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Keywords:

  • myelodysplastic syndrome;
  • refractory anaemia;
  • antithymocyte globulin

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

Summary. We report 30 ‘low-risk’ patients with myelodysplasia (MDS) (defined as < 10% bone marrow blasts) who were treated with antithymocyte globulin (ATG). In total, 20 patients were evaluable at the study end-point (response to treatment at 6 months). The diagnosis in these 20 patients was refractory anaemia (RA) in 13, RA with excess blasts in four, and RA with ringed sideroblasts in three. Median age was 54·5 years (range, 31–73 years). There were two cases of secondary MDS. The bone marrow was hypocellular in eight cases and cytogenetics were abnormal in four cases. All patients received lymphoglobuline (horse ATG; Sangstat, France) at a dose of 1·5 vials/10 kg/day for 5 d. The treatment was well tolerated. Three patients in the study died (disease progression, invasive aspergillosis and lung carcinoma respectively); 10 out of 20 evaluable patients (50%) responded to treatment and became transfusion independent; eight out of 13 (62%) patients with RA responded. The median duration of response was 15·5 months (2–42+ months) at the time of analysis.

The myelodysplastic syndromes (MDS) are characterized by progressive anaemia, thrombocytopenia and neutropenia, leading to transfusion dependence and an increased risk of infection. Death usually occurs because of the complications of marrow failure (bleeding or infection), or progression to acute leukaemia (Mufti & Galton, 1986). Patients with < 10% bone marrow blasts have a longer survival and lower rate of transformation to acute myeloid leukaemia (AML) than those with > 10% blasts (Greenberg et al, 1997). In the absence of curative intent (applicable to only a small proportion of younger patients), therapeutic intervention should be aimed at the amelioration of these cytopenias.

The pathogenesis of ineffective haematopoiesis remains unclear, but evidence is emerging that indicates immunological dysfunction as a contributor to ineffective haematopoiesis. Both serological and clinically significant autoimmune disorders are associated with MDS (Symeonidis et al, 1991; Okamura et al, 1997), as are increased concentrations of inflammatory cytokines in MDS patients' serum (Verhoef et al, 1992). Given the potential contribution of autoimmunity to the cytopenias in MDS, it is logical to extrapolate the experience of immunosuppressive therapy in aplastic anaemia (Marsh et al, 1987; Bacigalupo et al, 1988; Young et al, 1988) to therapy for MDS. A pilot study of 60 patients treated with antithymocyte globulin (ATG; ATGAM, Upjohn), demonstrated red cell transfusion independence in 33% MDS patients (Barrett et al, 1998).

The primary aim of this study was to determine the efficacy of lymphoglobuline (SangStat, France) as opposed to ATGAM for the treatment of patients with low-risk MDS (< 10% bone marrow blasts), such that blood products were no longer required or their requirement was reduced, and the risk of infection was reduced. The secondary aim was to assess the safety of lymphoglobuline in patients with low-risk MDS, as determined by acute toxicity and the occurrence of side-effects during follow up.

Patients.  A total of 30 ‘low-risk’ MDS patients (defined as < 10% bone marrow blasts) ≥ 18 years of age from eight hospitals in the UK were treated with ATG (Lymphoglobuline, SangStat). All patients had an established diagnosis of MDS, defined as dysplasia in two or more lineages and less than 10% bone marrow (BM) blasts. The subtype of MDS was defined by the French-American-British (FAB) criteria (Bennett et al, 1982) as refractory anaemia (RA), RA with ringed sideroblasts (RARS) and RA with excess of blasts (RAEB). In addition, the following haematological criteria were met: haemoglobin concentration (Hb) less than 10 g/dl or red cell transfusion dependence of greater than two units every 4 weeks for at least 2 months, or thrombocytopenia with platelets less than 100 × 109/l and with significant haemorrhage, or neutropenia with an absolute neutrophil count less than 1·5 × 109/l and recurrent infections.

Informed consent was obtained from all patients participating in the trial, and the local Hospital Research Ethics Committees approved the study.

Study design.  The study was a non-randomized phase I/II trial in 30 patients with MDS. A single treatment course of lymphoglobuline (SangStat) was administered (1·5 vials/10 kg/day for 5 d; 1 vial contains 100 mg protein). A test dose of one-tenth of a vial was given before giving the full dose. Before each daily dose of lymphoglobuline, hydrocortisone 100 mg and piriton 10 mg was given as hypersensitivity prophylaxis. Antibiotic and antifungal prophylaxis was given to all patients together with oral prednisolone for the prevention of serum sickness (1 mg/kg/day for 9 d commencing on d 5 of lymphoglobuline therapy).

The study end-point was response at 6 months.

Response criteria.  Response was defined as transfusion independence (red cells and platelets) for at least 8 weeks. In addition, complete response (CR) was defined as normalization of peripheral blood counts for at least 8 weeks and partial response (PR) as ≥ 50% increase of all blood counts (Molldrem et al, 1997).

As this study was performed, new standardized response criteria for MDS studies have been published (Cheson et al, 2000). Therefore the results have also been analysed using the criteria for haematological improvement.

Statistical analyses.  Duration of response among partial and complete responders was analysed using survival methods to give a Kaplan–Meier curve and hence the median duration of response. Responders and non-responders were compared using a Mann–Whitney U-test for age (continuous data) and using Fisher's Exact tests for all other variables (categorical data).

All patients.  The median age was 51·5 years (range 18–73 years) and the male:female ratio was 1·6 (Table I). The stated diagnoses (before central morphology review) were RA in 19 patients, RAEB in six, RARS in four and one patient had Monosomy 7 syndrome (RA) that arose in childhood. All cases underwent central morphology review by three investigators and thereafter were assigned a FAB diagnosis according to the consensus view. After the central morphology review, the diagnoses were RA in 19 patients, RAEB in four, RAEBt in one, RARS in four and alternative diagnoses in two. The median duration of disease before treatment was 15·5 months (range 2 weeks-20 years). One patient (unique patient number (UPN) 15) had received ATG 15 years previously, with a long-term response. There were four cases of secondary MDS: one after an autologous bone marrow transplantation for AML 7 years previously (UPN 14), one after untreated aplastic anaemia (AA; UPN 20), one after treatment for non-Hodgkin's lymphoma (UPN 22) and one after treatment for Hodgkin's lymphoma (UPN 17).

Table I.  Patient details.
UPNAgeSexFAB type pre reviewFAB type after reviewCellularityFibrosis 1°/2°CytogeneticsTransfusion dependentIPSPNH clone pre-treatment
  1. UPN, unique patient number; M, male; F, female; RA, refractory anaemia; RAEB, RA with excess blasts; RARS, RA with ringed sideroblasts; RAEBt, RAEB in transformation; 1°/2°, primary/secondary MDS; IPS, International Prognostic Score; NK, not known; Y, yes; N, no; NA, not available.

163FRARANormo/hyper1146,XX,t(2;11)(p21;p23) del(5)(q22;q33)Red cells Y, Plt N0·5N
255MRANot MDSHypo1146,XYRed cells Y, Plt YNKNK
365MRARSRARSNANA146,XYRed cells Y, Plt Y0·5NK
443MRARANormo/hyperNA146,XYRed cells Y, Plt N0·5NK
573MRARAHypo1146,XYRed cells Y, Plt Y0·5N
664MRARAHypo31FailRed cells Y, Plt YNKN
747MRARAEBHypo3146,XYRed cells Y, Plt N0·5N
871MRARAHypo1146,XYRed cells Y, Plt N0·5N
966MRAEBRAEBNormo/hyper2146,XYRed cells Y, Plt N1N
1046FRARAHypo1246,XX,del(5)(q13q22)Red cells Y, Plt N0·5N
1121FRANot MDSNormo/hyper1146,XXNoNKN
1231MRARAHypo1146,XYRed cells Y, Plt Y0·5Y(neutrophils)
1318FMonosomy 7RAHypoNA146,XX,i(7q)(q10)Red cells Y, Plt Y1·5N
1448FRAEBRAEBHypo2246,XXRed cells Y, Plt N1N
1551FRARAHypo2146,XXRed cells Y, Plt Y0·5N
1637MRARANormo/hyper3146,XYRed cells Y, Plt N0N
1742FRARANormo/hyperNA246,XXRed cells Y, Plt Y0·5NK
1859FRARANANA146,XXRed cell Y, Plt N0·5NK
1968MRAEBRAEBNormo/hyper1146,XYRed cells Y, Plt N1N
2033MRARANormo/hyper22del7Red cells Y, Plt N1·5N
2137FRAEBRANormo/hyper3146,XX,del20 (p11p13) (q11q13)Red cells Y, Plt N0·5N
2247MRARANormo/hyper42del4qRed cells Y, Plt N1NK
2351FRARANormo/hyper2146,XXRed cells Y, Plt N0NK
2465MRARAHypoNA1t(1;7)Red cells Y, Plt Y1N
2552MRARSRARSNormo/hyper3147,XY,+8Red cells Y, Plt N0·5NK
2647FRAEBRANA31FailRed cells Y, Plt YNKN
2769MRARAHypoNA1FailRed cells Y, Plt YNKN
2862MRARSRARSNormo/hyperNA146,XYRed cells Y, Plt N0·5NK
2971MRAEBRAEBtNK3146,XY,del21,del12(q23q24), inv12(p12–13q13)Red cells Y, Plt Y3NK
3066MRARSRARSNormo/hyper1146,XYRed cells Y, Plt Y0·5N

Patients eligible for evaluation at study end-point.  There were 20 patients who were eligible for evaluation at 6 months. The median age in this group was 54·5 years (range 31–73 years) and 13 were men. Diagnosis was RA in 13 patients, RARS in three and RAEB in four patients. Two patients had secondary MDS (UPN 14 and 17). From those in whom an International Prognostic Score (IPS) could be ascribed (Greenberg et al, 1997), the median score was 0·5 (range 0–1). Bone marrow cellularity was hypocellular in eight, normo/hypercellular in nine, and unknown in three. Hypocellular myelodysplasia was differentiated from aplastic anaemia by evidence of dysplasia in two or more haemopoietic lineages. All 20 patients in this group were red cell transfusion dependent and 8 were platelet dependent. The median neutrophil count was 1·3 × 109/l (range 0·2–11·0 × 109/l). Cytogenetic analysis was available in 18 patients. Only one patient (UPN 10) had a detectable paroxysmal nocturnal haemoglobinuria (PNH) clone (neutrophils) pre-treatment.

Reasons for exclusion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

A total of 30 patients were treated with ATG; 10 patients were excluded from the final analysis. Three of these patients did not fulfil the entry criteria at central morphology review; UPN 29 (blast count > 10% at central review) and UPNs 2 and 11 (alternative diagnoses). UPN 21 received danazol, cyclosporin and granulocyte colony-stimulating factor after ATG, and was therefore excluded from the trial. A further four patients (UPN 13, 15, 20 and 22) were excluded as the clinical research forms had not been completed for these patients. Two patients died before the study end-point and were excluded. UPN 6 died, 3 weeks after receiving treatment, due to aspergillosis and UPN 28 died with disease transformation (AML) 11 weeks after receiving treatment with ATG. UPN 12 received danazol 4 months after ATG, but had already responded to the treatment and therefore was included in the final analysis.

Treatment outcome ()

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

Table IIOut of 20 evaluable patients who fulfilled the entry requirements and reached the study end-point (6 months), one patient (RA) achieved CR, nine patients (7RA, 1RARS, 1RAEB) achieved a PR and 10 had no response (NR). One patient went on to achieve CR after 6 months (UPN 10) and one patient became platelet independent after 6 months (UPN 5). UPN 24 had a partial response to treatment but was simultaneously diagnosed with lung carcinoma and has since died.

Table II.  Response of evaluable patients to antithymocyte globulin (ATG).
UPN(Response: original Molldrem et al, 1997)(Response: Cheson criteria Cheson et al, 2000)Response duration (months)Outcome
  1. CR, complete responder; PR, partial responder; E, erythroid; N, neutrophil; P, platelet.

1CRHI-E major22+Alive in CR
5PRHI-E major13Alive, ongoing response
HI-P major after 6 months  
8PRHI-P,E,N 2Relapsed retreated but no response
10PRHI-P,E major24+Achieved CR after 6 months
HI-N minor  
12PRHI-P,E major42+Alive, ongoing response
17PRHI-P,E major24Relapsed Hodgkin's disease; died
19PRHI-E minor18+Alive, ongoing response
23PRHI-E major 5Relapsed
24PRHI-P,N major 2Died of lung cancer
30PRHI-P,E major12+Alive, ongoing response

According to the recently published standardized response criteria for MDS (Cheson et al, 2000), one patient had a major erythroid, platelet and neutrophil response (RA), three patients had a major erythroid and platelet response (2RA, 1RARS), three patients had a major erythroid response (all RA), one patient had a major platelet and neutrophil response (RA), one patient had a major platelet and haemoglobin response with a minor neutrophil response (RA), and one had a minor haemoglobin response (RAEB).

The median duration of response among the 10 responders was 15·5 months (range 2–42+ months) at the time of analysis (Fig 1). Three patients relapsed; UPN 5 after 13 months, UPN 8 after 2 months and UPN 23 after 5 months. UPN 8 was subsequently retreated with ATG but did not respond. In total, 50% of evaluable patients treated with ATG had responded at the study end-point. The majority of responders had RA, of whom 62% achieved a response. Responders and non-responders are compared in Table III.

image

Figure 1. Duration of response for partial and complete responders.

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Table III.  Comparison of clinical characteristics in responders and non-responders in those who were eligible.
VariableResponders* (n = 10)Non-responders (n = 10)P-value
  1. *According to Cheson et al (2000).

Median age (years)64 (31–73)50 (37–69)0·45
Gender M/F1·502·331
FAB subtype
 RA85 
 Non-RA250·35
Abnormal cytogenetics310·58
Hypocellular BM530·65
Median IPS0·5 (0–1·0)0·5 (0–0·5)0·92

Complications of therapy

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

The majority of side-effects from ATG were anticipated; fever (n = 19), fluid retention (n = 6), rash (n = 17), reported serum sickness (n = 4). There were seven further patients who had joint pains, which probably represented serum sickness. UPN 21 had parotitis 15 d after ATG infusion, which settled with corticosteroids.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

Current treatment options for patients with MDS are limited. Allogeneic stem cell transplantation is the only curative treatment but, due to patient age, and the availability of suitable donors, only a minority of patients are eligible for this treatment. The majority of patients remain on supportive care alone as conventional chemotherapy regimens offer poor response rates and a high risk of morbidity and mortality (Hirst & Mufti, 1993). Recent interest has focused on the use of haemopoietic growth factors such as erythropoietin, granulocyte colony-stimulating factor and granulocyte monocyte colony-stimulating factor, or combinations of these, which may induce response in some patients (Hellstrom-Lindberg et al, 1997, 1998; Thompson et al, 2000). The use of amifostine, an antioxidant agent, has also been evaluated in MDS with only limited success in vivo (List et al, 1997; Bowen et al, 1998).

Antithymocyte globulin has recently been introduced as a new therapy for patients with MDS (Molldrem et al, 1997; Barrett et al, 1998), and has shown promising results. The treatment is aimed at patients who are either transfusion dependent, or have severe cytopenias leading to bleeding or infections. The only prospective study to date has shown that those patients with the highest response rate to ATG are under 60 years, have a diagnosis of RA, a normal karyotype and low marrow cellularity (Molldrem et al, 1997; Barrett et al, 1998). An alternative immunosuppressive modality cyclosporine A, has also been shown to be effective in MDS patients, with multilineage responses in 23% patients and transfusion-independence in a higher proportion (Jonasova et al, 1998).

The mechanism of action of ATG in MDS, like AA, is unknown. Preliminary data suggests that in MDS, ATG may be involved in the elimination of CD8+ lymphocyte-mediated suppression of granulocyte/monocyte progenitor cells (Molldrem et al, 1998). This mechanism of action may be the preferential elimination of clonally expanded T cells, as it has been shown that patients with MDS may have abnormal expression of T-cell receptor Vβ families, which are lost or reduced after treatment with ATG in those that respond to therapy (Molldrem et al, 1998). It has also been shown that myelodysplastic haemopoietic stem cells in vitro can be directly stimulated in culture by ATG (Killick et al, 2000). Of note, the presence of a glycosylphosphatidylinositol-deficient clone in MDS is strongly correlated with a haematological response to ATG (Dunn et al, 1999). Although this was evaluated in most of our patients, only one patient tested had a pretreatment PNH clone. This patient had a response to treatment, but the numbers in this study are too small to allow conclusions to be made.

The pilot study presented here recruited only those patients with ‘low-risk’ (< 10% bone marrow blasts) MDS as previous studies have reported superior response rates with ATG in this group (Barrett et al, 1998). Our study set out to determine whether a course of ATG (lymphoglobuline) could improve haemopoiesis in MDS. From those evaluable patients, 10 out of 20 patients (50%) became transfusion independent, although only one patient had complete haematological recovery with normal peripheral blood counts at the 6 month follow up. Two patients with secondary MDS responded to treatment (UPN 10 and 17). Three patients relapsed after therapy; the other surviving patients have remained transfusion independent without further treatment. The only factor found to possibly favour response was the diagnosis of RA, where 62% of patients had a haematological response, but this was not significant (P = 0·35). We found no relationship between age, gender, presence of a cytogenetic clone or BM cellularity and response rate, although numbers were small. This study documents a response to ATG in a patient with RARS, which has not been described before. The patient is currently red cell transfusion independent and has a platelet count > 100 × 109/l. Five of our responders were aged > 65 years (oldest 73 years), and these represent the oldest MDS patients yet to be reported as responders to ATG. These data support the efficacy of ATG in older patients with AA (Tichelli et al, 1999), although in AA, age is an adverse risk factor for mortality after ATG therapy, due to infection and bleeding. Importantly, apart from the expected side-effects of early allergic reactions and serum sickness, ATG was well tolerated, even in the elderly patients.

With treatment options remaining limited in MDS, ATG may represent a cost-effective choice for patients with refractory anaemia, in which haematological recovery can occur in approximately half the cases after a single course. This study confirms that the major advantage of ATG therapy over alternative agents is the durable nature of clinically meaningful responses after a single course of therapy (Molldrem et al, 1997). Future randomized studies to compare other immunosuppressive agents alone or in combination with ATG are warranted, as are studies in elderly patients, for whom options remain extremely limited.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References

We would like to thank the following clinicians who recruited patients into this trial: Dr Dominic Culligan (Aberdeen), Dr Christopher Fegan (Birmingham Heartlands Hospital), Alison Brownell, David Lewis (Oldchurch Hospital), Andy Hughes (Harold Wood Hospital), Ayed Eden, Mike Mills (Southend General Hospital), Ian Grant, Naim Akhtar (King George's Hospital, Ilford), Vij Chowdhury, Hazel Baugh (Broomfield Hospital, Chelmsford), Gerry Robbins (Royal Surrey County Hospital, Surrey), Lydia Jones (Epsom Hospital, Surrey), Hugh Williams (Maidstone Hospital, Kent), Judith Behrens, Jane Mercieca (St Helier Hospital, Surrey), Tony Roques (Worthing Hospital, Sussex), Chris Mattock (Jersey). We thank SangStat for their continued support.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Patient characteristics
  6. Reasons for exclusion
  7. Treatment outcome ()
  8. Complications of therapy
  9. Discussion
  10. Acknowledgments
  11. References
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