Bone Marrow Transplantation (2000) 26, 697–699
 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00
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Case report
Complete remission of idiopathic myelofibrosis following donor
lymphocyte infusion after failure of allogeneic transplantation:
demonstration of a graft-versus-myelofibrosis effect
F Cervantes, M Rovira, A Urbano-Ispizua, M Rozman, E Carreras and E Montserrat
Institute of Hematology and Oncology, Department of Hematology, IDIBAPS, Hospital Clı́nic, University of Barcelona, Spain
Summary:
A patient with idiopathic myelofibrosis (IM) in the
osteosclerotic phase received an allogeneic stem cell
transplant. Hemopoietic engraftment was rapid, and
full donor chimerism was observed on day +70.
However, a few months later, replacement of donor
hemopoiesis by the patient’s 20q− cell clone was
observed, followed by reappearance of the blood IM features, marrow fibrosis and osteosclerosis. At 8 months
from transplant donor lymphocytes were infused, which
induced chronic GVHD. This resulted in normalization
of the blood, with disappearance of the fibrosis and
osteosclerosis, effects which persisted 20 months later.
This case provides evidence for a graft-versus-disease
effect in IM. Bone Marrow Transplantation (2000) 26,
697–699.
Keywords: idiopathic myelofibrosis; agnogenic myeloid
metaplasia; allogeneic transplantation; donor lymphocyte
infusion; graft-versus-host disease; graft-versus-disease
effect
Idiopathic myelofibrosis (IM), also known as agnogenic
myeloid metaplasia, is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, extramedullary hemopoiesis, splenomegaly, and leukoerythroblastic
blood picture,1 with the fibrosis being a secondary phenomenon to the clonal proliferation of a stem cell common
to the three hemopoietic cell lines.2 Treatment of IM is
palliative and consists mainly of administration of oral
chemotherapy or androgens, depending on the disease
characteristics of an individual patient, in addition to transfusion support.3 Although IM is typically a disease of the
elderly, almost a quarter of patients are 55 years old or
younger.4 In the latter patients allogeneic stem cell transplantation (allo-SCT) is a therapeutic alternative with the
potential for cure.5 In this setting, lack of graft-versus-hostdisease (GVHD) or the presence of only grade I GVHD has
been demonstrated to be the main factor related to treatment
Correspondence: Dr F Cervantes, Hematology Department, Hospital
Clínic, Villarroel 170, 08036 Barcelona, Spain
Received 16 March 2000; accepted 20 May 2000
failure after allo-SCT in IM.5 This suggests that, as in other
hematological malignancies,6–8 a graft-versus-disease effect
could play a role in the eradication of IM.
We report a patient in whom complete remission of IM
was achieved following induction of GVHD by donor
lymphocyte infusion after failure of allo-SCT.
Case report
A 48-year-old woman was referred to our center in January
1997. She had been diagnosed with IM in another hospital
18 months earlier, after the discovery of splenomegaly, anemia and thrombocytosis. The patient complained of malaise
and sweats, and had had several splenic infarcts in the previous months. On physical examination, the spleen and
liver were palpable at 20 and 6 cm below the respective
costal margins. Hb was 11.3 g/dl (with anisopoikilocytosis,
tear-drop cells, and 4% circulating erythroblasts per 100
leukocytes), WBC count was 12 × 109/l (with 50% neutrophils, 15% band forms, 3% basophils, 8% lymphocytes, 7%
monocytes, 4% metamyelocytes, 8% myelocytes and 5%
blasts), platelet count was 513 × 109/l, and serum LDH
1198 UI/l. A bone marrow aspirate yielded a dry tap, but
cytogenetic study of unstimulated peripheral blood demonstrated the presence of a clone with the 20q− (q11q13)
abnormality. A bone marrow biopsy disclosed decreased
hemopoietic cellularity, with diffuse reticulin and collagen
fibrosis, and osteosclerosis (Figure 1a), confirming the diagnosis of IM at advanced histologic stage. A splenectomy
was performed followed by an allogeneic peripheral blood
progenitor cell transplant (allo-PBCT) from her HLA-compatible brother, in November 1997. After administration of
busulfan (4 mg/kg p.o. daily for 4 days) and cyclophosphamide (60 mg/kg once daily i.v. for 2 days) as conditioning, 7.4 × 106 CD34+ cells/kg and 391 × 106 CD3+ cells/kg,
obtained from the donor’s unmodified peripheral blood
were infused. Cyclosporin A and methotrexate (days +1,
+3 and +6) were used as prophylaxis for GVHD. At day
13 post transplant, the patient developed a mild facial and
plantar skin rash, corresponding to grade I GVHD, which
disappeared in a few days following a short course of
methylprednisolone (1 mg/kg/day). At day 20 post transplant, hematological recovery was observed, and 70 days
from transplant, complete donor chimerism (46XY
Remission of idiopathic myelofibrosis after DLI
F Cervantes et al
698
total discontinuation 1 year after starting it. Currently, 28
months from allo-SCT and 20 months from DLI, the patient
has slight oral and ocular signs of chronic GVHD, her peripheral blood has remained normal for the last 14 months,
a recent marrow biopsy has displayed normal hemopoietic
cellularity (Figure 1b) with no fibrosis, and bone marrow
cytogenetics show a 46XY karyotype in the 36 metaphases
analyzed, whereas analysis of 10 short-tandem repeats by
an automated method (AmpFISTR Plus; PE Biosystems,
Foster City, CA, USA) shows complete donor chimerism
in both T cells and granulocytes.
Discussion
Figure 1 (a) Pre-transplant bone marrow biopsy of the patient, showing
scarce hemopoietic cellularity and osteosclerosis (trichromic staining
× 100). (b) Bone marrow biopsy obtained at 20 months from the donor
lymphocyte infusion, showing a normal hemopoietic cellularity and disappearance of the osteosclerosis (hematoxylin–eosin × 100).
karyotype) was demonstrated on bone marrow cytogenetics. A further marrow biopsy performed 3 months from
transplant showed a reduction in the osteosclerosis and disappearance of the collagen fibrosis, with persistence of the
diffuse reticulin fibrosis. One month later, progression of
IM was seen, with anemia, leukocytosis, leukoerythroblastic blood picture, thrombocytosis, and reappearance of the
46XX 20q− cell clone. In an attempt to induce a graftversus-disease effect, cyclosporin A was discontinued.
However, since the patient did not develop signs of GVHD,
a donor lymphocyte infusion (DLI) was planned. In June
1998, the patient received a total of 296 × 106 CD3+ cells/kg
and 5.5 × 106 CD34+ cells/kg, obtained from the donor’s
peripheral blood after G-CSF administration. Two and a
half months later, a mild, generalized skin rash developed,
followed by the appearance of lichenoid oral and ocular
lesions typical of chronic GVHD. Methylprednisolone (1
mg/kg/day) was given and cyclosporin A was restarted,
resulting in good control, although without complete disappearance of the chronic GVHD. Concurrently with the
appearance of the chronic GVHD, progressive normalization of the patient’s blood features was noted. A bone marrow biopsy performed 6 months from DLI disclosed normal
hemopoietic cellularity, with moderate reticulin fibrosis.
The cyclosporin A dose was progressively tapered, until its
Bone Marrow Transplantation
Idiopathic myelofibrosis (IM), a more uncommon chronic
myeloproliferative disorder, is a clonal hemopoietic stem
cell disorder characterized by bone marrow fibrosis, extramedullary hemopoiesis, splenomegaly, and a leukoerythroblastic blood picture. The disease usually affects old
people and is associated with a median survival ranging
from 3.5 to 5 years. Currently, treatment of IM remains
mostly palliative, since no significant prolongation in survival is achieved with the available therapeutical
modalities. In a recent analysis including cases from four
European institutions,4 we observed that almost a quarter of
IM patients were 55 years old, or younger, at presentation.
Survival of these younger patients was substantially longer
than that of the overall IM population, since their median
survival exceeded 10. years. In such a subgroup of patients,
the initial features associated with an unfavorable prognosis
were the presence of constitutional symptoms, a Hb value
⭐10 g/dl, and blast cells ⭓1% in the peripheral blood.
Based on the number of the latter three factors, two risk
groups of younger IM patients were identified. Thus,
median survival of patients with no, or only one bad prognostic factor approached 15 years, whereas the minority of
patients with two or the three adverse prognostic factors
survived for a median of less than 3 years.
Allo-SCT has emerged as a treatment with the potential
for cure in younger patients with IM. Guardiola et al5 analyzed the outcome of 55 IM patients younger than 55 years
undergoing allo-SCT in 28 centers world-wide. Graft failure was 9%, 1-year probability of transplant-related mortality 27%, and 5-year probability of survival 47%. With a
median post-transplant follow-up of 36 months, 22 of the
55 patients were in complete ‘histohematologic’ remission,
with the 5-year probability of event-free survival being
39% for the overall group and 48% for those patients
receiving an unmanipulated HLA matched related graft.
When the factors influencing treatment failure were analyzed, lack of or a mild degree of GVHD were found to
be the most important, followed by the presence of an
abnormal karyotype at transplantation, and older age.
A graft-versus-disease effect has been demonstrated in
several hematological malignancies6–8 and a 60 to 73%
response rate has been reported after donor lymphocyte
infusion (DLI) in CML patients relapsing post-transplant.8
Lymphocytes collected from the donor are proported to
have a highly efficient immune effect because they are not
impaired by the immunosuppressive drugs given to the
Remission of idiopathic myelofibrosis after DLI
F Cervantes et al
patient and are not inactivated by the tumor escape mechanisms that allow disease relapse.7 Based on this, DLI is
currently used to treat many tumors relapsing after allogeneic transplantation.
The significant association found by Guardiola et al5
between grades II–IV GVHD after allo-SCT and low treatment failure rate in IM led these authors to suggest a possible graft-versus-IM effect. The findings in our patient (who
was also included in the aforementioned study) strongly
support the above notion. The patient had IM of advanced
histologic stage with poor prognosis features, including the
presence of a cytogenetic abnormality, a feature that has
been linked to an increased tendency of IM to evolve into
acute leukemia.9 Following allo-SCT, she developed mild
GVHD, which was rapidly controlled by immunosuppressive treatment. Although a response to allo-SCT was
initially obtained, disease progression was observed a few
months later. Because of this, when no effect could be achieved by cyclosporin A discontinuation, DLI was undertaken. Analysis of the sequence of facts observed after the
latter measure, with chronic GVHD development followed
by long-lasting ‘histohematologic’ remission of IM, clearly
demonstrates the existence of a graft-versus-myelofibrosis
effect in this patient. This observation therefore provides a
background for designing new therapeutic strategies for IM,
such as less intensive transplant modalities, which take
advantage of the existence of a graft-versus-disease effect.10
Further experience will allow the optimum DLI dose for
the treatment of post-transplant IM relapse to be defined,
as well as the intensity of the conditioning regimen in the
setting of future non-myeloablative transplantation
protocols.
Note added in proof
Since submission of this paper, Byrne et al (Br J Haematol
2000; 108: 430–433) have reported a 54-year patient in
whom remission of IM was achieved following infusion of
a lower dose of donor lymphocytes (107/kg CD3 cells),
after failure of allogeneic transplantation.
699
Acknowledgements
This work was supported in part by grants 99/103 from the Fondo
de Investigaciones Sanitarias, Spanish Ministry of Health, and
FIJC-00/P-EM from the José Carreras International Leukemia
Foundation.
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