The Systemic Administration of Intravenous Melphalan
By Gisele Sarosy,Brian Leyland-Jones,Patricia Soochan,and Bruce D.Cheson
Melphalan (L-phenylalanine mustard) is a bifunc-tional alkylating agent that is commonly adminis-tered orally to treat a wide variety of malignancies, including cancers of the breast and ovary,as well as multiple myeloma.Although commercially avail-able in Europe and Canada,intravenous (IV) mel-phalan remains investigational in the United States.The role of IV melphalan in cancer chemo-therapy is not well defined,despite its manageable toxicity and higher and more predictable blood lev-els following IV administration compared with oral administration.In addition,unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken.At lower doses (eg,30 to 70 mg/㎡2),both as a single agent and in combina-tion, the activity of IV melphalan has been evaluat-ed in only a limited number of diseases.However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma,a dis-
N 1953, Bergel and Stock described the syn-porates the alkylating agents nitrogen mustard and phenylalanine.Since phenylalanine is a pre-cursor of melanin, it was initially thought that melphalan might be a particularly useful agent in the treatment of melanoma.’ Larionov et al reported the synthesis of sarcolysin, the racemic mixture,which underwent extensive evaluation in the clinic in Russia in the late 1950s.2 The activity of melphalan was approximately twice that of D-phenylalanine mustard (medphalan),3 and therefore the former was chosen for further development.
Melphalan has been used in the treatment of patients with cancer for more than three dec-ades.Although the oral form has been commer-
From the Investigational Drug Branch,Cancer Therapy Evaluation Program,National Cancer Institute,Bethesda, MD.
Submitted January 11, 1988;accepted July 1,1988.
Address reprint requests to Gisele Sarosy,MD,Investigation-al Drug Branch,Cancer Therapy Evaluation Program, Nation-al Cancer Institute,Executive Plaza North,Room 731,Bethes-da, MD 20892.
This is a US govemnment work.There are no restrictions on its use.

ease not generally considered responsive to alky-lating agents.When administered at high doses (> 140 mg/㎡2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no im-provement in survival) in a variety of nonhematolo-gic tumor types,including resistant tumors such as melanoma and colon carcinoma.In contrast,in poor-prognosis patients with non-Hodgkin’s lym-phoma,Hodgkin’s disease, multiple myeloma, or neuroblastoma,high-dose melphalan-containing regimens have yielded both high response rates and improved survival,despite considerable toxic-ity.Additional clinical trials will be necessary to de-fine the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan. J Clin Oncol 6:1768-1782. This is a US government work.There are no restrictions on its use.
cially available in the United States since the mid-1960s,the intravenous (IV) form, which is commercially available in Europe and Canada, remains investigational in this country. IV mel-phalan may offer several advantages. First, blood levels are higher and more predictable following IV administration of melphalan than following oral administration.Hence, clinical trials performed with IV melphalan may show higher activity of this compound than those with oral melphalan.Second,IV melphalan has been an integral component of many high-dose mye-loablative regimens in bone marrow transplant protocols;however,its role in cancer therapy remains to be clearly defined.
We feel that it is timely to summarize what is known concerning the activity and toxicity of systemically administered IV melphalan, and to suggest future directions for its development.
Melphalan is a bifunctional alkylating agent that effects cytotoxicity by forming either inter-strand, intrastrand, or DNA-protein cross links.4Similar to other alkylating agents,mel-phalan is non-cell cycle specific.’ Brox et al stud-ied the effect of concentration and duration of exposure on the extent of melphalan-induced

Journal of Clinical Oncology, Vol 6, No11 (November), 1988: pp 1768-1782
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cross-linking in a human lymphoblastoid cell line RPME 6410.Following a one-hour expo-sure to melphalan 1 μg/mL, an increase in DNA cross-linking and a block of 38 to 48 hours dura-tion in G2 were observed. However, the S-phase block became irreversible if cells were exposed to melphalan 1 μg/mL for four to six hours, or to concentrations of melphalan >2 μg/mL for one hour.°Similarly,Ross et al have shown that,in murine L1210 leukemia, the extent of DNA cross-linking increases over five hours following exposure to melphalan,7 suggesting that mel-phalan quickly forms monoadducts which then only slowly convert to cytotoxic DNA-DNA or DNA-protein bonds.
Because phenylalanine is an intrinsic part of its structure, melphalan is unique among alky-lating agents in the manner in which itis trans-ported into cells. Vistica et al have shown that melphalan is transported into murine L1210 cells by two separate amino acid carrier systems, a 2-amino-bicyclo [2,2,1]heptane-2-carboxylic acid (BCH) sensitive, sodium-independent L system, which is responsible for cellular uptake of leucine and glutamine, and a BCH-insensi-tive,sodium-dependent L system.8Evidence for these two carrier systems has also been shown in LPC-1 plasmacytoma cells,L5178Y lympho-blasts,10 and MCF-7 human breast cancer cells.11 Because leucine, glutamine, and melphalan compete for the same carrier system, the cyto-toxicity of melphalan is markedly less in vitro when either leucine or glutamine is present in the culture medium. In contrast, basic amino acids such as L-lysine and L-arginine increase the intracellular concentration of melphalan through their interaction with the BCH-insensi-tive,sodium-dependent L system,thereby in-creasing melphalan’s cytotoxicity.2 The pres-ence of amino acids in the media may also influence the efflux of melphalan in a concen-tration-dependent manner. Leucine markedly enhanced the efflux of melphalan from murine L1210 leukemia cells cultured in vitro.13 Hence, the rate and degree to which melphalan accu-mulates intracellularly are the result of complex interactions between extracellular amino acids and melphalan.
Other agents that may influence sensitivity to melphalan include the synthetic vasopressin analog,1-deamino-8-D-arginine vasopressin

(dDAVP),which increases the intracellular concentration of melphalan in L5178Y lym-phoblasts in vitro by increasing uptake and de-creasing efflux.’4 Elliott and Ling have suggest-ed that decreased active transport of melphalan into the melphalan-resistant CHOC5 cell line is mediated by the surface P-glycoprotein.Howev-er,these same investigators have shown that less melphalan accumulates inthe nucleus of the melphalan-resistant Chinese hamster ovary cell line (MelR)compared with the parental cell line, suggesting that an alteration in the nuclear membrane is responsible for resistance in this in vitro model.15
Intracellular glutathione concentrations have also been shown to modulate the cytotoxicity of melphalan. Suzukake et al described two L1210 leukemia cell lines that were fivefold and eight-fold more resistant to melphalan and possessed twofold and fourfold more reduced glutathione, respectively.When these resistant cell lines were cultured in growth medium deficient in L-cystine, resulting in a decrease in intracellular glutathione,their sensitivity to melphalan was reestablished.16 Similar observations have been made in a melphalan-resistant ovarian cancer cell line,1847ME,whose levels of glutathione were twofold higher compared with that of the parental cell lines. Depletion of glutathione by DL-buthionine-S, R-sulfoximine (BSO) or growth in cystine-free medium resulted in mark-edly increased melphalan cytotoxicity.” Be-cause a small increase in the intracellular con-centration of melphalan (2 to 5 pmol/105 cells) results in markedly increased cytotoxicity,12 any clinical intervention that accomplishes the same may translate into dramatic therapeutic im-provement.
The limited data concerning the pharmacoki-netic behavior of melphalan indicate that sys-temic levels are variable following oral adminis-tration.18-21 Alberts et al examined plasma and urine samples from 14 patients treated with oral melphalan.The time at which melphalan first appeared in plasma ranged from 15 minutes to six hours following administration; in one pa-tient treated with oral melphalan under direct supervision,plasma and urinary levels were not detectable for up to 24 hours.19
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Defining the pharmacokinetic behavior of melphalan is difficult since the drug undergoes spontaneous hydrolysis in aqueous media,is ex-tensively bound to plasma proteins, and is not significantly metabolized. Chang et al have shown that, in vitro, melphalan is completely hydrolyzed after eight hours in water at 37C, and that hydrolysis decreases with decreasing temperature and increasing concentration of bovine serum albumin and human plasma pro-teins.22 Although Furner et al described at least three metabolites in mice and dogs in addition to two products of hydrolysis,23 these metabo-lites have not been described in humans,sug-gesting that melphalan is not extensively metab-olized.18,24,25
After IV administration, melphalan rapidly disappears from the plasma and is distributed in whole body water (Vd=0.66 L/kg).24 Most of the evidence suggest that the plasma elimina-tion curve is biphasic following administration of melphalan.18,20,24,26-28 Tattersall et al reported plasma half-lives of 67 minutes and 160 hours for total radioactivity following administration of radiolabeled melphalan.18 Using a high-pres-sure liquid chromatography assay previously de-scribed by Chang et al,29 Alberts et al reported plasma half-lives of 7.7 ± 3.3 minutes and 108 ±120.8 minutes for free drug.24 Similar values were reported by Bosanquet et al2 and Brox et al.27
The pharmacokinetics of melphalan appear to be dose-independent.Hersh et al adminis-tered melphalan 180 mg/㎡ IV,a dose that is often used in bone marrow preparative regi-mens.The mean terminal plasma half-life,61 minutes,25 is somewhat lower than that de-scribed by Alberts et al following administration of melphalan 0.6 mg/kg IV,24 but similar to the plasma half-life of 63.3± 8.7 minutes reported by Woodhouse et al in patients who received melphalan 10 mg IV.21
Similarly, melphalan pharmacokinetics ap-pear to be independent of age.Taha et al pub-lished a study of high-dose IV melphalan (140 mg/㎡ or 220 mg/㎡2) in children. Pharmacoki-netic parameters, including a mean half-life of 1.3±1.0 hours,28 were similar to those pre-viously defined for adults.25
Several investigators have shown that sponta-neous degradation,not renal function,is the

primary route for melphalan elimination. Fol-lowing administration of IV melphalan to two patients, Alberts et al demonstrated that virtu-ally all radiolabel in the plasma within the first 24 hours consisted of the parentcompound, monohydroxy melphalan,dihydroxy melphalan, and that which was protein bound. The mean melphalan 24-hour urinary excretion was only 13.0% ±5.4%.24 Similarly, Bosanquet et al re-ported that only 14.2% of a dose of IV adminis-tered melphalan was excreted within the first 24 hours.20 The small amount of urinary melphalan observed by most investigators suggests that renal function is not important in the elimina-tion of IV administered melphalan.Further-more,although the data are scanty,no relation-ship has been established between abnormal renal function and the pharmacokinetic behav-ior of IV administered melphalan.2028 In con-trast,a study conducted by the Cancer and Leu-kemia Group B (CALGB) suggests that the toxicity of IV melphalan may be increased in patients with renal dysfunction. Patients with multiple myeloma whose baseline BUN was >30 mg/100 mL experienced a 50% incidence of severe leucopenia (ie, total WBC count <1,000/μL) following 10 weeks of treatment with IV melphalan. In contrast, only a 15% inci-dence of severe leucopenia was observed in pa-tients with a baseline BUN <30 mg/100 mL treated in an identical fashion.3° The disposition of melphalan in patients with hepatic dysfunc-tion is even less well characterized.18.31 Although melphalan is distributed in whole body water,the extent to which it is concentrat-ed in the CSF is not well established. Hedley et al reported that the concentration of melphalan in the CSF was not negligible in one patient after treatment with high-dose melphalan.32 However, Lazarus et al examined CSF samples from intraventricular Rickham reservoirs from four patients receiving melphalan 60 mg/㎡ dai-ly for three days.In three of these patients,CSF levels of melphalan were detectable for up to three hours and reached a maximum of 10% of the corresponding plasma levels within 30 to 60 minutes after melphalan had been administered IV.26 Gouyette et al also reported detectable levels of melphalan in the CSF following IV ad-ministration of melphalan in doses ranging from 140 to 180 mg/m2.33 Downloaded from by RB DRAUGHTON LIBRARY on April 25, 2019 from Convright ©2019 American Society of Clinical Oncology. All rights reserved.  INTRAVENOUS MELPHALAN CLINICAL TRIALS Initial clinical trials with IV melphalan in-cluded patients with a wide variety of diagnoses. Occasional papers did not differentiate between those treated with sarcolysin from those treated with melphalan.34 In addition,the response cri-teria were not as rigorous as those commonly used today, and subjective and objectivere-sponses were frequently pooled.3s In the present analysis,we have included only data from pa-tients treated with IV melphalan,whose objec-tive responses totherapy were reported as ei-ther complete or partial, and we have accepted the response criteria for complete and partial responses used by the authors of these trials.We have also attempted to include only the most recent or most comprehensive reports from in-vestigators who have published their results at several points in time. Definition of the Dose for Clinical Trials Melphalan has been used in clinical trials over a wide range of doses that were,for the most part,selected empirically.The dose-limit-ing toxicity of this agent is myelosuppression, which may be related to the extent of prior ther-apy.36 Although published data are scanty, a dose of melphalan of 30 mg/㎡ IV for patients with minimal prior therapy and a dose of 20 mg/㎡2 IV for previously treated patients36 are associated with acceptable myelosuppression for a phase II trial. Because the toxicity of mel-phalan may be exacerbated in the presence of renal dysfunction,Alberts et al have recom-mended that the initial dose of IV melphalan should be 50% of the projected full dose in pa-tients with multiple myeloma and renal failure.37 Cycles should be repeated every 3 weeks assum-ing blood count recovery,and dose escalation can take place in the absence of significant mye-losuppression in the initial cycle. When used at higher doses with marrow rein-fusion,the nonhematologic dose-limiting toxic-ity of melphalan is mucositis. Lazarus et al re-ported that eight patients among nine treated with melphalan 225 mg/㎡ IV experienced se-vere stomatitis,esophagitis, and diarrhea, whereas only three of 24 who had received mel-phalan 180 mg/㎡ IV experienced these symp-toms with comparable severity.26 Based on this 1771 observation,many trials of high-dose melphalan and marrow reinfusion have been conducted at a dose of 180 mg/㎡2 with tolerable nonhemato-logic toxicity. The highest dose that can be safely adminis-tered without autologous bone marrow trans-plantation has not been defined conclusively. Barlogie et al described four early deaths among 17 patients with multiple myeloma treated with melphalan 90 to 100 mg/㎡ IV without autolo-gous marrow support and only one early death among seven patients treated with melphalan 140 mg/㎡ IV followed by autologous marrow reinfusion. In this study,the median time to a neutrophil count >500/μL was 25 days in pa-tients who had received the higher dose of mel-phalan followed by marrow reinfusion, which is approximately 3 weeks less than that observed in patients treated with the lower dose of mel-phalan without marrow reinfusion.38 Increasing the dose of melphalan above 120 mg/㎡ IV in patients who received marrow reinfusion did not increase the rate at which white cells and platelets decline or their rate of recovery follow-ing marrow reinfusion; granulocytes increased over 500/μL and platelets over 20,000/μL at a median of 19 and 24 days,respectively,follow-ing marrow reinfusion.26
Although bone marrow reinfusion does not appear to affect the severity of myelosuppres-sion following high doses of melphalan, it does shorten the duration of myelosuppression. Therefore,most studies of IV melphalan at doses >100 mg/㎡ IV have used marrow reinfu-sion as part of the treatment regimen.
Some preclinical data suggest that priming doses of cyclophosphamide may protect against melphalan-induced toxic effects,such as gastro-intestinal toxicity.3 However,it has not yet been shown that cyclophosphamide provides a similar protective effect in humans. In one series,the WBC in seven patients,treated with cyclophos-phamide 500 mg IV 1 week before melphalan 140 mg/㎡ IV, returned to baseline within a month, whereas significant myelosuppression was still apparent at this time in the three pa-tients treated with melphalan 60 to 125 mg/㎡IV alone.32 However, other investigators using similar doses of cyclophosphamide have failed to confirm this finding,26,36 and the efficacy of cyclophosphamide priming remains undefined.
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Activity of Intravenous Melphalan as a Single Agent:Lower Doses
Table 1 lists clinical trials with single-agent IV melphalan at “conventional”doses,ie,those not requiring autologous bone marrow transplant support.Because the maximally tolerated dose of IV melphalan without marrow reinfusion is not rigidly defined, the dose of melphalan used in the trials listed in this table ranges from ap-proximately 25 mg/㎡ IV4 to 62 mg/㎡ IV.49 IV melphalan at these lower doses has been ade-quately evaluated in only a limited number of disease sites. Minimal activity was noted in pa-tients with non-small-cell lung cancer,colon cancer,and pancreatic carcinoma,diseases gen-erally considered resistant to alkylating agents. Surprisingly, no responses were observed among 28 patients in the only trial in patients with breast carcinoma; however,the majority of these patients had received extensive prior ther-apy.4 The level of activity of IV melphalan in patients with breast cancer, not previously treat-ed for metastatic disease,will be defined in a phase II study conducted by the CALGB.
IV melphalan has been most widely used at conventional doses in the treatment of ovarian carcinoma. Rutledge reported a 63% objective response rate among 185 evaluable patients with all stages of ovarian cancer treated during the early 1960s with phenylalanine mustard, usually IV,34 and Nevin et al described 39 objec-tive responses at second-look laparotomy fol-
Table 1.Single-Agent Activity of Intravenous
Melphalan<65 mg/㎡ Remission (N) Disease Site Evaluable Patients Breast40 28 0 0 0 Lung Non-small-cell36,41 74 0 0 0 Small-cell36 7 0 0 0 Pancreas42 15 0 2 13 Colon43 28 1 1 7 Anaplastic glioma44 37 0 4 11 Medulloblastoma45 9 1 1 22 Sarcoma Ewing's46,47 5 0 0 0 Rhabdomyosarcoma 26 0 11 42 Osteosarcoma49 Ovary50 19* 50 0 22 2 17 11 78 *Includes two patients treated with melphalan 3 mg/kg who required white cell transfusions. SAROSY ET AL lowing six cycles of IV melphalan among 50 pa-tients.50 Although these data suggest that IV melphalan is an active agent in the treatment of ovarian cancer, its precise level of activity and efficacy relative to other agents is difficut to establish because second-look surgery is re-quired to assess response to therapy and older trials defined objective responses less precisely. Although oral melphalan is widely used in the treatment of multiple myeloma,only a limited number of studies have been reported in which melphalan is administered IV at conventional doses.In a study conducted by the CALGB,139 patients with multiple myeloma, similar with re-spect to pretreatment prognostic factors,were randomized to one of three treatment regimens: oral melphalan, IV melphalan, and the same regimen of IV melphalan administered with car-mustine. All patients also received prednisone. Myelosuppression was more common in pa-tients receiving either of the IV melphalan regi-mens.However,the median survival in patients receiving IV melphalan was significantly longer than that observed among those receiving IV melphalan and carmustine or those receiving oral melphalan.1 Based on these data suggest-ing that treatment with IV melphalan resulted in improved survival, a subsequent CALGB trial randomized patients to one of four treatment regimens.Among the 295 patients who received either IV melphalan or oral melphalan, both with prednisone,there was no significant differ-ence in survival.30 However,patients with renal insufficiency treated with IV melphalan exper-ienced greater myelosuppression.Although the relative efficacy of these two routes of adminis-tration in this disease site remains unclear, IV administration appears to effect greater toxicity, perhaps due to its more reliable bioavailability. A recent study indicates that IV melphalan at conventional doses may possess greater activity in patients with minimal prior therapy. Horo-witz et al observed only one partial response in 13 heavily pretreated patients with rhabdomyo-sarcoma.In contrast, ten partial responses were noted among 13 patients with no prior therapy.48 Activity of Intravenous Melphalan in Combination Regimens Not Requiring Bone Marrow Transplant Support Few trials of melphalan as part of combina-tion regimens not requiring bone marrow trans- Downloaded from by RB DRAUGHTON LIBRARY on April 25,2019 from Convright © 2019 American Society of Clinical Oncology.All rights reserved.  INTRAVENOUS MELPHALAN plant support have been conducted (Table 2). Although the data are limited, the addition of melphalan does not appear to significantly im-prove the response rate of the other compo-nents of a combination. Gough et al reported no responses among 14 patients with colorectal carcinoma treated with fluorouracil and mel-phalan52;an objective response rate within simi-lar confidence limits, 7%,was observed in pa-tients treated with single-agent melphalan.43 Carlson et al recently reported a randomized phase II trial in which a 14% objective response rate was observed in 44 patients with non-small-cell lung cancer receiving misonidazole and mel-phalan, whereas no responses were noted among 45 patients treated with melphalan alone.4 To determine whether misonidazole po-tentiates the activity of melphalan would re- 1773 quire a large sample size in a randomized phase III comparison. Intravenous Melphalan:Activity at Higher Doses Table 3 summarizes data concerning the ac-tivity of melphalan at higher doses, usually ad-ministered with bone marrow support. Trials that include cyclophosphamide priming have been pooled with those conducted without be-cause it is unlikely that one dose of cyclophos-phamide 500 mg IV 1 week before therapy significantly influences response.Several obser-vations are immediately apparent. Most are broad phase II trials, which include a small number of patients with various malignancies, heterogeneous with respect to the extent and type of prior therapy. In addition, the variable dose of melphalan lessens confidence in defin- Table 2. Intravenous Melphalan:Combination Trials at Doses not Requiring BMT No.of Evaluable Remiss Overall Response Disease Site Regimen Patients (%) Colon52 5-FU 50 mg/kg IV; 14 0 0 0 melphalan 0.3 mg/kg IV Ovary Melphalan 12 mg/m2 IV; 19 10 1* 58 cisplatin 80 mg/㎡2 IV53 Melphalan 12 mg/㎡2 IV; cisplatin 80 mg/㎡2 IV; 108 26 37* 58 HMM 133-135 mg/㎡ POx14 d53,54 Testicular55 Melphalan 0.5-1.0 mg/kg IV; 11 2 3 46 vinblastine 3.5-4.0 mg/kg IV Lung Melphalan 0.6 mg/kg IV; 44 4 2 14 Non-small-cell41 misonidazole 4 g/m2 PO Melanoma Melphalan 60 mg/㎡; 6 0 1+ 17 vincristine 1.4 mg/㎡2 d1& 856 Melphalan 30 mg/㎡2 IV; 29# 1 4 17 DTIC 250 mg/㎡2 IV d 1-5; Connaught BCG 6x108 organisms d 7, 12, & 17 by scarification;transfer factor 1 unit SC d 1257 Multiple myeloma58 Melphalan 16 mg/㎡2 IVd 21; 6 4 0 67 peptichemio 25 mg/㎡2 IV d 1,3,&5; Abbreviations:BMT,bone marrow transplant;HMM,hexamethylmelamine; DTIC, dacarba-zine;SC,subcutaneously; 5-FU,fluorouracil;PO,by mouth. ·Includes patients rendered without evidence of disease at time of second-look laparotomy. tSite of response:brain metastases. EIncludes nine patients who received melphalan orally. Downloaded from by RB DRAUGHTON LIBRARY on April 25,2019 from Convricht ©2019 American Society of Clinical Oncology.All rights reserved.  1774 Table 3.Single-Agent Activity of Intravenous Melphalan ≥65 mg/m2 Remission (N) N Eva Disease Site Pa (%) Breast43,59.60 20 4 9 65 Lung Non-small-cell61 4 1 - 25 Small-cell59.61 4 0 2 50 Colon43,59,60,62 64 5 25 47 Melanoma32,43,59,60,63-66 92 10 40 54 Testis60,61,65,67 12 2 5 58 Ovary59,60.65 12 3 2 42 Sarcoma Soft tissue65 Ewing's59,68-71 4 1 1 50 23 9 10 83 Synovial cell43 1 0 1 100 Bone (giant cell)59 1 0 1 100 Wilms'59,70 6 6 0 100 Osteogenic59 6 1 1 33 Rhabdomyosarcoma59 6 1 1 33 Multiple myelomg38,72,73 Neuroblastoma59,60,70,74-76 96 37 17 39 58 7 5 32 Lymphoma Hodgkin's59,60,77,78 20 5 10 75 Non-Hodgkin's59,60,79,80 7 3 3 86 Leukemia ALL80,81 13 10 1 85 ANLL81,82 30 17 4 70 CGL80,81 4 2 2 100 Stomach59 1 0 0 0 Renal43 6 1 0 17 *Includes studies in which patients received cyclophos-phamide "priming". Abbreviations:ALL,acute lymphocytic leukemia;ANLL, acute nonlymphoblastic leukemia;CGL, chronic granulo-cytic leukemia. ing the activity of melphalan using such pooled data.Despite this limitation,one is struck by the extraordinarily high response rate particularly in “resistant” solid tumors such as melanoma and colon carcinoma. Although the response rates in melanoma are high,they are frequently of short duration,and the duration of survival in responding patients ranges from 4 to 11 months.63-65,83 McElwain et al reported seven objective responses among 11 patients treated with melphalan 200mg/㎡ IV or more and five objective responses among 17 treated with melphalan 185 mg/㎡ IV or less.64 Likewise,Herzig et al reported seven objective responses among seven patients receiving 180 mg/㎡ IV and 11 objective responses among 19 patients receiving 225 mg/㎡ IV.It is unclear whether there is a dose-response relationship SAROSY ET AL since the 6-month duration of objective re-sponse in patients treated with melphalan 225 mg/㎡ IV is only 2 months longer than that in patients treated with the lower dose, 180mg/㎡IV.59 In an effort to improve remission duration in responding patients, a few patients have re-ceived high-dose melphalan a second time.64.66 Although some responses have been converted to complete responses after the second course,64 response after the second course of therapy may be of shorter duration." In addition, hemato-logic recovery may be slower in patients receiv-ing a second treatment with a similar dose of melphalan.64 The response rate to melphalan in colon car-cinoma is also impressively high, but again of brief duration. Leff et al noted nine objective responses among 20 evaluable patients,with a median duration of survival of 198 days.62 In tumors generally considered responsive to alkylating agents, the activity of high-dose mel-phalan relative to other agents or to lower doses of melphalan remains undefined. Several small series of patients with Hodgkin's disease and non-Hodgkin's lymphoma suggest that melpha-lan induces a high response rate among heavily pretreated patients (Table 3). Occasional pa-tients experience long-term unmaintained com-plete remissions which may translate into cure.77,78 However, significant toxicity accompa-nies high-dose chemotherapy and the factors that predict which patients are more likely to respond to high-dose chemotherapy remain un-known. Single-agent high-dose melphalan has been extensively evaluated in newly diagnosed, as well as heavily pretreated, patients with multi-ple myeloma.The overall response rate using pooled data from several series is 58%.38,72.73 Selby et al reported 32 objective responses among 41 previously untreated patients,73 whereas Barlogie et al described 15 objective responses among 37 patients with prior ther-apy.38 Similar to the experience in other disease sites,response rate and toxicity appeared to in-crease with higher doses of melphalan.Howev-er, Barlogie et al observed that bone marrow reinfusion shortens the median time of severe neutropenia,suggesting that bone marrow rein-fusion is essential as part of this treatment regi-men in this patient population.38 Data concerning the activity of melphalan as Downloaded from by RB DRAUGHTON LIBRARY on April 25, 2019 from Convright ©2019 American Society of Clinical Oncology,All rights reserved.  INTRAVENOUS MELPHALAN a single agent for treatment of acute leukemia are limited.The majority of patients receiving autologous bone marrow reinfusion following high-dose melphalan had undergone extensive prior therapy. Again, a high response rate was observed with an occasional patient experi-encing a complete remission and prolonged survival.81 The toxicity of high-dose melphalan is sub-stantial.Profound myelosuppression occurs in all patients, and is dose-limiting. Accordingly, granulocytopenic fever,bleeding, and mucositis occur almost universally, with considerable morbidity. Among 33 patients treated with mel-phalan 120 to 225 mg/㎡ IV with autologous marrow reinfusion,three died secondary to neu-tropenic sepsis and two died of fatal hemor-rhage.26 Maraninchi et al reported two treat-ment-related deaths among 14 patients with refractory solid tumors who received melphalan 140 to 220 mg/㎡2 IV followed by marrow reinfu-sion.65 Although bone marrow reinfusion short-ens the duration of marrow aplasia, the mortal-ity rate remains approximately 10%. High-Dose Intravenous Melphalan:Combination Trials Requiring Bone Marrow Support High-dose melphalan has been incorporated into combination regimens necessitating bone marrow reinfusion to ameliorate myelotoxicity (Table 4). For most of the combinations listed, an insufficient number of patients have been entered to make a precise estimate of activity.In addition,no randomized trials have compared the activityof a high-dose melphalan-containing combination with that of its individual compo-nents.Despite these limitations,the following observations can be made: 1.In patients with metastatic melanoma,the addition of a second agent at a high dose does not necessarily result in greater antitumor activ-ity than melphalan alone.Herzig et al reported a 65% objective response rate among 46 evalua-ble patients treated with carmustine and mel-phalan, compared with a 71% objective re-sponse rate among 24 patients receiving melphalan alone. In addition,the duration of survival was similar between these two groups.59 2.In other diseases,the activity of combina-tion therapy is significantly better than that of melphalan alone. Barlogie et al noted that the duration of remission and survival in patients 1775 with refractory multiple myeicma treated with high-dose melphalan was increased from 3 to 13 and 5 to 13 months, respectively, with the addi-tion of total body irradiation(TBI).38 Similarly, in advanced neuroblastoma, the combination of melphalan, doxorubicin,teniposide (VM-26), and TBI appears to have greater activity com-pared with that of melphalan alone. Among eight patients with recurrent stage IV neuro-blastoma treated with this combination,four pa-tients,two of whom had received autologous marrow reinfusion and two of whom had re-ceived allogeneic marrow reinfusion,remained in complete remission for a minimum of 2 years of follow-up.85 However,three died secondary to chemotherapy-induced neutropenic sepsis. Trials are ongoing in the Pediatric Oncology Group and Children's Cancer Study Group to define more precisely the role of high-dose mel-phalan-containing regimens in patients with ad-vanced neuroblastoma. 3.Whereas most high-dose combination regi-mens have been developed in an attempt to combine drugs that have activity as single agents, some investigators have combined alky-lating agents whose single-agent activity has not yet been defined at conventional doses in refrac-tory solid tumors.Alkylating agents,in general, exhibit steep dose-response curves and fre-quently possess nonoverlapping, nonhemato-logic toxicity which make them ideal agents to combine at high doses. In addition, alkylating agents may also lack cross-resistance,and sever-al have been reported to exhibit synergism pre-clinically. At the Dana-Farber Cancer Institute,several combination regimens have been evaluated clinically as part of the Solid Tumor Autologous Marrow Program (STAMP),some of which con-tain melphalan. Although four objective re-sponses were observed in seven patients with solid tumors treated with high-dose melphalan, carmustine, cisplatin, and cyclophosphamide, melphalan was subsequently deleted from the combination because of an unacceptable inci-dence of severe nephrotoxicity." Since similar nephrotoxicity has not been reported following therapy with other alkylating agents adminis-tered in combination or with single-agent mel-phalan,this toxicity may preclude further devel-opment of melphalan-containing multiagent alkylator regimens. Downloaded from by RB DRAUGHTON LIBRARY on April 25, 2019 from Convright ©2019 American Society of Clinical Oncology,All rights reserved.  1776 SAROSY ET AL Table 4. Intravenous Melphalan: Combination Trials at Doses Requiring BMT No.of Evaluable Remiss Overa Respon Disease Site, Regimen Patients Complet (%) Neuroblastoma Melphalan; TBI59 9 5 3 89 Melphalan 140-200 mg/㎡2; 7 6 0 86 vincristine 0.5 mg/m CIV d 1-6; TBI84 Melphalan 140 mg/m2&70 mg/m2; 8 4 0 50 doxorubicin 45mg/㎡;VM-26 160 mg/㎡2+TBJ85 Melanoma Melphalan 35-180 mg/㎡2; 66 8 12 30 carmustine 400-1,200 mg/m2 59,86 Melphalan 90-180 mg/㎡2; 10 0 0 0 DBD 1,000-1,750 mg/m287 Melphalan 40-130 mg/m2; 6 0 4 67 cisplatin 165-180 mg/m2; cyclophosphamide 5,625 mg/m2 88 Melphalan 40-80 mg/m2; 3 0 3 100 carmustine 600 mg/m2; cisplatin 165-180 mg/㎡2; cyclophosphamide 5,625 mg/m289 Lymphoma Non-Hodgkin's Melphalan 140 mg/m2;TBI 170-180 6 3 3 100 cby BIDx5 doses90 Melphalan 140 mg/m2;etoposide 4 0 0 0 400 mg/㎡2;carmustine 300 mg/m2; cytarabine 800 mg/m291 Melphalan 140 mg/㎡2;etoposide 5 2 0 40 250 mg/m2;carmustine 300 mg/㎡2; cytarabine or thioguanine92 Melphalan 140 mg/m2;carmustine 300 6 4 0 67 mg/m2;vindesine 1.3 mg/m2 CIV d 2-6;cytarabine 200 mg/㎡ CIV d 2-679 Hodgkin's Melphalan 140 mg/㎡;etoposide 400 1 1 0 100 mg/㎡2;carmustine 300 mg/㎡2; cytarabine 800 mg/m291 Burkitt's Melphalan 120 mg/㎡2;etoposide 200 2 1 - 50 mg/m2;carmustine 300 mg/㎡2; cytarabine 200 mg/m2 93 Ewing's sarcoma Melphalan 120 mg/㎡2;cytarabine 1 0 0 0 12g/m294 Melphalan 40 mg/㎡2;carmustine 600 1 0 0 0 mg/㎡2;cisplatin 180mg/㎡; cyclophosphamide 5,625 mg/m2 89 CML-blast crisis Melphalan 140-160 mg/m2;cytarabine 5 2 0 40 6g/m295 Multiple myeloma Melphalan 140 mg/㎡2;prednisolone 22 6 13 86 Downloaded from by RB DRAUGHTON LIBRARY on April 25,2019 from Copvright©2019 American Society of Clinical Oncology. All rights reserved.  INTRAVENOUS MELPHALAN 1777 Table 4. Intravenous Melphalan:Combination Trials at Doses Requiring BMT(Cont'd) No.of Evaluable Remiss Overall Response Disease Site, Regimen Patients (%) Melphalan 140 mg/㎡2;TBI38 9 2 6 89 Colon Melphalan 40 mg/m2/d-50 mg/㎡2/dx3 5 0 3 60 misonidazole 1-2 g/㎡2/dx3 PO% Breast Meiphalan 40-120 mg/m2;cisplatin 4 2 0 50 165-180 mg/㎡2;cyclophospha- mide 5,625 mg/m2 88 Melphalan 40 mg/m2;carmustine 1 0 0 0 600 mg/㎡2;cisplatin 180 mg/m2; cyclophosphamide 5,625 mg/m2 89 Sarcoma Melphalan 120-140 mg/m2;cisplatin 1 0 1 100 165-180 mg/㎡2;cyclophosphamide 5,625mg/m2 88 Gastric Melphalan 120-140 mg/㎡2;cisplatin 1 0 1 100 165-180 mg/㎡2;cyclophosphamide 5,625 mg/m2 88 Abbreviations:BMT,bone marrow transplant; TBI, total body irradiation; DBD,dibromodul-citol; VM-26,teniposide; BID, twice daily; CIV, continuous IV infusion. TOXICITIES Bone marrow suppression is the dose-limiting toxicity of melphalan, including both leucopenia and thrombocytopenia. Both the severity and duration of myelosuppression are dose-depen-dent. At high doses requiring bone marrow transplant support, the nonhematologic dose-limiting toxicity of melphalan is gastrointestinal, consisting of mucositis, nausea and vomiting, and diarrhea.25 Alopecia is also reported at these high doses.73 Rare toxicities include tran-sient elevation in serum transaminases,74 vascu-litis,8 syndrome of inappropriate antidiuretic hormone secretion," interstitial pneumonitis,100 depression,32 and one case of possible venooc-clusive disease.9 Secondary leukemias have been reported after IV administration of single high doses101 or repeated high doses requiring autologous marrow reinfusion.102 A 3.9% incidence of hypersensitivity reac-tions was reported among 255 patients receiving IV melphalan as a single agent.These reactions ranged from anaphylaxis associated with hypo-tension to a generalized rash, and usually oc-curred during or immediately following admin-istration. Similar reactions have not been reported following administration of oral mel- phalan, indicating the diluent or a difference in the preparation of drug for IV use as the etiology.103 DISCUSSION Compared to oral melphalan, IV adminis-tered melphalan has markedly more predictable and greater bioavailability.Hence,IV melpha-lan should yield consistently greater clinical ac-tivity than oral melphalan.Furthermore, at con-ventional doses,the toxicities of IV melphalan are easy to manage and consist of reversible myelosuppression,mild nausea and vomiting, and rare allergic reactions. Despite its ease of administration and readily reversible toxicities, many issues remain unanswered in the develop-ment of IV melphalan. At conventional doses, the activity of IV mel-phalan as a single agent is not yet established in many disease sites. Minimal activity has been reported in patients with malignancies such as non-small-cell lung,pancreas,and colon carci-nomas,generally considered resistant to alkylat-ing agents, as well as in previously treated pa-tients with rhabdomyosarcoma.In contrast,a striking level of activity has been reported in previously untreated patients with rhabdomyo- Downloaded from by RB DRAUGHTON LIBRARY on April 25,2019 from Copvright © 2019 American Society of Clinical Oncology,All rights reserved.  1778 sarcoma.In the only trial in patients with breast cancer,a malignancy generally considered sen-sitive to alkylating therapy, no responses were observed in 28 patients who received IV mel-phalan at a conventional dose. However,the lack of activity may have been secondary to the extensive prior therapy of the patients enrolled on this trial. An ongoing CALGB trial in less heavily pretreated patients with breast cancer will soon be undertaken to explore this ques-tion.Although activity has been reported in pa-tients with ovarian carcinoma treated with con-ventional doses of IV melphalan, the efficacy of IV melphalan relative to oral melphalan re-mains undefined because no randomized com-parison of these two routes of administration has been undertaken in this disease site. Based on these data, additional phase II trials of IV melphalan in the conventional dose range ap-pear warranted in patients with minimal prior therapy and diseases in which its activity is not yet defined. The striking level of activity ob-served in previously untreated patients with rhabdomyosarcoma suggests that IV melphalan may possess activity in previously untreated pa-tients with other types of malignancies in which high-dose melphalan is active. In resistant solid tumors such as melanoma, conventional-dose melphalan may possess comparable activity and lack the substantial toxicity of a high-dose regimen. The CALGB undertook the only published randomized comparisons of melphalan adminis-tered IV or orally. In the first study, patients with multiple myeloma receiving IV melphalan experienced greater toxicity,as well as a longer median survival,than those receiving oral mel-phalan.51 This study suggests that IV melphalan may have greater efficacy in this disease site. Alternatively,it may represent indirect evidence for a dose-response relationship in myeloma. However,a subsequent CALGB trial showed no significant difference in survival between those treated with IV melphalan and those treated with oral melphalan, but patients receivingIV melphalan experienced greater toxicity.30 Al-though the relative efficacy of these two routes of administration remains undefined, IV mel-phalan appears to cause greater toxicity, perhaps secondary to its more reliable bio-availability. SAROSY ET AL Administered at high doses requiring bone marrow transplant support, melphalan as a sin-gle agent effects a high response rate even in solid tumors resistant to conventional-dose therapy. Although no randomized trials have compared the efficacy of two doses of IV mel-phalan,Herzig et al reported greater toxicity and similar survival among patients treated with melphalan 225 mg/㎡ compared with those treated with melphalan 180 mg/㎡2.The 50% response rate among patients with colon carci-noma treated with melphalan 180 mg/m259 is markedly higher than the 7% response rate seen in those treated with melphalan at 30 mg/m2.43 Melphalan as a single agent at high doses has shown promising activity in many disease sites, but it has not produced an increase in survival. There are several options that can be pursued in an attempt at improving survival. High-dose melphalan with bone marrow reinfusion may be attempted repeatedly. Limited experience would suggest that such an approach is feasible. However,responses after a second dose of mel-phalan are frequently of shorter duration than those after the first,with no increase in survival. Alternatively,high-dose melphalan could be ad-ministered earlier in the course of the disease, when the tumor burden is minimal, for example, as adjuvant therapy to patients in remission who are at high riskfor relapse. Combination regimens that include high-dose IV melphalan and require marrow reinfusion have been developed in an attempt to improve both response rate and survival.Most of these combination regimens have been evaluated in only a small number of patients, and no prospec-tive randomized comparison has been undertak-en of a multidrug regimen containing melphalan v melphalan alone. However, the following ob-servations can be made. In some disease sites, such as melanoma,combinations of two active agents, such as high-dose melphalan and car-mustine, do not effect a markedly higher re-sponse rate than either component and do not result in increased survival. However, inother disease sites,such as multiple myeloma, neuro-blastoma, and non-Hodgkin's lymphoma,com-bination regimens may improve survival.Al-though only a few patients with neuroblastoma treated with high-dose melphalan-containing regimens have been reported in the literature, Downloaded from by RB DRAUGHTON LIBRARY on April 25, 2019 from Convricht ©2019 American Society of Clinical Oncology.All rights reserved.  INTRAVENOUS MELPHALAN some remain in unmaintained continuous com-plete remission at 2 to 4 years of follow-up.85 A marked increase in survival has also been re-ported in patients with multiple myeloma treat-ed with melphalan and TBI compared with those treated with melphalan alone.38 Based on this limited data, additional trials appear war-ranted to confirm these early promising results. Such trials are planned in neuroblastoma by the pediatric oncology groups. In summary, IV melphalan, especially at high doses,has substantial activity against a number of tumor types, and may increase disease-free remission in some diseases when used in combi-nation regimens. Additional phase II trials are needed in patients with minimal prior therapy to define its activity at conventional doses in 1779 those disease sites in which its activity has not yet been evaluated.At higher doses requiring marrow reinfusion, additional trials may define patient populations most likely to benefit.In addition, trials that confirm the report of im-proved survival in small cohorts of patients with multiple myeloma, non-Hodgkin's lymphoma, or neuroblastoma appear warranted. Finally, clinical application of BSO, an agent that de-pletes intracellular glutathione,may increase the activity of IV melphalan and sensitize resis-tant tumors to this agent. 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