Busulfan, Cyclophosphamide, and Melphalan Conditioning for Autologous Bone Marrow Transplantation in Hematologic Malignancy By Gordon L. Phillips, John D. Shepherd, Michael J. Barnett, Peter M. Lansdorp, Hans-G. Klingemann, John J. Spinelli, Thomas J. Nevill, Ka-Wah Chan, and Donna E. Reece Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent conditioning with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (BUCY-2) plus melphalan (90 or 135 mg/m2) and autologous bone marrow transplantation (AuBMT) in a phase I study. At the melphalan dose of 90 mg/m 2, grade > 3 regimenrelated toxicity (RRT) was observed in five patients (31%; 95% confidence interval [CI], 11% to 59%), with hepatic (venoocclusive disease [VOD]) and urinary (hemorrhagic cystitis) RRT being the most frequent complications. Further escalation of the melphalan dose to 135 mg/m 2 was deemed excessively toxic, as three of five patients had grade > 3 RRT. Following this experience, 21 patients with multiple myeloma (MM) and chronic myelogenous leukemia (CML) were treated with BUCY-2 plus melphalan 90 mg/m 2 and AuBMT in separate studies. Three of these patientsall with extensively pretreated MM-had grade 2 3 RRT (14%; 95% CI, 3% to 36%); no others had grade > 3 RRT. Therefore, a total of eight of the 37 patients (22%; 95% CI, 10% to 38%) who received BUCY-2 plus

melphalan 90 mg/m 2 conditioning developed grade _ 3 RRT; three of these patients (8%; 95% CI, 3% to 25%) died of RRT. Although limited by the relatively small number of patients, our analysis of the patients receiving this regimen showed that the presence of parameters denoting the lymphoid diagnostic group (ie, ALL, NHL, and MM), more extensive pretreatment, and/or more advanced disease status were associated with a higher incidence of grade 2 3 RRT. Response data on the AML, ALL, and NHL patients who received BUCY-2 plus melphalan 90 mg/m2 were analyzed: three patients (all with AML in first or second remission) are leukemia-free at 3.0, 2.8, and 1.4 years after AuBMT. The actuarial 2-year event-free survival in this group is 17% (95% CI, 5% to 54%). Response data on the MM and CML patients will be reported subsequently. BUCY-2 plus melphalan at a dose of 90 mg/m2 before AuBMT produces acceptable toxicity in patients who are not heavily pretreated. A full evaluation of the antineoplastic effects of this regimen requires further study. J Clin Oncol 9:1880-1888. o 1991 by American Society of Clinical Oncology.

M

OST PATIENTS WITH leukemia and other

Since these relapses are presumed to be due

hematologic malignancies who undergo my-

chiefly to conditioning regimen failure (rather

eloablative therapy and autologous bone marrow

than to the reinoculation of occult malignant stem

transplantation (AuBMT) ultimately relapse.'

cells in the AuBMT 2), an approach to this problem is to produce more effective conditioning regi-

mens. Since standard conditioning regimens for From the Leukemia/Bone Marrow Transplantation Program of British Columbia, Division of Hematology, British Columbia Cancer Agency, Vancouver General Hospital and the University of British Columbia; Terry Fox Laboratory, British Columbia CancerAgency;Division ofPathology, University of British Columbia; Division of Epidemiology, Biometry and OccupationalOncology, British Columbia CancerAgency; and Department of Pediatrics, British Columbia Children's Hospital,British Columbia CancerAgency, and the University of British Columbia, Vancouver, Canada. SubmittedJuly 12, 1990; acceptedApril 16, 1991. Supported in part by grants from the National Cancer Institute of Canadaand Burroughs-Wellcome, Inc. Address reprintrequests to Gordon L. Phillips,MD, Leukemia/Bone Marrow TransplantationProgram ofBritish Columbia, Vancouver GeneralHospital,910 WlOthAve, Vancouver, Bntish Columbia, Canada V5Z 4E3. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0910-0012$3.00/0

1880

leukemia usually consist of two agents,3 4, the addition of other active agents may be beneficial.

Furthermore, the augmentation of existing regimens is, by virtue of simplicity, more attractive than the construction of an entirely new regimen.

Although chemoradiotherapy historically has been the standard in conditioning regimens,3 there

are reasons to avoid total body irradiation (TBI) if

possible, including the difficulty in arranging for TBI with the busy schedules of radiotherapy de-

partments. Certain regimens containing only chemotherapeutic agents, especially busulfan 16 mg/kg and cyclophosphamide 50 mg/kg for 4 days

(BUCY-4) 4 and the subsequent modification using cyclophosphamide 60 mg/kg for 2 days (BUCY2),5 are potent antileukemic regimens; the latter

Journalof Clinical Oncology, Vol 9, No 10 (October), 1991 : pp 1880-1888

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1881

BUCY + MEL CONDITIONING FOR AUTOLOGOUS BMT

may produce less regimen-related toxicity (RRT) than the parent regimen.' In an attempt to reduce relapses after AuBMT with these regimens," we elected to add melphalan to BUCY-2 for the following reasons: (1) Melphalan is an alkylating agent, the class of agents preferred in these studies.' (2) Melphalan is an active single agent against leukemia."1 (3) Melphalan is not usually used in conventional chemotherapeutic programs for leukemia1 ; its use in a conditioning regimen minimizes the chance of prior drug exposure. (4) Melphalan (even in high dose) does not have serious overlapping toxicities with either busulfan or cyclophosphamide.' 2 (5) Melphalan (even in conventional dose) is active against both multiple myeloma (MM) and chronic myelogenous leukemia (CML),'3 diseases in which we were particularly interested in investigating the role of AuBMT. (In addition, the BUCY-2 regimen is active against MM and CML, at least in the allogeneic BMT setting.)14,15

Therefore, we used BUCY-2 as a basic regimen before AuBMT and planned to add increasing doses of melphalan in a phase I fashion for

patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL). Later, we used BUCY-2 plus melphalan 90 mg/m2 in separate phase II studies using AuBMT in MM'6 and CML'7 patients.

PATIENTS AND METHODS Eligibility Criteria Eligibility criteria were as follows: (1) age < 60 years; (2) complete remission (CR) bone marrow histology at the time of harvest in patients with AML, ALL, and NHL, as indicated below (different criteria were used for MM and CML); (3) low chance of curability with conventional chemotherapy: for patients with AML, ALL, or NHL, disease status greater than first CR (CR-1); for selected AML patients, the presence of poor prognostic signs (eg, initial leukocyte counts > 100 x 109/L, French-AmericanBritish subtype M5 and/or unfavorable cytogenetics") while in CR-1; for MM patients, partial remission status (including < 10% marrow plasma cells) after conventional chemotherapy; for CML patients, any stable phase, ineligibility for allogeneic BMT, and demonstrated selective depletion of leukemic cells in long-term culture screening"l; (4) satisfactory general medical condition; and (5) institution-approved informed consent. Consecutive eligible patients were entered, and all were transplanted.

Patients Patient characteristics are detailed in Table 1. Patients were grouped by study phase, melphalan dose, and diagnosis (group A, phase I: 90 mg/m2 in AML, ALL, and NHL; group B, phase I: 135 mg/m' in AML, ALL, and NHL; and group C, phase II: 90 mg/mi in MM and CML). The median age of all patients was 47 years (range, 1 to 60 years). In the phase I study (groups A and B), there were 15 patients with AML, four with ALL, and two with NHL; all of these patients had previously received prior combination chemotherapy, and all but four had suffered at least one relapse. Repeated treatment with a discrete chemotherapy regimen was considered exposure to a single regimen.

Toxicity Grading All cases of nonhematologic organ dysfunction were considered RRT unless they could be clearly explained by another cause (eg, renal dysfunction markedly improved after discontinuation of nephrotoxic antibiotics). A previously published grading scale for RRT was used," except that day +100 (rather than +30) posttransplant was chosen as the end of the evaluation interval. Patients were also assigned a toxicity grade (0 to 4) representing the highest grade of RRT observed in any single organ; organ toxicity scores in individuals were not summed. In brief, grade 1 toxicity was not life-threatening and was fully reversible without specific intervention; grade 2 toxicity was also not life-threatening but was reversible only with intervention; grade 3 was life-threatening but reversible; and grade 4 toxicity was fatal.

Study Design In the setting of AuBMT for hematologic malignancies with high relapse rates, we considered a relatively high incidence of reversible toxicity to be acceptable. Moreover, since a simple assessment of the cause of transplant-related death is often difficult, and since grade 3 RRT may predispose to another cause of (nonrelapse) death, we grouped grade 3 and 4 RRT together for analysis. An initial group of five patients was to be entered; if no patient developed grade > 3 RRT, the next dose level would be administered to the next group of five patients. If three or more patients developed grade > 3 RRT, this dose level would be deemed too toxic. If one or two patients developed grade > 3 RRT, an additional five patients would be entered at that dose level; escalation to the next dose level would be allowable only if fewer than five of the 10 patients exhibited grade 3 to 4 toxicity.'

ConditioningRegimen It was our intent to keep BUCY-2 intact. Also, since we felt that the maximum-tolerated dose (MTD) of melphalan administered as a single agent was ~ 180 mg/m2',2 we chose a simple schema in which melphalan doses of 50% (90 mg/m2), 75% (135 mg/m'), and 100% (180 mg/m2) of this dose were to be added to BUCY-2. However, no patient received the highest dose of melphalan. Doses of chemotherapeutic agents were calculated using the lesser of ideal" or actual body weight. All patients

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1882

PHILLIPS ET AL

received full doses of each agent. Patients received routine antinauseant coverage, intrathecal cytarabine (30 mg/m 2 on day -9), phenytoin,'2 and uroepithelial protection.' As shown in Fig 1, busulfan 1.0 mg/kg was given orally every 6 hours (6:00 AM, 12:00 PM, 6:00 PM, 12:00 AM) on days -7, -6, -5, and -4 (total dose, 16 mg/kg). If the patient vomited less than 1 hour after a dose of busulfan, that dose was repeated immediately. Cyclophosphamide was given by intravenous infusion as a single daily dose of 60 mg/kg over 2 hours (10:00 AM to 12:00 PM) on days -3 and -2, a total dose of 120 mg/kg. Renal function was checked on the morning of day -1, and was required to be normal before the melphalan was given. Melphalan was given by a 15minute intravenous infusion as a single dose of 90 or 135 mg/m 2 (9:00 AM) on day -1. AuBMT In patients with a history of marrow involvement (ie, those with AML, ALL, MM, and CML), a marrow purging procedure was used. In AML, ALL, and MM patients, chemoseparation with 4-hydroperoxycyclophosphamide7 was used; in CML, the long-term culture method was used."7 Certain patients with leukemia had had marrow harvested in CR and cryopreserved for use in relapse. Routine

techniques of marrow aspiration, cryopreservation, and reinfusion were used.2 Marrow was reinfused no less than 48 hours after the cyclophosphamide, and no less than 24 hours after the melphalan infusion was completed.

StatisticalMethods We evaluated a series of clinical parameters with regard to the development of grade 2 3 RRT, including age, sex, diagnostic group (myeloid: AML and CML v lymphoid: ALL, NHL, or MM), disease status (early: initial therapy, first remission, or first stable phase v intermediate: first partial remission [MM only], untreated first relapse, or accelerated phase, any CR or stable phase beyond the first v advanced: induction failure, chemotherapy-resistant relapse or blast phase), and prior therapy (analyzed as < v > the median number of prior chemotherapeutic regimens and drugs, and by whether or not prior therapy was intensive [herein defined as therapy regularly producing myelosuppression of a degree that required continuous hospitalization for several weeks after the end of chemotherapy]). Independent predictors of the development of grade > 3 RRT were identified by logistic regression analysis. 26

Table 1. Patient Characteristics Patient No.

Age (years)/ Sex

Diagnosis*

Disease Status

Group A (melphalan dose 90 mg/m') 207 55/F AML M5 CR-2 212 AML M4 CR-2 55/M AML M5 CR-2 219 7/F 226 233 236 238 240

23/M 60/M 47/F 27/M 27/M

AML M2 AML M5 AML M4 AML M3 ALL L2

REL-1 CR-2 REL-2 CR-2 REL-1

259 290 298 301

55/F 22/F 38/M 25/M

AML M5 NHL IBL AMLM1 ALL L1

CR-1 REL-3 CR-1 REL-1

378 379 388

55/M 60/F 1/M

AML M4 AML M6 AML M5

CR-2 CR-2 CR-1

408 1/M AMLM5 CR-1 Group B (melphalan dose 135 mg/m2) 299 49/M AML M1 CR-2 310 24/F AMLM2 REL-1 318 41/F NHL DLC REL-2 367 30/F ALL L2 CR-3 374

13/F

ALL L1

CR-2

Previous Chemotherapeutic Drugs HDC+DNR; CY+VP16-213 HDC+DNR; HDC+MX CDC+6TG+VCR+5AZ+CY+DEX+VP16213+L-ASE+DNR; HDC+AMSA HDC+DNR HDC+VP16-213+DNR;CY+VP16-213 HDC+DNR; HDC+MX CDC+DNR; HDC+DNR; HDC+MX HDC+DNR+VCR+PDN; HDC+DNR+ VCR+PDN+L-ASE; VCR+L-ASE+ 6MP+PDN+MT HDC+DNR+VP16-213 BACOP; HDC+L-ASE; VACOP-BP HDC+DNR+VP16-213; HDC+L-ASE CY+VCR+DNR+PDN+L-ASE; CY+VBL+ HDC+L-ASE+PDN HDC+DNR; HDC+MX HDC+DNR; HDC+MX VM26+VPl6-213+CY; AMSA+VP16-213; CDC+MX CDC+DNR+VP16-213+6TG+DEX HDC+DNR; HDC+MX HDC+DNR VACOP-BP VCR+PDN+MT; CDC+VBL+DOX+PDN; CDC+VBL+DOX+PDN+L-ASP VCR+PDN+DNR+L-ASE; HDC+L-ASE; MT+L-ASE; 6TG+CY+VCR+PDN+CDC

Previous Radiotherapy

Cell Dose x 108/kg

Marrow Purging

3.60 1.50 3.20

4-HC 4-HC 4-HC

1.80 2.30 2.30 2.83 2.26

4-HC 4-HC 4-HC 4-HC 4-HC

2.05 2.40 2.80 2.95

4-HC None 4-HC 4-HC

2.40 2.74 2.70

4-HC 4-HC 4-HC

2.20

4-HC

Paraaortic, cranial

2.17 1.75 1.38 2.40

4-HC 4-HC 4-HC 4-HC

Cranial

3.57

4-HC

Abdominalt

Spinal

Thoracic Cranial

(Continued on following page)

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

BUCY + MEL CONDITIONING FOR AUTOLOGOUS BMT

1883

Table 1. Patient Characteristics (Cont'd) Patient No.

Age (years)/ Sex

Group C (melphalan dose 90 mg/m

268 292 321 329 337 341 351 364 365 392 399 409 418 423 448 472 486 491 506 511 547

49/F 48/M 60/M 48/M 30/M 39/M 57/M 52/M 22/M 43/M 27/F 53/M 47/M 52/M 33/M 57/M 38/M 42/M 59/M 52/F 50/M

Disease Status

Diagnosis*

MMA MMG MMG MMLC MMA CML P+ MMG MMLC CML P+ MMG CML P+ CML P+ MMA CML P+ CML P+ MMG MMG MMG CML P+ MMLC MMA

2

Previous Radiotherapy

Previous Chemotherapeutic Drugs

Cell Dose x 10'/kg

Marrow Purging

)

PR-1 PR- 1 PR-i PR-1 REL-1 SP-2 REL-1 PR-i SP-1 PR-1 AP-1 SP-1 PR-1 SP-1 SP-1 PR-1 PR-2 PR-1 SP-1 PR-1 PR-2

VAD VAD VAD MEL+PDN; VAD MEL+PDN; VAD MITH+HXU; LDC+VBL MEL+PDN; VAD VAD HXU MEL+PDN; VAD HXU MEL+ PDN; CY+PDN; VAD HXU HXU VAD; HICY VAD VAD HXU VAD; HICY VAD; HICY

Humerus Spinal Multiple Thoracic; spinal Left humerus Spinal Thoracic -

1.76 3.00 1.29 2.49 2.50 2.16 2.52 2.55 1.30 1.60 1.48 2.18 1.38 1.30 1.62 5.59 2.15 2.20 3.50 6.37 7.65

4-HC 4-HC 4-HC 4-HC 4-HC LTC 4-HC 4-HC LTC 4-HC LTC LTC 4-HC LTC LTC None* 4-HC 4-HC LTC§ Nonet None*

Abbreviations: IBL, immunoblastic; DLC, diffuse large-cell; P+, Philadelphia chromosome positive; AP, accelerated phase; REL, relapse; SP, stable phase; AMSA, amsacrine; BACOP, bleomycin, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, vincristine (Oncovin; Eli Lilly and Co, Indianapolis, IN), and prednisone; CDC, conventional-dose cytarabine; CY, cyclophosphamide; DEX, dexamethasone; DNR, daunorubicin; DOX, doxorubicin; HDC, high-dose cytarabine; HICY, high-dose cyclophosphamide; HXU, hydroxyurea; L-ASE, asparaginase; LDC, low-dose cytarabine; MEL, melphalan; MITH, mithramycin; MT, methotrexate; MX, mitoxantrone; PDN, prednisone; POMP, mercaptopurine, vincristine (Oncovin), methotrexate, and prednisone; VACOP-BP, VP16-213, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, bleomycin, and cisplatin; VAD, vincristine (Oncovin), doxorubicin (Adriamycin), dexamethasone; VBL, vinblastine; VCR, vincristine (Oncovin); VM26, teniposide; VP16-213, etoposide; 5AZ, azacytidine; 6MP, mercaptopurine; 6TG, thioguanine; 4-HC, 4-hydroperoxycyclophosphamide; LTC, long-term culture. *AML with French-American-British subtypes M1-6. ALL with French-American-British subtypes Ll-3. MM subclassified as light chain (LC), IgA (A), IgG (G). tFor prior gastric cancer. $Peripheral-blood stem cells used. §Had second transplant with peripheral-blood stem cells at day +50.

Event-free survival for group A patients was analyzed according to the method of Kaplan and Meier.2 7 Patients were censored if alive and relapse-free as of April 1, 1991; those who did not achieve CR posttransplant were considered to have failed on the date of AuBMT.

RESULTS

Results are shown in Table 2.

urinary). Later, an additional six patients received the melphalan dose of 90 mg/m2; two had grade 3 hepatic RRT. As indicated in Table 3, although only two patients had no RRT graded, five of these 16 patients receiving BUCY-2 plus melphalan 90 mg/m 2 (31%; 95% confidence interval [CI], 11% to 59%) had grade 3 RRT. No patient had grade 4

Phase I Study in AML, ALL, and NHL Group A. Of the initial five patients treated with BUCY-2 and the melphalan dose of 90 mg/m2, one had grade 3 RRT in a single organ

ROUTE

-7

-6

-5

DAY -4 -3 -2

4 mg/kg

PO

U

1

U

U

system (urinary). Therefore, another five patients

CY

60 mg/kg

IV

were entered at this dose: one patient developed

MEL

go90 or 135 mg/m

grade 3 RRT in three organ systems (hepatic, renal, and urinary), and one other patient had grade 3 RRT in two systems (pulmonary and

AGENT

TOTAL DAILY DOSE

BU

2

IV

-1

0 A

E

a U

B M T

Fig 1. Schedule of BUCY-2 plus melphalan. BU, busulfan; CY, cyclophosphamide; MEL, melphalan; PO, orally; IV, intravenously.

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

PHILLIPS ET AL

1884 Table 2. Results Patient No.

Day ANC 2 0.5 x 10'/L

RRTGrade 1-2

RRTGrade 3-4

Best Response

Day of Relapse

Current Status KPS 4/1/91 (day post-AuBMT)

2

Group A (melphalan dose 90 mg/m ) H,M +21 207 212 +30 N M 219 +40 H,M,U,G +68 226 233 +15 G M DNR 236 H,M,R +27 238 G,N +32 240 M +54 259 R +33 290 G,H,M +64 298 G,M,R +23 301 U +34 378 M DNR 379 388 +41 408 +52 2 Group B (melphalan dose 135 mg/m ) H,M,U +39 299 310 DNR +34 318 G,M,P,U +15 367 C,G,M,P +20 374 Group C (melphalan dose 90 mg/m 2 ) G,M +20 268 G,M,U +15 292 G +14 321 329 +14 G,H,M,R +20 337 M +52 341 +23 351 G,H,R +19 364 G,H +19 365 +19 392 M +30 399 M +32 409 418 +26 M H,U +28 423 M,R +31 448 472 +15 R 486 +21 M +19 491 H,M DNR 506 G,M +10 511 G +15 547

U -H,R,U -P,U -H H

--

H,P,R H H,U H ---H H

CCR CCR CCR No CR CCR No CR CCR CR CCR No CR CCR CR CCR NA CCR CCR

+152 +102

+119 +151 +47

D/CHF (+254) D/sepsis (+584) D/leukemia (+294) D/leukemia (+113) D/leukemia (+120) D/leukemia (+95) A&W 100% (1,098+) D/sepsis (+52) A&W 100% (1,032+) D/lymphoma (+41) D/hemorrhage (+66) D/leukemia (+300) D/leukemia (+ 163) D/sepsis (+20) D/leukemia (+63) A& W 100% (508+)

CCR NA No CR CCR CCR

+153

A&W 100% (854+) D/pulmonary toxicity (+ 18) D/hemorrhage (+41) A& W 100% (644+) D/leukemia (+213)

CR PR PR CR CR CR NA CR CR NA CR CR CR CR CR PR CR CR NA CR NA

+136 +495 +543 +370* +307 +180* +381" +367* +193 -

D/myeloma (+153) A& W 90% (872+) A& W 100% (784+) A/myeloma 90% (762+) A/myeloma 70% (737+) A/leukemia 90% (731+) D/sepsis (+46) D/myeloma (+474) A&W 90% (654+) D/hepatotoxicity (+50) 100% (542+) A &&W A& W 100% (507+) A& W 100% (476+) A&W 90%(465+) A &W 100% (395+) A/myeloma 100% (336+) A&W 100%(312+) A&W100%(301+) D/pneumocystis pneumonia (+67) D/hepatotoxicity (+61) D/hepatotoxicity (+28)

Abbreviations: ANC, absolute neutrophil count; KPS, Karnofsky performance status; DNR, did not reach; C, cardiac; G, gastrointestinal; H, hepatic; M, mucosal; N, central nervous system; P, pulmonary; R, renal; U, urinary; CCR, continued complete remission; PR, partial remission; NA, not assessable; A & W, alive and well; D, dead; CHF, congestive heart failure. *Day of cytogenetic relapse.

toxicity. Also, grade 2 toxicity (excluding mucosal) was infrequent; all other cases of hepatotoxicity were grade 1. Group B. Three of the initial 10 Group A patients developed grade _ 3 RRT with BUCY-2

plus melphalan 90 mg/m 2; melphalan was therefore escalated to 135 mg/m 2. Five patients received this regimen. As indicated in Table 4, three patients had grade 3 hepatic RRT (one of these patients also had grade 4 pulmonary and grade 3

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1885

BUCY + MEL CONDITIONING FOR AUTOLOGOUS BMT Table 3. RRT in 16 Group A Patients (AML and ALL) Receiving Melphalan 90 mg/m2

Table 5. RRT in 21 Group C Patients (MM and CML) Receiving Melphalan 90 mg/m2

RRT Grade

RRTGrade

Organ System

0

Cardiac Gastrointestinal Hepatic Mucosal Neurologic Pulmonary Renal Urinary

16 11 9 7 15 15 12 11

5

-

-

-

4 7 3 1

2 1 1

3 1 1 3

-

2

6

3

5

-

Total*

1

2

3

4

Organ System

0

Cardiac Gastrointestinal Hepatic Mucosal Neurologic Pulmonary Renal Urinary

21 13 13 10 21 21 17 19

Total*

3

2

1 -

7 5 4 4 2 8

1 7 7

3

4

-

-

-

3 -

-

3

*Numbers refer to number of patients having this maximal grade RRT; since some patients had more than one organ system involved, the total may be less than the number of individual cases.

*Numbers refer to number of patients having this maximal grade RRT; since some patients had more than one organ system involved, the total may be less than the number of individual cases.

renal RRT, and another also had grade 3 urinary RRT).

Analysis of Risk Factorsfor Grade _ 3 RRT in PatientsReceiving BUCY-2 Plus Melphalan 90 mg/m 2

Studies in MM and CML

Group C. All of the patients with MM (n = 14) or CML (n = 7) received BUCY-2 plus melphalan 90 mg/m2. As shown in Table 5, three of these patients developed grade 2 3 RRT; all were MM patients and all died due to hepatotoxicity, including two who had received high-dose cyclophosphamide (ie, 7 g/m 2) to produce primed peripheralblood stem cells.' Other toxicities in MM and CML patients were relatively minor; only two patients had grade 2 nonmucosal RRT. In both of these cases, renal toxicity occurred in the presence of nephrotoxic antibiotics. Table 4. RRT in Five Group B Patients (AML, ALL, and NHL) Receiving Melphalan 135 mg/m2 RRTGrade Organ System

0

Cardiac Gastrointestinal Hepatic Mucosal Neurologic Pulmonary Renal Urinary

4 2 1 2 5 2 4 2

Total*

-

1

2

I 1 1 2

1 1 2 1 -

3

1

1 1

-

1

3

-

-

4

-

-

-

3

-

1

1

*Numbers refer to number of patients having this maximal grade RRT; since some patients had more than one organ system involved, the total may be less than the number of individual cases.

Given the heterogeneity of patient, disease, and

pretreatment characteristics, we analyzed the previously listed potential prognostic features for their effect in predicting the development of grade _ 3 RRT in those patients who received BUCY-2 and melphalan 90 mg/m2. The incidence of grade 2 3 RRT in this group was 22% (95% CI,

10% to 38%). In the univariate analysis, a greater number of prior chemotherapeutic regimens (P = .025) and drugs (P = .044), as well as lymphoid diagnostic group (P = .028) and more ad-

vanced disease status (P = .010), were associated with grade 2 3 RRT. After adjustment for disease status, only diagnostic group (P = .007) remained significant. Specific RRT Of the grade _ 3 RRT encountered, hepatotoxicity was the most frequent and severe; the clinical picture (and pathology in four of the five cases in which biopsy or necropsy material was available) was that of venoocclusive disease (VOD).29 (Patient no. 310 suffered vascular collapse with the marrow reinfusion and died on day + 18; severe

centrilobular congestion [only] was noted at necropsy.) Grade > 3 hepatic RRT also occurred in three of the 16 group A patients who received the melphalan dose of 90 mg/m2 and three of the 21 group C patients who received melphalan 90 mg/m2. Therefore, BUCY-2 plus melphalan 90 mg/m 2 produced six cases of grade 2 3 hepatic

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1886

PHILLIPS ET AL

RRT in 37 patients (16%; 95% CI, 6% to 32%). Grade 2 3 hepatic RRT occurred in three of the five group B patients who received the melphalan dose of 135 mg/m 2. The urinary, renal, CNS, and pulmonary organ systems also exhibited grade > 3 toxicity. Grade 3 urinary RRT (hemorrhagic cystitis) was noted in three of 16 group A patients (19%; 95% CI, 4% to 46%) but none of the group C patients-an overall incidence of 8% (95% CI, 6% to 32%) at the melphalan dose of 90 mg/m 2. One of the five patients receiving the 135 mg/m2 dose (group B) developed grade > 3 urinary RRT. All cases of nephrotoxicity occurred in the presence of the administration of nephrotoxic antibiotics (but could not be definitely ascribed to their use), and both cases of grade 3 renal RRT followed the development of grade 2 3 hepatotoxicity and were felt to represent cases of hepatorenal syndrome. Grade 2 3 pulmonary toxicity was noted in two patients, including patient no. 310, who died of the adult respiratory distress syndrome. Another patient (patient no. 290) had grade 3 pulmonary RRT. The single case of grade 2 CNS toxicity (major motor seizures) appeared to be due to busulfan and inadequate phenytoin dosing.30 Antitumor Effects Since BUCY-2 plus melphalan 135 mg/m 2 was felt to be excessively toxic, patients treated with BUCY-2 and melphalan 90 mg/m 2 were considered more appropriate for evaluation of antitumor effects. Therefore, patients with AML, ALL, and NHL who were treated with this regimen in the phase I study plus an additional six patients were assessed to obtain additional toxicity data as well as tumor response data.3 1 Three of these patients, all with AML in CR-1 or second CR (CR-2), remain alive in continuous remission at 3.0, 2.8, and 1.4 years after AuBMT. Eight died of their underlying disease, five due to infection or bleeding, and one of late-onset congestive heart failure. The 2-year actuarial event-free survival in this group is 17% (95% CI, 5% to 54%). Two patients (one AML and one NHL) were in advanced (ie, > first) relapse when transplanted with BUCY-2 plus melphalan 90 mg/m2; neither achieved CR. Of the three patients who had marrow harvested in CR and who were transplanted in first relapse (one AML and two ALL), two achieved CR: one later relapsed, and the

other died of a viral infection. Of the seven patients transplanted in CR-2 (all AML), five had a CR-2 longer than CR-1. However, two of these patients relapsed, two died of infective causes, and only one patient is alive in continuous CR-2 at 3.0 years. Of the four patients transplanted in CR-1 (all AML), two are alive at 2.8 and 1.4 years; one patient relapsed, and one died of an intracranial hemorrhage. At the melphalan dose of 135 mg/m 2, one patient died of RRT and one died due to thrombocytopenic hemorrhage. Neither patient transplanted in relapse achieved CR, but two of the three patients transplanted in advanced CR have not relapsed, including one with a CR-2 greater than CR-1 and another who is now in third CR (CR-3) but of a duration still shorter than CR-2. The results of the phase II studies in MM and CML will be presented subsequently. DISCUSSION We observed an incidence of grade > 3 RRT of 22% (95% CI, 9% to 35%) in the patients who received BUCY-2 plus melphalan 90 mg/m2, and 60% (95% CI, 15% to 95%) in those who received BUCY-2 plus melphalan 135 mg/m 2. While both regimens were toxic, the latter appeared to be more so. Whether BUCY-2 plus melphalan 90 mg/m2 is too toxic is a matter of opinion; despite the frequency of grade 3 RRT, only three of 42 patients (7%; 95% CI, 0% to 15%) who received that regimen before AuBMT died due to RRT. Moreover, grade 2 3 toxicity was unusual in patients with myeloid leukemias, as well as in those who were less heavily pretreated and/or had a less advanced disease status before AuBMT. However, these conclusions should be considered tentative in light of the relatively low number of patients analyzed. Several conclusions can be drawn from this experience. First, combining agents at escalated doses may produce unexpected side effects, at least in a quantitative sense. For instance, severe and/or fatal RRT is relatively uncommon using BUCY-2 in the AuBMT situation, which is wellsuited for the evaluation of RRT due to the absence of graft-versus-host disease and its therapy. Beelen et al8 noted a high incidence of abnormal liver function tests (85%) but no cases of clinical VOD in a group of 20 patients with AML in CR-1 undergoing AuBMT, whereas Brodsky et

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1887

BUCY + MEL CONDITIONING FOR AUTOLOGOUS BMT al6 reported VOD in five of 55 more heterogenous patients given this therapy. Therefore, although many of our patients were more heavily pretreated than patients in these series using BUCY-2 conditioning before AuBMT, this regimen appears to produce a relatively high incidence of abnormal liver function tests (perhaps indicative of subclinical damage) but clinical VOD only rarely. Moreover, since VOD is rare with the single-agent use of melphalan, even at doses up to 225 mg/m 2,21we feel that the incidence of VOD that we observed with BUCY-2 plus melphalan 90 mg/m 2 may have been increased compared with that with BUCY-2 alone. This postulate is strengthened, albeit indirectly, by the high incidence of VOD in the few patients receiving BUCY-2 plus melphalan 135 mg/m2. Conversely, this assumption is not definitive; a randomized trial would be necessary to evaluate this assertion. This experience also emphasizes the relatively limited degree of dose escalation allowable with the existing cytotoxic agents as usually used," and especially the difficulty in combining three agents at an escalated dose.' 2 In general, it has been difficult to bolster existing conditioning regimens with available cytotoxic agents without increasing RRT, and higher cure rates may not be produced-even if augmented antineoplastic effects are noted.32 This dilemma may reflect our lack of knowledge of the optimal use of existing agents, and it is possible that alteration in dose (or schedule) of this regimen33 would produce less toxicity. Conversely, our results may also indicate the limited curability of advanced human neoplasia by current cytotoxic agents (at tolerable doses) alone. 34 It is also clear that a major site of grade Ž 3 RRT, both with this regimen and with others, 33,35 is the liver. Such toxicity is usually manifested as VOD. While the etiology of VOD is likely to be complex, even in the AuBMT situation, specific considerations to diminish and/or measures to counteract such toxicity may be required.36

Finally, and most importantly, our results illustrate the problem of testing new conditioning regimens in patients with advanced, extensively pretreated malignant disease. Such patients are, in terms of prognosis, most suitable for phase I studies; however, subclinical organ damage produced by previous therapy or disease may predispose these patients to a greater incidence and severity of RRT than would be produced by such therapy in less extensively treated patients. The extent and degree of the subclinical damage produced by prior cytotoxic therapy is difficult to quantify and is likely to be complex; the specific agent(s) used, dose, schedule, and interval from last therapy, as well as other less obvious factors, are probably important. In any case, this factor should be taken into account when considering the use of BUCY-2 plus melphalan 90 mg/m2 and AuBMT. Conversely, the finding of more RRT in patients with lymphoid hematologic malignancy is less easy to explain. In summary, BUCY-2 plus melphalan 90 mg/m2 conditioning before AuBMT may be used in patients without extensive prior treatment. Whether or not one considers the degree of RRT observed to be excessive-will depend on a number of factors, including the potential curability of patients with other regimens and the curability of their disease with BUCY-2 plus melphalan 90 mg/m 2-currently, the latter is an incompletely known quantity, and one difficult to prove."37 We continue to use BUCY-2 plus melphalan 90 mg/m 2 in MM and CML patients undergoing AuBMT who have not received prior intensive therapy; continuing analysis will yield more information in this regard. ACKNOWLEDGMENT We gratefully acknowledge the expert technical assistance of Sara Abraham and Coleen McAloney (marrow processing), Gail Thierman (data collection), Sandra Bonner (typing), Linda Williams (editing), and the skills of the nursing staff of the Leukemia and Bone MarrowTransplant Unit of the Vancouver General Hospital and the Special Oncology Unit of the British Columbia Cancer Agency.

REFERENCES 1. Phillips GL: Autologous bone marrow transplantation for hematologic cancer, in Ragaz J, Simpson-Herrin L, Lippman ME, et al (eds): Effects of Therapy on Biology and Kinetics of the Residual Tumor, Part B: Clinical Aspects. New York, NY, Wiley-Liss, 1990, pp 171-184 2. Gale RP, Butturini A: Autotransplants in leukaemia. Lancet 2:315-317, 1989

3. Thomas ED: The use and potential of bone marrow allograft and whole-body irradiation in the treatment of leukemia. Cancer 50:1449-1454, 1982 4. Santos GW, Tutschka PJ, Brookmeyer R, et al: Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309:1347-1353, 1983

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

1888

PHILLIPS ET AL

5. Tutschka PJ, Copelan EA, Klein JP: Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70:1382-1388, 1987 6. Brodsky R, Topolsky D, Crilley P, et al: Frequency of veno-occlusive disease of the liver in bone marrow transplantation with a modified busulfan/cyclophosphamide preparative regimen. Am J Clin Oncol 13:221-225, 1990 7. Yeager AM, Kaizer H, Santos GW, et al: Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315:141147, 1986 8. Beelen DW, Quabeck K, Graeven U, et al: Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission acute myeloid leukemia. Blood 74:1507-1516, 1989 9. Frei E III, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69:585-594, 1980 10. Mascret B, Maraninchi D, Gastaut JA, et al: Repeated high-dose melphalan with autologous bone marrow transplantation in acute non lymphocytic leukemia. Rev Fr Transfus Immunohematol 28:477-488, 1985 11. Champlin R, Gale RP: Acute myelogenous leukemia: Recent advances in therapy. Blood 69:1551-1562, 1987 12. Herzig GP, Herzig RH: Current concepts in dose intensity and marrow transplantation, in Gale RP (ed): Acute Myelogenous Leukemia: Progress and Controversies. New York, NY, Wiley-Liss, 1990, pp 333-344 13. Sarosy G, Leyland-Jones B, Soochan P, et al: The systemic administration of intravenous melphalan. J Clin Oncol 6:1768-1782, 1988 14. Copelan EA, Tutschka PJ: Marrow transplantation following busulfan and cyclophosphamide in multiple myeloma. Bone Marrow Transplant 3:363-365, 1988 15. Copelan EA, Grever MR, Kapoor N, et al: Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 71:487-491, 1989 16. Reece DE, Barnett MJ, Connors JM, et al: Intensive therapy with busulfan, cyclophosphamide and melphalan (BUCY + MEL) and 4-hydroperoxycyclophosphamide (4HC) purged autologous bone marrow transplantation (AutoBMT) for multiple myeloma (MM). Blood 74:202a, 1989 (suppl 1, abstr) 17. Barnett MJ, Eaves CJ, Phillips GL, et al: Successful autografting in chronic myeloid leukaemia after maintenance of marrow in culture. Bone Marrow Transplant 4:345-351, 1989 18. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813-819, 1990 19. Bearman SI, Appelbaum FR, Buckner CD, et al: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 6:1562-1568, 1988

20. Lee YJ, Catane R, Rozencweig M, et al: Analysis and interpretation of response rates for anticancer drugs. Cancer Treat Rep 63:1713-1720, 1979 21. Lazarus HM, Herzig RH, Graham-Pole J, et al: Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1:359-367, 1983 22. Altman PL, Dittmer DS (eds): Growth Including Reproduction and Morphological Development. Washington, DC, Federation of American Societies for Experimental Biology, 1962 23. Grigg AP, Shepherd JD, Phillips GL: Busulphan and phenytoin. Ann Intern Med 111:1049-1050, 1989 (letter) 24. Shepherd JD, Pringle LE, Barnett MJ, et al: 2-Mercaptoethane sulfonate (mesna) vs hyperhydration (HH) for the prevention of cyclophosphamide induced hemorrhagic cystitis in bone marrow transplantation. Proc Am Soc Clin Oncol 9:12, 1990 (abstr) 25. Herzig GP: Autologous marrow transplantation in cancer therapy. Prog Hematol 12:1-23, 1981 26. Breslow NE, Day NE: Statistical Methods in Cancer Research, Volume 1: The Analysis of Case-Control Studies. Lyon, France, IARC, 1980 27. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 28. Kessinger A, Armitage JO: The evolving role of autologous peripheral stem cell transplantation following high-dose therapy for malignancies. Blood 77:211-213, 1991 29. Jones RJ, Lee KSK, Beschorner WE, et al: Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 44:778-783, 1987 30. Marcus RE, Goldman JM: Convulsions due to highdose busulphan. Lancet 2:1463, 1984 (letter) 31. Lee YJ, Staquet M, Simon R, et al: Two-stage plans for patient accrual in phase II cancer clinical trials. Cancer Treat Rep 63:1721-1726, 1979 32. Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76:1867-1871, 1990 33. Grochow LB, Jones RJ, Brundrett RB, et al: Pharmacokinetics of busulfan: Correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25:55-61, 1989 34. Gale RP, Champlin RE: How does bone marrow transplantation cure leukaemia? Lancet 2:28-30, 1984 35. Ayash LJ, Hunt M, Antman K, et al: Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas. J Clin Oncol 8:1699-1706, 1990 36. Bianco J, Nemunaitis J, Almgren J, et al: Pentoxifylline (PTX) diminishes regimen related toxicity (RRT) in patients undergoing bone marrow transplantation (BMT). Blood 76:528a, 1990 (suppl 1, abstr) 37. Gale RP, Horowitz MM: How best to analyse new strategies in bone marrow transplantation. Bone Marrow Transplant 6:357-359, 1990

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

Busulfan, cyclophosphamide, and melphalan conditioning for autologous bone marrow transplantation in hematologic malignancy.

Sixteen patients with poor-prognosis acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin's lymphoma (NHL) underwent ...
719KB Sizes 0 Downloads 0 Views

Recommend Documents