We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT). Bone Marrow Transplantation (2001) 28, 721–724.
Allogeneic blood or marrow transplantation is the only treatment of chronic myeloid leukemia (CML) with established curative potential.1 If CML recurs after allogeneic transplantation, discontinuation of immunosuppressive therapy and/or transfusion of donor lymphocytes is highly effective in patients with cytogenetic or molecular relapse or hematological relapse in chronic phase.2,3 In contrast, treatment outcome in patients who relapse in advanced stages of CML or in whom these treatment options fail is poor.4,5,6,7 In patients relapsing with advanced stage CML post transplant, long-term disease-free survival is exceedingly rare.3,8
STI571 (imatinib mesylate, Glivec), a competitive inhibitor of the BCR-ABL tyrosine kinase is highly effective in chronic phase CML,9 with less activity in advanced stage CML.10 Its role in the context of allogeneic stem cell transplantation (SCT) has not been established.
A 46-year-old female patient was diagnosed with Philadelphia (Ph) chromosome-positive CML in chronic phase in November 1994. She was treated with hydroxyurea (HU) followed by an allogeneic bone marrow transplantation (BMT) from her HLA-identical brother in November 1995. The conditioning regimen consisted of busulfan and cyclophosphamide, no graft-versus-host disease (GVHD) developed post transplant.
Cytogenetic relapse with 6% Philadelphia chromosome-positive metaphases occurred in August 1997. Repeated donor lymphocyte transfusions (DLT) failed to induce a complete cytogenetic response and the patient was treated with interferon alfa (IFN-α) for treatment of the 2nd chronic phase. There was no cytogenetic response to IFN-α by January 1999, when bone marrow histology revealed a CML in chronic phase and cytogenetic examination showed 35% Philadelphia chromosome-positive metaphases. Her disease progressed to accelerated phase in March 1999 as assessed by uncontrolled thrombocytosis (2.9 × 1012/l) and bone marrow histology, despite renewed administration of DLT with incremental CD3 doses.
A 2nd allogeneic transplantation was performed in AP in July 1999, using a dose-reduced conditioning regimen with fludarabine and busulfan with the patient's HLA-identical, CMV-positive sister as stem cell donor. GVHD prophylaxis consisting of cyclosporin A was tapered and terminated in October 1999, with no evidence of GVHD. Complete cytogenetic remission and donor chimerism levels of 93% were achieved briefly, but cytogenetic (88% Ph-positive metaphases) and hematologic relapse in chronic phase accompanied by declining levels of donor chimerism was documented by the end of October 1999. Administration of four DLT with incremental numbers of CD3+ cells between November 1999 and January 2000 had no effect, and platelet counts increased rapidly to 2.45 × 1012/l in January 2000 despite treatment with HU since December 1999. Therapeutic thrombapheresis was required repeatedly to control excessive thrombocytosis causing temporary loss of vision. In February 2000 the patient was enrolled in a multicenter clinical phase II trial of STI571 (Novartis protocol 0109) in CML accelerated phase after giving written informed consent. The criteria of accelerated phase as defined by the study protocol were met on the basis of at least 20% basophils in the peripheral blood. At this time the level of donor chimerism in peripheral blood had decreased to 7%. Treatment with STI571 as sole antileukemic agent was initiated with 600 mg p.o. per day. Treatment efficacy was assessed by morphology, cytogenetics and fluorescence in situ hybridization (FISH). Donor chimerism was quantified in peripheral blood and bone marrow. Safety was assessed clinically and by standard laboratory tests.
During the first 14 days STI571 was well tolerated, with side-effects limited to grade 1 nausea and diarrhea. During the third week of STI571 the white blood cell count declined progressively leading to grade 4 leukopenia and neutropenia (neutrophils <500 × 106/l). Liver enzymes increased transiently (GOT 30 U/l, GPT 78 U/l, GGT 207 U/l) and STI571 was temporarily discontinued on day 20. At this time the patient's condition deteriorated progressively, with onset of muscle pain, rash with pruritus and watery, severe diarrhea. On day 22 febrile neutropenia combined with nausea, emesis and heavy diarrhea necessitated hospitalization for antibiotic therapy and fluid substitution. G-CSF was initiated. Ultrasound examination revealed wall thickening of the ascending colon (15 mm) and neutropenic colitis was diagnosed. Chest X-ray revealed no infiltrates, blood and stool cultures tested negative. Reactivation of CMV was ruled out. Bone marrow cytology showed a profoundly hypocellular marrow with heavily reduced granulopoiesis and no signs of maturation. Repeated granulocyte transfusions from the stem cell donor were performed because of septicemia in the face of persistent granulocytopenia. First evidence of granulopoietic recovery was apparent by bone marrow cytology on day 35 and regeneration of white blood cell counts to above 1.0 × 109/l on day 39, with clinical improvement. Donor chimerism levels in peripheral blood increased from 7% at the start of STI571 treatment to 87% on day 22 and to 91% on day 52 (Figure 1). Cytogenetic assessment showed complete cytogentic response, FISH analysis showed 10% BCR-ABL-positive nuclei, equivalent to the threshold of detection.
Concurrently with increasing chimerism levels and white blood cell count, clinical signs of GVHD of gut and liver (grade III) with diarrhea, elevated liver enzymes and bilirubin occurred. Results of ultrasound examination of the colon, endoscopy and histologic examination of gut and stomach biopsies were consistent with GVHD of the GI tract. Treatment with prednisolone, cyclosporin A (CsA) and mycophenolate mofetil was initiated with clinical improvement. Due to decreasing levels of donor chimerism to 87% on day 71, STI571 was reinitiated at a daily dose of 300 mg. White blood cell count and neutrophils remained stable and no further STI571-related toxicity occurred permitting dose increase to 400 mg. Fourteen months after start of STI571 treatment the patient shows a continuing complete hematologic and cytogenetic response with 7% BCR-ABL-positive nuclei in FISH analysis. There is still active GVHD of the gut and she remains on low-dose GVHD therapy. CsA dosing was guided by serum levels, with no conspicuous need for dose modifications due to concomitant administration of STI571.
CML recurring after allogeneic BMT is frequently treated with discontinuation of immunosuppressive therapy or DLT, but results are poor in patients who relapse in advanced stages of CML.7,11 Second BMT is the most aggresive attempt to induce long-term leukemia-free survival; its success depends on the time interval from the first transplant, disease stage, intensity of prior conditioning regimen and performance status of the patient. Transplant-related mortality is high and long-term leukemia-free survival is low.12,13 Accordingly, the need for new strategies is obvious, with the novel ABL kinase inhibitor STI571 being currently the most promising agent.14
The clinical course of this patient demonstrates the validity of this concept, but at the same time highlights the potential risks that are associated with a highly effective antileukemic activity of STI571 in CML patients who relapse after allogeneic BMT and have little residual normal, ie donor, hematopoietic reserve. We show that STI571 is indeed able to establish a selective advantage of donor hematopoesis over the Ph-positive leukemic population, but that a low level of donor-derived hematopoietic cells present prior to initiation of STI571 therapy (7% based on analysis of donor chimerism in the patient described in this report) may be the basis for severe STI571-induced myelosuppression. In the patient described here, this clinical constellation caused life-threatening neutropenic colitis that was barely manageable by granulocyte transfusions amd G-CSF application. Rising levels of donor chimerism heralded recovery of donor hematopoiesis after prolonged cytopenia and led to abandonment of the scheduled transfusion of donor stem cells. The complication of STI571-induced bone marrow aplasia was succeeded by the onset of GVHD, which was temporally associated with re-establishment of donor chimerism to levels exceeding 90%. While plausible, development of GVHD nevertheless had not been expected since two prior allogeneic transplantations using different donors and repeated application of DLT had not induced GVHD.
The complete and prolonged hematologic and cytogenetic response that is ongoing after 14 months of STI571 is remarkable in view of two preceding relapses after BMT and unresponsiveness to DLT. In contrast to chronic phase CML, in which complete hematologic responses have been observed in 98% of patients and major or complete cytogenetic responses in 31% of patients receiving STI571 at doses of or above 300 mg,9 patients with CML in myeloid or lymphatic blast crisis or Ph-positive ALL have substantially lower complete hematologic response rates (11% in myeloid blast crisis, 20% in lymphoid blast crisis or Ph-positive ALL).10,15 Major cytogenetic responses were observed in only 12% of patients and relapses have occurred as early as 42 days after initiation of STI571 therapy.10,16 Early achievement of a complete cytogenetic remission by day 29 indicates a pronounced sensitivity of the leukemic cells to inhibition of the ABL kinase, particularly as major or complete cytogenetic remission in chronic phase patients is observed between 2 and 10 months after onset of STI571 therapy.9 With an initial donor chimerism of 7%, it is unlikely that immunological mechanisms contributed significantly to this early response. Conversely, subsequent acute and then chronic GVHD, the onset of which coincided with re-establishment of donor chimerism, may enhance the antileukemic activity of STI571. This remains conjectural, however, as experience with STI571 in CML patients relapsing after allogeneic BMT is limited and prolonged follow-up data are as yet unavailable. The safety of STI571 in the post-BMT setting will have to be established in further clinical studies, which are ongoing. These will also have to focus on the effects of drug interactions between STI571 and drugs commonly used post transplant, eg CsA, antiviral and antifungal agents. Clearly, the clinical management of patients starting STI571 post transplant necessitates particularly close monitoring in the setting of low-level donor chimerism and development of cytopenias, which should prompt early bone marrow analysis and consideration of STI571 dose modifications or interruptions. This case illustrates the ability of STI571 to induce sustained hematological and cytogenetic remission even in patients in whom these therapeutic goals were not achieved by successive prior allogeneic transplantations and repeated donor lymphocyte transfusions (DLT).
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We are indebted to Frau Kilb for donor chimerism analyses and to S Kriener MD for the pathological review of marrow histologies.
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Cite this article
Wassmann, B., Klein, S., Scheuring, U. 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 28, 721–724 (2001). https://doi.org/10.1038/sj.bmt.1703222
- chronic myeloid leukemia
- tyrosine kinase
- allogeneic stem cell transplantation
- cytogenetic remission
- donor chimerism
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