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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Hematology, Department of
Medicine, University of Texas Health Science Center at San Antonio;
South Texas Veterans Health Care System, Audie L. Murphy Division; both
of San Antonio, TX; Hematology Division, Mayo Clinic, Rochester, MN;
Clinical Research Division, Fred Hutchinson Cancer Research Center;
University of Washington School of Medicine; Seattle Veterans
Administration Hospital; both of Seattle, WA; and Hospital St Louis,
Paris, France.
Current therapeutic options for myeloid metaplasia with
myelofibrosis (MMM) are limited. A pilot study was conducted of
autologous peripheral blood stem cell (PBSC) collection in 27, followed
by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2),
after granulocyte colony-stimulating factor (G-CSF) alone (n = 17),
or after anthracycline-cytarabine induction plus G-CSF (n = 8). A
median of 11.6 × 106 (range 0 to
410 × 106) CD34+ cells per kilogram were
collected. Twenty-one patients then underwent myeloablation with oral
busulfan (16 mg/kg) and PBSC transplantation. The median times to
neutrophil and platelet recovery after transplantation were 21 (range
10-96) and 21 (range, 13 to Agnogenic myeloid metaplasia (AMM), one of the
chronic myeloid disorders, is characterized by marrow fibrosis,
splenomegaly, extramedullary hematopoiesis (ie, myeloid metaplasia),
and a leukoerythroblastic peripheral blood smear.1 The
other members of the group, which include chronic myeloid leukemia,
essential thrombocytosis, and polycythemia vera, occasionally progress
into a clinical picture that is similar to AMM. The term
myelofibrosis with myeloid metaplasia (MMM) encompasses AMM
and the progressive, fibrotic phase of essential thrombocytosis and
polycythemia vera. In MMM, the hematopoietic stem cell The median survival after diagnosis of MMM is less than 5 years.1 Progressive peripheral cytopenias occur frequently
in MMM and may in part be related to hypoproliferative marrow, fibrotic marrow, and splenomegaly. Standard treatments, which consist primarily of transfusions, androgens, corticosteroids, hydroxyurea, and splenectomy, are of limited value due to toxicities and/or minimal efficacy.1 For example, anemia improves in only 25% to
30% of patients treated with hormonal therapy or splenectomy, and it
often worsens with use of hydroxyurea.
In this communication we report on a novel approach to the treatment of
advanced MMM with autologous peripheral blood stem cell (PBSC)
collection followed by myeloablative chemotherapy and PBSC infusion. We
hypothesized that there would be a high level of hematopoietic stem
cells in the peripheral blood of patients with MMM, allowing for
collection of PBSCs. We further hypothesized that myeloablation with a
single-drug regimen of busulfan would be safely tolerated and would
result in reduction of marrow fibrosis and splenomegaly and improvement
in anemia despite reinfusion of clonal hematopoietic stem cells to
rescue the ablated marrow.
Patient enrollment and eligibility
PBSC mobilization
PBSC collection Patients underwent apheresis on the fourth day after starting G-CSF or, in the case of patients receiving induction chemotherapy, when the circulating CD34+ level was at least 0.01 × 109/L (10/µL) or WBC was more than 3000 × 109/L (3 × 106/µL). Apheresis was performed according to standard techniques for each institution. Although the goal was to collect at least 10 × 106 CD34+ cells per kilogram, apheresis was stopped prior to reaching that number in 10 cases at the physician's choice. No PBSCs were collected in 3 patients (02-008, 02-014, 02-015) after induction chemotherapy, 2 of whom (02-008, 02-014) then underwent mobilization with G-CSF (32 µg/kg/d) alone. PBSCs were cryopreserved according to standard techniques for each institution.Myeloablation All patients who underwent transplantation received busulfan 1 mg/kg orally every 6 hours for a total of 16 doses. No busulfan pharmacokinetic studies were performed. Phenytoin was given for seizure prophylaxis during busulfan administration.PBSC infusion PBSCs were infused 36 to 48 hours after the last dose of busulfan according to the standard practice at each institution. The general guidelines were to reinfuse 5 × 106 to 10 × 106 CD34+ cells per kilogram. However, because of the recognized arbitrary nature of this range, alternative cell infusion numbers were chosen in 6 cases.Posttransplantation supportive care Myeloid growth factors were not routinely used because of concern for stimulating growth of clonal hematopoietic stem cells. However, in 6 cases, myeloid growth factors were used because of neutropenic fever or graft failure. Other supportive care, including prophylactic antimicrobial agents and transfusions, was provided according to the standard practice at each institution.Disease measurement and end points Neutrophil recovery was defined as the first of 2 days with an absolute neutrophil count (ANC) at least 0.5 × 109/L (500 cells/µL). Platelet transfusion independence was defined as the first of 7 days with platelet counts above 20 × 109/L (20 000/µL) and without transfusion. Red blood cell transfusion independence was defined as the first of 8 weeks without transfusion. Survival was calculated from the day of PBSC infusion to the day of last contact or death. Survival curves were calculated according to the method of Kaplan and Meier.18 The study was designed to close early if any of these 3 end points were met, using 80% one-sided confidence intervals: (1) the occurrence of graft failure (defined as ANC below 0.1× 109/L [100/µL] on day 28 after transplantation) exceeded 10%; (2) the occurrence of death by day 100 after transplantation exceeded 10%; or (3) the occurrence of death during hypoplasia or ANC below 0.5 × 109/L (500/µL) on day 28 after induction chemotherapy exceeded 20%.Bone marrow biopsies (and aspirates when possible) were performed
before transplantation and at approximately 1, 3, and 12 months after
transplantation. Biopsies were reviewed in a blinded fashion (except
cases from San Antonio, which were not blinded) by a single
hematopathologist (F.C.). Cellularity, reticulin fibrosis, collagen
fibrosis, and osteosclerosis were graded according to modifications of
published systems19-21 (Table
1).
The baseline clinical characteristics of all 27 patients enrolled
are shown in Table 2. The median age was
59 (range 45-75) years. In 15 patients, the baseline number of
CD34+ cells per microliter in the peripheral blood was
measured before the PBSC mobilization procedure of G-CSF or
chemotherapy, and the median was 0.08 × 109/L (range,
0.0032 × 109 to 3.575 × 109/L) (80/µL;
range 3.2 to 3575/µL) (Table 2). The lowest value was seen in the one
patient (02-003) with polycythemia vera with early development of
myelofibrosis. PBSC mobilization and collection was generally well
tolerated. Three patients were noted to have a mild increase in spleen
size during G-CSF administration. One patient (01-002) with baseline
ascites had progressive ascites and dyspnea during this period. The
details of PBSC mobilization are shown in Table
3. In all patients but one (02-015), a
minimum of 4.8 × 106 CD34+ cells per
kilogram was collected. Patient 02-015, who had 20% blasts at time of
induction chemotherapy, failed collection and subsequently died of
disease progression. Cytogenetics of the PBSC product were normal in 3 of 4 with baseline cytogenetic abnormalities. Two patients mobilized
with GCSF alone had the same cytogenetic abnormalities in the PBSC
product as the marrow prior to mobilization. Five patients in whom
PBSCs were collected have not proceeded to transplantation: 2 (02-004, 04-001) because of poor performance status and 3 (02-003, 02-009, 02-011) because of planned delay for transplantation until time of
disease progression.
Twenty-one patients have undergone myeloablation and PBSC
transplantation, and their outcome is shown in Table
4. Regimen-related toxicity (Table 4)
consisted predominantly of gastrointestinal tract symptoms (less than
grade II in all patients except 01-003, with grade III diarrhea on 1 day, and in 03-003, with grade IV nausea and vomiting) and mucositis
that was severe enough to require parenteral nutrition in 11 patients
(ie, grade III by National Cancer Institute common toxicity criteria).
The sole death attributable to the tranplantation procedure was due to
graft failure, described as follows.
Three patients met the criteria of graft failure (ANC < 0.1 × 109/L [100/µL] on day 28) (02-008, 01-005, 03-005). One patient (02-008) died because of graft failure on day 31; this patient had been neutropenic both before and after chemotherapy mobilization for PBSCs. The second patient with graft failure (01-005) received a second infusion of stored PBSCs (10.6 × 106 CD34+ cells/kg) on day 28. This patient recovered to ANC of at least 0.5 × 109/L (500/µL) 68 days later (day 96) but soon thereafter progressed to acute leukemia and died. The third patient with graft failure (03-005), who was neutropenic before transplantation, recovered neutrophils on day 91 but died on day 223 with respiratory failure. One additional patient (03-001) received a second infusion of stored PBSCs (6.5 × 106 CD34+ cells/kg) on day 26 (ANC 0.16 × 109/L [160/µL]) because of a life-threatening infection and engrafted to ANC of at least 0.5 × 109/L (500/µL) on day 32. For the entire group of 21 patients, the median time to achieve neutrophil engraftment was 21 (range 10 to 96) days. Seventeen patients achieved platelet transfusion independency with a
median time to platelet recovery of 21 (range 13 to Red cell transfusion independency developed in 14 patients at a median of 49 days (range 9 to 273) after transplantation. The erythroid response has been maintained in all but 4 patients (01-001, 02-002, 02-005, 02-006) between 97 and 1623 days (median 316) after transplantation. Seventeen patients received transplants at least in part because of anemia (all but one requiring red cell transfusions). Ten of these 17 became transfusion independent, with durable hemoglobin levels at least 100 g/L (10 g/dL). There was significant reduction in spleen size (defined as at least a one-third reduction in spleen span) and improvement in related symptoms after transplantation in 7 of 10 patients with splenomegaly. In one patient with splenomegaly (02-008) there is a lack of data due to early death. One patient (01-005) had progressive splenomegaly and received 150 cGy splenic irradiation on days 34 to 37. Two of 3 patients in whom symptoms of bone pain were noted reported improvement. One (02-012) of 2 patients with severe ascites had clinical resolution of portal hypertension and ascites. The median follow-up of the patients who received transplants is 390 days (range 70 to 1623). The 2-year actuarial survival from time of
transplantation is 61% (Figure 1). Six
patients died after transplantation. One patient (01-004) who achieved
a complete hematologic response died on day 531 from fungal infection
of the sinuses and brain. This patient had underlying diabetes and was
on iron chelation therapy because of iron overload secondary to
transfusion requirements prior to achieving hematologic remission after
transplantation. One patient (02-008) died on day 31 with graft
failure, and 1 patient (03-005) died on day 223 from respiratory failure. Three patients (01-005, 03-001, 03-004) died with progressive disease. Results of the morphologic review of bone marrow cellularity and fibrosis before transplantation and after transplantation are shown
in Table 5. In several patients there was
convincing evidence of regression of fibrosis (eg, 01-004, Figure
2). However, in some patients there was
either no change (eg, 01-001) or variable findings over time (eg,
03-001). Osteosclerosis was present in all examined samples and did not
change significantly after transplantation in any patient. No
association was detected between histologic findings and engraftment or
clinical response.
MMM comprises a group of myeloproliferative disorders that are associated with a short median survival and few effective therapies. Symptomatic peripheral cytopenias and symptomatic splenomegaly are common clinical problems requiring medical attention. In this pilot study we investigated the feasibility of a novel therapy designed to reduce complications associated with the disease without causing undue morbidity or mortality. Twenty-seven patients were enrolled at 5 centers and underwent PBSC collection; 21 patients have received myeloablation with busulfan followed by PBSC infusion. The results presented here are encouraging and suggest that further investigation is warranted. Following PBSC mobilization, there were no unforeseen difficulties with the mobilization procedures. Following transplantation, 15 of 21 patients showed evidence of clinical improvement. Ten of 17 patients with anemia, 7 of 10 patients with symptomatic splenomegaly, and 6 of 8 patients with thrombocytopenia had clinically significant responses, with the longest response duration continuing more than 4 years. Only 2 of 6 patients with a high peripheral blast count (> 10%) appeared to obtain durable benefit, but these numbers of patients are too small to make significant conclusions. There were insufficient numbers of patients with neutropenia or with other symptoms to judge the likelihood of clinical benefit, although clinical improvement was observed in 2 patients with bone pain and 1 with portal hypertension. The mechanism for response among the patients with improvement in cytopenias is not clear. Possible explanations include (1) reduction in fibrosis resulting in restored intramedullary hematopoiesis, (2) reduction in spleen size resulting in reduced sequestation, (3) preferential stimulation of nonclonal stem cells, and (4) overall debulking of the disease burden resulting in decreased ineffective hematopoiesis. It is likely that all of these mechanisms occurred to varying degrees in this group of patients. Evidence for reduction in fibrosis was noted in 6 patients, all of whom
had improvement in cytopenias. In several patients there was no
consistent pattern of fibrosis over time, suggesting intrapatient
variability, which decreases the predictive ability of scoring
fibrosis. However, in one patient (01-004) with minimal splenomegaly at
baseline, serial posttransplantation marrows demonstrated gradual
reduction in fibrosis from grade 4c to 4a and improvement in
cellularity concomittently with resolution of biweekly transfusion requirements (Figure 2). The possibility of reduced splenic
sequestration as the mechanism for response to cytopenia is supported
by the results in patient 02-001. In this patient, there was no
demonstrable change in fibrosis (although lack of immediate
pretransplantation marrow evaluation prohibits definitive comparison),
but there was marked reduction in spleen size. Cytogenetic studies
performed before transplantation detected an abnormal clone in 10 of 23 patients studied. Two patients (02-006, 02-012) demonstrated reduction in the percentage of clonal cells in the marrow after transplantation, both of whom had received induction chemotherapy for PBSC mobilization. Finally, there is a possibility that ablation of the patient's clonal
stem cells followed by infusion of a comparatively smaller number of
clonal stem cells resulted in reduction of clonal megakaryocytes and
monocyte function and reduction in release of cytokines inhibiting hematopoiesis, such as tumor necrosis factor- This tranplantation procedure was designed to be palliative, not curative, and to be suitable for older patients with MMM. Therefore, we chose a preparative regimen of single-agent busulfan with the goal of minimizing toxicity.22 Despite the median age of 59 years with 6 patients aged 65 to 75, the only regimen-related toxicities were mucositis (n = 16) and gastrointestinal symptoms (n = 8). Although the number of patients receiving transplants in this study is small, the day 100 mortality (1 of 21 patients) did not appear to be greater than the 10% reported for splenectomy for AMM23 and was considerably lower than the approximately 25% for allogeneic transplantation for AMM.10 Furthermore, the occurrence of prolonged cytopenias appears no higher than that reported for patients receiving palliative splenic irradiation for AMM.24 The main risk associated with this procedure was that of the period of pancytopenia. The median time for both neutrophil and platelet recovery was 21 days despite the infusion of a median of 8.4 × 106 CD34+ cells per kilogram. We initiated this study with the hypothesis that the high level of circulating progenitor cells in the peripheral blood of patients with MMM11-13 would allow for adequate PBSC collection and engraftment. Our data confirm recent observations that such patients also have a high level of circulating CD34+ cells14,25 in addition to committed progenitor cells.11-13 We collected large numbers of CD34+ cells from patients at steady state, after G-CSF alone, or after induction chemotherapy and G-CSF. However, we observed longer times to engraftment than those observed for autologous PBSC transplantation for other diseases in which similar quantities of CD34+ cells are infused. Three of the 8 patients in this study with delayed neutrophil or platelet recovery after transplantation had evidence of leukemic progression prior to enrollment, suggesting that leukemic evolution might be a risk factor for delayed engraftment. Although the methods we used to mobilize and enumerate PBSCs are standard for other diseases, these methods may not be ideal for this disease in part because myeloblasts, which are increased in the peripheral blood of patients with MMM, often express CD34+ cell surface markers. Clearly, further studies are needed to determine the in vivo and in vitro factors that predict for delayed engraftment and to determine approaches that can effectively prevent this complication. Furthermore, it is possible that collection of PBSCs soon after diagnosis to be used later in the disease course might be an approach that optimizes the stem cell collection. In summary, the results of our pilot study suggest that in most patients with MMM we obtained adequate PBSC collection to allow for engraftment after transplantation. We also found that the toxicity of this busulfan-only preparative regimen was acceptable, even in patients up to 75 years of age. Finally, these results suggest that a significant proportion of patients derived clinical benefit, mostly in regard to anemia and symptomatic splenomegaly. However, because this was a pilot study, there was great heterogenicity in the patient population studied and in the actual treatment received. Therefore, generalization of these results for future transplantation patients or comparisons to patients who do not receive transplants is not possible. Further evaluation of this promising therapy is ongoing.
Submitted December 15, 2000; accepted April 4, 2001.
Supported in part by National Institutes of Health grants HL-36444, CA-18029, and CA-87948. J.E.A. is an award recipient of the Paul Beeson Physician Faculty Scholars in Aging Research Program.
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: Jeanne E. Anderson, Katmai Oncology Group, 3260 Providence Dr, Suite 526, Anchorage, AK 99508-4627.
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Top
Abstract
Introduction
246) days, respectively. Five patients
received back-up PBSC infusion because of delayed neutrophil or
platelet recovery. The median follow-up is 390 (range 70-1623) days
after transplantation, and the 2-year actuarial survival is 61%. After
transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response
(hemoglobin 
and resulting
hematopoiesis
and transforming growth factor-
. This possibility, however, was not investigated in
this study.