A Phase I Trial: Dose Escalation of Melphalan in the “BEAM” Regimen Using Amifostine Cytoprotection

A Phase I Trial: Dose Escalation of Melphalan in the ‘‘BEAM’’ Regimen Using Amifostine Cytoprotection Gordon L. Phillips, II,1 Steven H. Bernstein,1 Jane L. Liesveld,1 Camille N. Abboud,1,3 Michael W. Becker,1 Louis S. Constine,2 J. J. Ifthikharuddin,1 John E. Loughner,4 Laurie A. Milner,1 David H. Vesole,5 Jonathan W. Friedberg1 With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m2, a substantial increase from the usual dose of 140 mg/m2 in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned. Biol Blood Marrow Transplant 17: 1033-1042 (2011) Ó 2011 American Society for Blood and Marrow Transplantation

KEY WORDS: Phase I, Melphalan, Amifostine, Autologous stem cell, Regimen-related toxicity

INTRODUCTION The utility of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) for patients with selected, usually relapsed or refractory lymphoma (both certain ‘‘aggressive’’ non-Hodgkin [NHL] and Hodgkin [HL]) was formally established by randomized clinical trials over a decade ago [1,2]; such is now a standard of care [3,4]. (The precise role of this modality in other NHL patients is less well defined [5].) In any case, the curability of this approach is limited by a high post-AHSCT relapse From the 1Hematology Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, Strong Memorial Hospital, Rochester, New York; 2Hematology Oncology, University of Rochester Medical Center, Department of Radiation Oncology, James P. Wilmot Cancer Center, Strong Memorial Hospital, Rochester, New York; 3Division of Oncology, Washington University School of Medicine, St. Louis, Missouri; 4 Hematology Oncology, University of Rochester Medical Center, Pharmacy Department, James P. Wilmot Cancer Center, Strong Memorial Hospital, Rochester, New York; and 5John Theurer Cancer Center at HUMC, Hackensack, New Jersey. Financial disclosure: See Acknowledgments on page 1041. Correspondence and reprint requests: Gordon L. Phillips, II, MD, Hematology Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, Strong Memorial Hospital, 601 Elmwood Avenue, Box 704, Rochester, NY 14642 (e-mail: [email protected]). Received July 14, 2010; accepted November 2, 2010 Ó 2011 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2010.11.003

rate, even in patients with ‘‘chemosensitivity’’ (ie, greater than or equal to partial remission) to salvage regimens; indeed, the relapse rate is so high in those deemed ‘‘chemorefractory’’ that HDT/AHSCT is usually not recommended [3,4]. Although there are a number of potential approaches to this problem, improving the antitumor activity of the conditioning regimen is obvious and has been the focus of a number of clinical trials. No strategy has been proven to the extent that it is standard therapy [6]. Moreover, it is likely that improvements in the primary treatment regimens [7,8] will leave smaller, more refractory residua of relapsed lymphoma patients. Such is suggested by results from the CORAL study; prior exposure to rituximab had a pronounced negative effect on post-AHSCT event-free survival (EFS) in diffuse large B-cell lymphoma (DLBCL) patients [9]. Although this postulate is somewhat controversial [10], substantial improvements to existing regimens are required to improve upon—or arguably even maintain—current results. That said, the optimal method of improving current regimens is not known. The use of total-body irradiation (TBI) does not seem helpful [11], and most centers use chemotherapy-based regimens preferentially [12]. Although the use of alternative chemotherapy regimens [13], dose escalation of intrinsic agents [14], and/or the addition of ‘‘newer’’ agents such as radioimmunopharmaceuticals [15] have been tried, each approach is potentially limited by increased toxicity, notably regimen-related toxicity (RRT) [16,17]. 1033

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Thus, care must be undertaken with such measures to minimize additional, especially fatal RRT that would abrogate the gains of a reduced relapse rate. Even lesser degrees of increased RRT may be unacceptable if they substantially diminish quality of life and/or increase costs. Dose augmentation of existing agents beyond that utilized in current HDC regimens is complicated; although this strategy has sound theoretic grounds [18], supportive clinical data are inconclusive [6], possibly because of the relatively minor degree by which drug doses can be increased due to increasing RRT [14]. The cytoprotective agent amifostine [19] may offer an approach to this dilemma [20]; in a prior Phase I trial [21], the use of amifostine permitted the safe escalation of single-agent melphalan to at least 280 mg/m2, a substantial dose increment from the standard melphalan dose (without amifostine) of 200 mg/m2 in this setting [22]. Additional analysis of the data indicated significant antilymphoma activity [23]. Given these encouraging results, and in light of the intrinsic limitations of single-agent therapy, we sought to incorporate this experience into combination chemotherapy. Our strategy was to modify and hopefully optimize—a minor (and simpler) variant [24] of the original [25] carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen by dose escalation of the key cytotoxic drug melphalan, using the cytoprotectant amifostine, in a Phase I trial. The BEAM regimen [24,25] was chosen for a number of reasons, including its wide utilization [12], its welldefined and ‘‘acceptable’’ rate of RRT (mostly mucosal barrier injury [MBI]) [24-26]), as well as our prior experience with single-agent melphalan and amifostine in the AHSCT setting [21,23]. A preliminary report of this study has been published [27]; reported herein are comprehensive results. MATERIALS AND METHODS Study Design When possible, recommendations involving dose escalation studies in the situation of high-dose chemotherapy [28] and those involving cytoprotectants [29] were followed. A standard schema of dose escalation was used, mirroring our prior Phase I study [21]. Beginning at the usual melphalan dose in BEAM (ie, 140 mg/m2) and escalating in fixed, 20 mg/m2 increments, cohorts of 4 patients were treated. (In this report, each dose level will be indicated by a Roman numeral with the melphalan dose in mg/m2 following; ie, dose level VII 5 260.) Dose escalation was allowed when none of the 4 (or no more than 1 of 8) patients manifested severe RRT, defined as equal to or greater than grade III [16].

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After completion of each cohort, entry was halted for formal Data Safety Monitoring Board (DSMB) and Research Subjects Review Board (RSRB) review until all patients in the cohort passed day (D) 1100. This produced inevitable delays in patient entry; during the study, a total of 140 otherwise potentially eligible lymphoma patients (including 99 who received standard BEAM without amifostine) were transplanted as a standard of care. Because an evaluation of RRT was the key parameter measured in this study, patients who died before D 128 of causes other than RRT, and without developing gradable RRT, were deemed not evaluable for assessment and replaced on a per-patient basis. All such patients were independently and fully evaluated by the DSMB and the RSRB before replacement with other patients. Informed Consent Fully documented informed consent was obtained on all patients according to institutional guidelines, as formulated by the RSRB. RRT Scale The Seattle RRT scale [16] was used for a variety of reasons, including its simplicity, clinical impact as previously demonstrated in lymphoma patients [17], utilization in our prior studies [21,23], and comparability to other scales [30]. RRT was graded weekly with a ‘‘final’’ determination at day (D) 128 for most organ systems and D 1100 for pulmonary toxicity. (A minor issue with this scale involves grading stomatitis as I versus II, a distinction made on the basis of whether opioids are given by continuous intravenous infusion. Because an often-utilized alternative to continuous infusional opioid involves the use of patient-controlled analgesia (PCA), which may or may not involve basal (ie, continuous) infusion, a distinction between these grades could be made on this basis. However, we believe the use of a PCA is indicated with ‘‘more’’ rather then ‘‘less’’ stomatitis pain, and have scored stomatitis as grade II if a PCA was used, irrespective of the use of a basal infusion.) Organ dysfunction was considered RRT unless another obvious etiology was found. Other Definitions Patients who died following progression or relapse were coded as death because of lymphoma. (Gradable RRT after early lymphomatous progression was reportable in theory, but did not occur.) Death from any other cause was considered nonrelapse mortality (NRM). Progression-free (PFS) and overall survival (OS) were calculated from D 10, the day of AHSCT.

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Table 1. Administration Schedule Day

Time*

Agent

28 27 27 27 27 26 to 22 26 25 to 22 21 21 21 21 0

Bedtime 0800-1000 0900 1000-1005 Bedtime 0800 1020-1220 1020-1220 0900-1000 1000 1000-1005 1020-1035 1130 (or later)

Dexamethasone 20 mg p.o. 500-1000 mL NS + 2 g Ca gluconate Antiemetic regimen Amifostine dose #1 5 740 mg/m2 i.v. Dexamethasone 20 mg p.o. Repeat above daily, days –6 through –2 BCNU (carmustine), 300 mg/m2 i.v., 1 dose only Etoposide 200 mg/m2 i.v. + cytarabine, 400 mg/m2, each i.v., 1 dose daily 500-1000 mL NS + 2 g Ca gluconate Antiemetic regimen Amifostine dose #7 5 740 mg/m2 i.v. Melphalan IV (140-260 mg/m2) AHSCT

AHSCT indicates autologous hematopoietic stem cell transplantation; p.o., orally; i.v. intravenously. *Times could be modified as long as sequences were identical.

Responses were judged by International Working Group (IWG) criteria [31]. D 1100 restaging was used to assess disease response. Subsequent restaging was performed as indicated by clinical events and/or on D 1365 and yearly thereafter.

amifostine by 5-minute intravenous (i.v.) push, exactly 15 minutes before the chemotherapy dose was given. Dexamethasone, antiemetics, and intravenous fluids with calcium salts were given as previously reported [21,23] and as indicated in Table 1. Neither cryoprotection [34] nor palifermin was allowed.

Eligibility Criteria

Additional Therapy

(1) Age 18-70 years; (2) confirmation of diagnosis of lymphoma, either NHL or HL of any histologic subtype [32]; (3) a history of prior standard conventional primary and/or secondary (etc.) chemotherapy and/or local radiotherapy; (4) although ‘‘chemosensitivity’’ was preferred, any disease status was allowed, except that central nervous system (CNS) involvement, if present previously, was required to be in complete remission (CR); (5) ECOG PS #3; (6) collection of $2.0  106 CD341 cells/kg; (7) acceptable criticalorgan function, including left ventricular ejection fraction of $50%, creatinine clearance $50 mL/min, diffusing capacity for carbon monoxide $40%, and liver function tests less than or equal to twice the upper limits of normal; (8) absence of severe, ongoing infection; (9) absence of another active malignancy; (10) no evidence of pregnancy or human immunodeficiency virus infection; (11) RSRB-approved informed consent.

Although not formally a part of this Phase I study, post-AHSCT involved-field radiotherapy (IF-RT) and/or allogeneic HSCT was utilized in selected patients. Post-relapse therapy was individualized.

Responses

Stem Cell Mobilization All patients underwent routine, successful autologous stem cell mobilization. Regimen Administration Manufacturer’s recommendations for the preparation and administration of amifostine were followed [33]. All drug doses were determined using the lesser of actual or corrected ideal body weight (corrected 5 ideal 1 25% of [actual-ideal]). Amifostine was given daily before the first dose of chemotherapy that day; particular attention was paid to the administration of

Supportive Care Supportive care was given as per routine. Filgrastim was started on D 15 at a dose of 5 mg/kg/day until sustained absolute neutrophil count (ANC) recovery of $0.5  109/L. Table 2. Patient Characteristics No. evaluable Age, median (range) Diagnoses Non-Hodgkin DLBCL (transformed) MCL Other Hodgkin Disease status Chemosensitive Other No of prior regimens, median (range) Prior local radiotherapy Duration, diagnosis to AHSCT median (range) Dose level I 5 140 II 5 160 III 5 180 IV 5 200 V 5 220 VI 5 240 VII 5 260 CD34+ dose, 106/kg median (range)

28 54 (21-69)

13 (6) 3 3 9 23 5 2 (1-4) 13 641 4 4 4 4 4 4 4 5.87 (2.39-13.81)

AHSCT indicates autologous hematopoietic stem cell transplantation; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.

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RESULTS Patient Characteristics As indicated in Table 2, the median age of the 28 evaluable patients was 54 (range: 21-69) years. Diagnoses included DLBCL in 13 (transformed from other histologies in 6), Hodgkin lymphoma in 9, mantle cell lymphoma (MCL) in 3, and other NHL histologies (ie, chronic lymphocytic leukemia/small cell lymphocytic lymphoma (SLL), peripheral T cell lymphoma, and marginal-zone lymphoma) in 3 other patients. All patients had been previously treated with primary and subsequent, salvage chemotherapies after progression or relapse (median number of regimens 2, range: 1-4). All patients with B cell NHL had previously received rituximab, usually in multiple cycles (median 2, range: 1-4). Salvage therapy produced a state of ‘‘chemosensitivity’’ in 23, whereas 5 had lesser degrees of response.

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during the regimen and withdrew consent on D 25. Because he was being treated at the usual melphalan dose in BEAM of 140 mg/m2, the remainder of the regimen was given without amifostine; he had an uncomplicated recovery but eventually died because of progression at D 1792. (2) PSN 05-03 (I 5 140) developed ‘‘sepsis syndrome’’ on D 110 and subsequently, multiorgan dysfunction syndrome; death because of this complication occurred on D 121. (3) PSN 1205 (III 5 180) had no early RRT and was discharged home on D 114; he was found unconscious at home on D 116 and died on D 118. (This case is discussed in more detail below under ‘‘Cardiotoxicity.’’) (4) PSN 24-07 (VI 5 240) withdrew consent before receiving the first dose of amifostine and was subsequently given ‘‘standard’’ BEAM (ie, melphalan 140 mg/m2) without amifostine; he is alive and well at D 1492. In each case, the DSMB and RSRB independently deemed the removals and/or death to be because of non-RRT causes, and another patient was entered at that level.

Patients Entered and Those Evaluable Between the inclusive dates of 30 July 2003 and 25 November 2009, a total of 32 patients were screened, entered, and treated, after informed consent was obtained, at the dedicated facilities of Strong Memorial Hospital, Wilmot Cancer Center, University of Rochester Medical Center. Four of these patients were later deemed not evaluable, as detailed below. All surviving patients have a minimum follow-up of more than 1 year.

Acute Amifostine Infusion Toxicity Although a number of patients had transient symptoms of mild severity (eg, sneezing, flushing, nausea, emesis, etc.) during the amifostine infusions, none required cessation of the infusion. Postchemotherapy hypocalcemia was frequent despite routine replacement, but no patient developed clinical signs of hypocalcemia. Stem Cell Mobilization Results

Overall Outcomes As of September 1, 2010, 9 evaluable patients were alive without progression or relapse at median D 11551, range D 1466 to D 12065. One of these patients, PSN 07-05, received Level II 5 160 while in a salvage chemotherapy-resistant relapse; he achieved CR and subsequently underwent consolidative radiation and later, reduced-intensity conditioning and allogeneic stem cell transplant; 4 other patients had post-AHSCT consolidative radiation alone. Five patients are alive following post-AHSCT relapse, including 2 whose lymphoma recurred following subsequent allogeneic transplants, and another who is scheduled to undergo an allograft in the near future. Twelve other patients died after recurrence, including 2 who underwent subsequent allotransplants. Two patients died of ‘‘late’’ NRM as discussed below. Patients Not Evaluable Of the 4 patients deemed not evaluable, 2 patients were entered at dose level I 5 140, 1 at III 5 180, and another at VI 5 240. Currently, 1 is alive and well at D 1492, 1 died at D 1 792 of progression, and 2 others died of NRM. Details of these cases are as follows: (1) PSN 03-03 (I 5 140) developed nausea and emesis

In 16 cases, mobilization was performed using filgrastim after the final course of salvage chemotherapy (in 1 case, plerixafor was included). In 11 cases, a combination of cyclophosphamide 2.0-3.0 g/m2 and filgrastim was used, and 1 case was mobilized with filgrastim and plerixafor without chemotherapy. The median CD341 dose infused was 5.87 (range: 2.3913.81)  106/kg. Hematologic Toxicity and Recovery All patients developed profound pancytopenia; as indicated in Table 3, all also had prompt and sustained hematologic recovery. There was no effect of Table 3. Hematologic Recovery Melphalan Dose Levels

ANC,* D+

Platelets,† D+

Level I 5 140 Level II 5 160 Level III 5 180 Level IV 5 200 Level V 5 220 Level VI 5 260 Level VII 5 260 Totals

10.5 (5-11) 11 (9-12) 11 (9-11) 12 (5-18) 11 (10-12) 11 (10-12) 11 (10-12) 10 (5-18)

14.5 (9-24) 12 (11-13) 11 (9-13) 13 (12-21) 14 (11-31) 14.5 (11-15) 14.5 (11-15) 13 (9-31)

*Greater than or equal to 0.5  109/L, the first of 3 consecutive days. †Greater than or equal to 20  109/L, the first of 7 consecutive days.

Dose Escalated Melphalan in BEAM Regimen

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increasing melphalan dose on blood count recovery. For the entire group, recovery of a sustained ANC $0.5  109/mL occurred on median D 110 (range: 15 to 118), and a sustained platelet recovery $20  109/mL on median D 113 (range: 19 to 131). (All not-evaluable patients had prompt hematologic recoveries as well.) Interestingly, 4 patients had ANC recovery at either D 15 or 16; corresponding CD341 cell doses were 5.94, 3.20, 3.38, and 6.65  106/kg, respectively. Also, only 4 patients had platelet recoveries later than D 115 and none later than D 131. No cases of treatment-related myelodysplastic syndrome (MDS) or acute myeloid leukemia have been observed. Nonhematologic Toxicity (ie, RRT) As indicated in Table 4, gradable RRT was relatively mild. Furthermore, no patient developed otherwise gradable RRT between D 128 and D 1100. Mucosal barrier injury All patients save 1 had some evidence of MBI. Notably, however, no patient had either manifestation of MBI (‘‘oral stomatitis (OS)’’ or ‘‘gastrointestinal (GI) toxicity’’) graded in this schema that reached grade III (ie,‘‘need for preventive intubation, aspiration pneumonia, noninfective ileus, or hemorrhagic enterocolitis’’) [16], even at level VII 5 260. Stomatitis and gastrointestinal toxicity occurred together in 16 cases. No patient required total parenteral nutrition. There was no obvious worsening MBI with the higher melphalan dose levels. Cardiotoxicity Three patients had gradable cardiotoxicity in the form of atrial fibrillation. Two patients (1 at IV 5 200, and 1 at VII 5 260), neither with a history of cardiac disease, and both with normal cardiac screening studies, developed grade II cardiotoxicity (ie, atrial fibrillation) on D 17 and 18, respectively. Another patient (V 5 220) with a history of atrial fibrillation (but

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who was in sinus rhythm at the beginning of therapy) developed recurrent atrial fibrillation on D 18. In all cases, control was achieved easily with medical therapy alone; atrial fibrillation was not persistent or recurrent. Two other cases bear amplification regarding possible cardiotoxicity—even if not so graded. PSN 12-05 (III 5 180), a 65-year-old man with a history of severe (yet compensated and stable) coronary artery disease and ventricular tachyarrhythmias, previously had undergone nodal ablation and pacemaker placement. Shortly after AHSCT, he developed unstable angina (without arrhythmias) that was treated medically; he recovered and was discharged on D 114. He was found unconscious at home, in asystole, on D 116. He was successfully resuscitated but felt to have irreversible anoxic brain damage and was removed from life support on D 118. Permission for an autopsy was refused. Following a DSMB and RSRB review, his death was deemed to be because of coronary artery disease and not RRT. A second patient (PSN 16-06), a 32-year-old female with no history of cardiac disease (but multiple intrinsic risk factors for cardiovascular disease, including obesity, hypertension, and dyslipidemia) died of an apparent myocardial infarction while in remission and otherwise well on D 1299. Previous therapy for Hodgkin lymphoma had included anthracycline chemotherapy and 2 courses of thoracic radiation. Pulmonary toxicity Gradable pulmonary toxicity was minimal; 2 patients (1 at III 5 180 and 1 at VII 5 260) developed grade I RRT. Both patients developed early, unexplained mild hypoxia with nonspecific clinical and radiologic findings that resolved with routine supportive measures that did not include corticosteroids. Although 1 had an increasing pleural effusion, probably tumor related, in neither case could pulmonary RRT be excluded. Notably, 1 other patient (PSN 27-08) treated at VI 5 240 developed bronchiolitis obliterans, which

Table 4. Regimen-Related Toxicity (RRT)* Dose Level

No. Pts/Eval

None

MBI* (OS)

MBI* (GI)

Cardiac

Pulmonary

Hepatic

Renal

I (3) II (1) I (4) I (1) II (2) I (2) II (2) I (1) II (2) II (3) I (1) II (2)

I (2) I (3) — — I (1) I (3) —

—

—

—

—

I (1)

I (1) —

— —

—

—

—

—

— —

I (1) —

I 5 140

6/4

—

II 5 160 III 5 180

4/4 5/4

— 1

IV 5 200

4/4

—

V 5 220

4/4

—

VI 5 240 VII 5 260

5/4 4/4

— —

I (4) I (4) I (2) —

MBI indicates mucosal barrier injury; OS, oral stomatitis; GI, gastrointestinal toxicity. *No. of patients in parentheses; note some patients had >1 RRT.

—

II (1)

II (1) II (1)

I (1)

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was not graded because of the time of onset (ie, D 1265). She survived until D 1834 free of lymphoma, but was severely debilitated because of this complication from its onset until her death. Hepatic toxicity One patient (PSN 10-04) treated at II 5 160 developed transient and mild (grade I) elevation of liver function abnormalities on D 17 that resolved spontaneously on D 110. Although we could not exclude that this finding was because of the conditioning regimen, it is of note that this patient had mild, unexplained, fluctuating liver function studies before AHSCT. Renal toxicity One patient (PSN 25-08) treated at VI 5 240 developed transient elevation of serum creatinine (grade I) that resolved with conservative management. We could not exclude a contribution by the regimen. Other toxicities No other RRT, graded (ie, bladder or CNS) or nongraded (ie, cutaneous, endocrine, muscle, etc.) by this scale, were noted.

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Table 5. Response and Outcome Summary Entry Disease Response Alive Without Progression/ Stat (d +100) No. Pts. Relapse Relapse NRM PIF (S)/SR PIF (R)/RR PIF (S)/SR PIF (R)/RR Total

CR CR
14 1 9 4 28

8 1* — — 9

2 — — — 2

CR indicates complete remission; NRM, nonrelapse mortality; CR, complete remission; PIF (R or S), primary induction failure (resistant or sensitive); RR, resistant relapse; SR, sensitive relapse. *This patient subsequently received an allogeneic HSCT as consolidation on D+ 162.

these data. Overall, CRs occurred in 15/28 (54%), including 14/23 (61%) of those judged ‘‘chemosensitive’’; responses were noted at all dose levels. The CR rate in patients deemed ‘‘chemorefractory’’ was low: 1/5 (20%). PFS and OS Because only 4 patients were accrued at each dose level, study patients at all dose levels were combined for these analyses. As indicated in Figure 1A and 1B, median PFS and OS were 423 (range: 55 to .2065)

Late (ie, .D 1100) toxicities The cases of bronchiolitis obliterans and (late) myocardial infarction are noted above. No other late toxicities or second malignancies have been observed. Length of hospital stay Admittedly an indirect parameter of overall toxicity, the median duration of primary hospitalization (ie, for AHSCT) was 20 days (range: 11-37). This duration was similar to that observed in the 99 other lymphoma patients given ‘‘standard’’ BEAM before AHSCT during this period (ie, median 19 days, range: 16-64). Four study patients were readmitted within 6 weeks after discharge, although none for RRT; 1 had a central line–associated blood stream infection, 1 had deep venous thrombosis because of a central venous catheter, and 2 had complications related to early disease progression. Disease responses Although determination of degree of response and other, long-term outcome parameters were not primary goals in this Phase I study, such were of obvious interest. Unfortunately, interpretation of these parameters is complicated by heterogeneity of various disease-related and treatment-related factors (eg, the variable melphalan doses), as well as the use of posttransplant ‘‘consolidation’’ modalities such as involved-field radiotherapy and/or (in 1 case) an allogeneic transplant. In any case, Table 5 summarizes

4 — 9 4 17

Figure 1. Study group. (A) PFS. (B) OS.

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meaningful comparison would require a detailed analysis well beyond the scope of this Phase I study.

DISCUSSION

Figure 2. ‘‘Control’’ group. (A) PFS. (B) OS.

and 1852 (range: 74 to .2174) days, respectively. Overall probabilities of PFS and OS at 1, 3, and 5 years were 0.54, 0.35, and 0.30 and 0.71, 0.53 and 0.53, respectively. As discussed above, it is difficult to identify a suitable control group with which to compare these data regarding response in the context of a Phase I trial. However, and as noted above, the substantial delays in patient entry encountered while awaiting day 1100 evaluations for the last patient in each cohort led to the contemporaneous treatment of 99 patients with ‘‘standard BEAM’’ (ie, 140 mg/m2 melphalan and no amifostine) and AHSCT. Therefore, in the interest of assessing the relative efficacy of the study regimen, we evaluated OS and disease-related deaths for this contemporary cohort of ‘‘control’’ patients, notably ‘‘matched’’ by no other criteria. As shown in Figure 2A and 2B, the median PFS and OS for standard BEAM patients were both 2033 (range: 37 to .2443). Also, the probabilities for DFS at 1, 3, and 5 years were 0.67, 0.51, and 0.51; values for OS at these intervals were 0.80, 0.67, and 0.54. Thus, and within the constraints inevitable with the comparison noted above, study patients appeared to fare about as well as the ‘‘control’’ patients. A more

In this study, the use of amifostine allowed safe dose escalation of melphalan in the BEAM regimen to at least 260 mg/m2, roughly an 85% increase of the usual dose of 140 mg/m2. No dose-limiting toxicity or maximal tolerated dose was found. Again, it is important to emphasize the difference between this study and most prior studies using amifostine in the highdose chemotherapy and AHSCT setting. Although it is beyond the scope of this discussion to review these studies in detail, most utilized amifostine with ‘‘conventional’’ high-dose regimens [35-42], whereas this study involved dose escalation beyond the doses used in these regimens of the putative key cytotoxic element of BEAM—high-dose melphalan. At the time this study was undergoing development, we were unsure regarding the need for amifostine doses before the nonmelphalan drugs. In consideration of this uncertainty, as well as what was felt to be a favorable risk:benefit ratio, we decided to administer amifostine before each agent. Subsequent data suggest such a strategy to not be of benefit for BCNU [41], and arguably it may not be for etoposide and cytarabine either. Although we are now dubious that amifostine is required for these agents, our results reflect usage in this manner. The postulate of significant cytoprotection of melphalan-related RRT is based on the absence of severe gradable RRT at all dose levels studied. More conclusive evidence is lacking; however, in our opinion, it is not ethical to perform a trial of augmented melphalan without cytoprotection. Moreover, although we feel that cytoprotection was essential to this result, reduction of RRT (especially MBI) in this setting is not unique to amifostine, as other investigators have found that other agents such as palifermin can protect from both oral [43] and (perhaps less convincingly) more distal gastroenterologic toxicity [44] resulting from ‘‘standard’’ high-dose TBI-containing regimens. Also, other colleagues have reported the utility of ‘‘ice chip’’ cryotherapy [34] to reduce MBI with high-dose melphalan at a dose of 200 mg/m2. Whether such would be effective in patients given augmented, high-dose chemotherapy regimens such as ours is untested. Given that MBI is the chief RRT of BEAM and AHSCT [25,26], prevention of severe MBI was critical to the success of our study. Although an increased frequency and severity of MBI was possible, our prior experience with high-dose melphalan as a single agent with amifostine was reassuring, and indeed, we did not observe severe (ie, equal to or greater than grade III) MBI in the current trial. Although admittedly best

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viewed as an indirect comparison, the incidence and severity of MBI observed in the current study, as well as the use of various supportive care modalities used to treat MBI, compare favorably with the ‘‘standard’’ BEAM dose of melphalan (ie, 140 mg/m2) without amifostine [24-26]. We also hoped that the amifostine would also protect against RRT other than MBI; because such did not regularly occur, this postulate remains difficult to assess. In particular, we anticipated protection from pneumonitis, a potentially severe complication of BEAM [24,25]. Although the date of occurrence (D 1265) was well beyond the evaluation period of D 1100 (and thus it was not formally included as a RRT by the scale used [16]), the finding of bronchiolitis obliterans in a single patient was very concerning. This ominous complication is variably observed in the allogeneic setting, especially in the presence of chronic graft-versus-host disease (GvHD) [45], but is distinctly unusual in the AHSCT setting [46]. Accordingly, we cannot exclude the possibility that this complication was because of toxicity of the study regimen; both melphalan and BCNU produce lung toxicity, albeit of different types [47], and both pneumonitis and pulmonary fibrosis have been reported with BEAM [24,25]. Admittedly less likely, one could speculate that bronchiolitis obliterans in this case was a manifestation of autologous GvHD [48], although the patient had no other clinical manifestations of this process, and to our knowledge such has never been reported. In any case, 5 other patients treated at doses of 240-260 mg/m2 and followed for longer intervals have not developed bronchiolitis obliterans (or other noninfectious pulmonary findings)—admittedly an inadequate basis to provide assurance this was only a chance occurrence. We will, of course, continue to evaluate the pulmonary function studies and clinical status of our surviving patients. Based on our prior Phase I experience using amifostine with high-dose melphalan as a single agent [21], we anticipated possible cardiotoxicity in the form of atrial dysrhythmias, which is a known, if relatively infrequent, complication of high-dose melphalan therapy (ie, 200 mg/m2) in standard AHSCT regimens [49]. We observed 2 clear (ie, de novo) cases of atrial fibrillation in the current study; this complication produced minimal symptomatology, and both were converted (and controlled) with medical management alone. Unexpectedly, 2 patients experienced apparent myocardial infarctions on D 116 and D 1299. Although neither was deemed to be RRT, such is impossible to exclude; we cannot find a report in the literature of severe cardiotoxicity due to high-dose melphalan [50]; these reports obviously did not use our regimen. In any case, our findings emphasize the need for complete cardiac evaluation pretransplant,

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and close posttransplant assessment as well, especially in patients with a history of cardiac disease and/or recognized risk factors. More provocatively, one could consider excluding patients with a history of severe cardiac disease on future trials involving augmented high-dose melphalan therapy. Interestingly, it is also possible that amifostine protected and/or stimulated normal hematopoietic precursors to hasten count recovery in some patients. The finding of rapid count recovery, notably the D 15 or 16 ANC recovery seen in 4/28 patients, contrasts with such rapid ANC recovery being observed in only 4/325 other AHSCT patients similarly treated during the same time frame (data not shown). Such an effect should not be completely unexpected, as both preclinical and clinical [51] data suggest this possibility—a finding that could conceivably be exploited clinically. Also, and although amifostine has modest favorable effects in MDS therapy [52], its role in preventing therapy-related MDS is speculative. As noted previously, it is difficult to compare our response data to other studies, due not only to the inevitable patient and disease-related heterogeneity but also to treatment heterogeneity (especially variable doses of melphalan; only 4 patients were treated at each dose). That said, comparison of response data is of obvious interest, as Phase I trials such as this are unlike ‘‘first in man’’ Phase I studies; substantial responses are anticipated with the former. In brief, our comparison between mephalan-augmented BEAM and standard BEAM patients indicates no major differences in outcomes. As before, a more detailed comparison would involve a more complicated analysis or, ideally, a randomized controlled trial. It is also important to note that 2 elements of this study may, at least possibly, produce opposite effects— namely, tumor cytoprotection because of amifostine, and increased cytoreduction with the augmented doses of melphalan. Although neither could be addressed definitively in our trial, a critical question in all cytoprotection studies is whether the cytoprotective agent might compromise the antineoplastic effect of the regimen. Although the bulk of existing evidence, both preclinical and clinical [53], suggests amifostine does not have a profound cytoprotective effect on lymphoma cells, such cannot be excluded from our data. The potential benefits of the dose-augmented regimen were also difficult to discern, although our limited comparison indicated at least rough equivalency to standard therapy. Also, although only 4/14 chemosensitive patients who achieved CR after AHSCT on this protocol have relapsed (at least comparable to what one sees using the standard BEAM regimen [24,25]), even the augmented doses of melphalan utilized in some patients did not abrogate progression and/or relapse (especially in ‘‘chemorefractory’’ patients), and it seems unlikely that we are close to developing

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conditioning regimens with more than incrementally improved antitumor efficacy. Thus, continued attention must be paid to known factors such as the production of a ‘‘minimal residual disease’’ state before AHSCT procedures, as well as various post-AHSCT modalities such as local irradiation [54] and perhaps immunotherapy [55] and/or allogeneic transplantation [56]. Finally, and admittedly based on limited data, the role of the ‘‘nonmelphalan’’ elements in BEAM may be questioned, as results from this study at least superficially resemble those from our earlier Phase I-II study using escalated-dose melphalan as the sole antineoplastic agent in another heterogenous group of lymphoma patients [23]. If the results are indeed comparable—and we would emphasize that available data is inadequate for a definitive judgment—the simplicity of the single agent therapy may be preferred. Alternatively, this element could be ‘‘extracted’’ from BEAM and used as the basis of a novel regimen using other agents. In any case, a Phase II trial is planned using BEAM with the melphalan dose of 260 mg/m2 with amifostine. In summary, we have presented evidence that amifostine cytoprotection is effective in the BEAM regimen involving dose-escalated melphalan. Additional studies may be required to optimize this regimen and/or assess its efficacy in selected ‘‘high-risk’’ patients [56].

ACKNOWLEDGMENTS The authors thank Dr. Donna Reece for her review of the manuscript and helpful comments; Ms. Sarah Duffy for assistance with data collection; Ms. Diane Nichols and Andrea Berry, MS, for help with data collection and statistical analysis; Ms. Louise Haskins for typing the manuscript; the nursing and nursing practitioner staff on the Blood and Marrow Transplantation Unit at Strong Memorial Hospital for their superb care of these patients; and finally, the patients and their families for their participation in this research. Financial disclosure: The authors have nothing to disclose.

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