with Recurrent or Refractory
`Follicular Lymphoma or Mantle Cell Lymphomaa
`
`Regimen
`
`FL
`FCM
`R-FCM
`MCL
`FCM
`R-FCM
`
`No. of
`patients
`
`30
`35
`
`24
`24
`
`CR/OR (%)
`
`Median PFS (mos)
`
`2 yr OS rate (%)
`
`23/70
`40/94b
`
`0/46
`29/58b
`
`21
`n.a.
`
`4
`8
`
`70
`90
`
`35
`65b
`
`CR: complete remission; OR: overall response; PFS: progression-free survival; OS: ov