Leukemia (2003) 17, 19671972

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A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa,

dexamethasone, and gemcitabine for relapsed or refractory acute leukemia
EA Kolb1 and PG Steinherz1
1

Department of Pediatrics at Memorial Sloan-Kettering Cancer Center, New York, NY, USA

We report the results of a phase 2 nonrandomized single-arm

trial of a combination therapy for relapsed or refractory
leukemia. From January 1999 to June 2002, 28 patients with
multiple relapsed or refractory acute leukemia received a
combination of topotecan, vinorelbine, thiotepa, dexamethasone, and, for patients with an M3 marrow on day 7,
gemcitabine. A total of 14 patients had pre-B-ALL (acute
lymphoblastic leukemia), three had T-cell leukemia, nine acute
myeloblastic leukemia (AML), and two biphenotypic leukemia.
In all, 13 patients achieved a significant response (10 complete
responses and three partial responses). Among the responders, five had pre-B-ALL, two had T-cell leukemias, five had
AML, and one had biphenotypic leukemia. In total, 10 of these
patients subsequently underwent hematopoietic stem cell
transplantation, and four are alive without disease. One patient
died, while in remission, of complications resulting from an
episode of sepsis and pneumonia that occurred during
topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine (TVTG) reinduction. Other toxicities included grade 4
neutropenia in all patients and transient grade 2 hepatotoxicity
in 10 patients (36%). In summary, we report that 47% of heavily
pretreated pediatric patients with multiply relapsed or refractory leukemia achieved a significant response after therapy on
the TVTG protocol. Further studies are warranted to evaluate
the role of the TVTG combination in the treatment of leukemia.
Leukemia (2003) 17, 19671972. doi:10.1038/sj.leu.2403097
Keywords: topotecan; thiotepa; vinorelbine; gemcitabine; leukemia

Introduction
Topotecan is a semisynthetic water-soluble inhibitor of topoisomerase I, and acts in the S-phase of the cell cycle.15 The
unique, cell-cycle-specific effect of topotecan suggests that its
antitumor activity may be schedule dependent. Accordingly,
results in murine xenograft models of human tumors demonstrate peak activity when the drug is given as a protracted
infusion.3 Using similar schedules, excellent antitumor activity
is observed in L1210 leukemia, an aggressive murine leukemia,6
and xenografts of human poor risk acute lymphoblastic
leukemia (ALL).7 Furthermore, recent clinical trials in adults813
and children14 demonstrate that continuous infusion topotecan has antileukemia activity.
Preclinical data suggest that the inhibition of topoisomerase I
by topotecan will render the cell more susceptible to DNAdamaging agents.15 The combination of topotecan, plus either
cyclophosphamide,16 idarubicin,17 etoposide,18 cisplatin,19 or
cytarabine9,11,16,18 exhibits antitumor activity in adult patients
with leukemia9,11,1618 and solid tumors.19 In hematologic
malignancies, thiotepa is an active antileukemic agent that is
successfully used in the cytoreduction regimens preceding
allogeneic stem cell transplantion (SCT).20,21 Additionally, the
Correspondence: E Anders Kolb, Department of Pediatrics, Memorial
Sloan-Kettering Cancer Center, P.O. Box, 1275 York Avenue, New
York, NY 10021, USA; Fax: 1 212 717 3239
Received 28 March 2003; revised 28 May 2003; accepted 24 June
2003

combination of thiotepa, topotecan, and carboplatin followed

by autologous SCT offers a favorable antitumor effect for
pediatric solid tumors.22
Vinorelbine is a semisynthetic Vinca rosea alkaloid.23,24 Early
in vitro data suggest that vinorelbine may have a role in the
treatment the acute leukemias, although it appears to be less
active in acute myeloblastic leukemia (AML) when compared to
acute lymphoblastic leukemia (ALL).23,25,26 In adult solid
tumors, vinorelbine has been used successfully in combination
with both gemcitabine and topotecan,27 but there are no clinical
data to define its role in the treatment of leukemias.
Gemcitabine is a novel deoxycytidine analog with activity in
hematogenous malignancies. The structure and metabolism of
gemcitabine resemble that of cytarabine.28,29 However, after
phosphorylation, gemcitabine achieves higher relative concentrations, and is retained longer than cytarabine.3031 In vitro
cytotoxicity data suggest that gemcitabine has significant activity
in acute leukemias.3234 Furthermore, in clinical studies, either
alone,3538 or in combination with other agents,39,40 gemcitabine has activity against human leukemias.
Glucocorticoids are a mainstay in the treatment of pediatric
lymphoid and myeloid leukemias. Dexamethasone may be
preferable to prednisone due to enhanced penetration into the
cerebral spinal fluid.41 Many hypothesize that saturation of the
glucocorticoid receptor over extended periods of time with high
doses of corticosteroids will optimize the antileukemic effect of
these agents. Results of a recent trial at the Dana-Farber Cancer
Institute support this hypothesis. They observed enhanced bone
marrow and peripheral blood blast response to 18 and 150 mg/
m2/day dexamethasone when compared to the standard 6 mg/
m2/day.42
We report results of an institutional phase 2 nonrandomized
single-arm reinduction protocol, incorporating a combination of
topotecan, vinorelbine, thiotepa, gemcitabine, and high-dose
dexamethasone, for patients with multiple relapsed or refractory
acute leukemias. While the chemotherapeutic agents employed
all share the dose-limiting toxicity of myelosuppression, they
differ in mechanism of action and metabolism. Furthermore,
these are agents not commonly used in current leukemia
protocols, and they therefore offer potentially novel mechanisms
of action, either alone or in combination, against otherwise
heavily pretreated leukemia cells. The TVTG (topotecan,
vinorelbine, thiotepa, dexamethasone, and gemcitabine) protocol is designed to induce disease remission that is of sufficient
duration to identify a matched unrelated stem cell donor, and to
permit hematopoietic stem cell transplantation in a recipient
free of infections and vital organ dysfunction.

Patients and methods

Patients with acute leukemias, who had disease recurrence
despite exhausting all conventional therapeutic options, and/or
were refractory to conventional therapeutic agents, were eligible
for treatment. Between January 1999 and June 2002, 28 patients

Re-induction therapy for refractory leukemia

EA Kolb and PG Steinherz

1968
were treated with a combination of topotecan, vinorelbine,
thiotepa, and dexamethasone, with or without gemcitabine
according to the Memorial Sloan-Kettering Cancer Center TVTG
protocol. All patients had relapsed and/or refractory leukemia,
and no patient had therapeutic options of greater curative
potential. The diagnosis of ALL or AML was made according to
the FAB classification. Confirmation of immunophenotype was
available prior to treatment. All patients had a normal serum
creatinine, liver transaminases less than five times normal, and a
total serum bilirubin less than 1.5 times normal.
According to institutional guidelines, written informed consent was obtained from all patients or their guardians before the
initiation of therapy. Institutional Review Board approval was
obtained for the analysis of the results.
The specific schedule and dosages of the prescribed
chemotherapy is shown in Table 1. Gemcitabine was infused
on day 7 if the following criteria were met: there were greater
than 25% leukemic blasts in the day 7 bone marrow or a
persistence of circulating blasts in the peripheral blood; and
liver transaminases were less than five times normal, with a
bilirubin less than 1.5 times normal. Starting on day 7,
administration of daily subcutaneous granulocyte colonystimulating factor was initiated and continued until leukocyte
recovery. Additional courses of TVTG were offered to those
patients with a significant response to the first cycle, and
only when the absolute neutrophil count (ANC) exceeded
1000/ml and the platelet count exceeded 75,000/ml (Table 1). All
patients received either intrathecal methotrexate or cytarabine within 2 weeks of the start of each cycle of TVTG.
Subsequent intrathecal chemotherapy was administered at the
discretion of the investigator. One patient (patient 21) received
intrathecal methotrexate, cytarabine, and thiotepa on days 7,
14, and 21.
A complete response (CR) was defined as no measurable
extramedullary disease, and less than 5% blasts in the bone
marrow (M1 marrow) in a patient with an ANC greater than 500/
ml, and platelet count greater than 75 000/ml. Patients with a
partial response (PR) had 525% bone marrow blasts, with an
ANC greater than 500/ml, and platelet count greater than 75 000/
ml. It is not uncommon for heavily pretreated patients, especially
those with extensive bone marrow infiltration, to have a
significant response to therapy but have a delayed recovery of
platelet production. Therefore, patients who had an ANC greater
than 500/ml, a platelet count less than 75 000/ml, and 525%
leukemic blasts in the bone marrow were defined as having a PR
except platelets (PR-P). Patients who did not meet the above
response criteria were defined as unresponsive (n 15) and
were not offered additional courses of TVTG. Toxicities were

Table 1

graded according to the National Cancer Institute common

toxicity criteria, version II.

Results
Among the 28 patients enrolled (Table 2), 19 were male and
nine female. The mean age at the initial leukemia diagnosis was
8.1 years (range 3 months21 years), and the mean age at
enrollment was 10.8 years (124 years). A total of 14 patients
(50%) had Pre-B-cell ALL, three (11%) T-cell ALL, two (7%)
biphenotypic leukemia, and nine (32%) AML. Three of the nine
cases of AML were secondary to treatment for a previous
malignancy (t-AML). A total of 12 patients (43%) had disease
refractory to either first remission induction (n 3) or refractory
to remission reinduction after the first (n 6) or subsequent
relapse (n 3). The remaining 16 patients (57%) had a median
of two relapses (range 19) per patient, including five patients
who relapsed after myeloablative therapy and subsequent
allogeneic SCT (patients 4, 6, 10, 14, and 19). There were six
patients (21%) who received TVTG as the primary remission
reinduction therapy following a first relapse: patient 3 relapsed
while on a high-risk ALL protocol, patient 16 had relapsed AML
after only 6 weeks of remission, patients 18 and 19 experienced
an early relapse after primary refractory disease (refers to disease
that was refractory to standard initial remission induction
therapy, but ultimately these patients did achieve a first
remission with additional therapy), patient 22 had relapsed
t-AML, and patient 24 relapsed during consolidation therapy for
AML.
In all, 10 of the 28 patients (36%) achieved a CR, one patient
(4%) a PR, two (7%) a PR-P (Table 3), and 15 (53%) had no
response following the first cycle of TVTG. A total of 20 patients
(71%) had either an M3 marrow on day 7, or a persistence of
circulating blasts, and 15 subsequently received gemcitabine.
Three of these 15 patients achieved a CR (20%), one a PR (7%),
and one a PR-P (7%) after gemcitabine. Reasons to not give
gemcitabine in the remaining five patients included: hepatotoxicity (n 2), and a decision by the medical providers and
family that additional therapy would be futile due to rapid
progression of disease (n 3).
Four of the 14 patients (29%) with pre-B-ALL had a CR and
one a PR. Two of the three patients with T-cell leukemias had a
CR. Four of the nine patients (44%) with AML (including one
with t-AML) had a CR, and one a PR-P. One of the two patients
with biphenotypic leukemia had a PR-P (Table 3). Eight of the 13
patients with a response received more than one cycle of TVTG
(mean 3.6 cycles/patient, range 15 cycles).

TVTG treatment schedule

Dose

Topotecan
Vinorelbine
Thiotepa
Gemcitabine
Dexamethasone
G-CSF
a

Day
2

1 mg/m /day as a continuous i.v. infusion

20 mg/m2/day i.v. push
15 mg/m2/day i.v. over 4 h
10 mg/m2/min continuous i.v. infusion over 6 h. Total dose is 3600 mg/m2/dose
45 mg/m2/day P.O. or IV divided TID
5 mcg/kg/day SQ

15
0, 7, 14, 21b
2
7c
714
Start day 7 and continue until ANC 4500/ml

All patients had a central venous catheter with at least two lumens so the infusion of topotecan did not need to be interrupted for the administration
of other medications or blood products.
b
Day 21 vinorelbine is given only if the ANC is greater that 500/ml.
c
Administered if there are greater than 25% leukemic blasts in the bone marrow or a persistence of circulating blasts in the peripheral blood, and if
liver transaminases are less than five times normal, with a bilirubin less than 1.5 times normal.
Leukemia

Re-induction therapy for refractory leukemia

EA Kolb and PG Steinherz

1969
Table 2

Characteristics of patients treated with TVTG (n 28)

Pt. Diagnosis

Age (years) at
diagnosis/at TVTG

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

9/10
F
11/11
M
14/18
F
2/5
M
5/9
M
6/9
M
3/6
F
8/8
M
11/12
M
3/7
F
16/20
M
2/3
M
15/16
M
1/4
M
14/16
M
5 months/8 months F
23/23
M
4/5
F
2/3
F
17/18
M
8/13
M
20/22
F
3/8
M
14/17
F
2/3
M
4/6
F
21/22
M
6/8
F

T-cell ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
T-cell ALL
Bp
Pre-B ALL
AML
Pre-B ALL
Pre-B ALL
Bp
AML
t-AML
Pre-B ALL
AML
AML
T-cell ALL
t-AML
t-AML
AML
AML
Pre-B ALL
Pre-B ALL
Pre-B ALL

Sex Prior therapy

Disease status
at enrollment

V, P, As, Dn, Cp, Tg, Ac, HDM,

V, P, As, Dn, Cp, Ac, Mp, M
V, P, As, Dn, Cp, Ac, Mp, M, D, Dx, Tg
V, As, D, Cp, Ac, Mp, M, Tg, Dn, P, RT, TBI/Th/Cp SCT
V, Dx, As, D, Cp, Ac, Mp, M, Tg, HDM, VP, Flu, RT
V, Dx, As, D, Cp, P, Ac, Mp, M, Tg, Th, VP, HDM, RT, TBI/Cp SCT
V, Dx, As, D, Cp, Ac, Mp, M, Tg, P, Ida, RT
V, Dx, As, Mp, M, Ac
V, P, D, As, Mp, M, HDM
V, Dx, A, D, Cp, Ac, Mp, M, Tg, Dn, P, Ida, If, VP, HDM, TBI/Cp SCT
V, P, As, D, Cp, Ac, Mp, M, Tg, Dn, AD,
V, P, As, Dx, Ac, Tg, VP, Dn
V, P, As, Dn, Cp, Ac, Mp, M, Dx, Tg, VP, Th, CRT
V, P, As, D, Cp, Ac, Mp, M, Tg, Dn, Tm, Flu, TBI/Mel SCT
V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P, VP, If, Flu, RT
Dx, Ac, Tg, VP, Dn
Dx, Ac, Tg, VP, Dn
V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P
Dx, Ac, Tg, VP, Dn, As, Ida, Flu, V, P, Cp, M, TBI/Th/Cp SCT
Ac, Tg, Dn, VP, Mito, CSA, GO
V, Dx, As, D, Cp, Ac, Mp, M, Tg, Dn, P, If, VP, HDM
Dx, Ac, Tg, VP, Dn, Ac
Ac, As
Dx, Ac, Tg, VP, Dn, Ac, Cl, VP,
Ac, Tg, Dn, VP, Dx, As, Ida
V, P, As, Dn, Mp, M, VP, Cp, Ac, HDM,
V, P, As, Dn, Mp, M, Cp, Dx, Ep
V, P, As, M, Mp, D, Cp, Ac

11 ref
11 ref
1st rel
2nd rel
2nd rel
4th rel
3rd rel
2nd rel
1st rel, ref
2nd rel
2nd rel
1st rel, ref
2nd rel
3rd rel, ref
3rd rel, ref
1st rel
1st rel, ref
1st rel, after 1st ref disease
1st rel, after 1st ref disease
1st rel, ref
9th rel, ref
1st rel
11 ref
1st rel
1st rel, ref
2nd rel
1st rel, ref
3rd rel

Rel, relapse; ref, refactory; 11 ref, prime reference; Bp, biphenotypic leukemia; SCT, stem cell transplantation; Ac, cytarabine; AD, actinomycin D;
As, asparaginase; Cl, cladribine; Cp, cyclophosphamide; CSA, cyclosporin A; D, doxorubicin; Dn, daunorubicin; Dx, dexamethasone; Ep,
epirubicin; Flu, fludarabine; GO, gemtuzumab ozogamicin; HDM, high-dose methotrexate; Ida, idarubicin; If, ifosfamide; M, methotrexate; Mel,
melphalan; Mito, mitoxantrone; Mp, mercaptopurine; P, prednisone; RT, craniospinal radiation; TBI, total body irradiation; Tg, thioguanine; Th,
thiotepa; Tm, temozolomide; V, vincristine; VP, etoposide.

Table 3

Description of those patients who demonstrated a response

No.

Diagnosis

Response to
TVTG

1
2
3
4
7
11
12
15
20
21
22
23
24

T-cell ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
Pre-B ALL
AML
Biphenotypic
AML
T-cell ALL
t-AML
t-AML
AML

CR
CR
CR
CR
CR
PR
CR
PR-P
CR
CR
CR
PR-P
CR

No. of
cycles
2
2
5
2
2
1
2
1
2
2
1
1
1

Gem

Yes
Yes
Yes
Yes

Yes

SCT After
TVTG

Current status

Yes
Yes
Yes
Yes
Yes
Yes
Yesb
No
Yes
Yesc
No
Yes
No

Alive
Alive
Died in remission of pneumonitis
DOD
Died of VOD, in remission
Died after graft failure
Alive
DOD
DOD
Alive
DOD
Died of disseminated Aspergillus
Died of complications
of sepsis that occurred 1 week after TVTG

Follow-up timea
(months)
32
10
13
3
3
5
9
4.5
13
50
6
17
1.6

t-AML, therapy related, or secondary AML; SCT, stem cell transplant; CR, complete response; PR, partial response; PR-P, partial response except
platelets; DOD, died of disease recurrence, VOD, veno-occlusive disease.
a
Follow-up time is measured from the start of the TVTG protocol.
b
The patient relapsed after the second cycle of TVTG. The patient subsequently achieved remission after therapy with another protocol and was
able to undergo an SCT.
c
Patient received intrathecal therapy with methotrexate, cytarabine, thiotepa, and hydrocortisone concomitantly with TVTG.

Eight of the 10 patients who achieved a CR, and two of the

three patients with a PR underwent an allogeneic hematopoietic
SCT after TVTG. The median time from achieving a CR to
transplant (n 7) was 3.9 months (range 1.510.9 months). Four
patients (patients 1, 2, 12, and 21) had a CR after TVTG,

underwent an allogeneic SCT, and are alive and disease free 8,

19, 30, and 49 months from the start of TVTG, respectively.
Patient 12 relapsed after the second cycle of TVTG. He again
achieved a remission with idarubicin and cytarabine, and is
currently alive and well after a mismatched SCT. Of the
Leukemia

Re-induction therapy for refractory leukemia

EA Kolb and PG Steinherz

1970
remaining six patients who were transplanted, two died with
relapsed disease, one viral pneumonitis, one veno-occlusive
disease, one disseminated aspergillus, and one of complications
associated with graft rejection (Table 3). All transplant-related
morbidities were within the range of that which is normally
expected in a heavily pretreated cohort of patients, and none
could be directly correlated with the prior administration of
TVTG.
Three patients were not transplanted after a response to TVTG
(patients 15, 22, and 24). Patient 24 had hematopoietic recovery
and confirmation of a CR, but the patient died of complications
of sepsis and ARDS that occurred during reinduction therapy.
This is the only TVTG-associated morbidity or mortality that
prevented SCT. After an initial PR-P on TVTG, patient 15 opted
to go off protocol and receive consolidation therapy with
fludarabine and cytarabine. No stem cell donor was identified,
and the patient died of relapsed disease 4.5 months from the
start of TVTG. Patient 22 refused additional chemotherapy after
a documented CR. This patient ultimately relapsed and died of
progressive disease.
The 13 patients who responded to therapy were evaluated for
hematopoietic recovery following TVTG. The median time to
achieve an ANC of 500/ml was 27 days (range 640 days), and
median time to achieve a platelet count of 75 000/ml (n 11)
was 30 days (range 048 days). The addition of gemcitabine
delayed the recovery of both the ANC and the platelet count
(Table 4). Transient grade 1 or 2 hepatic toxicity is documented
in 10 patients. Eight of these 10 patients received gemcitabine.
Three patients died within 1 month of starting therapy with
TVTG. All three patients had progressive disease on day 7, and
ultimately succumbed to disease and/or sepsis. One patient, as
mentioned above, developed sepsis and ARDS during cycle 1 of
chemotherapy of TVTG. This patient subsequently died 6 weeks
after initiation of TVTG, and was in remission at the time.

Discussion
Patients with multiply relapsed or refractory leukemia have a
dismal prognosis. Agents available for salvage therapy are
limited by: (1) the development of multidrug resistance in the
leukemia cells; and (2) the capacity for these heavily pretreated
patients to tolerate the side effects of additional high-dose
therapy. We present the results of 28 patients treated with a
protocol containing topotecan, vinorelbine, thiotepa, gemcitabine, and dexamethasone. A total of 13 of these patients (47%),
with multiply relapsed or refractory leukemia, achieved either a
CR (10 patients) or a PR (three patients) after one cycle of TVTG.
Additionally, 10 of the 13 patients subsequently underwent

Table 4
(n 13)a

Median hematopoietic recovery after one cycle of TVTG

Parameter
ANC greater than 500/ml
All patients (n 13)
No gemcitabine (n 8)
Gemcitabine (n 5)

27
23
32

Platelets greater than 75 000/ml

All patients (n 11)
No gemcitabine (n 7)
Gemcitabine (n 4)

30
29
32

Leukemia

Time (days)

Analysis includes only those patients with a CR, PR, or PR-P.

allogeneic SCT, and four of these are currently alive and diseasefree. It is interesting to note that remission reinduction with
TVTG was possible regardless of immunophenotype of the
leukemia cells (Table 3).
Recent clinical trials of topotecan as a single agent demonstrate that the drug has activity in relapsed leukemias.810,13,14
The maximum tolerated dose of topotecan in a heavily
pretreated cohort of pediatric patients with refractory leukemia
is reportedly 2.4 mg/m2/day for 9 days.14 However, the dose
employed in the multidrug protocols is necessarily lower and
some investigators have successfully used topotecan at a dose of
1.25 mg/m2/day in combination with other agents.11,17 In this
report, seven patients (25%) achieved a CR, and one a PR-P
when topotecan (1 mg/m2/day for 5 days) was used in
combination with vinorelbine, thiotepa, and dexamethasone
(ie without the addition of gemcitabine).
The role of gemcitabine in this combination of drugs is not
clear. In total, 15 patients had M3 marrow disease on day 7, and
received gemcitabine. Three subsequently achieved a CR, one a
PR and one a PR-P. Among the patients who received
gemcitabine, ANC recovery (see Table 3) was delayed 9 days
(32 days with gemcitabine, n 5 vs 23 days without gemcitabine, n 8), and the recovery of the platelet count was delayed
3 days (32 days with gemcitabine, n 4 and 29 days without,
n 7). However, only patients with refractory or progressive
disease received gemcitabine, and accordingly were expected
to have delayed or no recovery of hematopoiesis. Eight patients
experienced grade 2 hepatic toxicity following gemcitabine
infusion as compared to only two who did not receive
gemcitabine. Nonetheless, three CRs, one PR and one PR-P
among 15 patients with a slow response to reinduction are
encouraging. Careful consideration of acute toxicities is
necessary prior to the administration of gemcitabine.
The role of reinduction chemotherapy in multiply relapsed or
refractory patients is not an attempt at cure. Long-term remission
duration is unrealistic. Without an SCT, sooner or later these
patients will experience disease recurrence. The goal is to
administer therapy that will: (1) achieve a clinical response with
as little residual disease as possible; (2) maintain the response
long enough to identify a matched-unrelated stem cell donor;
and (3) permit the patient to undergo an SCT free of infections
and vital organ dysfunction. We were able to achieve this goal
in 47% of the patients. Unfortunately, one patient with a CR
died of complications resulting from ARDS that occurred during
induction. Additionally, two patients, with extensive disease at
the time of enrollment, experienced increased LFTs during the
first week of induction, and were subsequently unable to
potentially benefit from gemcitabine despite an M3 day 7
marrow.
In summary, we report a 47% response rate (36% CR, 11%
PR) in patients with multiple relapsed leukemia using a new
combination of chemotherapeutic agents. Toxicities primarily
include grade 4 neutropenia, which is difficult to assess in the
setting of a relapsed leukemia, and transient grade 2 hepatic
toxicity. Given the remission reinduction rate in this heavily
pretreated cohort of patients, these toxicities are acceptable.

Acknowledgements
This work would not be possible were it not for the help of many
colleagues. We are especially indebted to Maura Byrnes-Casey,
PNP, Rosemarie Corless, PNP, and Kateri Sullivan, PNP for their
skilled assistance with patient care; and Michael Kellick, RPh for
his assistance in designing and naming this protocol.

Re-induction therapy for refractory leukemia

EA Kolb and PG Steinherz

1971
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