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Keywords:

  • haemolytic anaemia;
  • thrombocytopenia;
  • mycophenolate mofetil;
  • immunosuppression;
  • auto-immunity

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Summary.  The treatment of both auto-immune haemolytic anaemia (AIHA) and auto-immune thromobocytopenic purpura (AITP) remains unsatisfactory in those refractory to first-line management. Mycophenolate mofetil (MMF) is an immunosuppressive agent originally used to prevent acute rejection of solid organ transplants and used more recently in the management of auto-immune conditions. We report its use in four patients with AIHA and six patients with AITP. All four patients with AIHA and five of the six patients with AITP showed a complete or good partial response to treatment with MMF, confirming a possible role in the treatment of these conditions.

Auto-immune thrombocytopenic purpura (AITP) is a relatively common haematological condition. Approximately 80% of patients respond to treatment with corticosteroids and/or intravenous immunoglobulin and/or splenectomy. Second-line therapy for symptomatic non-responding patients includes high-dose pulsed corticosteroids, azathioprine, cyclophosphamide, vincristine, vincristine-loaded platelets, danazol, dapsone and cyclosporin A. Although these may be effective in some patients, there are no randomized controlled trials of these drugs in this clinical setting (George et al, 1996; Lilleyman, 1999). Furthermore, the American Practice Guideline produced by the American Society of Haematology reached no consensus about second-line treatments, concluding that there is a lack of evidence that any single agent is more effective than another (George et al, 1996). All the second-line drugs have significant side-effects.

Warm-type auto-immune haemolytic anaemia (AIHA) is less common than AITP. Initial treatment consists of steroid therapy with splenectomy reserved for non-responders. Second-line agents include intravenous immunoglobulin, azathioprine, cyclophosphamide and cyclosporin A. As with AITP, all these second-line drugs have potentially serious side-effects and have not been compared in randomized controlled trials.

Mycophenolate mofetil (MMF) is an immunosuppressive agent. It is a pro-drug of mycophenolic acid: a fermentation product derived from several Penicillium species. Mycophenolic acid is a potent inhibitor of inosine 5′-mono-phosphate dehydrogenase, a crucial enzyme in purine synthesis. Its principal mechanism of immunosuppression is inhibition of lymphocyte proliferation but, in addition, by causing a depletion of guanosine triphosphate (GTP), it results in a reduction of adhesion molecule expression on leucocytes, decreasing their recruitment to sites of inflammation or graft rejection (Allison & Engui, 2000; Smak Gregoor et al, 2000). MMF is generally well tolerated with few side-effects, the commonest being gastrointestinal intolerance and bone marrow suppression (Simmons et al, 1997). It is licensed for use in the prevention of acute rejection of cardiac, renal and hepatic allogeneic transplants. It is also used in allogeneic haemopoietic stem cell transplantation to prevent acute rejection and in the treatment of graft-versus-host disease. In addition it has been used as second-line treatment in auto-immune diseases including rheumatoid arthritis, psoriasis, Crohn's disease and primary biliary cirrhosis (Smak Gregoor et al, 2000).

There is limited data on the use of MMF in patients with refractory AITP and AIHA. We have investigated the role of this immunosuppressive agent in the treatment of 10 patients with these auto-immune haematological disorders.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Between November 1999 and March 2001 MMF was given to 10 patients with refractory AIHA or AITP. The four patients with AIHA were male with an age range of 31–74 years (Table I). One patient also had chronic lymphocytic anaemia (CLL) and one had Waldenström's macroglobulinaemia. Patients 1 and 3 had undergone splenectomy and were subsequently treated with azathioprine and cyclophosphamide. Patients 2 and 4 had not responded to prednisolone and had received cyclophosphamide.

Table I.  AIHA patient details and results.
PatientAge (years)SexAssociated diseaseTime from diagnosis to treatment with MMFRx prior to MMFRx when MMF commenced Hb (g/dl) when MMF commenced* Max Hb (g/dl)*Time to max Hb (months) Duration of Rx† (months)Comments
  1. Rx, treatment; M, male; WM, Waldenström's macroglobulinaemia; CLL, chronic lymphocytic leukaemia; Pred, prednisolone; Aza, azathioprine; Cyclo, cyclophosphamide; Methylpred, methylprednisolone; ivIg, intravenous immunoglobulin; o.d., once daily. *Reticulocyte percentage and absolute reticulocyte count (× 109/l) if known. †+Implies treatment with MMF was continuing at time of submission.

150MITP5 yearsPred, Aza, Splenectomy Cyclo Pred 10 mg9·1 13·8% 36011·2 11% 357415+Pred dose decreased to 1 mg o.d.
252MWM5 weeksPred, CycloPred 60 mg Cyclo 150 mg 6·5 10·2% 1999·8 1·5% 496 6+Pred dose decreased to 5 mg o.d., Cyclo decreased to 100 mg o.d.
331MNo5 yearsPred, Aza, Splenectomy Cyclo Pred 40 mg9·6 5·8% 14911 5·5% 1629 9Pred dose decreased. MMF stopped as paraprotein rising
474MCLL11 monthsPred, CycloMethylpred, ivIg3·8 n/a 11·4 n/a 112Relapse at 5/12 which responded to splenectomy

The six patients with AITP had an age range of 39–84 years and three were female (Table II). Patients 5 and 6 had been previously treated only with prednisolone and intravenous immunoglobulin. The other four patients had undergone splenectomy and were refractory to second-line agents.

Table II.  AITP patients and results.
PatientAge (years)SexAssociated diseaseTime from diagnosis to treatment with MMFRx prior to MMFRx when MMF commenced Hb (g/dl) when MMF commenced Max plt (g/dl)Time to max plt (months) Duration of Rx* (months)Comments
  1. Rx, treatment; M, male; F, female; Plt, platelet; MGUS, monoclonal gammopathy of undetermined significance; Pred, prednisolone; Aza, azathioprine; Cyclo, cyclophosphamide; Methylpred, methylprednisolone; ivIg, intravenous immunoglobulin; Vinc, vincristine; Dex, dexamethasone. *+Implies treatment with MMF was continuing at time of submission.

563FAutoimmune neutropenia and AIHA2 yearsPred, ivIgPred27210613+Normal plt count within 2/12. Pred stopped
684MMGUS15 monthsPred, ivIgPred 60 mg81141 7+Pred dose decreased to 10 mg o.d.
739FNo32 monthsPred, ivIg Splenectomy Danazol, Aza Cyclo, VincAza17294 8+Plt count has remained above 20 × 109/l and patient is asymptomatic
845FNo11 monthsPred, ivIg Splenectomy Aza, Danazol VincVinc, ivIg31901 8+Plt count has remained above 20 × 109/l and patient is asymptomatic
965MNo18 yearsPred, ivIg SplenectomyAzaPred, ivIg42942 2+Pred stopped within 6 weeks
1070MNo41 yearsPred, ivIg Splenectomy Aza, Danazol Cyclo, VincDex307n/a 2No response seen

MMF was commenced at a dose of 500 mg/d b.d. in all patients and increased to 1 g/d b.d. after 2 weeks. Complete response was defined as achievement of normal haemoglobin concentration or platelet count that was maintained after complete withdrawal of all other immunosuppressive treatments. Partial response was defined as an improvement in haemoglobin or platelet count, and in symptoms of anaemia and thrombocytopenia, allowing reduction in other immunosuppressive treatments.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

All patients with AIHA showed a partial response to MMF with an improvement in haemoglobin and in parameters of haemolysis, allowing doses of other immunosuppressive agents to be reduced. Patient 3 had previously received high doses of prednisolone for over 5 years and MMF had a significant steroid sparing effect, allowing the prednisolone dose to be reduced, while the haemoglobin remained stable. In patient 4 MMF as sole treatment maintained a stable haemoglobin for 4 months. However, brisk haemolysis recurred at this time requiring red cell transfusion and emergency splenectomy, to which the patient has shown a sustained response.

Two patients with AITP (patients 5 and 6) had previously relapsed rapidly after treatment with prednisolone and intravenous immunoglobulin. They both responded well to MMF, patient 5 had a complete response and patient 6 had a partial response. Patients 7 and 8 both had a 2-year history of refractory AITP with recurrent haemorrhagic episodes despite treatment with splenectomy, danazol, azathioprine and vincristine. Both showed a partial response to MMF, with platelet counts remaining above 20 × 109/l, and no bleeding despite stopping all other immunosuppressive drugs. Patient 9 had an 18-year history of recurrent episodes requiring treatment with prednisolone, intravenous immunoglobulin, azathioprine and splenectomy in the past; he had a complete response to MMF. Patient 10 showed no response to treatment with MMF.

MMF was well tolerated in all patients. Side-effects were seen in only one patient (Patient 7) who complained of headache and backache when on the higher dosage of 2 g/d. Treatment was stopped and reinstituted at 1 g/d and no further symptoms were noted.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Our preliminary studies suggest that MMF might be an effective second-line agent in the treatment of both refractory AIHA and AITP. It may be used alone, as a steroid-sparing agent or alongside other second-line immunosuppressive therapy. Nine of the 10 patients in the study showed a complete (n = 2) or partial (n = 7) response to MMF. The drug was well tolerated with few side-effects in the short term but long-term use needs further evaluation (Simmons et al, 1997). Its use has previously been described in two patients with AIHA with disease unresponsive to prednisolone treatment. Both these patients had chronic lymphocytic leukaemia (CLL) and had recently been treated using the nucleoside analogue 2-chlorodeoxyadenosine (2-CDA) (Zimmer-Molsberger et al, 1997). One study used MMF in patients with AITP and Evan's syndrome, and showed that 62% of patients achieved a complete or partial remission (unpublished observations). Patients with refractory AIHA or AITP typically receive more than one second-line agent at the time of relapse, making it difficult to define the specific contribution of individual agents. Our study confirms that MMF has a useful role as a second-line agent in the treatment of both AIHA and AITP. MMF merits further investigation in larger numbers of patients in a randomized study to fully assess its efficacy and safety in these conditions.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References
  • Allison, A.C. & Engui, E.M. (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacology, 47, 85118.DOI: 10.1016/S0162-3109(00)00188-0
  • George, J.N., Woolf, S.H., Raskob, G.E., Wasser, J.S., Aledort, L.M., Ballem, P.J., Blanchette, V.S., Bussel, J.B., Cines, D.B., Kelton, J.G., Lichtin, A.E., McMillan, R., Okerbloom, J.A., Regan, D.H. & Warrier, I. (1996) Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood, 88, 340.
  • Lilleyman, J.S. (1999) Management of childhood idiopathic thrombocytopenic purpura. British Journal of Haematology, 105, 871875.
  • Simmons, W.D., Rayhill, S.C. & Sollinger, H.W. (1997) Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection. Drug Safety, 17, 7592.
  • Smak Gregoor, P.J.H., Van Gelder, T. & Weimar, W. (2000) Mycophenolate mofetil, Cellcept, a new immunosuppressive drug with great potential in internal medicine. Netherlands Journal of Medicine, 57, 233246.
  • Zimmer-Molsberger, B., Knauf, W. & Thiel, E. (1997) Mycophenolate mofetil for severe autoimmune haemolytic anaemia. Lancet, 350, 10031004.