EXHIBIT 2011
`
`EXHIBIT 201 1
`
`
`
`

`
`Fludarabine, Mitoxantrone, and Dexamethasone: An
`Fludarabine, Mitoxantrone, and Dexamethasone: An
`Fludarabine, Mitoxantrone, and Dexamethasone: An
`Effective New Regimen for Indolent Lymphoma
`Effective New Regimen for Indolent Lymphoma
`Effective New Regimen for Indolent Lymphoma
`
`By Peter McLaughlin, Fredrick B. Hagemeister, Jorge E. Romaguera, Andreas H. Sarris, Odeal Pate, Anas Younes,
`By Peter McLaughlin, Fredrick B. Hagemeister, Jorge E. Romaguera, Andreas H. Sarris, Odeal Pate, Anas Younes,
`By Peter McLaughlin, Fredrick B. Hagemeister, Jorge E. Romaguera, Andreas H. Sarris, Odeal Pate, Anas Younes,
`Forrest Swan, Michael Keating, and Fernando Cabanillas
`Forrest Swan, Michael Keating, and Fernando Cabanillas
`Forrest Swan, Michael Keating, and Fernando Cabanillas
`
`Purpose: Although most patients with
`indolent
`Purpose: Although most patients with indolent
`Purpose: Although most patients with indolent
`lymphomas respond to initial therapy, virtually all expe-
`lymphomas respond to initial therapy, virtually all expe-
`lymphomas respond to initial therapy, virtually all expe-
`rience relapse. Secondary therapy is often beneficial, but
`rience relapse. Secondary therapy is often beneficial, but
`rience relapse. Secondary therapy is often beneficial, but
`responses are rarely, if ever, durable. We conducted this
`responses are rarely, if ever, durable. We conducted this
`responses are rarely, if ever, durable. We conducted this
`phase II trial to evaluate the therapeutic efficacy and tox-
`phase II trial to evaluate the therapeutic efficacy and tox-
`phase II trial to evaluate the therapeutic efficacy and tox-
`icity of fludarabine, mitoxantrone, and dexamethasone
`icity of fludarabine, mitoxantrone, and dexamethasone
`icity of fludarabine, mitoxantrone, and dexamethasone
`(FND) in patients with relapsed indolent lymphoma.
`(FND) in patients with relapsed indolent lymphoma.
`(FND) in patients with relapsed indolent lymphoma.
`Patients and Methods: Fifty-one patients with recur-
`Patients and Methods: Fifty-one patients with recur-
`Patients and Methods: Fifty-one patients with recur-
`rent or refractory indolent lymphoma were treated with
`rent or refractory indolent lymphoma were treated with
`rent or refractory indolent lymphoma were treated with
`a regimen of fludarabine 25 mg/m 2/d intravenously (IV)
`a regimen of fludarabine 25 mg/m2/d intravenously (IV)
`a regimen of fludarabine 25 mg/m2/d intravenously (IV)
`on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1,
`on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1,
`on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1,
`and dexamethasone 20 mg/d IV or orally on days 1
`and dexamethasone 20 mg/d IV or orally on days 1
`and dexamethasone 20 mg/d IV or orally on days 1
`to 5. Treatment was repeated at 4-week intervals for a
`to 5. Treatment was repeated at 4-week intervals for a
`to 5. Treatment was repeated at 4-week intervals for a
`maximum of eight courses. Late in the course of this trial,
`maximum of eight courses. Late in the course of this trial,
`maximum of eight courses. Late in the course of this trial,
`trimethoprim-sulfamethoxazole (TMP-SMX) was incor-
`trimethoprim-sulfamethoxazole (TMP-SMX) was incor-
`trimethoprim-sulfamethoxazole (TMP-SMX) was incor-
`porated for Pneumocystis carinii (PCP) prophylaxis.
`porated for Pneumocystis carinii (PCP) prophylaxis.
`porated for Pneumocystis carinii (PCP) prophylaxis.
`Results: Responses were complete (CR) in 24 patients
`Results: Responses were complete (CR) in 24 patients
`Results: Responses were complete (CR) in 24 patients
`(47%) and partial (PR) in 24 (47%). The median failure-
`(47%) and partial (PR) in 24 (47%). The median failure-
`(47%) and partial (PR) in 24 (47%). The median failure-
`free survival time was 21 months for CR patients and 9
`free survival time was 21 months for CR patients and 9
`free survival time was 21 months for CR patients and 9
`
`ALTHOUGH INDOLENT lymphomas are often tran-
`ALTHOUGH INDOLENT lymphomas are often tran-
`A LTHOUGH INDOLENT lymphomas are often tran-
`siently controlled by standard chemotherapeutic
`siently controlled by standard chemotherapeutic
`siently controlled by standard chemotherapeutic
`regimens, they are ultimately progressive, fatal diseases.'
`regimens, they are ultimately progressive, fatal diseases.'
`regimens, they are ultimately progressive, fatal diseases.'
`New therapeutic agents, including the purine analog flu-
`New therapeutic agents, including the purine analog flu-
`New therapeutic agents, including the purine analog flu-
`darabine phosphate and the anthracenedione mitoxan-
`darabine phosphate and the anthracenedione mitoxan-
`darabine phosphate and the anthracenedione mitoxan-
`trone, have shown promise in recurrent low-grade
`trone, have shown promise in recurrent low-grade
`trone, have shown promise
`in
`recurrent
`low-grade
`lymphoma (LGL) when used as single agents. Response
`lymphoma (LGL) when used as single agents. Response
`lymphoma (LGL) when used as single agents. Response
`rates of 52% to 64% have been reported for fludarabine
`rates of 52% to 64% have been reported for fludarabine
`rates of 52% to 64% have been reported for fludarabine
`and 27% to 67% for mitoxantrone in recurrent LGL; most
`and 27% to 67% for mitoxantrone in recurrent LGL; most
`and 27% to 67% for mitoxantrone in recurrent LGL; most
`of the reported responses were partial.'-7
`of the reported responses were partial.'-7
`of the reported responses were partial.-'
`We previously conducted a phase I trial of fludarabine,
`We previously conducted a phase I trial of fludarabine,
`We previously conducted a phase I trial of fludarabine,
`mitoxantrone, and dexamethasone (FND) for the treat-
`mitoxantrone, and dexamethasone (FND) for the treat-
`mitoxantrone, and dexamethasone (FND) for the treat-
`ment of recurrent LGL.8 While the primary objective of
`ment of recurrent LGL.8 While the primary objective of
`ment of recurrent LGL.' While the primary objective of
`that study was to define the maximum-tolerated dose of
`that study was to define the maximum-tolerated dose of
`that study was to define the maximum-tolerated dose of
`the combination, clinical responses were seen at every
`the combination, clinical responses were seen at every
`the combination, clinical responses were seen at every
`dose level tested. The overall response rate was 71%,
`dose level tested. The overall response rate was 71%,
`dose level tested. The overall response rate was 71%,
`with 43% of patients having a complete response (CR)
`with 43% of patients having a complete response (CR)
`with 43% of patients having a complete response (CR)
`and 29% having a PR. The median duration of response
`and 29% having a PR. The median duration of response
`and 29% having a PR. The median duration of response
`was 18 months for patients who achieved a CR and 12
`was 18 months for patients who achieved a CR and 12
`was 18 months for patients who achieved a CR and 12
`months for patients who achieved a PR.
`months for patients who achieved a PR.
`months for patients who achieved a PR.
`
`From the Department of Hematology, The University of Texas
`From the Department of Hematology, The Untversav of Texas
`From the Department of Hematology, The Untversav of Texas
`M.D. Anderson Cancer Center. Houston, TX.
`M.D. Anderson Cancer Center. Houston, TX.
`M.D. Anderson Cancer Center. Houston, TX.
`Submitted June 29, 1995: accepted October 27, 1995.
`Submitted June 29, 1995. accepted October 27, 1995.
`Submitted June 29, 1995. accepted October 27, 1995.
`Address reprint requests to Peter McLaughlin, MD. Department
`Address reprint requests to Peter McLaughlin, MD, Department
`Address reprint requests to Peter McLaughlin, MD, Department
`of Hematology, Box 68, The Universiry of Texas M.D. Anderson
`of Hematology, Box 68, The University of Texas M.D. Anderson
`of Hematology, Box 68, The University of Texas M.D. Anderson
`Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
`Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
`Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
`© 1996 by American Society of Clinical Oncology.
`© 1996 by American Society of Clinical Oncology.
`© 1996 by American Society of Clinical Oncology.
`0732-183X/96/1404-0028$3.00/0
`0732-183X/96/1404-0028$3.00/0
`0732-183X/96/1404-0028$3.00/0
`
`months for PR patients. Notable activity of FND was seen
`months for PR patients. Notable activity of FND was seen
`months for PR patients. Notable activity of FND was seen
`even in the elderly, in those with high serum lactate dehy-
`even in the elderly, in those with high serum lactate dehy-
`even in the elderly, in those with high serum lactate dehy-
`drogenase (LDH) or 1f2-microglobulin levels, and in those
`drogenase (LDH) or (32-microglobulin levels, and in those
`drogenase (LDH) or (32-microglobulin levels, and in those
`with multiple prior treatment regimens. The predominant
`with multiple prior treatment regimens. The predominant
`with multiple prior treatment regimens. The predominant
`toxic effects were myelosuppression and infections;
`toxic effects were myelosuppression and infections;
`toxic effects were myelosuppression and infections;
`other toxic effects were modest. Infections occurred in
`other toxic effects were modest. Infections occurred in
`other toxic effects were modest. Infections occurred in
`12% of courses. Almost half of the infections were proven
`12% of courses. Almost half of the infections were proven
`12% of courses. Almost half of the infections were proven
`or suspected opportunistic infections, including six cases
`or suspected opportunistic infections, including six cases
`or suspected opportunistic infections, including six cases
`of dermatomal herpes zoster and two cases of proven
`of dermatomal herpes zoster and two cases of proven
`of dermatomal herpes zoster and two cases of proven
`PCP pneumonia.
`PCP pneumonia.
`PCP pneumonia.
`Conclusion: The FND combination is highly active in
`Conclusion: The FND combination is highly active in
`Conclusion: The FND combination is highly active in
`patients with recurrent or relapsed indolent lymphoma
`patients with recurrent or relapsed indolent lymphoma
`patients with recurrent or relapsed indolent lymphoma
`and results in a high percentage of CRs. Because of the
`and results in a high percentage of CRs. Because of the
`and results in a high percentage of CRs. Because of the
`risk of opportunistic infections, we currently recommend
`risk of opportunistic infections, we currently recommend
`risk of opportunistic infections, we currently recommend
`prophylaxis with TMP-SMX and advise deletion of corti-
`prophylaxis with TMP-SMX and advise deletion of corti-
`prophylaxis with TMP-SMX and advise deletion of corti-
`costeroids for patients who develop opportunistic infec-
`costeroids for patients who develop opportunistic infec-
`costeroids for patients who develop opportunistic infec-
`tions.
`tions.
`tions.
`J Clin Oncol 14:1262-1268. © 1996 by American So-
`J Clin Oncol 14:1262-1268. © 1996 by American So-
`J Clin Oncol 14:1262-1268. © 1996 by American So-
`ciety of Clinical Oncology.
`ciety of Clinical Oncology.
`ciety of Clinical Oncology.
`
`Based on the encouraging results from the phase I trial,
`Based on the encouraging results from the phase I trial,
`Based on the encouraging results from the phase I trial,
`we conducted this phase II trial to define more clearly
`we conducted this phase II trial to define more clearly
`we conducted this phase II trial to define more clearly
`the therapeutic efficacy and toxicity of the FND combina-
`the therapeutic efficacy and toxicity of the FND combina-
`the therapeutic efficacy and toxicity of the FND combina-
`tion in patients with relapsed indolent lymphoma.
`tion in patients with relapsed indolent lymphoma.
`tion in patients with relapsed indolent lymphoma.
`
`PATIENTS AND METHODS
`PATIENTS AND METHODS
`PATIENTS AND METHODS
`
`Patients
`Patients
`Patients
`Between January 1992 and December 1993, 55 adult patients
`Between January 1992 and December 1993, 55 adult patients
`Between January 1992 and December 1993, 55 adult patients
`with recurrent or refractory LGL (small lymphocytic, follicular small
`with recurrent or refractory LGL (small lymphocyte, follicular small
`with recurrent or refractory LGL (small lymphocyte, follicular small
`cleaved, or follicular mixed) or follicular large-cell lymphoma were
`cleaved, or follicular mixed) or follicular large-cell lymphoma were
`cleaved, or follicular mixed) or follicular large-cell lymphoma were
`enrolled onto the study. Patients were excluded if they had positive
`enrolled onto the study. Patients were excluded if they had positive
`enrolled onto the study. Patients were excluded if they had positive
`serology for the human immunodeficiency virus. Patients with prior
`serology for the human immunodeficiency virus. Patients with prior
`serology for the human immunodeficiency virus. Patients with prior
`mitoxantrone or fludarabine exposure were excluded, unless the ex-
`mitoxantrone or fludarabine exposure were excluded, unless the ex-
`mitoxantrone or fludarabine exposure were excluded, unless the ex-
`posure was more than 12 months previously and they had been
`posure was more than 12 months previously and they had been
`posure was more than 12 months previously and they had been
`responsive. Eligibility requirements included adequate marrow func-
`responsive. Eligibility requirements included adequate marrow func-
`responsive. Eligibility requirements included adequate marrow func-
`tion (granulocyte count > 1,500/pL; and platelet count > 100,000/
`tion (granulocyte count > 1,500/µL; and platelet count > 100,000/
`tion (granulocyte count > 1,500/µL; and platelet count > 100,000/
`/L),
`liver function bilirubinn level : 2.0 mg/dL), renal function
`AL), liver function (bilirubin level (cid:9)
`2.0 mg/dL), renal function
`AL), liver function (bilirubin level (cid:9)
`2.0 mg/dL), renal function
`(creatinine concentration (cid:9)
`1.4 mg/dL), and cardiac function (ejec-
`(creatinine concentration
`t 1.4 mg/dL), and cardiac function (ejec-
`(creatinine concentration (cid:9)
`1.4 mg/dL), and cardiac function (ejec-
`tion fraction -,--_ 50%). Our institutional review board reviewed and
`tion fraction
`- 50%). Our institutional review board reviewed and
`tion fraction -,--_ 50%). Our institutional review board reviewed and
`approved the study, and signed informed consent was obtained from
`approved the study, and signed informed consent was obtained from
`approved the study, and signed informed consent was obtained from
`all participating patients.
`all participating patients.
`all participating patients.
`The pretreatment staging evaluation included a serum chemistry
`The pretreatment staging evaluation included a serum chemistry
`The pretreatment staging evaluation included a serum chemistry
`profile, including lactate dehydrogenase (LDH) level, bone marrow
`profile, including lactate dehydrogenase (LDH) level, bone marrow
`profile, including lactate dehydrogenase (LDH) level, bone marrow
`biopsy, chest x-ray, and imaging of the abdomen with either com-
`biopsy, chest x-ray, and imaging of the abdomen with either com-
`biopsy, chest x-ray, and imaging of the abdomen with either com-
`puted tomography, ultrasound, or lymphangiogram. Most patients
`puted tomography, ultrasound, or lymphangiogram. Most patients
`puted tomography, ultrasound, or lymphangiogram. Most patients
`also had determinations of serum /32-rincroglobulin level.
`also had determinations of serum 32-microglobulin level.
`also had determinations of serum /32-rincroglobulin level.
`
`Treatment Schedule
`Treatment Schedule
`Treatment Schedule
`Patients received fludarabine 25 ing/rn2/d intravenously (IV) on
`Patients received fludarabine 25 mg/m'l/d intravenously (IV) on
`Patients received fludarabine 25 ing/rn2/d intravenously (IV) on
`days I to 3, mitoxantrone 10 mg/m' IV on day 1, and dexamethasone
`days 1 to 3, mitoxantrone 10 mg/m2 IV on day I , and dexamethasone
`days 1 to 3, mitoxantrone 10 mg/m2 IV on day I , and dexamethasone
`20 mg/d IV or or orally days I to 5. Antiemetics, most commonly
`20 mg/d IV or or orally days 1 to 5. Antiemettes, most commonly
`20 mg/d IV or or orally days 1 to 5. Antiemettes, most commonly
`ondansetron, were routinely given before chemotherapy. Treatment
`ondansetron, were routinely given before chemotherapy. Treatment
`ondansetron, were routinely given before chemotherapy. Treatment
`
`1262
`1262
`1262
`
`Journal of Clinical Oncology, Vol 14, No 4 (April), 1996: pp 1262-1268
`Journal of Clinical Oncology, Vol 14, No 4 (April), 1996: pp 1262-1268
`Journal of Clinical Oncology, Vol 14, No 4 (April), 1996: pp 1262-1268
`
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2011 0001
`
`(cid:9)
`(cid:9)
`

`
`PHASE II STUDY OF FND IN INDOLENT LYMPHOMA
`PHASE II STUDY OF FND IN INDOLENT LYMPHOMA
`PHASE II STUDY OF FND IN INDOLENT LYMPHOMA
`
`was repeated at 4-week intervals for a maximum of eight courses.
`was repeated at 4-week intervals for a maximum of eight courses.
`was repeated at 4-week intervals for a maximum of eight courses.
`Patients with anticipated poor hematologic tolerance (poor prior che-
`Patients with anticipated poor hematologic tolerance (poor prior che-
`Patients with anticipated poor hematologic tolerance (poor prior che-
`motherapy tolerance, prior extensive radiotherapy, or age > 65
`motherapy tolerance, prior extensive radiotherapy, or age > 65
`motherapy tolerance, prior extensive radiotherapy, or age > 65
`years) started at 20% lower doses of fludarabine and mitoxantrone.
`years) started at 20% lower doses of fludarabine and mitoxantrone.
`years) started at 20% lower doses of fludarabine and mitoxantrone.
`If a course of FND was complicated by mucosal bleeding, platelet
`If a course of FND was complicated by mucosal bleeding, platelet
`If a course of FND was complicated by mucosal bleeding, platelet
`count less than 20,000/pt, sepsis, granulocyte count less than 100/
`count less than 20,000/gL, sepsis, granulocyte count less than 100/
`count less than 20,000/pt, sepsis, granulocyte count less than 100/
`pL, or delayed blood count recovery greater than 35 days, fludara-
`pL, or delayed blood count recovery greater than 35 days, fludara-
`pL, or delayed blood count recovery greater than 35 days, fludara-
`bine and mitoxantrone doses were reduced by 20% for subsequent
`bine and mitoxantrone doses were reduced by 20% for subsequent
`bine and mitoxantrone doses were reduced by 20% for subsequent
`courses. The use of granulocyte colony-stimulating factor (G-CSF)
`courses. The use of granulocyte colony-stimulating factor (G-CSF)
`courses. The use of granulocyte colony-stimulating factor (G-CSF)
`or granulocyte-macrophage colony-stimulating factor (GM-CSF)
`or granulocyte-macrophage colony-stimulating factor (GM-CSF)
`or granulocyte-macrophage colony-stimulating factor (GM-CSF)
`was not mandated by protocol, but was permitted.
`was not mandated by protocol, but was permitted.
`was not mandated by protocol, but was permitted.
`In September 1993, during the course of the trial, prophylaxis
`In September 1993, during the course of the trial, prophylaxis
`In September 1993, during the course of the trial, prophylaxis
`for Pneumocystis carinii pneumonia (PCP) was instituted, which
`for Pneumocystis carinii pneumonia (PCP) was instituted, which
`for Pneumocystis carinii pneumonia (PCP) was instituted, which
`consisted of trimethoprim-sulfamethoxazole (TMP-SMX), two dou-
`consisted of trimethoprim-sulfamethoxazole (TMP-SMX), two dou-
`consisted of trimethoprim-sulfamethoxazole (TMP-SMX), two dou-
`ble-strength tablets daily on Saturdays and Sundays. If PCP pneumo-
`ble-strength tablets daily on Saturdays and Sundays. If PCP pneumo-
`ble-strength tablets daily on Saturdays and Sundays. If PCP pneumo-
`nia occurred, subsequent FND cycles were given without dexametha-
`nia occurred, subsequent FND cycles were given without dexametha-
`nia occurred, subsequent FND cycles were given without dexametha-
`sone.
`sone.
`sone.
`Patient Monitoring During Therapy
`Patient Monitoring During Therapy
`Patient Monitoring During Therapy
`Monitoring of response included repetition of abnormal pretreat-
`Monitoring of response included repetition of abnormal pretreat-
`Monitoring of response included repetition of abnormal pretreat-
`ment examinations after the first two courses and after every subse-
`ment examinations after the first two courses and after every subse-
`ment examinations after the first two courses and after every subse-
`quent three or four courses. Monitoring of cardiac status was per-
`quent three or four courses. Monitoring of cardiac status was per-
`quent three or four courses. Monitoring of cardiac status was per-
`formed after every two to three courses with cardiac scan or
`formed after every two to three courses with cardiac scan or
`formed after every two to three courses with cardiac scan or
`echocardiogram. For patients who had received prior anthracyclines,
`echocardiogram. For patients who had received prior anthracyclines,
`echocardiogram. For patients who had received prior anthracyclines,
`a potential cumulative cardiotoxic dose was estimated by assuming
`a potential cumulative cardiotoxic dose was estimated by assuming
`a potential cumulative cardiotoxic dose was estimated by assuming
`that a full cardiotoxic dose of mitoxantrone was 160 mg/m2, and that
`that a full cardiotoxic dose of mitoxantrone was 160 mg/m2, and that
`that a full cardiotoxic dose of mitoxantrone was 160 mg/m2, and that
`of doxorubicin by bolus, 450 mg/m2. (For doxorubicin by continuous
`of doxorubicin by bolus, 450 mg/m2. (For doxorubicin by continuous
`of doxorubicin by bolus, 450 mg/m2. (For doxorubicin by continuous
`infusion, the thresholds used were 675 mg/m 2 for 48-hour infusion
`infusion, the thresholds used were 675 mg/m2 for 48-hour infusion
`infusion, the thresholds used were 675 mg/m2 for 48-hour infusion
`and 800 mg/m2 for 96-hour infusion). The following calculation was
`and 800 mg/m2 for 96-hour infusion). The following calculation was
`and 800 mg/m2 for 96-hour infusion). The following calculation was
`used: if the total doses of mitoxantrone and doxorubicin per square
`used: if the total doses of mitoxantrone and doxorubicin per square
`used: if the total doses of mitoxantrone and doxorubicin per square
`meter are "m" and "d" respectively, then m/160 + d/450 must be
`meter are "m" and "d" respectively, then m/160 + d/450 must be
`meter are "m" and "d" respectively, then m/160 + d/450 must be
`less than 1. If this potential cardiotoxic threshold was exceeded, or
`less than 1. If this potential cardiotoxic threshold was exceeded, or
`less than 1. If this potential cardiotoxic threshold was exceeded, or
`if cardiac symptoms occurred, discontinuation of mitoxantrone was
`if cardiac symptoms occurred, discontinuation of mitoxantrone was
`if cardiac symptoms occurred, discontinuation of mitoxantrone was
`advised.
`advised.
`advised.
`Response Criteria and Data Analysis
`Response Criteria and Data Analysis
`Response Criteria and Data Analysis
`CR was defined as the disappearance of all clinical evidence of
`CR was defined as the disappearance of all clinical evidence of
`CR was defined as the disappearance of all clinical evidence of
`active tumor for a minimum of 8 weeks and absence of other symp-
`active tumor for a minimum of 8 weeks and absence of other symp-
`active tumor for a minimum of 8 weeks and absence of other symp-
`toms. PR was defined as 50% decrease in the sum of the products
`toms. PR was defined as >- 50% decrease in the sum of the products
`toms. PR was defined as 50% decrease in the sum of the products
`of diameters of all measured lesions that persisted for at least 4
`of diameters of all measured lesions that persisted for at least 4
`of diameters of all measured lesions that persisted for at least 4
`weeks. No lesions could increase in size and no new lesions could
`weeks. No lesions could increase in size and no new lesions could
`weeks. No lesions could increase in size and no new lesions could
`appear. Any response less than a PR was considered a treatment
`appear. Any response less than a PR was considered a treatment
`appear. Any response less than a PR was considered a treatment
`failure for this analysis. Monitoring of follicular lymphoma patients
`failure for this analysis. Monitoring of follicular lymphoma patients
`failure for this analysis. Monitoring of follicular lymphoma patients
`for molecular remission, ie, for the presence of circulating cells with
`for molecular remission, ie, for the presence of circulating cells with
`for molecular remission, ie, for the presence of circulating cells with
`bcl-2 gene rearrangement by the polymerase chain reaction,9 was
`bc1-2 gene rearrangement by the polymerase chain reaction,' was
`bc1-2 gene rearrangement by the polymerase chain reaction,' was
`not performed in this trial. Survival and failure-free survival were
`not performed in this trial. Survival and failure-free survival were
`not performed in this trial. Survival and failure-free survival were
`measured from entry into the protocol until death or treatment failure
`measured from entry into the protocol until death or treatment failure
`measured from entry into the protocol until death or treatment failure
`(ie, relapse or toxic death), respectively.'0
`(ie, relapse or toxic death), respectively.'
`(ie, relapse or toxic death), respectively.'
`Data were tabulated to assess the utility of prognostic models that
`Data were tabulated to assess the utility of prognostic models that
`Data were tabulated to assess the utility of prognostic models that
`have been devised for previously untreated patients with aggressive
`have been devised for previously untreated patients with aggressive
`have been devised for previously untreated patients with aggressive
`lymphomas, including the international index" and a serologic
`index" and a serologic
`lymphomas, including the international index" and a serologic
`including the international
`lymphomas,
`model that incorporated serum LDH and 6/2-microglobulin level.' 2
`model that incorporated serum LDH and /32-microglobulin level.'2
`model that incorporated serum LDH and /32-microglobulin level.'2
`Both of these models appear to be applicable to patients with pre-
`Both of these models appear to be applicable to patients with pre-
`Both of these models appear to be applicable to patients with pre-
`viously untreated indolent lymphoma.13' 4 Likewise, information on
`viously untreated indolent lymphoma.'" Likewise, information on
`viously untreated indolent lymphoma.'" Likewise, information on
`prior therapy was correlated with response according to the analysis
`prior therapy was correlated with response according to the analysis
`prior therapy was correlated with response according to the analysis
`reported by Weisdorf et al."
`reported by Weisdorf et al."
`reported by Weisdorf et al.'s
`RESULTS
`RESULTS
`RESULTS
`
`Patients
`Patients
`Patients
`Of 55 patients enrolled, 51 could be evaluated for re-
`Of 55 patients enrolled, 51 could be evaluated for re-
`Of 55 patients enrolled, 51 could be evaluated for re-
`sponse. The four patients who could not be evaluated
`sponse. The four patients who could not be evaluated
`sponse. The four patients who could not be evaluated
`
`1263
`1263
`1263
`
`included three who refused any therapy after signing in-
`included three who refused any therapy after signing in-
`included three who refused any therapy after signing in-
`formed consent, and one who was ineligible by virtue of
`formed consent, and one who was ineligible by virtue of
`formed consent, and one who was ineligible by virtue of
`known refractoriness to mitoxantrone. The 51 patients in
`known refractoriness to mitoxantrone. The 51 patients in
`known refractoriness to mitoxantrone. The 51 patients in
`this report include five with mantle cell lymphoma, who,
`this report include five with mantle cell lymphoma, who,
`this report include five with mantle cell lymphoma, who,
`when entered, were categorized as having variants of
`when entered, were categorized as having variants of
`when entered, were categorized as having variants of
`small lymphocytic lymphoma (ie, disease considered to
`small lymphocytic lymphoma (ie, disease considered to
`small lymphocytic lymphoma (ie, disease considered to
`be low grade). Mantle cell lymphoma is often responsive
`be low grade). Mantle cell lymphoma is often responsive
`be low grade). Mantle cell lymphoma is often responsive
`to initial therapy, but, like indolent lymphomas, control
`to initial therapy, but, like indolent lymphomas, control
`to initial therapy, but, like indolent lymphomas, control
`is transient and there is no plateau of the failure-free
`is transient and there is no plateau of the failure-free
`is transient and there is no plateau of the failure-free
`survival curve. However, the median survival of patients
`survival curve. However, the median survival of patients
`survival curve. However, the median survival of patients
`with mantle cell lymphoma is shorter than with LGL, and
`with mantle cell lymphoma is shorter than with LGL, and
`with mantle cell lymphoma is shorter than with LGL, and
`many regard it as an intermediate-grade lymphoma.' 6
`many regard it as an intermediate-grade lymphoma.I6
`many regard it as an intermediate-grade lymphoma.I6
`Pertinent patient features are listed in Table 1. The
`Pertinent patient features are listed in Table 1. The
`Pertinent patient features are listed in Table 1. The
`median age was 62 years. For all patients but one, abdom-
`median age was 62 years. For all patients but one, abdom-
`median age was 62 years. For all patients but one, abdom-
`inal imaging included computed tomography; the re-
`inal imaging included computed tomography; the re-
`the re-
`inal imaging included computed tomography;
`maining patient had an ultrasound. Ten patients also had
`maining patient had an ultrasound. Ten patients also had
`maining patient had an ultrasound. Ten patients also had
`lymphangiography. Prior therapy included doxorubicin in
`lymphangiography. Prior therapy included doxorubicin in
`lymphangiography. Prior therapy included doxorubicin in
`all but four. Fourteen had received prior mitoxantrone (>
`all but four. Fourteen had received prior mitoxantrone (>
`all but four. Fourteen had received prior mitoxantrone (>
`12 months previously). None had received purine analogs.
`12 months previously). None had received purine analogs.
`12 months previously). None had received purine analogs.
`The median number of prior regimens was two. The prior
`The median number of prior regimens was two. The prior
`The median number of prior regimens was two. The prior
`therapy was often intensive: 10 of those listed as having
`therapy was often intensive: 10 of those listed as having
`therapy was often intensive: 10 of those listed as having
`received one or two prior regimens had received front-
`received one or two prior regimens had received front-
`received one or two prior regimens had received front-
`line therapy with an alternating program of three chemo-
`line therapy with an alternating program of three chemo-
`line therapy with an alternating program of three chemo-
`therapy combinations using 11 drugs.'
`therapy combinations using 11 drugs.'
`therapy combinations using 11 drugs."
`
`Response
`Response
`Response
`There were 24 CRs and 24 PRs, for an overall response
`There were 24 CRs and 24 PRs, for an overall response
`There were 24 CRs and 24 PRs, for an overall response
`rate of 94%. The median time to attainment of CR was
`rate of 94%. The median time to attainment of CR was
`rate of 94%. The median time to attainment of CR was
`after five courses (range, one to eight); all CR patients
`after five courses (range, one to eight); all CR patients
`after five courses (range, one to eight); all CR patients
`had achieved at least a PR after four courses (median,
`had achieved at least a PR after four courses (median,
`had achieved at least a PR after four courses (median,
`two). For those whose maximum response was a PR, the
`two). For those whose maximum response was a PR, the
`two). For those whose maximum response was a PR, the
`median time to PR was two courses (range, one to six).
`median time to PR was two courses (range, one to six).
`median time to PR was two courses (range, one to six).
`The median duration of CR was 21 months (range, 4 to
`The median duration of CR was 21 months (range, 4 to
`The median duration of CR was 21 months (range, 4 to
`25 +)