Haematologica 2002; 87:(12)ECR37
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STI571 (Glivec) induced hematologic, cytogenetic and molecular remission in a chronic myeloid leukemia patient relapsing with accelerated phase after allogeneic stem cell transplantation.
Ugo Consoli, Giuseppe Milone, Giulia Guido, Carla Consoli, Giuseppe A. Palumbo, Rosario Giustolisi
Chair and Division of Haematology with Bone Marrow Transplantation, University of Catania, Italy.
Correspondence: Dr Ugo Consoli, M.D., Cattedra e Divisione di Ematologia, Ospedale Ferrarotto, Via Citelli 6, 95124 Catania, Italy. Phone/Fax: international +39-095-7435913. E-mail: ugo.consoli@tin.it

We describe the efficacy of treatment with STI571 in a patient relapsing after allogeneic bone marrow transplant with accelerated phase chronic myeloid leukemia (CML). STI571 at a dose of 400 mg daily led within three months to a rapid, complete hematologic response and restoration of donor type hematopoiesis. This result was obtained without any DLI (donor leukocytes infusion) and with the appearance of mild GVHD.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only treatment capable of curing patients with chronic myeloid leukemia (CML). Ref.1 CML relapse is one of the major causes of treatment failure after ASCT, in particular when donor marrow cells are T-depleted. Ref.2 Discontinuation of immunosuppressive therapy, donor leukocyte infusion and second allogeneic transplant have been the treatments of choice for molecular, cytogenetic or hematologic relapse. Ref.3 These approaches are used with excellent results in patients relapsing in chronic phase but the treatment outcome in patients relapsing with advanced stages CML is poor.Ref. 4
STI571 (imatinib mesylate, Glivec), a competitive inhibitor of the BCR-ABL tyrosine kinase is highly effective in chronic phase CML, with less activity in advanced stage CML. Ref.5 The optimum clinical use of Glivec and its efficacy in the context of ASCT has not yet been established.
A 43-year-old male patient was diagnosed with Philadelphia (Ph) chromosome-positive CML in chronic phase in December 1997. He was treated with interferon-a (IFN-a) which failed to elicit a cytogenetic response. He underwent, in our Institution, allogeneic bone marrow transplantation (BMT) from his HLA-identical sister in April 1999. The conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (150 mg/kg), graft-versus-host disease (GVHD) prophylaxis consisted in cyclosporin plus short term metotrexate. Grade I GVHD developed post-transplant. Despite complete cytogenetic remission maintained for 3 year, cytogenetic and hematologic relapse occurred in April 2002. During these three years reverse transcription-polymerase chain reaction (RT-PCR) for BCR-ABL transcript was intermittently positive in three out of eight analyses (Table 1). At the time of relapse, cytogenetic examination showed 60% Philadelphia chromosome-positive metaphases 60% which with additional chromosomal aberration [-Y, add(17)(p11)] and 20% of myeloid blasts were detected at the morphologic evaluation of bone marrow aspirate. The immunophenotyping performed on the blasts at diagnosis of accelerated phase CML showed positivity for the myeloid markers CD33, CD13 and myeloperoxidase reaction.
In April 2002 the patient started STI571 treatment as sole antileukemic agent at the dose of 400 mg p.o. per day. No significant side effects were noted with the exception of mild arthralgia and muscle pain which required STI571 50% dosage reduction for three days. No decline in white cell, platelet or red cell counts was observed. Concurrently with STI571 treatment only mild signs of GVHD were registered (grade I ocular) and no immunosuppressive treatment was started.
Three months later, morphologic, cytogenetic and molecular analysis (Table 1) of the bone marrow aspirate revealed complete hematologic, cytogenetic and molecular remission with restoration of full donor hematopoiesis.
Complete hematologic and cytogenetic remission is still continuing six months after the start of STI571 treatment.
Recurrence of CML is a frequent event in patients treated with allo-SCT. Ref. 2 This occurrence is generally treated with discontinuation of immunosuppressive therapy or DLI. A second allo-SCT is also within the treatment of choice but represents a more aggressive procedure. All these approaches are more effective when the relapse has the characteristic of a chronic phase CML. Donor lymphocyte infusions, in particular, have become the treatment of choice for patient in relapse after allo-SCT but results in patients who have relapsed in advanced phase are poor. Ref. 6 GVHD and marrow aplasia remain two of the most important complications of DLI although the use of DLI at escalating dose schedule has greatly reduced the complications. Ref. 3
STI571 is a competitive inhibitor of the BCR-ABL which binds to the adenosine triphosphate-binding site of the BCR-ABL tyrosine kinases maintaining them in an inactive conformation. Ref. 7 The risk associated with GVHD development after DLI and second transplant-related toxicity point out the need for new therapeutic strategies in CML relapsed after allo-SCT, with STI571 being currently the most promising agent.
Phase I and II clinical trials have shown that STI571 induces substantial and durable hematologic response in nearly all patients with chronic-phase CML and major cytogenetic remission in 50% of treated patient with minimal toxicity. Ref. 5,8
STI571 has been already successfully used in inducing complete cytogenetic remission in two patients with relapsed CML after allo-SCT. Ref. 9,10 In these two case reports STI571 was used to treat a patient with accelerated phase of CML relapsing after a second allogeneic BMT and a patient who, after CML relapse, did not benefit from DLI. In both cases STI571 treatment was followed by rapid complete hematologic and cytogenetic response combined with controllable GVHD.
The clinical course of our patient confirms the ability of STI571 to induce complete cytogenetic and molecular remission in patients who have relapsed in accelerated phase after allo-SCT for CML. As described by other authors, rising levels of donor chimerism may be associated with the onset of GVHD. Our patient developed only clinically mild signs of GVHD (xerostomia and xerophthalmia).
Our findings suggest that there could be a role for STI571 in the management of CML patients relapsed after allo-SCT. A higher number of patients treated and longer follow up are necessary in order to evaluate the duration of clinical response.

 

References

1. Goldman JM. Chronic myeloid leukemia. Curr Opin Hematol 1997; 4:277-85.
2. Apperley JF, Jones L, Hale G, Waldmann H, Hows J, Rombos Y, et al. Bone marrow transplantation for patients with chronic myeloid leukemia: T-cell depletion with campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukemic relapse. Bone Marrow Transplant 1986; 1:53-66.
3. Dazzi F, Szydlo RM, Craddock C, Cross NC, Kaeda J, Chase A, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 2000;95:67-71.
4. Carlens S, Remberger M, Aschan J, Ringden O. The role of disease stage in the response to donor lymphocyte infusion as treatment for leukemia relapse. Biol Blood Marrow Transplant. 2001;7:31-8.
5. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia. N Engl J Med 2001;344:1031-7.
6. Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, et al. Donor leukocyte infusion in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997;15:433-44.
7. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000;289:1938-42.
8. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. The International STI571 CML Study Group.Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. New Engl J Med 2002;346:645-52.
9. Olavarria E, Craddock C, Dazzi F, Marin D, Marktel S, Apperley JF, et al. Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation. Blood 2002;99:3861-2.
10. Wassmann B, Klein SA, Scheuring U, Pfeifer H, Martin H, Gschaidmeier H, et al Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation. Bone Marrow Transplant 2001;28:721-4.