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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1580-1587
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Rush Cancer Institute and the Departments of Pathology and
Biostatistics, Rush-Presbyterian-St. Luke's Medical Center, Chicago;
Ingall's Memorial Hospital, Harvey; and Northwest Community Hospital,
Arlington Heights, IL.
Thirty-five patients with myelodysplastic syndrome (MDS) were
registered on protocol MDS 96-02 and were receiving continuous therapy
with pentoxifylline 800 mg 3 times a day and
ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to
the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M2, 300 mg/M2, and 400 mg/M2) to cohorts of 10 patients each. Therapy has been
continued for 1 year in responders. Twenty-nine have completed at least
12 weeks of therapy and are available for response evaluation. Of the
21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess
blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five
had secondary MDS. No differences were noted in response rates among
the 3 dose levels. Seven patients did not respond at all, and 22 showed
an improvement in cytopenias (76%). Three had a triple lineage
response, 10 had a double lineage response, and 9 had a single lineage
response (8 of 9 in absolute neutrophil count [ANC] and 1 had more
than a 50% reduction in packed red blood cell transfusions). Fifteen
patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved
ANC, 11 of 22 demonstrated more than 50% reduction in blood
transfusions, improved Hb levels, or both, and 7 of 22 showed
improvement in platelet counts. Interestingly, the responses were
frequently slow to appear, and continued improvement in counts was seen
up to 12 months of therapy and beyond. This study supports the
feasibility of treating patients with MDS with the unique approach of
cytoprotection and anticytokine therapies as well as the principle that
prolonged commitment to treatment is desirable when noncytotoxic agents
are administered.
(Blood. 2000;95:1580-1587)
No single therapeutic approach appears to have made a
significant impact on survival of patients with myelodysplastic
syndromes (MDS).1,2 Allogeneic bone marrow (BM)
transplantation,3,4 a choice available to few patients
given that the median age at diagnosis is approximately 70 years, is
the only exception. Options range from supportive care to the use of
stem cell transplantation. Based on the assumption that the cytopenias
may reflect a primary bone marrow failure, colony-stimulating growth
factors with overlapping activities designed to stimulate proliferation
of hematopoietic progenitors have been extensively
investigated.5-7 The problem is that administered as single
agents, granulocyte-macrophage colony-stimulating factor (GM-CSF) or
G-CSF rarely improves the anemia and the thrombocytopenia so commonly
the pathognomonic features of MDS. Erythropoietin alone produces an
improvement in the anemias of approximately 20% of patients, which
increases to almost 50% when combined with G-CSF.8,9
However, only a proportion of patients respond, the response is usually
temporary, and there is some concern related to an incidence of
accelerated transformation.10
Acute leukemia-like intensive induction therapies have been attempted
in patients with high-risk MDS (those with excess blasts or chronic
myelomonocytic leukemia), with as many as half the patients achieving
complete remission.11,12 Short duration of remission marked
by a relentless return of MDS cells in most patients, treatment-related
complications or mortality, frequent encounters with drug-resistant
clones, and the morbidity caused by the appearance of unexpected and
unusual opportunistic infections reflecting the enormously compromised
state of the immune system in these patients make the intensive
chemotherapy option less desirable. In summary, save for allogeneic
transplantation, MDS is a universally fatal illness, and no single
approach has either altered the natural history of the disease or
improved survival.
Given the biologic complexity and the unpredictable course of the
disease ranging from chronic, insidious, and slowly progressive cytopenia to a rapidly evolving, lethal transformation to acute leukemia, it is not surprising that therapeutic options range widely
between supportive care to intensive induction-type chemotherapy. Clearly, a better understanding of the basis for cytopenias in MDS is
critical to design therapies tailored for individual needs. Recent
biologic studies have demonstrated that cytokine-mediated excessive intramedullary apoptosis of hematopoietic cells may form this basis in most patients with MDS.13-16 This
insight offers a novel therapeutic window of opportunity because it
naturally follows that suppression of the proapoptotic cytokines should lead to an improvement in cytopenias. The proinflammatory/proapoptotic cytokines that have so far been demonstrated to be candidates for this
role are tumor necrosis factor More recently, the cytoprotective agent amifostine has been found to
have substantial activity in improving cytopenias of patients with
MDS.29 In the current study, therefore, the anticytokine and cytoprotective approaches were combined to determine whether the
gains in improving ineffective hematopoiesis of MDS could be further
enhanced. This article reports on the first trial that combined all 4 agents namely, pentoxifylline, ciprofloxacin, amifostine, and dexamethasone.
All patients were entered on the protocol MDS 96-02. The protocol
was reviewed and approved by the Institutional Review Board (IRB) of
the Rush-Presbyterian-St. Luke's Medical Center and by the IRBs of
other participating institutions. All patients considered potential
candidates for treatment on MDS 96-02 had the protocol explained to
them by the Principal Investigator, and if they agreed to participate
in the study, they signed an informed consent form before therapy
began. All patients underwent a bone marrow examination before the
start and after approximately 12 weeks of therapy. Weekly complete
blood counts with differentials were obtained on all the patients; only
adults older than 18 years of age were eligible for the study. All
pretherapy and posttherapy bone marrow examination results were
reviewed at Rush University by a hematopathologist.
Clinical studies
Response criteria
Cytogenetic studies Standard karyotypic analysis using GTG banding was performed on every case before therapy was started and each time a marrow was performed thereafter.Statistical analysis Mann-Whitney U tests were used for 2 sample comparisons of continuous variables. Contingency tables with 2
statistics or the Fisher exact test were used for analysis.
Results Thirty-five patients with a confirmed diagnosis of MDS were registered on protocol 96-02, and 29 patients could be evaluated because they completed the minimum specified period of 12 weeks on the study. Of the 29 patients who are the subject of this report, there were 21 men and 8 women, 27 were white, 1 was Hispanic, and 1 was African American. The median age was 67 years (range, 46-81 years), and 5 patients had a history of toxic exposure (secondary MDS). Of the 5 patients with secondary MDS, patient 2 had a history of myelofibrosis but did not receive any cytotoxic therapy (Table 1), patient 17 underwent autologous stem cell transplantation for non-Hodgkin's lymphoma, patient 19 underwent autologous bone marrow transplantation for AML 10 years before the diagnosis of MDS, patient 23 had breast cancer and underwent 6 cycles of chemotherapy 1 year before the diagnosis, and patient 29 underwent multiple cytotoxic therapies for chronic lymphocytic leukemia. Twenty patients had refractory anemia (RA) according to the French-American-British (FAB) classification, 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). These data are shown in Table 1.
Protocol compliance and toxicity Of the 35 patients registered on MDS 96-02, 3 died before 12 weeks of therapy could be completed, 1 discontinued therapy because of intolerable nausea, 1 had a myocardial infarction and discontinued therapy within 4 weeks, and 1 was registered but never started treatment. Of the 29 patients who could be evaluated for response because they completed at least 12 weeks of therapy, 9 were treated on the 200 mg/M2 dose of amifostine, 8 on the 300 mg/M2 dose, and 12 on the 400 mg/M2. Twelve patients received the highest dose of amifostine because 3 patients in the lower dose groups could not be evaluated. No differences were noted in response rates among these groups. Responses were seen in 22 of 29 (76%) patients, 7 of 9 (78%) received the lowest dose of amifostine, 6 of 8 (75%) received the intermediate dose, and 9 of 12 (76%) received the highest dose of amifostine (P = .98). Although 29 patients completed 12 weeks of therapy, only 8 patients completed 6 months, 5 completed 9 months, and 3 completed the full year of treatment specified in the protocol. Sixteen patients stopped treatment because there was no further improvement in their cytopenias, 5 stopped because of intolerable side effects, 5 showed progression of disease, and 3 completed the full year of therapy. Approximately half the treated patients experienced some side effects from the drugs (Table 2). Briefly, 57% patients experienced nausea and 10% vomiting. Among the patients who experienced nausea, vomiting, or both there was a difference in those who received the higher doses of amifostine compared with those who received the lowest dose. For example, in the 200 mg/M2 amifostine dose group, the incidence for nausea was 11% compared with 25% and 26% at the higher doses. Similarly, though 7% of patients at the lowest dose of amifostine experienced vomiting, 14% had vomiting at both the higher doses. From 17% to 20% of patients experienced decreased appetite, hypotension, rash, and fever, whereas depression (13%) and anxiety (3%) were rarer. Once again, all these side effects were experienced primarily in the 2 higher dose groups rather than the lowest dose amifostine group (Table 2).
Hematologic responses Of the 29 evaluable patients, 7 had no response after at least 12 weeks of therapy whereas 22 of 29 (76%) showed partial response in that there was improvement in their cytopenias. There were no complete responders. Seven patients showed some improvement before the addition of dexamethasone, and 15 only responded after PCD + amifostine. The median time to response varied depending on the lineage and on whether the patient received dexamethasone. Nineteen patients showed an improvement in ANC, 11 in hemoglobin or transfusion requirements, and 7 in platelet count. Overall, there were 3 triple lineage responders, 10 double lineage responders, and 9 single lineage responders (8 of 9 in ANC only; 1 showed more than 50% reduction in PRBC transfusions). The details of these responses and the precise blood counts are shown in Table 1. In summary, two-thirds of the responding patients had improved ANC, half showed improvement in the erythroid lineage, and one-third showed improvement in their platelet counts. Improvements in these cytopenias were noted more rapidly after the addition of dexamethasone, whereas a more gradual improvement occurred in the patients who did not receive the additional steroid therapy.
Patient 14
Patient 12 This 58-year-old white man was diagnosed with RA in June 1997 when he sought treatment for profound pancytopenia and severe fatigue (Table 1, Figure 2b). He had a hypercellular BM and cytogenetic abnormality 46, XY, del20(qll .2ql3.3)/46 × Y). After several PRBC transfusions, his Hb level increased to 9.6 g/dL, WBC was 1500/µL, and platelet count 54 000/µL when he started on the protocol. As seen in Figure 2B, he did require PRBCs twice in the next 3 months, but then his Hb level continued to improve, reaching a maximum of 13.9 g/dL. His WBC and platelet counts also improved (8200 µL and 180 000 µL, respectively). After approximately 11 months of treatment, the patient experienced a severe hypotensive episode after a routine amifostine injection. All study drugs were stopped at this point (6/12/98), and the patient began to experience a slow decline in all his counts within 6 weeks of halting therapy. By October, he was placed on PCD therapy because his Hb fell to 8.5 g/dL and his platelet count decreased to the 70 000/µL range. He has been showing response to this therapy.Patient 6 This 82-year-old white man was diagnosed with RARS on 9/9/96 (Table 1, Figure 2C). He was started on MDS 96-02 on 3/31/97, at which time his WBC count was 1100/µL, Hb level was 7.3 g/dL, and platelet count was 44 000/dL. He had normal cytogenetics and hypercellular BM with 3% blasts. He required 2 U PRBC almost every 7 to 10 days and platelets every 2 to 3 weeks. After treatment with amifostine + PC, the patient continued to require the same level of transfusions until dexamethasone was added. At that point, he showed a dramatic response by becoming transfusion independent for 5 months. After approximately 8 months of therapy, the patient was taken off all medications because no further improvement was noted in the cytopenias. He began to require transfusions within 8 weeks of halting therapy and was started on another protocol. His condition eventually transformed to AML 6 months later, and he died on 8/13/98.Patient 7 This 52-year-old white man was diagnosed with RA in 1992 and underwent multiple therapies for MDS before he started on this protocol (Table l, Figure 2D). He began treatment on 1/13/97 when his Hb was 8.9 g/dL (after PRBC transfusion), WBC count was 3000/µL, and platelet count was 18 000/µL. He was receiving 2 U PRBC every 7 to 10 days and platelet transfusions every 1 to 3 weeks. His BM was hypocellular (10% cellularity), and cytogenetics showed an abnormal karyotype with 46XY, de(7) t(1;7) (q10; p10)/46, XYde(14) t(1;14) (q10; p10)(2)/46XY(14). He continued to require both blood and platelet transfusions until the dexamethasone was added on 5/21/97. After approximately 2 months of therapy with APC + D, this patient became completely transfusion independent. Eventually, amifostine + PC was stopped (7/9/97), and the patient has been maintained on a 5 day per month cycle of dexamethasone at 4 mg by mouth 4 times a day. He has only required blood and platelet transfusions twice in the last year, both times because he was undergoing elective hip replacement surgery. At present, he continues to be transfusion independent.Cytogenetic studies Detailed karyotypes were performed in every patient. Fourteen patients had normal karyotypes when therapy was begun, and 15 patients showed abnormal chromosomes. The most frequent abnormalities affected chromosome 5 or 7 (8 patients), 2 had del20 abnormality, 1 had an isochromosome 17 (ql0), and 4 had other cytogenetic anomalies. Serial studies were performed when possible and showed clonal evolution with the appearance of new abnormalities in 4 patients. No cytogenetic responses were observed in this group of 29 patients.
Myelodysplastic syndromes are universally fatal disorders. Because
erythroid, myeloid, and megakaryocytic cells, and occasionally B
lymphocytes, have been found to be clonal in nature, it is likely that
the transforming event(s) has occurred at a pluripotential stem cell
stage.31 One approach to treating this illness with a
curative intent would be to target the abnormal clone directly by using
intensive chemotherapy, stem cell transplantation, or both. The
associated prohibitive morbidity and mortality, however, especially in
an elderly group of patients, render these procedures applicable only
to a select subgroup of MDS patients. An alternative approach, which
may not be curative but could provide substantial palliation, would be
to suppress the cause of cytopenias in these patients. We have observed
the presence of extensive apoptosis in the bone marrows of as many as
75% of patients with MDS.14 The parallel high levels of
TNF-
We thank Dr Rohit Shah and Dr Israel Wiznitzer (Lake Forest Hospital, Lake Forest, IL) for study participation. We also thank Ms Lakshmi Venugopal and Ms Sandra Howery for excellent administrative and secretarial assistance. The drug amifostine was provided free of charge to the patients by a grant from the Alza Corporation.
Submitted June 16, 1999; accepted November 3, 1999.
Supported by the National Cancer Institute (grant PO1CA 75606), The Markey Charitable Trust, and the Dr Roy Ringo Grant for basic research in myelodysplastic syndrome.
Reprints: Azra Raza, Pre-Leukemia and Leukemia Program, Rush Cancer Institute, Rush-Presbyterian-St. Luke's Medical Center, 2242 West Harrison Street, Suite 108, Chicago, IL 60612-3515; e-mail: araza{at}rush.edu.
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.
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Top
Abstract
Introduction
(TNF-
(TGF-
