GYNECOLOGIC ONCOLOGY 6, 115-120 (1978)

CASE REPORT

Acute Leukemia following Chlorambucil Therapy of Advanced Ovarian and Fallopian Tube Carcinoma’

JOHN MORRISON, LCDR, MC USN,* AND JOSEPH L. YON, CAPT, MC USNtx2

*Department of Internal Medicine, Hematology-Oncology Branch, and TDirector, Division of Gynecologic-Oncology, Naval Regional Medical Center, San Diego,

California 92 134

Received May 9, 1977

Acute leukemia developed in two patients, one with advanced ovarian carcinoma and the other with advanced carcinoma of the fallopian tubes. Both patients received chlorambucil as a part of their treatment regimen. The literature is reviewed and updated since the report of Sotrel et a/. [O&et. Gynecol. 47, No. I (Suppl.), 67s-71s (1976)], and a rationale for the use of high-dose intermittent chlorambucil therapy in the treatment of ovarian carcinoma is presented for consideration.

In a recent report, Sotrel el al. [I] summarized the nine known cases of acute leukemia occurring after chemotherapy of advanced ovarian carcinoma. Since that report, four additional cases have occurred; two of these have been reported elsewhere [21, and the remaining two are reported herein. Pertinent aspects of the cases are shown in Table I.

Case I CASE REPORTS

A 47-year-old Caucasian female was seen in consultation by the Hematology Department in July 1974 for pancytopenia. Past medical history and examination of medical records showed that she underwent a total abdominal hysterectomy and a bilateral salpingo-oophorectomy in December 1972 for Stage III ovarian carcinoma. At the time of surgery, a papillary cystadenocarcinoma of the right ovary invading the right meso-ovarium was found. Postoperatively, she received 3000 rad (cobalt-60) to the midplane of the abdomen and 5000 rad to the midplane of the pelvis. X-ray therapy was completed in February 1973. In May 1973, chlorambucil therapy was begun at a dose of 2 mg po daily and continued at this dose level until July 1973, when the dose was reduced to 2 mg po qod. In August

I The opinions or assertions expressed herein are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the naval service at large.

E Address reprint requests to Joseph L. Yon, CAPT, MC USN, Director, Division of Gynecologic-Oncology, Naval Regional Medical Center, San Diego, California 92134.

0090-8258/78/0061-01 ISSOl .00/O Copyright @ 1978 by Academic Press. Inc.

All rights of reproduction in any form reserved.

TABL

E I

REPO

RTED

CA

SES

OF

ACUT

E LE

UKEM

IA

AFTE

R CH

EMOT

HERA

PY

FOR

OVAR

IAN

CARC

INOM

A,

1976

-1977

Inter

val

from

Do

se

of pr

imar

y to

PlW.e”

Ce

Leng

th of

chem

o-

seco

ndary

Su

rviva

l tim

e Ca

se

Initia

l of

prim

ary

chem

othera

py

therap

y Ty

w

of m

align

ancy

aft

er

diagn

osis

tum

or

on r

e-

num

ber

Refer

ence

Ag

e m

align

ancy

Tr

eatm

ent

(mon

ths)

(mg)

leu

kem

ia (ye

ars)

(mon

ths)

eXplO

Mi0”

IO

2 39

Ov

aria”

Su

rger

y, 30

IO

-12

Eryth

ro-

4 7

Not

report

ed

carci

nom

a, ch

loram

bucil

daily

leuke

mia

stage

III

II

2 62

Po

orly

differ

entia

ted

Surg

ery,

50

6 da

ily Er

ythra

- 4

2 No

t rep

orted

ad

enoc

arcino

ma,

4ooo

rad

leuke

mia

right

“va

ry to

pelvis

, ch

loram

bucil

Pres

ent

- 47

Pa

pillar

y Su

rger

y, 4

7-w

Acute

2.7

5 IO

Ye

s (a

t po

st-

case

I

CYSt%

k”O-

8MlO

rad

, da

ily x

3 “ly

elo-

(No.

12)

mor

tem

) ca

rcino

ma,

chlor

ambu

cil m

onths

; 2

cytic

sta

ge

III

@

x leu

kem

ia I

mon

th Pr

esen

t -

45

Papil

lary

Surg

ery,

I9 16

PO Ac

ute

2.5

Still

living

No

(on

ca

se

2 alV

eOlW

ch

loram

bucil

daily

x un

differ

entia

ted

(No.

13)

in re

miss

ion

seco

nd

look)

aden

ocarc

inoma

2

mon

ths;

8 leu

kem

ia of

fallop

ian

po

daily

tubes

, x

17 m

onths

sta

ge

III

CANCER CHEMOTHERAPY AND ACUTE LEUKEMIA 117

1973, therapy was discontinued because of leukopenia. A bone marrow examina- tion was performed at the time of initial consultation in July 1974. The marrow was markedly damaged and hypocellular without any evidence of leukemia or lym- phoma.

The patient was next seen on September 17, 1974, when she was hospitalized with a 2-week history of fever, “cold sores” on the lower lip, and ulcerations of the uvula and the soft palate. Initial CBC showed a leukocyte count of 37,000/mm3 with 6% blast forms, 32% atypical monocytoid forms, 18% polymorphonuclear leukocytes, 22% band forms, and 22% lymphocytes, a platelet count of 61 ,OOO/ mm3, and a Hct of 24%. Repeat bone marrow examination revealed a hypercellular marrow with 50% blasts, some of which contained Auer rods. A diagnosis of acute granulocytic leukemia was made, and she was started on chemotherapy with 6-thioguanine and Ara-C. After a stormy course complicated by sepsis, she was discharged in November 1974, in complete remis- sion.

Relapse of the leukemic process occurred in February 1975. Weekly pulses of cyclophosphamide, Ara-C, and methotrexate again resulted in complete remission of the leukemic process. This time, however, the course was complicated by sepsis with Escherichia coli and Klehsiella. The patient was finally discharged on April 29, 1975.

The last admission, for gastrointestinal bleeding and progressive abdominal distention, occurred on May 22, 1975. The patient expired on May 27, 1975. At postmortem examination, the pathologic findings were: metastatic adenocar- cinema to the liver, abdominal soft tissue and hilar lymph nodes, bilateral pleural effusions, and multiple abdominal adhesions with functional bowel obstruction. A bone marrow examination revealed 8% blast forms.

Case 2

A 42-year-old G,P,A, Caucasian female was admitted to the hospital in May 1974, with the clinical impression of bilaterial adnexal masses. Exploratory celiotomy revealed a 7-cm left adnexal mass and a 6-cm right adnexal mass. Frozen section revealed adenocarcinoma. A total abdominal hysterectomy, bilat- eral salpingo-oophorectomy, open biopsy of the sigmoid colon, biopsy of the retroperitoneal para-aortic nodes, and sigmoid colostomy were performed.

The pathologic report showed papillary alveolar adenocarcinoma of the fallopian tubes with metastasis to the ovary and retroperitoneal nodes. The colon wall showed endometriosis. Peritoneal washings were positive for malignancy.

Postoperatively, in May 1974, the patient was begun on continuous chemotherapy with chlorambucil, 16 mg po daily. This was continued until July 1974. At this time, an uneventful reanastomosis of the sigmoid colon was per- formed. The patient was again placed on chlorambucil at a dose of 8 mg po daily, and she continued chemotherapy until December 1975. She did not become overly suppressed hematologically during this period and did not discontinue chemotherapy.

A second-look operation was performed in January 1976. Cell washings and multiple biopsies failed to reveal any evidence of tumor persistence. Chemotherapy was discontinued.

118 MORRISON AND YON

The patient did well until February 1977, when she presented to the Gynecologic Oncology Outpatient Clinic with a 2-month history of malaise, a 3-week history of fever and pain over the right maxillary sinus, and a five-day history of petechial lesions over the trunk and lower extremities. A routine blood count showed a leukocyte count of 82,00O/mm”, hematocrit of 30%, and platelet count of 19,00O/mm”. Peripheral smear revealed 80% of the leukocytes to be blast forms, and the patient was admitted to the hospital.

The admission physical examination was normal with the following exceptions: T = 100(O); gums around both upper and lower molars bilaterally swollen with purplish discoloration; tenderness over the right maxillary sinus; and petechial lesions of the trunk, buttocks, and upper and lower extremities. Bone marrow examination revealed a hypercellular marrow with 80% blast forms which failed to stain with Sudan Black B or with periodic acid-Schiff. A diagnosis of acute undifferentiated leukemia was made, and the patient was treated with Doxorubi- tin and Ara-C. A complete remission was achieved, and the patient is currently doing well as an outpatient in complete remission.

DISCUSSION

The oncogenic properties of X-ray therapy and of many commonly used chemotherapeutic agents have been well shown experimentally, but extrapolation of these data to human cases has been more difficult. At the present time, the role of these agents as inducers of secondary malignancy in humans is strongly suspect [3-51 but not proven.

Reports of acute leukemia complicating the course of advanced ovarian car- cinoma continue to accrue. In all of the cases reported to date [I, 2, 6-91 chemotherapy has been a part of the treatment regime; in one of our cases and in two others in the literature [6,9] X-ray therapy was also administered. Even more disturbing is the observation that in five of these cases [ 1,6,7,93, including one of our cases, complete eradication of the primary malignancy was achieved with the chemotherapy employed.

Since the last six patients reported in the literature (our cases included) have received continuous therapy with chlorambucil prior to the development of their leukemia, it may be advantageous in future cases to place these patients on a high-dose intermittent chlorambucil regime similar to the high-dose intermittent phenylalanine mustard regime used to treat myeloma and ovarian carcinoma. One regime used in the treatment of chronic lymphocytic leukemia employs chloram- bucil in doses of 0.4-0.5 mg/kg body weight as a single po dose which is repeated at 2-week intervals [IO].

Such a dose schedule, if effective, would offer the patient a possible advantage. It would allow time for recovery of both cellular and humoral immune function which had been suppressed by the agent employed and would allow the “rebound-overshoot” phenomenon of immune recovery to occur [ 111. The latter phenomenon has been associated with a good response of solid tumors to the chemotherapeutic agent employed [ 111. Moreover, it has been suggested that with continuous chemotherapy, one runs the risk of suppressing those elements of the immune response necessary for tumor destruction [12, 131.

CANCER CHEMOTHERAPY AND ACUTE LEUKEMIA 119

At present, the optimal length of time to achieve a chemotherapeutic cure of advanced ovarian carcinoma is unknown. The length of time may vary and may depend on the type of chemotherapeutic agent or agents employed, the dose of the drug used, and the timing of drug administration. It is apparent that answers to the above questions will be forthcoming only through the use of prospective, con- trolled trials employing judicious use of ultrasound, peritoneoscopy, and, if neces- saw , “second-look” procedures.

ADDENDUM: CASE REPORT

We have recently encountered a case of di Guglielmo’s syndrome in a 56-year- old Caucasian female successfully treated with high-dose pulse phenylalanine mustard (Alkeran) therapy for Stage III serous cystadenocarcinoma of the ovaries.

The patient, a G,P,A, female with LMP in 1967, presented in February 1975 with abdominal bloating and superficial thrombophlebitis of the right leg. At the time of her surgery in April 1975, 2 liters of abdominal ascitic fluid and serous cystadenocarcinoma of both ovaries with studding of the small bowel and omen- turn was found. After a total abdominal hysterectomy, bilateral salpingo- oophorectomy, and omentectomy, the patient was begun on high-dose pulse Alkeran therapy. Therapy consisted of 30-46 mg of Alkeran taken over a 2-day period, with repeat courses every 3 to 4 weeks. Between May 1975 and November 1976, the patient received 14 courses of chemotherapy, with no evidence of tumor recurrence. The patient received no chemotherapy after November 1976 because of persistent pancytopenia.

Hematologic consultation was obtained in May 1977 because of a slowly falling hematocrit in the absence of bleeding or hemolysis. At this time, a Hemogram revealed an RBC count of 2.41 million/mm3, hemoglobin of 6.5g %, hematocrit of 20. I%, MCV of 83 pm”, platelets of 82,000/mm3, reticulocyte count of 0.6%, and WBC of 3200/mm” with 39 polymorphonuclear leukocytes, 56 lymphocytes, 3 monocytes, and 1 myelocyte/lOO white cells. Peripheral smear showed a dual population of cells; one was normochromic, normocytic and the other hypo- chromic, microcytic. Peripheral smear also showed severe anisocytosis and poikilocytosis, nucleated red blood cells, and target cells; granulocytes were decreased with an absolute count of 1248/mm” and occasional myelocytes were noted; and platelets were decreased with numerous large bizarre forms. Bone marrow examination revealed a fat to cell ratio of 5 to 95, a myeloid to erythroid ratio of less than 1 to 10, and a hypercellular bone marrow with markedly increased, severely dysplastic erythropoiesis, markedly decreased granulopoiesis with few mature forms, dysplastic megakaryopoiesis, and increased iron with numerous ringed sideroblasts. Cytochemistries showed a large number of erythroid precursors containing cytoplasmic periodic acid-Schiff globules ringing the nuclei of the cells. Sudan black stain showed only a very small number of myeloid precursors.

At the present time the patient is being followed with serial bone marrow examinations, and her hematocrit is maintained with transfusions of packed leukocyte poor blood at approximately S-week intervals.

120 MORRISON AND YON

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