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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2255-2258
BRIEF REPORT
Allogeneic blood cell transplantation following reduced-intensity
conditioning is effective therapy for older patients with myelofibrosis
with myeloid metaplasia
Steven M. Devine,
Ron Hoffman,
Amit Verma,
Rajul Shah,
Basil A. Bradlow,
Wendy Stock,
Vera Maynard,
Ellen Jessop,
David Peace,
Marianne Huml,
Deana Thomason,
Yi-Hsiang Chen, and
Koen van
Besien
From the Blood and Marrow Transplantation Program,
Section of Hematology/Oncology, University of Illinois College of
Medicine, Chicago, IL
 |
Abstract |
Standard myeloablative conditioning prior to allogeneic
hematopoietic stem cell (HSC) transplantation has been associated with
significant toxicity in patients older than 45 years of age with
myelofibrosis with myeloid metaplasia (MMM). We sought to evaluate the
efficacy of a reduced-intensity conditioning regimen for allogeneic
HSC transplantation in this setting. A regimen consisting of
fludarabine (30 mg/m2 intravenously daily for 5 days) and
melphalan (70 mg/m2 intravenously daily for 2 days)
followed by transplantation of filgrastim-mobilized peripheral blood
cells from HLA-identical siblings was administered to 4 older patients
(median age, 56 years; range, 48-58 years) with advanced MMM. All
patients achieved prompt neutrophil and platelet engraftment and have
experienced a significant regression of splenomegaly and bone marrow
fibrosis. All now have normal bone marrow cellularity. With a median
follow-up of 13 months (range, 11-19 months), all 4 patients are alive
with stable full-donor hematopoietic chimerism. These results support the feasibility and effectiveness of reduced-intensity conditioning prior to allogeneic HSC transplantation for older patients with advanced MMM.
(Blood. 2002;99:2255-2258)
© 2002 by The American Society of Hematology.
| |
Introduction |
Myelofibrosis with myeloid metaplasia (MMM) is a
clonal hematopoietic disorder characterized by bone marrow fibrosis, a
leukoerythroblastic blood picture, splenomegaly, and extramedullary
hematopoiesis.1,2 The average age at diagnosis of MMM is
approximately 60 years, most patients being diagnosed at 50 to 69 years
of age.3 With a median survival of between 3 to 5 years,
it has the worst prognosis of all the chronic myeloproliferative
diseases.3-5 Conventional therapies are often ineffective
and only palliative.6-8 Recently, a report on 55 patients
younger than age 55 years with MMM who underwent allogeneic
hematopoietic stem cell (HSC) transplantation indicated that 48% of
the recipients of an HLA-identical transplant survived event-free at 5 years.9 Nevertheless, the 1-year treatment-related mortality in this study was 27% in spite of the relatively young age
(median, 42 years) of the patients receiving transplants. Further, a
recent follow-up from this same group of investigators noted only a
14% 5-year overall survival in a subgroup of transplant recipients
older than 45 years of age.10 Although selected older patients may fare well with standard myeloablative
conditioning,11 such data raise concern that this
conventional approach may be too toxic for the majority of patients
with MMM owing to their advanced age. Recently, older recipients of
allogeneic HSC transplantation have been treated successfully following
a variety of less intensive nonmyeloablative conditioning
regimens.12-14 On the basis of previous observations, we
hypothesized that a reduced-intensity
fludarabine-and-melphalan-containing conditioning regimen would
promote initial engraftment and establish full-donor chimerism yet
result in a lower risk of transplantation-related morbidity in older
patients with MMM receiving an HSC transplant from an HLA-identical
sibling.15 This approach could be questioned because of
concerns that severe marrow fibrosis might adversely affect
hematopoietic reconstitution.16 The preliminary results in
4 patients with MMM described in this report suggest both the feasibility and the effectiveness of this approach.
| |
Study design |
Patients were considered eligible for HSC transplantation with a
nonmyeloablative conditioning regimen if they were older than age
45 years, had an HLA-identical sibling donor, and had a diagnosis of
MMM based on the criteria proposed by Laszlo.17 Furthermore, at the time of diagnosis, patients had to be categorized as having an intermediate or high risk for early disease-related mortality on the basis of the criteria of Dupriez et al.4
All 4 patients were enrolled in a treatment protocol that was approved by the Institutional Review Board of the University of Illinois at
Chicago. Written informed consent was obtained in all cases. HLA typing
was based on serologic methods for HLA-A and HLA-B and low-resolution
molecular typing at HLA-DRB1. Each donor received filgrastim (Neupogen)
(Amgen, Thousand Oaks, CA) by subcutaneous injection at a dose of 5 µg/kg every 12 hours. Donor blood cells were collected via
leukapheresis by means of a Cobe Spectra (version 5.0) (Cobe BCT,
Lakewood, CO) with a target volume of 15 L commencing on day 5 of
filgrastim administration. The CD34+ cell content
of the leukapheresis product was enumerated by means of the ProCount
method (Becton Dickinson, Mountain View, CA). The collection target was
4.0 × 106 CD34+ cells per kilogram of
recipient weight. All leukapheresis products were collected prior to
recipient conditioning and cryopreserved in 10% dimethyl sulfoxide.
Recipient conditioning consisted of fludarabine at 30 mg/m2
intravenously over 30 minutes daily for 5 days (days  6 to 2) and
melphalan at 70 mg/m2 intravenously over 20 minutes daily
for 2 days (days 3 and 2). The donor grafts were then thawed and
infused on day 0. Graft-versus-host disease (GVHD) prophylaxis
consisted of tacrolimus at 0.03 mg/kg/d by continuous intravenous
infusion beginning on day 2 and methotrexate at 5 mg/m2 intravenously on days +1, +3, and +6. Filgrastim was
given subcutaneously at a dose of 5 µg/kg/d beginning on day +7 and
continuing until neutrophil engraftment was achieved.
Regimen-related toxicity was graded according to the criteria of
Bearman et al.18 Neutrophil engraftment was defined as the
first of 3 consecutive days with an absolute neutrophil count (ANC) of
at least 0.5 ×109/L (500/µL). Platelet
engraftment was defined as the first day with a platelet count of at
least 20 ×109/L (20 000/µL) without
transfusion for a week. Acute and chronic GVHD were graded according to
standard criteria.19,20 Posttransplantation donor-recipient chimerism was assessed by means of DNA microsatellite analysis as previously described.21 Hematologic response
was defined as complete if all peripheral blood counts had become normal with or without the persistence of splenomegaly as long as 100%
donor bone marrow chimerism was achieved. Bone marrow biopsies were
performed at frequent intervals after transplantation to assess
donor/host chimerism, the degree of bone marrow fibrosis, and overall
bone marrow morphology. The degree of bone marrow fibrosis was graded
according to the criteria of Bauermeister.22
| |
Results and discussion |
The clinical characteristics of the 4 patients included in this
report are summarized in Table 1. All 4 were male with a median age at transplantation of 55.5 years (range,
48-58 years). The median time from diagnosis to transplantation was 9.5 months (range, 5-11 months). At diagnosis, all patients were considered to have intermediate-risk (n = 3) or high-risk (n = 1) disease. None had any history of antecedent myeloproliferative disorder. Three
patients were moderately anemic (Hb lower than 10 g/dL), and 2 had
required red blood cell transfusions. All 4 had between 1% and 9%
circulating blasts prior to transplantation. All had experienced
constitutional symptoms related to MMM. One patient had massive
splenomegaly (spleen tip palpable in the right lower quadrant) at the
time of transplantation. Morphologically, each patient had grade 4 bone
marrow fibrosis on the basis of the reticulin and Masson trichrome
stains. None of the patients had evidence of the BCR/ABL
gene rearrangement by reverse-transcriptase-polymerase chain
reaction performed on peripheral blood samples. Chromosomal analysis of bone marrow revealed normal metaphases (n = 2) or no
growth (n = 2) prior to transplantation.
All patients tolerated conditioning well, and there were no grade 3 or
4 regimen-related toxicities. All patients developed transient but
profound pancytopenia (ANC below 0.1 ×109/L [100/µL]
and platelet count below 20 ×109/L [20 000/µL]) and
required both red blood cell and platelet transfusion support.
Neutrophil engraftment was achieved at a median of 14 days (range,
12-18 days). Platelet engraftment was achieved at a median of 28 days
(range, 16-77 days). Three of 4 patients have achieved a sustained
platelet count exceeding 100 ×109/L (100 000/µL). Red
blood cell transfusion independence was achieved in all patients at a
median of 45 days (range, 19-110 days). Only one patient
experienced grade 1 acute GVHD and none grade 2-4 acute GVHD. Three
patients have developed limited (n = 2) or extensive (n = 1)
chronic GVHD that is completely responsive to prednisone and
tacrolimus. One patient is off all immunosuppressive therapy without
evidence of chronic GVHD. With a median follow-up of 13 months (range,
11-19 months), all patients have achieved either complete (n = 2) or
marked (n = 2) resolution of splenomegaly, and all have achieved a
normocellular bone marrow with marked regression of bone marrow
fibrosis (from grade 4 to grade 1 in each) (Figure
1). Full-donor chimerism was achieved by
day +30 in all patients. All 4 patients have maintained full-donor
chimerism within the bone marrow and peripheral blood compartments
without requiring donor leukocyte infusion or rapid tapering of
tacrolimus. Three recipients of sex-mismatched grafts underwent
chromosomal analysis of bone marrow at approximately 1 year after
transplantation, revealing a normal female complement in each. The 4 patients currently have Karnofsky performance scores of either 90%
(n = 2) or 100% (n = 2).
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| Figure 1.
Normalization of bone marrow morphology following reduced-intensity
conditioning.
Hematoxylin and eosin stain of bone marrow prior to transplantation (A)
and 11 months after transplantation (B). Reticulin stain of bone marrow
prior to transplantation (C) and 11 months after transplantation (D).
Masson-trichrome stain prior to transplantation (E) and 11 months after
transplantation (F). Figures are from patient 4 and are representative
of results observed in each patient. All magnifications are
× 20.
|
|
Although follow-up is short, the results obtained in this small series
of patients suggest that a fludarabine-and-melphalan-based conditioning regimen is well tolerated, is associated with a low risk
of acute GVHD, promotes stable full-donor chimerism, and results in
resolution of disease stigmata in older patients with advanced MMM
receiving an HSC transplant from an HLA-identical sibling. If verified
in a larger number of patients, the use of less intensive conditioning
may extend the option of a potentially curative procedure to those
individual patients who typically develop this disease rather than to a
select group of younger individuals with MMM who happen to have an
HLA-identical sibling.9 It remains unclear whether our
patients have been "cured" given that splenomegaly, although
markedly diminished, has persisted in 2 patients and that grade 1 bone
marrow fibrosis was still present in each patient at approximately a
year following transplantation. Nevertheless, the maintenance of
full-donor hematopoietic chimerism in each patient at a median of 1 year is encouraging. The results suggest that reversal of the effects
of the malignant clone following this conditioning regimen either
occurs over a prolonged period of time or may not be entirely complete.
In more practical terms, this approach has resulted in effective
palliation of disease in a group of patients who would ordinarily be
considered a poor risk for standard myeloablative conditioning. A
similar argument has recently been made for the consideration of
autologous HSC transplantation in older patients with MMM lacking an
HLA-identical sibling.23 The fact that 3 of 4 patients
have developed steroid-responsive chronic GVHD is notable given the
risk of late complications associated with chronic GVHD. On the other
hand, recent data suggest that a low level of GVHD may be beneficial
since a graft-versus-myelofibrosis effect has recently been
demonstrated in patients with MMM following donor leukocyte
infusion.24,25
To our knowledge, this is the first description of the use of
reduced-intensity conditioning for patients with MMM. In light of the
relatively small number of transplantations that any one center
performs each year for such patients, these encouraging preliminary
results may form a reasonable basis for the development of a
multicenter study designed to determine the ultimate impact of
reduced-intensity conditioning prior to HSC transplantation in older
patients with advanced MMM.
| |
Footnotes |
Submitted July 25, 2001; accepted November 1, 2001.
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: Steven M. Devine, 840 South Wood St, M/C 787, Chicago, IL 60612; e-mail: sdevine{at}uic.edu.
| |
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Abstract
Introduction