Case report Stable molecular remission induced by imatinib mesylate ...

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We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-.

Bone Marrow Transplantation (2003) 31, 611–614 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

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Case report Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation B Wassmann1, U Scheuring1, C Thiede2, H Pfeifer1, M Bornha¨user2, F Griesinger3, A Hochhaus4, E Schleyer2, H Gschaidmeier5, D Hoelzer1 and OG Ottmann1 1

Medizinische Klinik III, Abteilung fu¨r Ha¨matologie und Onkologie, Johann Wolfgang Goethe-Universita¨t, Frankfurt, Germany; Medizinische Klinik I, Universita¨tsklinikum Carl Gustav Carus, Dresden, Germany; 3Medizinische Klinik und Poliklinik, Georg-August-Universita¨t, Go¨ttingen, Germany; 4Medizinische Klinik III, Klinikum Mannheim, Germany; and 5Novartis Pharma AG, Nu¨rnberg, Germany 2

Summary: We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dosereduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT. Bone Marrow Transplantation (2003) 31, 611–614. doi:10.1038/sj.bmt.1703885 Keywords: chronic myeloid leukemia; lymphoid blast crisis; BCR-ABL; tyrosine kinase; allogeneic stem cell transplantation; molecular remission

Patients with chronic myeloid leukemia (CML) in blast crisis (BC) have a poor prognosis even with allogeneic stem cell transplantation (alloSCT).1 In these patients relapse after alloSCT is frequent, and donor lymphocyte infusions (DLI) and withdrawal of immunosuppressive agents has limited efficacy in contrast to chronic phase (CP) CML.2–4 Second alloSCT is possible in few patients and is associated with substantial treatment-related mortality and a high relapse rate. Accordingly, long-term survival of patients relapsing with advanced stage CML after alloSCT is rare.4,5 In clinical phase I and II trials, imatinib mesylate (Glivec, formerly STI 571) induced complete hematologic responses

Correspondence: Dr OG Ottmann, Medizinische Klinik III, Abteilung fu¨r Ha¨matologie und Onkologie, Johann Wolfgang Goethe-Universita¨t, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany Received 3 July 2002; accepted 7 October 2002

in 95% and major cytogenetic responses in 60% of patients treated in CP.6,7 Hematologic and major cytogenetic response rates in AP are 82 and 24% compared to 52 and 12% in BC. Median time to progression is frequently brief; however, particularly in lymphoid BC (58 days).8–12 A limited number of patients have been treated with imatinib following relapse after alloSCT, but long-term results are not yet available.13–15 Thus, the clinical role of imatinib in advanced Philadelphia chromosome positive (Ph+) leukemias and in the setting of allogeneic SCT remains to be defined.

Case report A 25-year-old man was diagnosed with Ph+ CML in CP in February 1999 and treated with hydroxyurea. Cytogenetic analysis revealed an additional translocation t(6;14)(q23;q32). The patient´s past medical history included an episode of i.v. heroin abuse until 2 years prior to the diagnosis of CML, and acute hepatitis B 3 years previously, with no detectable sequelae. He was enrolled in a methadone substitution program, with good compliance. B-lymphoid BC developed 1 month after diagnosis. Second CP with major cytogenetic response (1/26 metaphases Ph+) was induced by a single course of high-dose Ara-C (6 g/m2  3) and mitoxantrone (10 mg/m2). He underwent allo SCT from his HLA-identical brother in May 1999. Dose-reduced conditioning with fludarabine (30 mg/m2/day on days 6 to 2) and busulfan (3.3 mg/kg/ d i.v. on days 6 and 5) was used because of the patient’s history of hepatitis B and impaired renal function following amphotericin B. Unmanipulated peripheral blood nucleated cells (11.6  108) were given, corresponding to 9.9  106/kg CD34+ cells. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CSA) and mycophenolate mofetil (MMF). No GvHD developed despite rapid tapering of immunosuppression. A second lymphoid BC occurred in August 1999. Discontinuation of immunosuppression resulted in acute grade III GvHD of the skin and intestine, which responded

Imatinib for relapsed CML after allogeneic SCT B Wassmann et al

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#

##

imatinib 100

% donor chimerism (PB)

90 80

chronic skin GvHD

2nd BC

prednisone 70

AP

MMF

60 50

RT-PCR +++

40

nested PCR+

(+)

-

-

(+)

- -

-

Cytogen. compl. 46XY

-

46XY 46XY

46XY

- - -

-

46XY

-

-* -* -* - *

46XY

30 20 10

Lamivudine + + HBs-Ag HBV-DNA + +++

+ +++

+ +++

-

+ + + +

- -

0 -3

0

3

6

9

12

15

18

21

24

27

30

Months since start of imatinib 1st SCT

2nd SCT

Figure 1

Overall levels of donor chimerism (mean percent) determined in peripheral blood MNC. BCR-ABL expression was quantitated by RT-PCR (Taqman) and negative results confirmed by ‘nested-PCR’ in BM mononuclear cells (MNC), except for time points marked by an asterisk (*), where PB MNC were used. Cytogenetic analysis was performed by standard techniques using BM cells during treatment with imatinib. Interruption of imatinib due to elevated transaminases associated with reactivation of hepatitis B (#) and due to suspected drug interaction with lamivudine (##). HBs-Ag: + indicates a positive result by ELISA. HBV-DNA: +++ indicates X6000 pg/ml; + indicates p102 pg/ml.

to prednisone and CSA. A second stem cell graft from the same donor (6.7  108 MNC corresponding to 10.1  106/ kg CD34+ cells) was given in September 1999 after chemotherapy with cytarabine (100 mg/m2  6 days), daunorubicin (60 mg/m2  3 days) and vincristine (2 mg). After 1 month, he was readmitted in poor clinical condition with fever, anemia, thrombocytopenia and massive diarrhea attributed to grade III intestinal GvHD, which again responded rapidly to steroid therapy. Bone marrow (BM) analysis showed an accelerated phase (AP) and a complex aberrant karyotype in 15/18 analyzed metaphases (45,XY,t(6;14)(q23;q32),-7,+dic(7;12)(p10;q10),t(9;22) (q34,q11),-12). The patient was enrolled in an openlabel, multicenter, multinational clinical phase II study of imatinib in accelerated phase (Novartis trial CSTI571 109).8 Physical examination revealed a chronically ill, underweight patient (196 cm, 70 kg) with no signs of active GvHD (ECOG performance status 2). Splenomegaly (14.8 cm) and hepatomegaly (18.5 cm) were detected sonographically. Baseline WBC count was 5  109/l, hemoglobin was 11 g/dl, platelets were 112  109/l, differential count showed 65% neutrophils, 3% bands, 12% lymphocytes, 4% monocytes, 1% eosinophils, 3% promyelocytes, 7% myelocytes, 3% metamyelocytes and 2% blasts. BM cytology and histology showed a hypercellular marrow reflecting accelerated phase. Donor cell chimerism in PB was 80%. Imatinib was given as a single daily oral dose of 400 mg. Prednisone (60 mg/d) was given concurrently as GvHD therapy with tapering and discontinuation in the fourth Bone Marrow Transplantation

month of imatinib treatment. Treatment efficacy was assessed by morphology, cytogenetics, fluorescence in situ hybridization (FISH) and quantitative real-time PCR using both Taqman and Light Cycler technology, as previously described.16,17 Quantitative analysis of donor chimerism in PB and BM was performed using multiplex PCR amplification of short tandem repeat markers.18 Chimerism analysis in leukocyte subsets was performed as described.19 Imatinib serum concentrations were measured by HPLC technology. Performance status improved to ECOG 0-1 and body weight normalized in the first 2 months of imatinib. Splenomegaly and hepatomegaly had resolved by week 9 and platelet counts normalized within 4 weeks. Hemoglobin values declined to 9.3 g/dl after 3 weeks and normalized within 6 months. ANC remained above 1  109/l throughout treatment. BM cellularity was reduced to 25 and 15% after 4 and 9 weeks, respectively, but normalized (50%) after 3 months. All cytogenetic and FISH analyses performed between week 4 and month 27 were normal. The BCR-ABL/GAPDH ratio in PB declined from 1.38  102 at study start to 7.66  104 after 4 weeks of treatment, and has remained undetectable thereafter with the exception of a single very weakly (1.81  106) positive analysis of a PB sample after 15 months. BCRABL transcripts in BM decreased by 44 logs and became undetectable after 9 weeks of treatment. Parallel nested PCR using external and internal primers was performed repeatedly for both b3a2 and b2a2 transcripts in three independent laboratories and was negative after 9 weeks and has remained negative throughout imatinib therapy

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Donor cell chimerism in subsets of PB- and BM-derived MNC

Cell Source

Subset

Time after start of imatinib (months) 3

6

16

19

27

99.471% 99.570.9% 99.670.8%

10070 10070 10070

PB

CD4+ CD8+ CD15+

91.872.2% 99.570.8% 99.570.8%*

99.770.6% 99.670.8% ND

99.470.8% 10070% 99.670.8%

BM

CD34+

99.770.5%

99.371.2%

ND

99.471%

98.671.3

To determine whether the overall level of donor chimerism determined during treatment with imatinib corresponded to the chimerism levels within subpopulations of MNC, CD34+ bone marrow (BM) cells and CD4+, CD8+, CD15+ (* CD14+) cells from peripheral blood (PB) were positively selected by FACS sorting. The percentage of donor signals in the individual subsets was measured at different time points during treatment with imatinib. Results given are the mean7S.D. ND: not done.

(Figure 1). Donor cell chimerism in PB increased from 80% to 94.4% after 4 weeks of imatinib and remained 498% throughout therapy (Figure 1). Chimerism studies in CD34+, CD8+ and CD14+ subsets in PB and BM showed 499% donor cells after 3 months of treatment. The CD4+ compartment contained 91% donor cells with a residual population of recipient cells. Complete donor chimerism was demonstrated in the CD4+, CD8+ and CD34+ positive subpopulations after 6, 16, 19 and 27 months of treatment (Table 1). There was no evidence of GvHD during the first 13 months of imatinib. Limited chronic GvHD with manifestation as lichen ruber of the skin and mucous membranes first became detectable after 14 months. Prednisone (60 mg/ day with subsequent tapering) and MMF were initiated in the 18th and 24th month of treatment because of progression to extensive chronic GvHD with bullous skin lesions, alopecia and sicca-syndrome of mucous membranes and eyes. Nonhematologic toxicity attributable to imatinib consisted of mild nausea, occasional muscle cramps and myalgias (grade I) that resolved without pharmacological intervention. Hepatitis B reactivation with profoundly elevated transaminases was diagnosed 7 months after starting imatinib necessitating brief interruption of imatinib. Antiviral therapy with lamivudine (100 mg/day) was initiated resulting in a marked decline of HBV DNA within 6 weeks. Imatinib was restarted after liver enzymes had normalized and was given concurrently with lamivudine. Transaminases again increased markedly (WHO grade 3) 9 weeks later. Imatinib was temporarily stopped as a drug interaction between imatinib and lamivudine was suspected. Analysis of serum imatinib concentrations did not show elevated serum levels during coadministration of lamivudine. Following reinitiation of imatinib (300 mg) with subsequent dose increase to 400 mg after discontinuation of lamivudine, no recurrence of hepatotoxicity4grade I was observed.

Discussion Few patients with CML in BC survive long-term, particularly if relapse follows allogeneic transplantation.1,4,5 The patient described here displayed additional poor prognostic features, including short intervals between allogeneic SCT and relapse, complex cytogenetic aberrations20 and lack of

response to termination of immunosuppression,4 despite ensuing severe acute GvHD. The clinical course of this patient illustrates the potential value of imatinib in CML patients with lymphoid BC who relapse after alloSCT. In phase II trials in advanced stages of CML or Ph+ acute lymphoblastic leukemia (ALL) imatinib induced hematologic responses in 52–82% of patients.8–12 In Ph+ ALL and lymphoid BC responses were short-lived and disease progession occurred after a median of 2 months.9,11 To date, there are only few reports of the use of imatinib in the setting of CML relapse after alloSCT, and no data on long-term outcome in patients with lymphoid BC.13–15 In the largest study of 28 patients (CP ¼ 5, AP ¼ 15, BC ¼ 8) reported so far, complete hematologic and complete cytogenetic response rates were 74 and 35%, respectively; complete molecular responses were seen in four patients (14%). Follow-up is still short with a median of 16 (range 9–24) months and estimated 1-year survival rate of 74%.15 The striking features of this case are the rapid induction of a complete molecular response, which is sustained 27 months after initiating imatinib. Complete hematologic, cytogenetic and molecular response were documented 2 months after starting imatinib. To date, no confirmed long-term molecular responses have been reported in CML patients with lymphoid BC after SCT. We confirmed the molecular response by repeated analysis in three independent laboratories excluding technical reasons for the inability to detect bcr-abl transcripts. In addition, the PCR data are consistent with the results obtained by FISH, conventional cytogenetics, morphology and chimerism studies, which were likewise performed in separate laboratories. Our finding that donor chimerism was rapidly reestablished in different cell fractions (CD4, CD8, CD14, CD34) is consistent with the concept that imatinib confers a selective advantage to the normal donor stem cells and immune effector cells that are present at the start of treatment.14 The early increase of donor-derived T cells during imatinib in our patient may have augmented the antileukemic efficacy of the kinase inhibitor by means of a graft-versus-leukemia (GvL) effect that by itself had been therapeutically insufficient, particularly as previous episodes of GvHD had failed to show any antileukemic activity. It is possible that imatinib reduces the level of residual leukemia to a minimum, but it is the GvL effect that is responsible for the complete Bone Marrow Transplantation

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eradication of CML below the detection level of current PCR techniques. The GvL effect appears to have been dissociated from GvHD, which appeared more than 1 year after imatinib was started. The contribution of GvL activity accompanying late-onset chronic GvHD to ongoing disease-free survival is unknown. Reactivation of hepatitis B is a known complication of immunosuppressive or cytotoxic therapy including SCT.21 Treatment with lamivudine, which was given parallel to imatinib, resulted in a prompt decrease of viral DNA titers, but was temporally associated with elevated liver function tests. Consideration of a drug interaction between imatinib and lamivudine was purely conjectural, as lamivudine is not metabolized by hepatic enzymes but is excreted renally. Also, imatinib serum concentrations were not increased above levels measured in the absence of lamivudine. On clinical grounds, nevertheless, there is need for caution whenever the combination of imatinib with other drugs is accompanied by hepatic or other organ toxicity. In summary, the ABL kinase inhibitor imatinib may induce sustained hematologic, cytogenetic and even molecular remissions in some patients with advanced CML relapsing after alloSCT, suggesting that its administration may enhance the GvL activity associated with alloSCT. It will be of interest to determine whether rapid response kinetics, documented in our patient by quantitative RT-PCR and donor chimerism analysis, or other patient characteristics are predictive of a favorable treatment outcome.

Acknowledgements We are indebted to S Kriener, MD, for the pathological review of marrow histologies, to Anja Binckebanck for study coordination, to Holger Thu¨ringer, Heike Nu¨rnberger, Martine Pape and Sandra Wagner for their excellent technical assistance, and to U Oelschla¨gel for FACS sorting. This work was supported by the BMBF, Competence Network Leukemias, Grant No. 01GI9971, by a grant from the Adolf Messer Foundation, and by Novartis Pharma AG, Nu¨rnberg, Germany.

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