Randomized Comparison of Busulfan and Hydroxyurea in Chronic

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1993 82: 398-407

Heinze and A GeorgiiR Hehlmann, H Heimpel, J Hasford, HJ Kolb, H Pralle, DK Hossfeld, W Queisser, H Loffler, BGerman CML Study Groupmyelogenous leukemia: prolongation of survival by hydroxyurea. TheRandomized comparison of busulfan and hydroxyurea in chronic

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Randomized Compar i son o f Busu l fan and Hydroxyurea in Chron icM y e l o g e n o u s L e u k e m i a : P r o lo n g a ti o n of Surv iva l by Hydroxyurea

By R. Hehlmann, H. Heimpel, J . Hasford, H.J . Kolb, H. P ralle, D.K. Hossfeld, W . QueiBer, H. Lbffler, B.Heinze, A. G eorgii,

P .v. Wussow, C. Bartram, M . GrieBhammer, L. Bergmann, U. Essers, C. Falge, A. Hochhaus, U. QueiBer, C. Sick,

P. Meyer, N. Schmitz, K. Verpoort, H. Eimermacher, F. Walther, M. Westerhausen, U.R. Kleeberg, A. Heilein,

A. Kabisch. C. Barz, R . Zimmermann, G. Meuret, A . Tichelli, W.E . Berdel, L. Kanz, B. Anger, F. J . Tigges, L. Schmid,

W . Brockhaus, R. Zankovich, U. Schlafer, 1. WeiBenfels, K. Mainzer, A. Tobler, M . Perker, J . Hohnloser,

D. Messener, J . Thiele, T. Buhr, H. Ansari, and the German CML Study Group

In a randomized multi center study the influence of hydrox-

yurea versus busul fan on the duration of th e chronic phase

and on survival of chronic myelogenous leukemia (CML)

was determined. In addition cross resistance and adversereactions of the drugs were analyzed. From July 1 983 t o

January 19 91, 441 CML patients were randomized to re-ceive hydroxyureaor busul fan. Of these, 90.7% were Phila-

delphia positive; 25.7% were low, 38.2% intermediate,and 36.2% high risk patients according to Sokal‘s score.

The median survival of the busulfan treated Philadelphia-

positive patients is 45. 4 months and of t he hydroxyurea

group 58 .2 months (P =.008) . The surv ival advantage for

th e hydroxyurea treated patients is recognized in all riskgroups. Sixty four patients reached therapy resis tance be-

RUG THER APY of chronic myelogenous leukemia

D CML ) has basically been palliative until now , withthe d rug of choice being busulfan for the past 40 years. Little

prolongation of life has been observed since the report by

Minot et al in 1924.’ Curative therapy can be offered only to

those 10% o 20% of CM L pa tients of sufficiently young age,

who have an HLA compatible, related or unrelated, bone

marrow donor.’z3 Median survival of CML patients from

the time of diagnosis varied between 30 and 55 months,

depending less on the mode of therapy than on patient se-

lection and exclusion of high risk patients such as Philadel-phia-negative or preblastic ones.4

Busulfan, an alkylating agent active a t the stem cell level,

is known to control CML-related signs and symptoms in

95% of patients for at least 3 months.’ All studies have

shown its efficacy and reliability since its introduction in

1953. Controlled com parison with a n um ber of single

agents, radiotherapy, a nd w ith intensive combination ther-apy has show n its superiority w ith regard to efficacy, adversereactions, and/ or duratio n of disease control.”” Th e me-

From Klin ikum Man nheim , Universitat Heidelberg, Man nheim ,

Submitted December 21 , 1992; accepted February 25 , 1993.

The study was initiated by the Sueddeutsche Haemoblastose-

gruppe and is supported by the German Bundesminister fuer

Forschung und Technologie, Foerderkennzeichen 01Z W044,

01ZP900I -01ZP90019, an d 01Z W8503.

Address reprint requests to R. Hehlmann, MD , I I I . Medizinische

Klinik, Kliniku m M annh eim der Universitiit Heidelberg, Wiesba-denerstr. 7-11, 6800 Mannheim , Germany.

The publication C O SIS of this article were defiayed i n part by page

charge payment. This article must therefore be hereby m arked

“advertisement” in accordance with 18 U.S.C.section 1734 solely to

indicate this act.

Deutschland.

0 9 9 3 by T he American Society of Hematology.

0006-4971/93/8202-0031$3.00/0

fore blast crisis and were crossed over to the alternative

drug. The 23 patients wi th primary hydroxyurea had a me-

dian survival of 5.6 years, the 41 patients with primary

busulfan herapy a median survivalof 2.7 years (P = .02).

Adverse reactions were less frequent w ith hydroxyurea

wi th no severe adverse effects (lung fibrosis, long lasting

bone marrow aplasia). The analysis of white blood cell

counts in the course of tr eatment showed lower counts in

the hydroxyurea patients. We conclude that hydroxyurea

is superior to busulfan n therapy of CML in chronic phase

and should be used as firs t li ne therapy. Busulfan may have

a role as secondary herapy after hydroxyurea resistance or

intolerance.0 993b y The American Society of Hematology.

dian (or mean) survival times of busulfan-treated CM L pa-

tients range from 35 to 47 m ont hs4

More recently, hydroxyurea, an inh ibitor oft he ribonucle-

otide reductase, became increasingly popular because of its

rapid action and low level of adverse effects.” Some retro-

spective studies on small series of patients ind icated a sur-

vival advantage of hydro xyurea-treated patients,12-” which,

however, was never substantiated by a controlled study. As

early as 1972, Kenne dy” reported in a retrospective study

on 20 patients with unknown Philadelphia chromosome

status that hydroxyurea controlled all CML-related symp-tom s as well as busulfan. Hydroxy urea did not prevent pro-

gression to blast crisis, but the investigator felt that it could

prolong the duratio n of the chronic phase as compared withbusulfan. The median duration of response to hydroxyureawas 41 months for 10not pretreated patients and 8 months

for 10 pretreated and busulfan-resistant patients. Schwar-zenberg et al, in a study of 43 patients who were treated withhydroxyurea, leukapheresis, and splenectomy, reported

that survival was similar to that after busulfan therapy,l3Schwarz and Canellos14 reated 35 patients, m ostly resistant

to busulfan an d/o r in accelerated phase, with hydroxyureaan d had good results. Bolin et all5 reported th e results of a

retrospective study on 30 busulfan- and 14 hydroxyurea-treated patients. Expected median survival was 48 monthsand >90 months for the busulfan and the hydroxyureagroups, respectively. However, this difference was not signif-icant due to the small sample size.

In 1983, the Ge rma n CM L study group, therefore, de-cided to compare in a randomized study the influence ofhydroxyurea versus busulfan on t he dur atio n of the chronicphase and on survival of CML. Further goals of the studywere the examination of cross resistance of hydroxyurea

and busulfan and the determination of duratio n of efficacyafter cross over; the dev elopment of a prognostic score onthe basis of prospectively docum ente d parameters of possi-ble significance for the prognosis of CM L; the com parison

398 Blood, VOI82, NO 2 (J uly 15). 1993: p 398-407










CML: PROLONGATION OF SURVIVAL BY HYDROXYUREA 399

of th e terminal phases of CML under the different treat-

ment modalities; the determination of adverse drug reac-tions; and th e comparison of the outcome of bone marrow

transplantations after the different drug therapies. In th epresent report the results of the comparison of hydroxyurea

with busulfan, and in particular, the prolongation of sur-vival of CM L patients treated with hydroxyurea will be re-

ported.

PATIENTS AND METHODS

Study design. The study outline is shown in Fig 1 (see Hehl-

mann et all6 for comparison). After development of resistance to

the randomized drug, therapy was crossed over to the other drug.

Checkpoints were 1) the end of the chronic phase, defined as resis-

tance to doubling of the initial dose of the randomized drug with

cross over of drugs (hydroxyurea for busulfan resistant patients,

busulfan for hydroxyurea resistant patients); 2) resistance to the

alternative therapy; 3) diagnosis of blast crisis; and 4) death. Blast

crisis was diagnosed, if blasts and promyelocytes were more than

30% of peripheral white blood cells (WBCs), or more than 50%ofnucleated cells in the bone marrow. Patients with bone marrow

transplantations were censored as lost to follow up at the time of

transplantation.

Patients. All newly diagnosed patients with CML in chronic

phase were randomized to receive either busulfan or hydroxyurea

when they fulfilled at least one of the following six criteria: general

ill feeling and fatigue, weight loss of more than 10% in 6 months,

unexplained fever of more than 38.5"C on 5 consecutive days, or-

ganomegaly related symptoms, eukocytosisof more than 50 X IO9/

L, thrombocytosis of more than 1 X IO'*/L.Exclusion criteria were no chronic phase (n=5), no treatment

required (n= IO), pretreatment with cytostatics, interferon alphaorsplenic irradiation (n= 6) , lack of informed consent (n= 38), sec-

ond neoplasia (n=

IO), and other reasons that made a therapyaccording to protocol a priori unlikely (n= 1I).

From July 1983 to January 1991,458 patients were randomized

by 60 centers in Germany and Switzerland,226 to receive busulfan

and 23 2 hydroxyurea (see f low diagram in Fig 2). A third arm with

interferon alpha was opened later and is not yet evaluable. Eleven

RA

N

D

0 Busulfan

Whentreatment M Jrequired

I

S L

CML patients had exclusion criteria recognized after randomiza-

tion: not in chronic phase (acceleratedor blastic phase, 9 patients),

decision of patient ( 1 patient), and other reasons ( 1 patient).

One hundred seven patients were censored (52 in the hydrox-

yurea arm, 55 in the busulfan arm) when the following events hap-

pened bone marrow transplantation (44 patients), diagnosis of sec-

ond neoplasia, withdrawal of consent, or noncompliance (63patients). One hundred ninety two patients died- 13 in blast cri-

sis, 34 of CML independent causes. Other causes of death (20 pa-

tients) were infection, hemorrhage, marasm, bone marrow aplasia,

and bone marrow fibrosis. In seven patients the cause of death was

unknown. One hundred forty two patients are in-study and alive

(88 in the hydroxyurea arm, 54 in the busulfan arm).

The present report is based on the 44 1documented and random-

ized CML patients on an intention-to-treat basis. The median ob-

servation time of all 441 patients is 2.03 years (range 0-7.83 years).

Diagnostic investigations. Pretherapeutic diagnostic evaluation

consisted of history, physical examination, complete blood count

including reticulocytes, alkaline leukocyte phosphatase (ALP), and

lactate dehydrogenase (LDH), chromosome analysis, and bone

marrow cytology and histology. Review panels controlled quality of

bone marrow histology and chromosome analyses.

Follow up investigationswere performed and documented every

6 months, at 12 months, and at disease progression (checkpoints I ,

2, and 3). Investigations at 6 month intervals included inquiry for

symptoms (fever, fatigue, drug side effects), physical examination

(spleen size, extramedullary manifestations, adverse drug reactions,

weight), complete blood count including reticulocytes, and LDH.

Investigations at 12 month intervals included chromosome analysis

and bone marrow cytology and histology. In addition, the annual

dosages of the respective drugs were determined.

Therapy. Busulfan was administered in a dosage of 0.I mg/kg/

d. The dosage was reduced when thrombocytopenia ( < I O 0 X IO 9

platelets/L) was present. The initial dosage was continued until the

WBC count was reduced by 50%,and then it was reduced by 50%.

WBC counts were controlled weekly. The dosage was further re-duced by 50%with each further reduction of WBC counts by 50%.

Therapy was discontinued, when the WBC count dropped below 20X 109/L.Therapy was renewed at a WBC count of more than 50 X

109/L. If there was no sufficient therapeutic response or disease

progression the dosage was increased up to twice the initial dose. In

Checkpoint 1 Checkpoint 2 Checkpoint 3 Checkpoint 4

1 r J 1Therapy II) herapy II) iagnosis+eath

resistance resistance of blast

I against crisis

alternative

1 ""i~ Hydroxyurea

T

I Cross over Free

Fig 1. Study outline.

of drugs therapy0

NBMT-patients counted as "lost to follow up "










400 HEHLMANN ET AL

Total no. of randomized patients 622

IFNa Hydroxyurea Busulfan(HU) (sv)

164 232 226

\/Evaluable patients

Excluded becauseofrejectionof CML-I Diagnosis

1Patients enteredin the intcntion-to-treat analysis

HU BU

2 1 216

Hu BU5 7

Drop&t Death Alive

(censored)

HU BU

52 55

(event) (censored)

HU BU Hu BU85 107 Q 54

4

Death after

dropout

Hu BU

12 8

Fig 2. Flow diagr am of r andomiz e d pat ie n t s .

the presence ofrapidly rising WBC coun ts (cell doublin gin less than

2 months) low dose continuo us busulfan therapy was acceptable.

Hydroxyurea was administered a t an initial dosage of 40 mg/kg/

d. Th e initial dosage was reduced in the presence of thromboc yto-

penia (<100X IO 9 platelets/L). Control ofthe blood counts initially

was three times weekly due to the rapid action of hydroxyurea.When the WBC count dropped to below 20 X 109/L the hydrox-

yurea dosage was reduced to 20 mg/kg/d. This dosage was then

adapted individually. If WBC counts rose above 20 X 109/L, thedosage was increased. The dosage was reduced, if the WBC count

dropped below I O X 109/L,and was interrupted, if the WBC count

was below 5 X IO’/L. Therap eutic goal was a normal W BC coun t

(range 5 to 15 x lo9&).

Documentation, At diagnosis and randomization all data were

documented in an initial docum entation form. During the course

of the study docume ntation forms were completed every 6 months.

Whenever a checkpoint was reached (see study outline) a separate

checkpoint form was filed. After a patient had died or was lost tofollow up (including bone marrow transplantation), a final docu-

mentation form was filed. Adverse events were documented ac-cording to WH O grading.

Sample size estimation was done according toGeorge and Desu.” Assuming 01 = 0.05 (two-sided) and 6 =0.20,388 patients (1 94 per group) w ere necessary to detect a relative riskof at least 1.42 in the med ian survival time in favo r of hydroxyurea.

The randomization lists were computed according to Efronl’stratified for participating h ospitals. After getting informed consent

suitable patients were randomized centrally by phone by the Bio-metric Center for Therapeutic Studies.

Five interim analyses were performed as planned in the trial pro-

tocol. The probability for type I error 01 was adjusted followingOB rie n and Fleming,’’ safeguarding an overall error probability <

Biostatistics.

0.05. The required 01 for the final analysis was 0.04009. Th e analy-ses followed the intention-to-treat strategy. Survival was analyzed

with the Kaplan-Meier estimator an d logrank test.20 Analyses for

prognostic factors were performed with Cox proportional hazards

regression model.2’ The calculation of risk groups was performed

with the equation ? Score = exp. [0.0116 (age, 43.4) + 0.0345

(spleen size, 7.51) + 0.0188 ((pla te le t~ /700 )~ 0.563) +0.0887

(peripheral blasts, 2. IO)]. All analyses were performed by the Bio-

metric Cen ter with th e program package SAS.’’The protocol followed the declaration of Helsinki an d

was approved by the ethics committees o f the Universities of M u-

nich and U lm. Informed consent w as obtained from all patients.

RESULTS

Initial patients’ characteristics. The initial characteris-

tics of the 44 1 randomized and documented CML patients

are shown in Table 1 according to treatment group and

Philadelphia (Ph) status. The Ph status was known for 409

patients of which 37 1 (90.7%) were Ph positive ( 187 in the

hydroxyurea, 184 in the busulfan arm). All patients are

shown including the nine patients who were not in chronic

Ethics.

T a b l e 1. C M L Initial P a t i e n t s ’ C h a r a c t e r i s t i cs

BU HU P h f

(n=216) (n=225) (n=371)

Age (vr )

Sex (% male)

Fatigue, general ill feeling (%)

Symptom s due to organomegaly (%)

Weight loss (%)

Fever (%)

Karnofsky index (%)

Splenomegaly (%)Hepatomegaly (%)

Spleen size in cm below cost al margin

Liver size in cm in MCL

Extramedullary manifestatio ns

(skin, lymp hnodes)(%)

Ph-positive (%)*

Additional cy togenetic aberrations (%)

Platelets x 109/L

Hemoglobin (g/dL)

LDH (U/L)

Circulating blast s (%)

Circulating prom yelocy tes (%)

Basophils (%)

Reticulocytes (%o)

Erythroblasts (per 100 WBC)

ALP (index)’

BM blasts (%)tBM promyelocytes (%)t

Grouping int o risk groups (Ph+ only)*

WBCx IO=L

Lo w (%)

Intermediate (%)

High (%I

50.2

60.7

69

37

24

9.4

87.1

72.2

54.6

6. 4

12.9

9

91.5

1 1

161.9

454.3

12.2

725

2.9

4. 5

4. 5

23.0

1 .1

15.2

4. 1

10.1

25.3

41.6

33.1

49.2

52

59

34.7

20.7

4. 5

88.7

72.4

46.6

6. 3

12.6

3.6

89.9

12.9

156.6

488.4

11.9

72 0

3.4

4.5

4.5

23.7

0.9

16.0

4.4

10.7

26.0

35.0

39.0

47.8

58.8

64

36

19

7

88.2

71.9

49.2

6.5

12.6

6

100

9. 8

169.1

493.9

12.1

749

3.1

4.7

4. 9

23.3

1 .o15.5

3.9

10.1

25.7

38.2

36.2

All features not specified as otherwise were recor ded n 95% to 100%

Features recorded n 93% (cytogenetics)an d 80% ALP) of pat ients.

t Features recorded n 74% of cases.

t Features recorded in 92.5%o f Ph+ patients.

of pat ients.












402

0 . 2 :

0 . 1 :

Hydroxyurea, n =225, median: 47 months

............ Busulfan, n =216, median: 37 months

:.......,..........

......, ..........

HEHLMANN ET AL

p =0.04

0 I 2 3 1 5 6 7 8

busulfan therapy was 20 months, that of secondary hydrox-

yurea therapy I I .7 months. Eleven patients progressed to

blast crisis within 1 m ont h after crossover (four in the group

with primary hydroxyurea therapy, seven in the group with

primary busulfan therap y). Because of secondary resistance

before blast crisis (checkpoint 2) interferon alpha was addedin seven cases (four busulfan patients, three hydroxyurea

patients), othe r chemotherapy (arabinosylcytosin, mitomy -

cin, thioguanin) in 10 patients (five in each therapy group).

It is evident from Fig 7 that secondary busulfan after hy-

droxyurea resistance has an additional im pact on survival.

There is a survival advantage for primary hydroxyurea an dsecondary busulfan in all subgroups of Table 2. Most nota-

bly, patients with cytopenia and/or bone marrow aplasia,who carry a poor prognosis, are only found in the primary

busulfan group. But even w ithout the 16 cytopenic patients,

the survival difference between the treatm ent groups after

crossover is significant (P= .01).

Once blast crisis has developed no survival difference is

observed between the treatment groups (data not shown).

Cytogenetic response rates. Fo ur patients in the hydrox-

yurea arm and two patients in the busulfan arm showed

cytogenetic responses (redu ction of Ph-po sitive cells by 10%

to 100%)during the course oftherapy corresponding to 3%

and 2% of the evaluable patients. O ne complete cytogeneticremission was observed in a hydroxyurea treated case. Someof the responses may be du e to additional therapy added tothe monotherapy later on when secondary resistance was

observed (checkpoint 2) (the on e case with a com plete cyto-genetic remission also had polychemotherapy, ano ther casealso had interferon alpha).

Data were available from 20 9 patientstreated with hydroxyurea and from 204 patients treatedwith busulfan. T he frequency of adverse effects is lower withhydroxyurea tha n with busulfan ( 1 5. 8 vs 24.2 symptoms per100 patient years). Most impo rtantly, serious adverse effectssuch as long lasting bone marrow aplasia or lung fibrosiswere virtually not observed in the hydroxyurea arm (one

Adverse effects.

Fig 5. Duration of chronic

phase (time from diagnosis to

resistance to randomized ther-

years apy or blast crisis).

transient event under hydroxyurea vs 13 events in the bu-

sulfan arm). This low toxicity may have facilitated a possi-

bly mo re intensive treatm ent with hydroxyurea.

Since one rea-

son for the difference of survival might be a difference in

disease control, we analyzed the WBC cou nts in both grou ps

during the first 24 mon ths of treatment. After 18 and 24

months 43 % and 34% of the hydroxyurea-treated, but only

11 % an d 16% of the busulfan-treated patients h ad norm alWBC counts, respectively. In the hydroxyurea group pa-

tients with normal WBC counts had a survival advantage

compared with those with elevated counts (P<.06).

Correlationof survival with WBC counts.

DISCUSSION

Th e most im port ant observation in this study is the signifi-

cantly better median survival of the patients treated with

hydroxyurea as compared w ith those treated with busulfan.

This result confirms som e reports of a possible survival ad-

vantage by hydroxyurea in small, uncontrolled

but the m agnitude of the survival advantage cam e as a sur-prise. Th e result raises several biologic as well as therapeutic

questions.First, the question has to be addressed whether hydrox-

yurea prolongs the survival of CML patients or whether

busulfan therapy was suboptimal. Th e median survival tim eof 45.4 mo nths with busulfan com pares well with an earliercontrolled study that finds a median survival of busulfan-treated CML patients of 44 months.6 In addition, it has to beexcluded that the survival difference is due to an unequaldistribution of prognostic factors. In Table 1 we show thatthe relevant prognostic parameters as well as the distribu-tion of risk groups did not favor the hydroxyurea group.

There were more hydroxyurea patients in the high riskgroup (39% vs 33%),although this was no t significant. Wetherefore conc lude tha t the survival difference is the resultof the different therapies.

Second, the apparent prolongation of survival of the hy-droxyurea group is contrary to so me earlier notions on pro-










CML: PROLONGATION OF SURVIVAL BY HYDROXYUREA

' . O

0 . 9

0 . 8

.2 0 . 1

e5 0 . 6

> 0 . 5

0 . 4

-m

L

0

---r)

403

.........7;:IBusulfan, n=42

L..+.+.

:.7 .............+i-4:

....

\:.....I.. 1 :.._____._.

*

I. ...............I... .-

L.1 ........................

g 0.3:

I . o

0.9

0 . 8

L) .........,.

- 0 7

2 0 6

m>

3

0

.-

2 0 . 5

0 . 2 :

x

Dm

=- 0 . 4

D 0 . 3

za 0 . 2

.-

4

0.

0 . 0

!... ...l e0 1 2 3 4 5 6 7 8

- ydroxyurea, n =69Busulfan, n=55

1 . 0

- 0 7 1CO>

3

0

.-0 . 6 -tz 0 . 5 :

.2 0 . 4 -

2a O . ? -

..........

treatment groups according to

risk group (Sokal's prognostic 0

0 . 0 '-,, , , , . , , , , , , , . . . . . . . , . . . . I " " " ' ' ' I " ' ' ~ ~ " ' ~ ~ " ' " ' " ~ ~ ~ ' " ~ ~ ' ' , ' ' I . ,ig 6. Survival curves of t he

. ,I 2 > 4 5 6 7 8

yearscore: [A ] low risk; [B ] interme-

diate risk; [C] high risk).










404 HEHLMANN ET AL- rimary hydroyurea (followed by busulfan) n =23.median survival 5.6 years

b 10 . 8 :

0 . 1 : p= 0.02

.... ............................

.(...,

............

............I +................

6 7 0years

0 . 6 -

0 .5 : -

0 . 4 :

0 3 - i j

, I , , , , , , , , , , , , I , , , a , : , , , , . , , , , , , , , , , , , , , , , , , , , , ( , I , , , , , , , ,~, , , , , , , , ,

0 1 2 3 4 5- rimary hydroxyurea (n =23). median survival 2.45 years

__ _._

rimary busulfan (n =41), median survival0.9years

p =0.002

0 . 6 -

0 . 5 :

0 . 4 -

0 . 3 :

0 . 2 -4 L........................

.__,LI............................. I....I

Fig 7. Survival after cross-

8 7 , I . , ' 1 I - * * 8 r r I 8 8 " 1 , I " ' I ' 9 I r l - rm-mq- over of therapy (checkpoint 1).

7 8 (A) Survival from diagnosis; (B )

years survival from crossover.0 1 2 3 4 5 6

gression of CM L that the course of CM L is determined by

intrinsic factors rather th an This has to be ana-

lyzed also in the context o fth e good survival data with inter-

feron alpha (our unpublished On e inter-

pretation would be tha t a decrease of tumo r mass and/or a

slowing of granulocyte proliferation rate decreases the pro-gression rate to blast crisis. The hypothesis would be th at thenumber of clonal cells in the mitotic pool correlates withlikelihood of blastic transformation implying that the less

tumor burden and proliferation are present the less likelyblastic transformation might occur. Th is hypothesis is sup-ported by the observation of Kolitz e t a129 tha t intensivehydroxyurea therapy induces cytogenetic responses in nineof 14 patients of 25% to 100%and that th e level of bonemarrow hypocellularity correlates with cytogenetic re-

sponse. If this hypothesis is true, the more efficient reduc-tion of WBC counts, which probably reflect tumor cellmass, by hydroxyurea m ight in part acco unt for the survivaladvantage.

Therefore, if there is a correlation between tumor mass

and probability of blastic transformation, a m ore efficient

reduction of WBC counts by the c omb ination of suitable

antiproliferative drugs might result in a further prolonga-

tion of survival in CM L (eg, hydroxyurea and interferon

alpha as in our ongoing randomized CM L study I1 or combi-nations wi th arab in osy lcy t~ sine ) .~~In this context, the question has to be addressed why in-

tensive combination chemo therapy did not show prolonga-tion of survival as observed w ith h y d r o x y ~ r e a . ~ ~ ' ~ ~ ~ ' ~ ~ ~hegoal of these studies, however, primarily w as cure of CML

by the intensive approach and not continuous control ofmyeloproliferation over extended periods of tim e as in ou r

study.Finally, the high mutagenic potential of busulfan with

subsequent promotion of acute leukemia as observed inpolycythemia verag3 as to be considered. Although the me-dian survival time of the busulfan-treated patients of morethan 45 months is longer than that of historic controls of











Table 2. Reasons for, and Survival After , Crossoverof Therapy

Before Blast Crisis

Patients (mean survival

after crossover in years)

Primary Primary

Reasons or Crossov er Busulfan Hydroxy urea C

Progressive thro mbocyto sis ' lO(1.8) 8(2.6) 18

Resistance with progression of disease 9 (0.4) 9 (2.1) 18

Resistance with progression of disease

and cytopenia and/or b one marrow

aplasia 16 (0.7) - 16

Various reasonst 6(1.7) 6(2.4) 12

c 41 (1.0) 23 (2.2) 64

Platelets of in general m ore than 1million/pL or rapidly rising plate-

lets above ca. 700.000/pL in spite of intensific ationof therapy (doubling

of initial dose).

t Intolerable adverse reactio ns ( 5 ) .primary (a priori) drug resis tance

(3). ecision of patients (2),BMT ( I ) ,unknown ( 1 ) .

untreated CML patients,' or of CML patients treated withsplenic irradiation,'.' it cannot be excluded that its muta-

genic effect has a negative impact on survival, which be-

comes visible, if busulfan is compared with hydroxyurea.

A third observation of interest is the apparent gain of

survival time by secondary busulfan after primary hydrox-

yurea therapy. Although the number of patients qualifying

for an adequate trial with secondary busulfan is small (n =

19, 8.4% of hydroxyurea-treated patients), the survival ad-

vantage is significant and adds to the survival advantage of

the hydroxyurea arm described in this report. Busulfan

turned out t o be inferior to hydroxyurea as first line therapy,

but apparently plays a role after hydroxyurea resistance.One reason for the poor success of secondary hydroxyurea

treatment after primary busulfan seems to be the high num-

ber of patients with cytopenias and/or bone marrow aplasia

after busulfan therapy, which was not observed after pri-

mary hydroxyurea therapy. This agrees well with the known

toxicity pattern of busulfan.24 t appears that in the presenceof busulfan-induced cytopenias hydroxyurea cannot add

any survival advantage.

We cannot entirely exclude that our survival results are

influenced by an earlier diagnosis than in previous eras. Our

inclusion criteria for randomization and therapy, however,excluded patients who were very early in the course of dis-

ease. In addition, the percentage of our patients in the low-risk group is in contrast to Sokal's patient^'^.^^ lower than

that in the intermediate- and high-risk groups. This distri-bution argues against the possibility that our favorable sur-

vival results are due t o a high number of low-risk patients orearlier diagnosis.

Since all parameters included in this report have beendocumented prospectively under the same mandatory mo-

dalities, the patient sample is well suited for the generationof a prognostic score (score 1) based on prospectively col-lected parameters35 as well as a detailed histomorphologiccharacterization of CML according to Ph status and clinicalcourse, which is ongoing.

We conclude that hydroxyurea is superior to busulfan in

therapy of CML in chronic phase and should be used as first

line therapy. Busulfan may, however, have a role as second

line treatment after hydroxyurea resistance or intolerance.The importance of the reduction of WBC in the chronic

phase for prolongation of survival in CML, irrespective of

the cytostatic drug used, will be analyzed further within on-

going randomized studies.

ACKNOWLEDGMENT

The assistance of Dr A. Kiittel, B. Knichel, M. Dumke, and G.

Alter is gratefully acknow ledged.

APPENDIX

Participating institutions: Hamatolog.-onkol. Praxis, Aa-chen; Abteilung fur Onkologie/Abteilung fur Hamatologie,

Kantonsspital Basel; Onkologische Praxis Basel; Abt. In-

nere Medizin U. Poliklinik, Universitatsklinikum Rudolf

Virchow, Berlin; Hamatologische Praxis, Berlin; Medizin-

ische Klinik, St. Joseph Hospital, Bremerhaven; Med.Klinik 11, St. Johannes Hospital, Duisburg; Abt.

Hamatologie/Onkologie, Med. Universitatsklinik, Frei-

burg; Zentrum der Inneren Medizin, Abt. f. HamatologieU.

Onkologie, Frankfurt; Med. Klinik IV mit Hamatologie

und Onkologie, GieBen; Medizinische Univ.-Klinik, Ham-

burg-Eppendofi, Hamatolog.-onkol. Praxis Altona, Ham-

burg; Allgemeines Krankenhaus Barmbek, Hamburg; On-

kologische Ambulanz, Med. Univ. Klinik, Heidelberg;Medizinische Poliklinik, Heidelberg; Innere Abteilung,

Stadtkrankenhaus Kempten; Med. Klinik 11, Universitilt

&el; I. Med. Klinik der Universitat Koln; 11. Med. Klinik,

Klinikum Karlsruhe; 111. Medizinische Klinik, Klinikum

Mannheim der Universitat Heidelberg, Mannheim; 111.Med. Klinik, Klinikum GroBhadern der Universitat

Miinchen; Med. Klinik Innenstadt der Universitat

Munchen; Med. Poliklinik der Universitat Miinchen;

Miinchner Onkologische Praxis; Med. Klinik, St. Elisa-

bethen Krankenhaus, Ravensburg; Onkologische Abtei-lung, Kantonsspital St. Gallen; Innere Medizin 111, Med.

Klinik U. Poliklinik, Ulm; Med. Poliklinik der Universitat

Wurzburg; Innere Abteilung, Kreiskrankenhaus Aalen; On-

kolog. Gemeinschaftspraxis, Frankfurt/M.; Allgem. Kran-

kenhaus Altona, Hamburg; Onkolog. hamatolog. Schwer-

punktpraxis, Berlin; I. Med. Abteilung, Stildt. Krankenhaus

Schwabing, Miinchen; IV. Med. Abt., Stildt. Krankenhaus

Miinchen-Harlaching; St. Willehad Hospital, Wilhelmsha-ven; Hamatologische Praxis, Miinchen; I. Med. Klinik,

Klinikum der Christian-Albrechts-Universitat Gel; IV.

Medizin. Abt., Krankenhaus Miinchen-Neuperlach; InnereAbt., Kreiskrankenhaus Boblingen; 11. Innere Abteilung,

Krankenhaus Berlin-Neukolln; Hamatologisches Zentralla-bor der Universitiit, Inselspital Bern; V. Med. Klinik desKlinikums Niirnberg; Stadt. Krankenhaus Kaiserslautern,Med. Klinik D 6, Kaiserslautern; Zentrum Innere Medizin,Abt. f. Himostaseologie, Klinikum Niirnberg; Klinik f. In-

nere Medizin, Onkologie/Hamatologie, Stildt. KlinikenOldenburg; Kinderklinik und Poliklinik, Universitats

klinikum Rudolf Virchow, Berlin; KreiskrankenhausFussen; Innere Abteilung, Luisenkrankenhaus, Lindenfels/










406 HEHLMANN ET AL

Odenwald; Poliklinik der Universitat Erlangen; Klinik f.

Hamatologie/Onkologie, St. Antonius Hospital, Esch-

weiler; I. Med. Klinik, Abt. f. Hamatologie U. Onkologie,

Klinikum rechts der Isar, Munchen; Onkologische Abtei-

lung, Krankenhaus der Barmherzigen Briider, Regensburg;

Innere Abteilung, Stadt. Krankenhaus, Penzberg; Medizin-

ische Klinik B, Klinikum der Landesh auptstadt Wiesbaden;Abt. Innere Medizin 11, Marien Hospital, Hagen; Med.

Klinik, Hans-Susemihl-Krankenhaus, Emden; Praxisge-

meinschaft Dr. Zankovich, Koln; Innere Abteilung, Dia-

konie-Kranken haus, Schwabisch Hall; Medicina interna ed

ematologia FMH, Lugano; I. Medizinische Klinik, Zen-

tralkrankenhaus St. Jurgen-StraBe, Bremen; Institut fu r

Med. Informationsverarbeitung, Statistik und Biomathe-

matik der LMU und Institut fur Med. Statistik und Epi-

demiologie der TU uber Biometrisches Zentrum fu r

Therapiesstudien (BZT), Munchen; Abt. f. Klinische Phy-

siologie U. Arbeitsmedizin der Universitat Ulm; Im-

munhamatologisches Labor der Med. Klinik und Poli-

klinik, Universitat Ul m; Pathologisches Institut der MH H,Hannover; Abt. f. Knochenmarksdiagnostik an der Med.

Klinik Innenstadt der Universitat Munchen; Institut f.

Klinische Immunologie der MHH, Hannover; Patholo-

gisches Institut der Universitat Koln; Sektion Molekular-

biologie/Padiatrie 11, Blutspendezentrale Ulm.

REFERENCES

I . Minot GR, Buckman TE, Isaacs R: Chronic myelogenous

leukemia. Age, incidence, duration and benefit derived from treat-

ment. JAMA 82:1489, 1924

2. Thom as ED, Clift RA: Indications for marrow transplanta-

tion in chronic myelogenous leukemia. Blood 732361, 1989

3. Beatty PG, Anasetti C, Hansen JA, Longton GM , Sanders JE,Martin PJ, Mickelson EM, Ch oo SY, Petersdorf EF, Pepe MS, Ap-

plebaum FR, Bearman SI, Buckner CD, Clift RA, Petersen FB,

Singer J, Stewart PS, Storb RF, Sullivan KM, Tesler MC, Wither-spoon RP, Thomas E D Marrow transplantation from unrelated

donors for trea tme nt of hematologic malignancies: Effects of mis-

matching for one HLA locus. Blood 8 1 249, 1993

4. Heh lmann R : Cytostatic therapy in chronic myelogenous leu-

kemia: Review and perspectives, in Hu hn D, Hellriegel KP, Nie-

derle N (eds): Chron ic Myelocytic Leukemia an d Interferon . Berlin,

Germ any, Springer Verlag, 1988, p 102

5. Hau t A, Abbott WS, Wintrobe MM , Cartwright GE: Busulfan

in the treatmen t of chronic myelocytic leukemia: Th e effect of long

term intermittent therapy. Blood 17: , I9 6 1

6. Canellos GP, Young RC, Nieman PE, DeVita VT, Jr: Dibro-momannitol in the treatm ent of chronic granulocytic leukemia: A

prospective randomize d com parison w ith busulfan. Blood 45: 197,1975

7. Medical Research Council’s Working Party for Therapeutic

Trials in Leukemia: Chronic granulocytic leukemia: Comparisonof radiotherapy and busulfan therapy. Br Med J (Clin Res) 1:201,

19688. Cunningham I, Gee T, Dowling M, Chaganti R, Bailey R,

Hopfan S, Bowden L, Tur nbu ll A, Knap per W, Clarkson B: Results

oftreatm ent of Ph’+ chronic myelogenous leukemia with an inten-sive treatment regimen (L-5 protocol). Blood 53:375, 1979

9. Go to T, Nishikori M, Arlin Z, Gee T, Kempin S, Burchenal J,Strife A, Wisniewski D, Lambek C, Little C, Jhanwar S, ChagantiR, Clarkson B: Growth characteristics of leukemic and normal he-

matopoietic cells in Ph ’+ chronic myelogenous leukemia and ef-

fects of intensive treatment. Blood 59:793, 1982

IO . Kantarjian HM, Velekoop L, McCredie KB, Keating MJ,

Hester J, Smith T, Barlogie B, Trujillo J, Freireich EJ: Intensive

combination chemotherapy (ROAPIO) and splenectomy in the

management of chronic myelogenous leukemia. J Clin Oncol

3:192, 19851 . Kennedy BJ: The evolution of hydroxyurea therapy in

chronic myelogenous leukemia. Semin Oncol 19:2 I , 1992 (supp l9)

12. Kennedy BJ: Hydroxyurea therapy in chronic myelogenous

leukemia. Cancer 29:1052, 1972

13. Schwarzenberg L, Math6 G, Pouillart P, Weiner R, Locour J,

Genin J, Schneider M, de Vassal F, Hayat M, Amiel JL, Schlum-

berger JF, Jasmin C, Rosenfeld C: Hydroxyurea, leukapheresis an d

splenectomy in chronic myeloid leukemia at the problastic phase.

Br Med J (Clin Res) 1:700, 1973

14. Schwartz JH, Canellos GP: Hydroxyurea in the manage-

ment of the hematologic complications of chronic granulocytic leu-

kemia. Blood 46:l I , 1975

15. Bolin RW, Robinson WA, Sutherland J, Ham man R F Bu-

sulfan Venus hydroxyurea in long -term therapy of chronic myeloge-

nous leukemia. Cancer 50:1683, 198216. Hehlmann R, Anger B, Messerer D, Zankovich R, Berg-

mann L, Kolb HJ, Meyer P, Essers U, QueiDer U, Vaupel H,

Walther F, Hossfeld DK, Zimmermann R, Heiss F, Mende S,

Tigges FJ, Kleeberg UR , Pralle H, Kayser W , Tichelli A, Faulhab er

JD, Rath U , Schubert H, Bross K, Schlag R, Schmid L, WeiGenfels

I, Heinze B, Georgii A, QueiDer W, Heimpe l H: Randomized study

on the treatment of CML in chronic phase with busulfan versushydroxyurea versus interferon alpha. Blut 56237, 1988

17. George SL, Desu MM: Planning of size and duration of a

clinical trial studying the time to some critical event. J Chron Dis

27: 15 , 197418. Efron B: Forcing a sequential experiment to be balanced.

Biometrika 58:403, 1971

19. OBrien PC, Fleming TR: Multiple testing procedure forclinical trials. Biometrics 35:549, 1979

20. Kalbfleisch JD , Prentice R L Th e Statistical Analysis of Fail-

ure Time Data. New York, NY, W iley, 1980

2 I . Cox D R: Regression models an d life-tables (with discussion).J Roy Stat SOC 4: 187, 1972

22. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez C A, Robert-

son JE, Tso CY, Braun TJ, Clarkson BD, Cervantes F, Rozm an C,

the Italian Cooperative CML Study Group: Prognostic discrimina-

tion in “good-risk’’ chronic granulocy tic leukem ia. Blood 63:789,

1984

23. SAS Institute Inc: SAS/STAT User’s Guide, version 6 ,

fourth ed, vol 1. Cary, NC, SAS Institute, 198 9,94 324. Galton DAG: Chemotherapy of chronic myelocytic leuke-

mia. Semin Hematol 6:323, 1969

25. Sokal JE: Evaluation of survival data for chronic myelocyticleukemia. Am J Hematol 1:493, 1976

26. Talpaz M, Kantarjian H , Kurzrock R, Trujillo JM, Gutte r-

man JU: Interferon alpha produces sustained cytogenetic responsesin chronic myelogenous leukemia. Ann In tern Med 1145 32, 1991

27. Alimena G , Morra E, Lazzarino M, Liberati AM, Montefu-sco E. Inverardi D, Bernasconi P, Man cini M, Do nti E, Grignani F,

Bernasconi C, Dianzani F, Mandelli F Interferon alpha-2b as ther-apy for Ph’-positive chronic myelogenous leukemia: A study of 82patients treated with intermittent or daily administration. Blood

72:642, 198828. Thaler J, Kiihr T, Gastl G, Huber H , Duba C, Kemmler G ,

Gattringer C, Fluckinger T, Niedenvieser D, Seewann H , Abbre-dens K, Lang A, Gadner H, Fereberger W, Schiller I, Hausman-inger H, W eitgasser R, Michlmayr G,Fridrik M, H uber C: Rekom-











binantes Interferon a-2c bei Ph-positiver chronischer myeloischer

Leukamie. Ergebnisse einer multizentrischen Phase-11-Studie.

Deutsche Med Wochenschr 116:72 , I991

29. Kolitz JE, Kempin SJ, Schluger A, Wong CY, Berman E,

Jhanwar S, Arlin ZA, Gee T, Clarkson BD: A phase I1 pilot trial of

high-dose hydroxyurea in chronic myelogenous leukemia. Semin

Oncol 19:27, 1992 (suppl 9)30. Guilhot F, Dreyfus B, Brizard A, Huret J-L, Tanzer J: Cyto-

genetic remissions in chronic myelogenous leukemia using inter-

feron alpha-2a and hydroxyurea with or without low-dose cytosine

arabinoside. Leuk Lymphoma 4:49, 1991

3 1. BaccaraniM , Corbelli G, Tura S, and the Italian Cooperative

Study Group on Chronic Myeloid Leukemia: Early splenectomy

and polychemotherapy versus polychemotherapy alone in chronic

myeloid leukemia. Leuk Res 5:149, 1981

32. Kantajian HM, Smith TL, McCredie KB, Keating MJ,

Walters R, Talpaz M, Hester JP, Bligham G, Gehan E, Freireich EJ:

Chronic myelogenous eukemia:A multivariate analysis ofthe asso-

ciations of patient characteristicsand therapy with survival. Blood

66:1326, 1985

33. Berk PD, Goldberg JD, Donovan PB, Fruchtman StM, Ber-

lin NI , Wasserman L R Therapeutic recommendations in polycy-

themia vera based on polycythemia vera study group protocols.

Semin Hematol 23:132, 1986

34. Sokal JE, Baccarani M, Tura S, Fiaccini M, Cervantes F,Rozman C, Gomez CA, Galton DAG, Canellos GP, Braun TJ,

Clarkson BC, Carbonell F, Heimpel H, Extra JM, Fiere D, Nissen

NI , Robertson JE, Cox E B Prognostic discrimination among

younger patients with chronic granulocytic eukemia: Relevance to

bone marrow transplantation. Blood 66: 1352, 1985

35. Hehlmann R, Heimpel H, Griesshammer M, Kolb HJ,

Heinze B, Hossfeld DK, Wickramanayake PD, EssersU, Thiele J,

Georgii A, Ansari H, Hochhaus A, Hasford J, and the German

CML Study Group: Chronic myelogenous leukemia: Recent devel-

opments in prognostic evaluation and chemotherapy. Leukemia

6: I IOS, 1992 (suppl3)








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