Myelodysplastic Syndrome

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study

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Summary:

The objective of this prospective study was to determine whether amifostine (Ethyol®) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 × 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m2 amifostine i.v. twice daily during conditioning (days –7 through –1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II–III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Main

Allogeneic hemopoietic cell transplantation (HCT) is currently the only potentially curative therapy for patients with myelodysplastic syndrome (MDS).1 Among patients with less advanced (defined as <5% marrow blasts) MDS, 3-year relapse-free survival of 60–70% is achievable with human leukocyte antigen (HLA)-identical related or unrelated donors.2,3,4 Among patients with advanced disease (>5% marrow blasts), 25–45% can be expected to survive in remission at 3 years after transplantation.3,4,5 However, among patients with both advanced and less advanced MDS, nonrelapse mortality (NRM) has been in the range of 25–70%.3,5,6,7,8

Amifostine (Ethyol®), also known as Walter Reed (WR)-2721, is a phosphorylated aminothiol compound originally developed by the WR Army Institute of Research as a potentially radioprotective agent for military personnel.9 Dephosphorylation to its active form WR-1065 occurs in normal tissues, but is almost negligible in tumors. These observations rendered amifostine attractive as a selective cytoprotective agent against radiation and possibly chemotherapy-induced tissue damage. Several trials have shown that amifostine reduces toxicity induced by cytotoxic agents as diverse as cyclophosphamide (CY), cisplatin, carboplatin, and radiotherapy given in nonmyeloablative doses.10,11,12,13,14 Reports on the use of amifostine in the transplant setting have so far been restricted to autologous transplants where mixed results were reported.15,16,17,18 Here, we evaluated whether amifostine offered protection against toxicity from a high-dose myeloablative regimen in patients receiving allogeneic stem cells.

Patients and methods

Patients

Between January 1999 and June 2000, 12 patients 41–60 (median 51) years of age with advanced MDS19 or acute myeloid leukemia (AML) evolved from MDS were enrolled in this pilot trial. One patient who was initially diagnosed with MDS based on clinical presentation, marrow morphology, and normal cytogenetics was included; however, subsequently, he was shown to have a bcr/abl rearrangement. The clinical characteristics of the patients are shown in Table 1. Disease risk at the time of HCT was assessed using the International Prognostic Scoring System (IPSS) (Table 1).20 The median interval from diagnosis of MDS to HCT was 5 (range 3–27) months. Seven patients had received induction chemotherapy, but only one was in complete remission (CR) at the time of HCT. In all, 11 patients had received packed red blood cell or platelet transfusions or both prior to HCT.

Table 1 Patient characteristics

Conditioning regimen and transplant procedure

Conditioning consisted of oral busulfan (BU) (0.44 mg/kg body weight (BW) per dose) every 6 h on days –7 through –4 for a total of 16 doses (total dose: 7 mg/kg BW), followed by total body irradiation given in fractions of 200 cGy twice daily on days −3, −2, and −1 (FTBI; total dose: 12 Gy). The median CD34+ cell dose was 7.9 × 106/kg BW (range 4.73–13.91) in the nine patients receiving peripheral blood. Three patients transplanted with marrow received 0.68, 1.34, and 2.18 × 108 mononuclear cells/kg BW, respectively. All patients were given infection prophylaxis with trimethoprim/sulfamethoxazole, acyclovir, and itraconazole. Graft-versus-host disease (GVHD) prophylaxis with methotrexate and cyclosporine was given as described.21 Acute and chronic GVHD were diagnosed and classified according to established criteria.22,23 Details of the long-term follow-up program have been reported recently.24

Amifostine administration

Amifostine (Ethyol®, Alza Pharmaceuticals, Palo Alto, CA, USA) was administered intravenously (i.v.) over 10 min at doses of 340 mg/m2 twice daily during conditioning with BU/FTBI. The amifostine infusion was started 15 min before the first and third doses of BU of each day, and before each increment of FTBI. Patients were kept in a supine position and received 500–1000 ml normal saline i.v. prior to and during the amifostine infusion. Blood pressure was monitored before, every 5 min during, and 5 min after completion of the infusion. Antiemetic premedication consisting of dexamethasone, granisetron, famotidine, diphenhydramine, and lorazepam was given 2 h prior to amifostine.

Assessment of toxicity

Regimen-related toxicity was graded according to the Bearman criteria.25 Liver toxicity was assessed by clinical evidence of sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD),26 and frequent measurements of total serum bilirubin through day +20. The maximum bilirubin value was used to quantify liver toxicity. Diagnosis of SOS was based on published criteria.27 Severity of SOS was classified as mild (no treatment required, complete resolution), moderate (treatment required, complete resolution), or severe (treatment required, incomplete resolution before death or day 100). Patients with liver disease who did not meet the criteria of SOS were categorized as having ‘liver disease of unknown etiology’. The protocol was approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center, and written informed consent was obtained from each patient before study entry.

Statistical considerations and study design

The primary objective of this single-arm phase I/II study was to determine whether there was at least moderately strong evidence for a reduction in the incidence of RRT with the addition of amifostine. The focus was on stomatitis and hepatic toxicity. With standard regimens, the incidence of such RRT has been 0.9 for stomatitis and 0.5 for hepatic toxicity. Considering the most frequent toxicity, stomatitis, moderately strong evidence was taken to mean that the upper boundary of a one-sided 90% confidence interval for the rate of RRT was less than 0.9; operationally, this means that the trial was considered a ‘success’ if 11 or fewer patients out of 15 patients experienced stomatitis. Similarly, a ‘success’ with respect to hepatic toxicity would be demonstrated, if four or fewer patients experienced RRT.

Results

Transplantation

Engraftment

Two patients died before day 28, and were considered not evaluable for engraftment. One patient died on day 40 post transplant with absolute neutrophil count (ANC) engraftment, but still requiring platelet transfusions. All the other patients showed sustained three-lineage engraftment; median time to achieve an ANC of >0.5 × 109/l was 18 (range 12–23) days and time to a platelet count of >20 × 109/l was 21 (range 15–33) days.

Graft-versus-host disease

Nine patients developed acute GVHD of grades II–IV, including five with grades III–IV. Chronic extensive GVHD occurred in two of three patients who survived beyond day 100.

Survival and causes of death

Eight patients died of nonrelapse causes between 27 and 82 (median 62) days after transplantation: three patients of multiorgan failure with or without infection (one of these patients also developed myocardial infarction), three patients with invasive aspergillosis, and one patient each with cytomegalovirus pneumonia and idiopathic interstitial pneumonitis. Two patients died in complete remission 193 and 607 days after transplantation of chronic respiratory failure. One of these two patients had interstitial pneumonitis. In the other patient, lung biopsy showed patchy organizing pneumonia with alveolar fibroblasts, focal hyaline membrane formation, and diffusely widened lung interstitium. Integrity of bronchioles, however, was not disturbed. One patient died from progressive disease at day 81 post transplant. One patient is alive in CR 31 months post transplant with chronic GVHD.

Regimen-related toxicity

Amifostine administration

Amifostine was well tolerated. The side effects included mild hypotension in one patient and asymptomatic hypocalcemia in four patients. One patient developed severe upper abdominal pain of unknown origin and had the second dose of amifostine withheld, but tolerated subsequent doses well.

Liver toxicity

Liver toxicity is summarized in Table 2. Eight patients developed peak serum bilirubin values >4 mg/dl between days 0 and +20. Median peak serum bilirubin was 6.1 (range 2.0–19.1) mg/dl. A weight gain of >5% from baseline within the first 20 days was observed in six patients. The overall median weight gain was 5.7% (range 0.6–14.2%). Eight patients had clinical evidence of sinusoidal liver injury related to the conditioning regimen. Six of them met the clinical criteria of SOS, which was severe in one patient, moderate in three, and mild in two patients.

Table 2 Liver toxicity and incidence of sinusoidal obstruction syndrome

Oropharyngeal mucositis

According to the Bearman toxicity-grading scheme, oropharyngeal mucositis was grade III in two patients. Both patients experienced aspiration pneumonia. Eight patients had grade II, and two grades I–II stomatitis.

Gastrointestinal toxicity

All the patients received total parenteral nutrition and patient-controlled analgesia (PCA) for the first 2–3 weeks after HCT. Clinically relevant gastrointestinal symptoms including abdominal pain, nausea, and vomiting were observed in four patients, and were thought to be related to regimen-related local mucosal damage and manifestations of gut GVHD.

Pulmonary toxicity

Early regimen-related pulmonary toxicity included autopsy-confirmed diffuse alveolar damage (DAD) in three patients (grade III: n=2; grade II: n=1) and interstitial pneumonitis in one patient (grade III). Symptoms of DAD/interstitial pneumonitis started between days 10 and 40 after HCT. Late pulmonary toxicity included one case of biopsy-proven interstitial pneumonitis and one case of biopsy-proven organizing pneumonia.

Renal toxicity

The median baseline creatinine level before HCT was 0.5 (range 0.75–1.8) mg/dl. In one patient, there was an elevated pretransplant creatinine level suggesting pre-existing chronic renal failure. The median peak creatinine level during the first 28 days after HCT was 1.45 (range 0.9–3.3) mg/dl. The peak values were reached at a median of 18 (range 1–27) days. On the basis of these findings, the study was closed after the enrollment of 12 patients.

Discussion

Amifostine has been shown in clinical trials to be cytoprotective for normal tissues without interfering with the desired antitumor activity of various therapeutic agents. Amifostine has been tested predominantly in patients with solid tumors receiving conventional chemotherapy or radiotherapy,10,11,12,13,14 and in a limited number of patients after high-dose chemotherapy with autologous stem cell rescue.15,16,17,18 While Chauncey et al15 found no evidence that amifostine reduced regimen-related mucositis or hepatic dysfunction, two other reports showed that amifostine had a positive impact on glomerular filtration rate, grade III/IV stomatitis, and engraftment in patients who received high-dose chemotherapy and autologous transplants.17,18

Studies in patients with MDS using CY and TBI-containing regimens showed relapse-free survival in the range of 30–40%, but relapse occurred in more than 30% of patients with advanced disease morphology.28 To determine if a more intensive conditioning regimen could improve results in patients with advanced MDS, BU was added to CY/TBI. Compared to historical controls conditioned with CY plus TBI, relapse rates were lower (28 vs 54%), but NRM was high (68 vs 36%).6 As CY is not stem cell toxic but has nonhemopoietic toxicities, CY was omitted from the regimen in the next trial. With such a regimen of BU and TBI, Jurado et al8 reported day 100 NRM of 38% among 60 patients with advanced MDS. In that trial, 19 patients died from organ failure+GVHD+infection, and four patients each from GVHD+infection or infection alone. Aspergillosis was the most common cause of infection. The current trial was an attempt to improve those results.

The reported incidence rates of sinusoidal liver injury or SOS after HCT range from 1 to 54%.26,29 As BU and TBI can act synergistically in causing sinusoidal liver injury, we hypothesized that amifostine would have a cytoprotective effect and would reduce the incidence and severity of liver damage. However, we observed VOD/SOS in 50% of patients, suggesting that amifostine prophylaxis as used here was not able to protect hepatic sinusoids or hepatocytes exposed to a conditioning regimen containing BU/FTBI.

Depending on the intensity of the conditioning regimen, the GVHD prophylaxis used, and the presence of additional factors facilitating mucosal damage (eg infections, trauma), up to 90% of patients who undergo HCT develop some degree of oropharyngeal mucositis.7,25,30,31 All patients in the present study had mucositis. In two patients, mucositis was presumably the cause of aspiration pneumonia and was, therefore, scored as grade III (Bearman score). Eight patients had grade II and two patients grades I–II mucositis. In addition, 50% of the patients developed early (n=4) or late (n=2) pulmonary toxicity. As with hepatic toxicity, administration of amifostine had no beneficial effect. Reassuring was the observation that amifostine did not interfere with allogeneic engraftment.

We concluded, therefore, that with the regimen used, amifostine did not ameliorate regimen-related toxicity in these heavily pretreated patients with advanced MDS who received transplant conditioning with BU/FTBI. These observations led to the omission of TBI from conditioning regimens for patients with MDS and to our current standard regimen of BU (targeted to plasma levels of 800–900 ng/ml) in combination with CY.4 Another trial is exploring the usefulness of fludarabine in combination with BU for transplant conditioning.32 Whether amifostine would be useful in reducing toxicity associated with these chemotherapy regimens or whether different regimens of amifostine might prove effective in reducing toxicity has not been determined.

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Acknowledgements

This work was supported by the National Institutes of Health Grants CA15704, CA18029, and CA87948. MB is funded by a fellowship from the Max Kade Foundation, New York.

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Correspondence to H J Deeg.

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Keywords

  • amifostine
  • myelodysplastic syndrome
  • busulfan
  • fractionated total body irradiation
  • regimen-related toxicity
  • transplantation

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