Blood, 1 March 2003, Vol. 101, No. 5, pp. 1713-1714
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Brief report
Successful treatment of juvenile myelomonocytic leukemia
relapsing after stem cell transplantation using donor
lymphocyte infusion
Austen Worth,
Kanchana Rao,
David Webb,
Judith Chessells,
Jane Passmore, and
Paul Veys
From the Great Ormond Street Hospital for Children,
London, United Kingdom.
 |
Abstract |
Juvenile myelomonocytic leukemia (JMML) is a rare
pediatric malignancy. Hematopoietic stem cell transplantation
(SCT) is the only curative approach. However, relapse after
SCT remains the major cause of treatment failure. Unlike most other
pediatric malignancies, JMML may be susceptible to a
graft-versus-leukemia (GVL) effect, although, unlike chronic myeloid
leukemia, reports of response to donor lymphocyte infusions (DLIs)
remain scanty. This is the first report that describes the successful
treatment of relapsed JMML with DLI in the absence of further
chemotherapy and provides definite proof of a GVL effect in JMML.
(Blood. 2003;101:1713-1714)
© 2003 by The American Society of Hematology.
| |
Introduction |
Juvenile myelomonocytic leukemia (JMML) is a rare
disorder, accounting for about 2% of all childhood hematologic
malignancies.1,2 It includes a heterogeneous spectrum of
myelodysplastic/myeloproliferative diseases, which has proved difficult
to classify and segregate into distinct clinical syndromes. In 1997, an
international consensus panel agreed on common clinical and laboratory
criteria to diagnose JMML.3
The initial course of JMML is varied with approximately one third
of patients developing a rapidly progressive course leading to early
death, yet occasional patients remain stable without any
treatment.1 Hence, although survival for 12 years after diagnosis without treatment has been described, the 10-year
disease-free survival without stem cell transplantation (SCT) is only
6%, and median survival time is approximately 10 months.2,4 Treatment of JMML with chemotherapy has been
unsuccessful with no sustained response to even high-dose
chemotherapy protocols.5,6 Hematopoietic SCT
has offered a chance of cure, but relapse rates and
transplantation-related mortality remain higher than with other
hematologic malignancies.4,7-9 However, unlike most other
pediatric leukemias, JMML may be susceptible to a graft-versus-leukemia
(GVL) effect with lower relapse rates following reduced
graft-versus-host disease (GVHD) prophylaxis,4 in the
presence of acute GVHD7,8 and chronic
GVHD.10,11 There are a few reports of post-SCT
relapse of JMML responding to withdrawal of
immunosuppression,8,10,12 but there has been only
one successful report of the use of donor lymphocyte infusion (DLI) in
this setting, and this treatment was given in conjunction with further
chemotherapy.9 Here we describe a child who relapsed early
after transplantation but who has subsequently gone into long-term
remission with the use of DLI without any further chemotherapy.
| |
Study design |
A 6-month-old girl presented with diarrhea and
vomiting, as well as bleeding from her right nipple. On assessment she
had fallen from the 50th to the 3rd centile for both height and weight and was pale with marked hepatosplenomegaly. She was anemic, had a
leucocytosis with a monocyte count of 18.5 × 109/L, and
was mildly thrombocytopenic. A blood film revealed immature neutrophils
and an increase in myelomonocytic cells, typical of a diagnosis of
JMML. A bone marrow aspirate revealed a hypercellular marrow with mild
dysplastic changes and 16% blast cells. Bone marrow cytogenetics
revealed 84% of cells showing a 45 XY 
7 karyotype. Hemoglobin
electrophoresis revealed 7.3% fetal hemoglobin (HbF). Hypersensitivity to granulocyte-macrophage colony-stimulating factor
and spontaneous colony formation was demonstrated in
granulocyte-macrophage colony-forming unit cultures.
Over the next few months, the white cell count remained stable, but she
required 2 hospital admissions for respiratory infections and had
continued failure to thrive. It was decided to treat with 2 cycles of
high-dose acute myeloid leukemia (AML)-type chemotherapy to
debulk her disease prior to bone marrow transplantation. Following recovery of blood counts, splenomegaly persisted and the blood film
continued to show features of JMML.
One month later (6 months after diagnosis) the patient underwent an
unrelated donor SCT from a male donor fully matched at HLA A, B, C,
DRB1, DQB1 loci. Conditioning consisted of Campath-1H 1 mg/kg,
busulphan 16 mg/kg, cyclophosphamide 120 mg/kg, and melphalan 140 mg/m2. GVHD prophylaxis consisted of methotrexate (15 mg/m2, 10 mg/m2 on days +3, +6 with folinic
acid rescue), and cyclosporin. T-replete bone marrow containing
16.6 × 106/kg CD34+ cells and
1.2 × 108/kg CD3+ cells were infused.
The immediate posttransplantation period was complicated by an episode
of pneumatosis intestinalis. This condition was treated with 10 days of
broad-spectrum antibiotics; nil by mouth and total parental nutrition,
and day +11 methotrexate was omitted. Neutrophil recovery to
0.5 × 109 occurred on day +14, and engraftment was
confirmed by XY fluorescent in situ hybridization (FISH) on day +19 and
found to be 100% donor in both mononuclear (MNC) and polymorphonuclear
(PMN) cell fractions.
Cyclosporin was weaned to zero between days +26 and + 56 in
an attempt to exploit a GVL effect. Grade I skin GVHD, not requiring treatment, occurred on day +40. The patient was discharged from hospital on day +48. On day +68, XY FISH on the blood showed recurrence of host hemopoiesis (5% in MNCs and 1.5% in PMNs). By day +102 this
had progressed to 83% host MNCs and 10% host PMNs. Clinically, she
remained well, but her splenomegaly had increased and she was febrile.
A blood film showed reappearance of abnormal monocytes and basophils,
although counts remained within the normal range. A repeat bone marrow
aspirate was of normal appearance, but FISH analysis revealed 52% of
interphase cells to be monosomy 7. A diagnosis of relapsed JMML was
therefore made.
On day +114, the patient was given a DLI containing
1 × 108 CD3+ cells/kg. Ten days later she
developed GVHD as manifested by a florid skin rash and abnormal liver
function tests. She was given a brief course of steroids for 1 week for
the GVHD. However, her spleen continued to increase in size following
DLI, and she remained persistently febrile. An emergency splenectomy
was performed 2 weeks after DLI for respiratory compromise and
malignant hypersplenism; respiratory symptoms improved and fever
resolved promptly. On day 24 after DLI she became profoundly
neutropenic. A bone marrow aspirate at this stage was acellular but
with no evidence of disease. She was started on granulocyte
colony-stimulating factor (G-CSF), which was given for 1 week
after which counts normalized.
By day +35 after DLI she was back at 100% donor MNCs and PMNs (Figure
1). Her cutaneous GVHD had improved (now
grade 1), and her liver function tests were normal. At 17 months after
DLI she remains well, continues to thrive, and has 100% donor
chimerism and no residual GVHD. Her blood counts have been normal for
the past 15 months, and her most recent blood counts show hemoglobin of
110 g/L (11.0 g/dL); white cell count of
11.85 × 109/L (neutrophils 5.10 × 109/L,
lymphocytes 5.81 × 109/L, monocytes
0.47 × 109/L) and a platelet count of
601 × 109/L.
View larger version (25K):
[in this window]
[in a new window]
| Figure 1.
Graphic depiction of the fall in donor chimerism at
relapse of JMML after transplantation and the response to DLI with
prompt and sustained return to donor chimerism.
This patient initially had recurrence of host hemopoiesis at day 68 after transplantation. By day +102 this had progressed to 83% host
MNCs and 10% host PMNs. DLI was given on day 114. GVHD that followed
the DLI was treated with steroids for 1 week from day +138 to day +145.
By day 35 following the DLI (day 148 after transplantation), there was
return to 100% donor chimerism, and the patient remains well and
disease free 17 months after transplantation. BMT indicates
bone marrow transplantation.
|
|
| |
Results and discussion |
Relapse of JMML after SCT remains the major cause of treatment
failure. This report describes the first response of relapsed JMML to
DLI in the absence of further chemotherapy and provides definite proof
of a GVL effect in JMML. The antileukemia effect of GVHD is well
documented in acute and chronic leukemia.13-15 DLI has
been particularly successful in the treatment of chronic myeloid
leukemia, in which induction of a GVL effect has led to subsequent
disease remission in 73% of patients.16,17 Matthes-Martin et al9 have described the use of DLI for relapsed JMML
previously in 2 cases. In the first case DLI (1 × 107
CD3+ cells) was unsuccessful, and the child received a
second transplant from which she developed grade IV GVHD but remains in
long-term remission. The second child relapsed on day +68 after
T-cell-replete unrelated donor transplantation and did not respond to
withdrawal of immunosuppression. Subsequently, the child underwent
splenectomy and received 6-mercaptopurine, followed by 2 DLIs of
5 × 105 and 1 × 106 CD3+
cells. This patient remained in complete remission 9 months later. That
case has striking similarities to ours. The patient also had monosomy
7, received a transplant from an unrelated donor, developed only
minimal GVHD after transplantation, and was treated with a debulking
splenectomy and DLI after relapse; the only difference being the
addition of further chemotherapy in the previous case. It is
interesting that the only 2 patients responding to DLI had monosomy 7;
despite this fact, only 24% to 29% of patients with JMML have this
karyotype.2,5 Monosomy 7 is a poor prognostic marker in
AML/MDS (myelodysplastic syndrome)18 but probably not in JMML.19
| |
Footnotes |
Submitted July 17, 2002; accepted September 20, 2002.
Prepublished
online as Blood First Edition Paper, October 3, 2002;
DOI 10.1182/blood-2002-07-2011.
A.W. and K.R. contributed equally to this 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: K. Rao, Great Ormond Street Hospital, Great
Ormond Street, London WC1N 3JH, United Kingdom; e-mail:
raok{at}gosh.nhs.uk.
| |
References |
1.
Arico M, Biondi A, Pui CH.
Juvenile myelomonocytic leukemia.
Blood.
1997;90:479-488[Free Full Text].
2.
Niemeyer CM, Arico M, Basso G, et al.
Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases.
Blood.
1997;89:3534-3543[Abstract/Free Full Text].
3.
Pinkel D.
Differentiating juvenile myelomonocytic leukemia from infectious disease.
Blood.
1998;91:365-367[Free Full Text].
4.
Locatelli F, Niemeyer CM, Angelucoi E, et al.
Allogeneic bone marrow transplantation for chronic myelomonocytic leukaemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood.
J Clin Oncol.
1997;15:566-573[Abstract].
5.
Festa RS, Shende A, Lanzkowsky P.
Juvenile chronic myelocytic leukemia: experience with intensive combination chemotherapy.
Med Pediatr Oncol.
1990;18:311-316[Medline]
[Order article via Infotrieve].
6.
Chan HSL, Estrov Z, Weitzmann SS, Freedman MH.
The value of intensive combination chemotherapy for juvenile chronic myelogenous leukemia.
J Clin Oncol.
1987;5:1960-1967[Abstract].
7.
Sanders JE, Buckner CD, Stewart P, Thomas ED.
Successful treatment of juvenile chronic granulocytic leukemia with bone marrow transplantation.
Pediatrics.
1979;63:44-46[Abstract].
8.
MacMillan ML, Davies SM, Orchard PJ, Ramsay NKC, Wagner JE.
Haemopoietic cell transplantation in children with juvenile myelomonocytic leukaemia.
Br J Haematol.
1998;103:552-558[CrossRef][Medline]
[Order article via Infotrieve].
9.
Matthes-Martin S, Mann G, Peters C, et al.
Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature.
Bone Marrow Transplant.
2000;26:377-382[CrossRef][Medline]
[Order article via Infotrieve].
10.
Veys P, Saunders JE, Calderwood S, et al.
The role of graft-versus-leukemia in bone marrow transplantation for juvenile chronic myeloid leukemia.
Blood.
1994;84(suppl 1):201a.
11.
Smith FO, King R, Nelson G, et al.
Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia.
Br J Haematol.
2002;116:716-724[CrossRef][Medline]
[Order article via Infotrieve].
12.
Orchard PJ, Miller JS, McGlennen R, Davies SM, Ramsay NKC.
Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia.
Bone Marrow Transplant.
1998;22:201-203[CrossRef][Medline]
[Order article via Infotrieve].
13.
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, and the Seattle marrow transplant team.
Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.
N Engl J Med.
1981;304:1529-1533[Medline]
[Order article via Infotrieve].
14.
Weiden PL, Flournoy N, Thomas ED, et al.
Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts.
N Engl J Med.
1979;300:1068-1073[Abstract].
15.
Sullivan KM, Weiden PL, Storb R, et al.
Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia.
Blood.
1989;73:1720-1728[Abstract].
16.
Kolb HJ, Mittermuller J, Clemm C, et al.
Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.
Blood.
1990;76:2462-2465[Abstract].
17.
Kolb HJ, Schattenberg A, Goldman JM, et al.
Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia.
Blood.
1995;86:2041-2050[Abstract/Free Full Text].
18.
Webb DK, Passmore SJ, Hann IM, et al.
Results of treatment of refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99.
Br J Haematol.
2002;117:33-39[CrossRef][Medline]
[Order article via Infotrieve].
19.
Passmore SJ, Chessells JM, Stiller CA, et al.
Paediatric myelodysplastic syndrome in Britain 1990-1999 [abstract].
Leuk Res.
2001;25(suppl 1):25.
Top
Abstract
Introduction
