Blood, 15 May 2003, Vol. 101, No. 10, pp. 3868-3871
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Gemtuzumab ozogamicin: first clinical experiences in children
with relapsed/refractory acute myeloid leukemia treated on
compassionate-use basis
Christian M. Zwaan,
Dirk Reinhardt,
Selim Corbacioglu,
Elisabeth R. van
Wering,
Jos P. M. Bökkerink,
Wim J. E. Tissing,
Ulf Samuelsson,
Jay Feingold,
Ursula Creutzig, and
Gertjan J. L. Kaspers
From the Department of Pediatric
Hematology/Oncology, Vrije Universiteit University Medical Center,
Amsterdam, the Netherlands; AML-BFM Study Group,
University Children's Hospital Münster, Germany;
Department of Pediatrics, University of Ulm, Germany;
Dutch Childhood Oncology Group, Den Haag, the Netherlands;
Department of Pediatric Hemato-oncology, University Medical Center St
Radboud, Nijmegen, the Netherlands; Department of
Pediatric Oncology, Sophia Children's Hospital, Erasmus University
Medical Center, Rotterdam, the Netherlands; Division of
Pediatrics, Department of Health and Environment, Linköping
University, Sweden; and Wyeth Pharmaceuticals, St
Davids, PA.
 |
Abstract |
Gemtuzumab ozogamicin (GO; Mylotarg) was developed to
treat CD33+ acute myeloid leukemia (AML). To date, only
studies in adults and preliminary data from a phase 1 study in children
have been reported. We report data on 15 children with
relapsed/refractory CD33+ AML who were treated with GO
monotherapy on compassionate use basis (4-9 mg/m2 up to 3 courses). Eight children showed a reduction in bone marrow blasts to
5% or less, including 5 in complete remission without full platelet
recovery (CRp). Three of the 5 children with CRp received transplants
almost directly following the last GO course, without awaiting further
platelet regeneration. Hence in these children no clear discrimination
between complete remission (CR) and CRp could be made. In 6 of 8 responding patients further treatment was given consisting of stem cell
transplantation (SCT). Two patients are still alive, currently 6 and 9 months after SCT. Hematologic toxicity was difficult to assess due to
subsequent SCT or leukemia. Side effects, in one patient each included
veno-occlusive disease, transient grade 3 hyperbilirubinemia, transient
grade 3 transaminase elevation, and grade 3 hypotension during GO
administration. No infections or mucositis occurred. This report
demonstrates clinical efficacy of GO in a subset of relapsed/refractory
pediatric CD33+ AML patients and suggests that intensive
postremission therapy after remission induction by GO may result in
durable responses in some patients, although follow-up is still short.
Further studies are needed to determine the efficacy and safety of GO
in children with AML.
(Blood. 2003;101:3868-3871)
© 2003 by The American Society of Hematology.
| |
Introduction |
Gemtuzumab ozogamicin (GO) is an immunoconjugate,
consisting of a humanized anti-CD33 antibody, to which the cytotoxic
compound N-acetyl-
-calicheamicin dimethylhydrazine, a member of the
enediyne antitumor antibiotic family, is linked.1,2 GO
selectively targets CD33+ cells and was developed as an
antileukemic drug for treatment of acute myeloid leukemia (AML), in
which CD33 positivity occurs in 80% to 90% of cases.3
After binding to the receptor, rapid internalization of the complex
occurs, after which calicheamicin is released intracellularly.
Calicheamicins are known for their extreme potency, and their
cytotoxicity has been described to arise through DNA
damage.4 Phase 1 and 2 studies of GO therapy in adults
with relapsed AML have been performed and have shown response rates in
approximately 30% of patients.1,2,5 Toxicity profiles
were relatively mild when compared with classical multiagent chemotherapy, especially with regard to mucositis and infections. However, severe liver toxicity, that is, hepatic sinusoidal obstruction syndrome, may occur. Several factors increase the risk for
hepatotoxicity, such as treatment in which GO is combined with
conventional chemotherapy, or when GO is administered after previous
stem cell transplantation (SCT).6,7 In addition, slow
platelet recovery has been described, probably due to damage of the
CD33-expressing platelet precursors.2 The drug has
recently been approved for use in the United States for elderly
patients with relapsed AML.5
So far, no clear relationship was found between the CD33
positivity of the leukemic cells and the clinical response to
GO.2 In a recent study, in which the exact number of CD33
antigens on the cell surface was precisely quantified, again no
relationship was found.8
Almost no data were available until now considering GO treatment of
relapsed or refractory AML in children. Sievers et al report the
preliminary data of a phase 1 study with GO in 18 children with
relapsed or refractory AML, and they conclude that the adverse events
are similar to those in adults.9,10
We report here on our experiences in 15 children with
relapsed/refractory AML, treated with GO monotherapy up to 3 doses on compassionate use basis.
| |
Patients and methods |
Fifteen children were treated with GO on compassionate use
basis, after approval was obtained from the local institutional review
board where the patient was treated. Informed consent was provided
according to the Declaration of Helsinki. The children were diagnosed
with de novo AML refractory to standard induction therapy (n = 4),
first relapse of AML refractory to reinduction treatment (n = 7), or
AML in second (or greater) relapse (n = 4).
The AML-BFM (Berlin-Frankfurt-Münster) Study Group
(Münster, Germany), the Dutch Childhood Leukemia Study Group
(DCLSG; Den Haag, The Netherlands) and the Nordic Society of Pediatric Hematology and Oncology (NOPHO, Stockholm, Sweden) centrally reviewed the diagnosis of AML in these children, as well as the clinical and
cell biologic data presented here. Patient characteristics at initial
diagnosis and at the time of GO administration are given in Table
1. All patients had CD33+ AML
at diagnosis, ranging from 27% to 97% CD33+ blasts
(positive defined as > 20% of the blasts positive for CD33,
results shown in Table 2). FAB M0 and M7
cases were overrepresented, reflecting the poor risk characteristics of
this patient group.
First-line chemotherapy was given according to 4 different protocols,
all based on intensive chemotherapy consisting of cytarabine plus
anthracyclines: AML-BFM 93, n = 3; AML-BFM 98, n = 9; MRC12/DCLSG ANLL 97 protocol, n = 2; NOPHO AML 93 protocol, n = 1.
Three of the 4 patients (Table 2: UPN 02, 05, and 09) with primary
refractory de novo AML had been treated with standard induction therapy
according to the AML-BFM 98 protocol and showed no response. Two
patients were treated further with FLAG (a combination of fludarabine,
cytarabine, and granulocyte colony-stimulating factor [G-CSF]) plus
liposomal daunorubicin or idarubicin, again without response. One of
these 2 received further treatment with a course of etoposide and
topotecan, before he was treated with GO. The fourth patient (Table 2:
UPN 15) with refractory disease was treated according to the
MRC12/DCLSG 97 protocol with the standard induction treatment, and was
further treated with a course of CLASP (high dose cytarabine plus
L-asparaginase) without any response, before treatment
with GO.
Most of the 11 patients having relapses had been treated with FLAG with
or without anthracyclines (either idarubicin or liposomal daunorubicin)
before receiving GO.
Two patients (Table 2: UPN 08 and 11) had undergone SCT before they
were treated with GO; in both cases this concerned a matched unrelated
donor (MUD) SCT. There were no signs of active graft-versus-host
disease of the liver and there was no transaminase or bilirubin
elevation at the time of GO administration in these patients, which was
given because of subsequent relapse. In one patient (UPN 08) this SCT
preceding GO treatment was complicated by veno-occlusive disease (VOD).
Twelve months later she had a relapse and was treated with GO.
GO was given at dosages of 4 to 9 mg/m2/course. Seven
patients only received one infusion of GO, 5 patients received 2 infusions, and 3 patients received 3 infusions (data summarized in
Table 2). Dose levels and frequency were extrapolated from the adult studies and the preliminary pediatric data from Sievers et
al,10 and were decided on by the physician in charge of
the patient. In some patients the schedule was also based on
availability and time needed for preparation of
SCT.1,2,10
We defined response to GO according to the following criteria: a bone
marrow blast percentage of 5% or less, in the absence of leukemia in
the peripheral blood or elsewhere. To diagnose a complete remission
(CR) sufficient recovery of peripheral blood values (> 1000 × 106/L granulocytes and > 100 × 109/L platelets) was required. A CRp was defined
as response plus incomplete regeneration of platelets but with platelet
transfusion independency.2 Side effects were described
according to the National Cancer Institute common toxicity criteria
(NCI-CTC; revised version 2.0 of 1999).
| |
Results |
After GO treatment a response was observed in 8 of 15 patients,
which included a CRp in 5 patients. In 3 patients no change in bone
marrow blast count was observed, and in 4 progressive disease occurred.
The response and major toxicity data are summarized in Table
2.
In the 8 patients with a response, the side effects of GO were moderate
with the exception of hematologic toxicity in all patients (NCI-CTC
grade 3-4). Two other patients had a febrile reaction during infusion,
and one patient (UPN 01) had an infusion-related drop in blood pressure
(NCI-CTC grade 3), which needed fluid replacement for 2 days. One other
patient (UPN 05) experienced transient NCI-CTC grade 3 hyperbilirubinemia, with normal transaminases and without ascites or
weight gain suggestive of VOD. One patient (UPN 08) developed severe
GO-related liver toxicity.
Six of the 8 patients with a response received further treatment with
SCT. In 3 children with CRp (UPN 01, 02, and 03) further platelet
regeneration was not awaited, and they received a transplant (2 matched
related donor and 1 MUD-SCT) almost directly following their last GO
course. In the 2 other children (UPN 04 and 05) with CRp the interval
to transplantation was longer. In one child (UPN 04) receiving a
MUD-SCT the interval was 44 days, and the bone marrow showed 8% blasts
directly prior to SCT, suggestive of subsequent relapse after GO
therapy. In the other patient (UPN 05) allogeneic SCT was performed 2 months after GO treatment.
So far, of the 5 CRp patients, 2 are in continuous CR 6 and 9 months
after SCT (UPN 01 and 02). Two patients (UPN 03 and UPN 04) have had a
relapse after SCT; UPN 03 died 6 months thereafter from progressive
leukemia. One patient died shortly after SCT due to septic shock
without peripheral blood regeneration (UPN 05). One other child (UPN
06) who responded to GO received an autologous SCT and died from fungal
sepsis 6 weeks following SCT, but without signs of leukemia.
The 2 other patients (UPN 07 and 08) showing a response did not receive
further therapy after GO. Interestingly, one of these children (UPN 07)
was treated with GO at relatively large time intervals. After the first
course of GO (9 mg/m2) he was in aplasia for 28 days and
platelets regenerated to a maximum of 27 × 109/L. The
bone marrow blasts percentage dropped from 7 to 0 after this course.
Three months later he had a relapse and was re-treated with GO (6 mg/m2), showing the same response without any additional
toxicity, which was repeated again 2 months later (6 mg/m2). He died of progressive disease 4 months after the
last dose. The other patient (UPN 08) with a response was the child
with preceding VOD complicating a MUD-SCT. Due to the known high risk for VOD with GO after SCT, the patient was started on prophylactic defibrotide. Despite the prophylaxis, 4 days following GO treatment, she developed NCI-CTC grade 4 liver problems, with the clinical picture
of VOD. She was treated with defibrotide and standard supportive care,
and recovered fully after 10 days of treatment. Although she responded
to GO with a bone marrow blast reduction from 25% to 4%, she relapsed
quickly and died 7 months after GO infusion.
The 3 patients (UPN 09, 10, and 11) with no change in the bone marrow
blast count received 1, 2, and 3 infusions of GO, respectively, but in
all cases no responses were obtained and all 3 children died of
progressive disease, after intervals of 2 weeks, 3 weeks, and 3 months
after the last infusion, respectively. Apart from NCI-CTC grade 3-4 hematologic toxicity, probably related to the underlying leukemia, no
side effects occurred from GO treatment in these children.
The 4 patients with progression (UPN 12-15) after GO treatment all
showed grade 4 hematologic toxicity related to underlying leukemia, and
one also showed NCI-CTC grade 2 transient transaminase elevation. Two
patients died after further palliative therapy and one underwent
transplantation and was treated with donor lymphocyte infusion for a
subsequent relapse. One child (UPN 15) died at day 6 after GO infusion
from progressive disease. This patient also developed grade NCI-CTC
grade 4 hepatotoxicty. A postmortem liver biopsy showed massive
leukemic infiltration of the liver, without any signs of VOD.
| |
Discussion |
Fifteen children, diagnosed with relapsed or refractory de novo
AML, were treated with gemtuzumab ozogamicin (4-9 mg/m2 up
to 3 courses) on compassionate use basis. The 11 patients having
relapses were either refractory to reinduction therapy after relapse or
suffered from subsequent relapse. Four patients with newly diagnosed
AML were refractory to several different induction regimens. Outcome in
this group of children is known to be extremely poor and almost no
curative treatment options are available, which is further limited by
the significant toxicity that these patients usually experience from
previous intensive therapy.11,12 Of the 15 patients, 8 showed a response, that is, a marked reduction of bone marrow blasts to
less than or equal to 5% after GO monotherapy. In 5 of these 8 patients a CR, although without full platelet recovery (CRp), was
diagnosed. No CRs were diagnosed, that is, absence of leukemia with
full hematologic regeneration.
Whether CR and CRp are equivalent in terms of long-term outcome is not
fully established as yet. Sievers et al reported that the relapse-free
survival between 23 patients in CR (median 7.2 months) and 19 in CRp
(median 4.4 months) was not significantly different.2 When
GO therapy was followed by SCT as postremission therapy, the 8 CR
patients showed similar survival times when compared with the 7 CRp
patients (14.5 versus 5.4 months, respectively, P = .272).
Although these differences were nonsignificant, the numbers preclude
any firm conclusions. In 3 of the 5 children with CRp reported here,
further platelet regeneration was not awaited and hence no clear
discrimination between CR and CRp could be made.
Our results are in line with the data on treatment of adults with
relapsed AML.1,2 However, the adult studies reported on
patients treated with GO at first relapse only, and according to a
fixed schedule, whereas the children included in this report were
treated at a later stage in their disease (which implies higher
cumulative toxicity) and with different dosages of GO varying from 4 to
9 mg/m.2 In the preliminary report of the phase 1 study
with GO in CD33+ relapsed/refractory AML in 18 children by
Sievers et al, 4 patients had less than 5% bone marrow blasts after
the second dose of GO.9,10 No data are provided
considering postremission therapy or longer follow-up of these children.
In our patients reported here, 2 children are still alive in remission
after treatment with GO monotherapy followed by intensive postremission
therapy with SCT, although follow-up is short. They both achieved a
partial complete remission (CRp) following GO treatment. The fact that
these children had not undergone transplantation prior to GO treatment
may have contributed to the relative paucity of treatment- and
transplant-related toxicity or morbidity. In addition, these data
suggest the need for intensive postremission therapy following
remission induction by GO, to induce a more durable therapy response
(now lasting 6 and 9 months in these 2 children). This is similar to
the experience in adults.13
Considering GO side effects, hematologic toxicity was difficult to
assess due to subsequent SCT or underlying leukemia. With regard to
nonhematologic toxicity, GO was relatively mild with the exception of
liver toxicity. No mucositis or severe infections were documented. In
this series only one patient developed GO-related VOD after a prior
SCT, which is a well-known risk factor to develop VOD after subsequent
GO treatment.7 Two others developed transient hepatic
toxicity, which resolved spontaneously. In one child the hepatic
toxicity could be attributed to progressive leukemia and infiltration
of the liver. In the phase 1 study by Sievers et al, 4 of 18 patients
experienced grade 3 or 4 side effects, including respiratory failure
and hyperbilirubinemia, prolonged pancytopenia, gastrointestinal
bleeding and congestive heart failure, and transient transaminase
elevation.10
It is noteworthy that one of our patients (UPN 07) had been treated
repeatedly with GO, with relatively long intervals between the
infusions, and responded each time without showing any signs of
additional toxicity. Although our experience is limited to this patient
only, it suggests that palliative treatment of some patients with AML
with repeated dosages of GO at relatively long time intervals is
feasible, and needs to be explored further.
In conclusion, this report on compassionate use of GO in children with
relapsed/refractory CD33+ AML demonstrates that GO has
clinical activity in these children. Further studies in children are
needed to clearly establish the clinical efficacy and safety of GO in
pediatric AML with more stringent eligibility and dose and scheduling
criteria. A phase 2 trial by the AML Committee of the International BFM
Study Group is currently recruiting patients in such a study.
| |
Acknowledgments |
The authors wish to thank all hospitals and clinicians who treated
the patients and provided us with the treatment data. We are indebted
to Wyeth Pharmaceuticals (St Davids, PA) for providing us with GO for
the treatment of our patients on compassionate use basis. We would also
like to thank Mrs A. Heus for her much appreciated secretarial help.
This is a report of the AML Committee of the International BFM
Study Group.
| |
Footnotes |
Submitted July 2, 2002; accepted January 13, 2003.
Prepublished
online as Blood First Edition Paper, January 23, 2003; DOI
10.1182/blood-2002-07-1947.
J.F. is employed by Wyeth Pharmaceuticals, whose product was studied in
the present work.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Christian M. Zwaan, Department of Pediatric
Hematology/Oncology, Vrije Universiteit University Medical Center, De
Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; e-mail:
cm.zwaan{at}vumc.nl.
| |
References |
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Top
Abstract
Introduction
