Relapse of leukaemia Tyrosine kinase inhibitor STI571 in the ... - Nature

Bone Marrow Transplantation (2002) 30, 453–457  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Relapse of leukaemia Tyrosine kinase inhibitor STI571 in the treatment of Philadelphia chromosome-positive leukaemia failing myeloablative stem cell transplantation WY Au1, AKW Lie1, SK Ma2, TS Wan2, R Liang1, EC Chan1 and YL Kwong1 1

Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong; and 2Department of Pathology, Queen Mary Hospital, University of Hong Kong, Hong Kong

Summary: Eight patients with Philadelphia chromosome-positive (Ph+) leukaemia relapsing from stem cell transplantation (SCT) (one syngeneic and seven allogeneic) were treated with the tyrosine kinase inhibitor STI571. Five patients relapsing as chronic myeloid leukaemia (CML) in chronic phase achieved a complete haematological response, with complete and major cytogenetic responses occurring in four and one cases, respectively. One patient became negative for BCR/ABL in the bone marrow. Three patients relapsed as acute leukaemia (two CML in myeloblastic crisis and one Ph+ acute lymphoblastic leukaemia), all of whom achieved haematological and cytogenetic responses. One patient also became BCR/ABL negative. However, pancytopenia and graft-versus-host disease led to cessation of treatment in the remaining two cases, which was followed by disease recurrence refractory to further STI treatment. Our results showed that Ph+ leukaemic relapses after SCT might respond well to STI571 therapy. Bone Marrow Transplantation (2002) 30, 453–457. doi:10.1038/sj.bmt.1703678 Keywords: Ph+ leukaemia relapse; stem cell transplantation; STI571

STI571 in eight patients (7 CML, 1 Ph+ ALL), who relapsed or failed to engraft after SCT.

Materials and methods Patients Consecutive patients who qualified for the extended release program for STI571 (Novartis) after SCT were studied. The dose was 400 mg daily for CML-CP and 600 mg daily for CML-AP/BT or Ph+ ALL. Cytogenetic and molecular studies Patients were monitored regularly by reverse transcription polymerase chain reaction (RT-PCR) for BCR/ABL.6 The proportion of Ph+ cells was estimated by conventional cytogenetics, and interphase cytogenetics by dual-colour labelled BCR and ABL probes (Vysis, Downers Grove, IL, USA).7 Marrow donor/recipient chimerism was determined semi-quantitatively with microsatellite markers.8

Results The tyrosine kinase inhibitor STI571 (Novartis, Basel, Switzerland) has shown promising therapeutic activity in leukaemias with the Philadelphia chromosome (Ph), which results from t(9;22)(q34;q11) and the BCR/ABL fusion. Initial experience with the drug is restricted to chronic myeloid leukaemia (CML) in chronic phase (CP) not responding to interferon-␣,1 or in accelerated phase (AP)/blastic transformation (BT), and in Ph+ acute lymphoblastic leukaemia (ALL).2 The role of STI571 in patients failing myeloablative stem cell transplantation (SCT) is less well defined,3 with only several successful cases described.4,5 We report the treatment results of Correspondence: Dr YL Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong Received 18 February 2002; accepted 8 July 2002

Patients The clinicopathological features of the patients are shown in Table 1. There were one syngeneic (patient 1) and seven allogeneic SCT. Three cases (patients 2 to 4) of mismatched SCT failed to engraft and reverted to CML-CP. The remaining cases achieved complete haematological and cytogenetic remission after SCT, with none to moderate acute graft-versus-host disease (aGVHD). Haematological relapse occurred 3 to 20 months afterwards. Five cases (patients 1 to 5) relapsing as CML-CP received prior treatment with hydroxyurea, donor lymphocyte infusion (DLI) and interferon-␣ (IFN). A complete cytogenetic response had already been achieved with IFN therapy in case 4, but IFN had to be stopped because of severe depression with suicidal tendency. Three cases (patients 6 to 8) relapsing as acute leukaemia were treated directly with STI571.

STI571 in treatment of post-transplantation relapse of Ph+ leukaemia WY Au et al

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Table 1 Clinicopathological features and outcome of eight patients treated with STI571 for relapse of Ph+ leukaemias after myeloablative stem cell transplantation No.

1

2

3

4

5

6

Sex/Age

Dx

M/54

CML-CP

M/17

M/23

F/19

M/47

M/30

Previous therapy

HU for 22 months

STI (time from SCT)

Ph+ cells by CG/FISH after STI treatment

36 months

Day 0: 80% (CG)

CML-CP

Syngeneic SCT (Bu/Cy) Relapse after 19 months IFN for 17 months, minor CG response IFN for 30 months, no CG 14 months response One HLA-B antigen mismatched SCT (Cy/TBI), Non-engraftment Re-infusion of autologous marrow, HU for 14 months IFN for 23 months, No CG 25 months response One HLA-B antigen mismatched SCT (Cy/TBI) + second PBSC boost Non-engraftment, spontaneous autologous regeneration IFN for 25 months, minor CG response IFN for 5 months, CP 9 months

CML-CP

One HLA-A antigen mismatched SCT (Bu/Cy), Nonengraftment Non-engraftment, IFN for 9 months, depression HU for 11months 69 months

CML-BT

HLA-matched SCT (Bu/Cy), relapsed after 20 months DLI for 2 times, IFN for 6 months, remission with grade IV aGVHD Second relapse after 58 months HU for 11 months Chemotherapy, CP2 11 months

CML-CP

CML-CP

MUD SCT (Bu/Cy), grade III aGVHD Relapse after 10 months 7

F/36

CML-BT

Chemotherapy, CP2 MUD SCT (Bu/Cy) Relapsed after 3 months

3 months

DNA donor chimerism

Outcome of STI treatment

Not applicable

CR, BCR/ABL positive

Day 0: 100% (CG)

Day 45: 0%


Day 30: 15% (CG)

Day 150: 0%

Day 180: 34% (CG) Day 200: 0% (FISH) Day 380: 0% (FISH)

Day 180: 0% (FISH) Day 0: 90% (CG)

Day 25: 0%

Day 40: 30% (CG)

Day 70: 0%

Day 70: 60% (CG) Day 80: 80% (FISH) Day 180: 65% (CG) Day 0: 0% (FISH) Day 60: 0% (CG+FISH)

Day 0: 0%

M/48

Ph+ ALL

Chemotherapy, CR1 6 months Matched Sib SCT (Cy/TBI), grade II GVHD Relapse after 6 months


Day 60: 0%

Day 0: 100% (CG+ Day 0: 0% FISH) Day 48: 50% (CG) Day 48: 48% 90% (FISH) Day 72: 8% (FISH) Day 72: 84% Day 100: 0% (FISH)

Day 95: 100%

Day 380: 0% (FISH) Day 0: 45% (CG)

Day 0: 52%

Day 70: 0% (FISH)

Day 24: 71%

Day 0: 100% (CG) Day 7: 33% (CG) Day 68: 100% (CG)

Day Day Day Day Day

38: 100% 80: 100% 7: 57% 29: 29% 53: 21%

Day 68: 0% 8


Day 0: 100% (CG)

Day 8: 100%

Day 41: 0% (CG)

Day 16: 100% Day 41: 100% Day 50: 41%

CR, BCR/ABL negative only after STI, no GVHD

CR, BCR/ABL negative by day 60 of STI treatment, no GVHD Transient response Severe cytopenia STI omitted between 7 and 42, STI stopped on day 80 Died on day 110 CR with STI, grade III aGVHD severe pancytopenia STI stopped on day 14 Frank relapse on day 50 Died on day 57

No. = case number; M = male; F = female; Dx = diagnosis; SCT = stem cell transplantation; CML = chronic myeloid leukaemia; CP = chronic phase; BT = blastic crisis; ALL = acute lymphoblastic leukaemia; GVHD = graft-versus-host disease; PBSC = peripheral blood stem cell; MUD = matched unrelated donor; CG = cytogenetics; FISH = fluorescence in situ hybridization; HU = hydroxyurea; IFN = interferon; Bu = busulphan; Cy = cyclophosphamide; TBI = total body irradiation; PBSC = peripheral blood stem cell; CR = complete remission.

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Response of patients relapsing as CML-CP All five cases (patients 1–5) relapsing as CML-CP achieved/maintained complete haematological response with normal peripheral blood counts after 30 days of treatment. All cases remained so at a median follow-up of 180 (range 71–414) days (Table 1). Cases 1 and 2 achieved a complete cytogenetic response, but BCR/ABL was still positive. Case 3 never reached complete cytogenetic response, owing to haematological toxicities caused by STI571 that prevented full dosing of the drug (presently on 200 mg daily). Case 4 was able to maintain complete cytogenetic response with STI571 treatment, after cessation of IFN therapy. Case 5 had the best therapeutic response, with complete cytogenetic remission and undetectable BCR/ABL in the marrow by day 180 and ever since after STI571 therapy. This response was remarkable, as the patient had never before had negative BCR/ABL, despite severe GVHD, DLI and IFN treatment after SCT (Figure 1). Response of patients relapsing with acute leukaemia Three patients relapsed with acute leukaemia, two as myeloid-BT (patients 6 and 7) and one as Ph+ ALL. Patient 6 had the best response, with a complete cytogenetic remission and undetectable BCR/ABL by day 60 of STI571 treatment, and has remained so ever since. Case 7 achieved a transient but unsustained haematological and cytogenetic response. Case 8 with Ph+ ALL reached a complete haematological and cytogenetic remission in 2 and 6 weeks, respectively (Table 1). However, this was associated with Case 5 b3a2

b2a2 M

32

44 48 54 58

0

3

4

5

P

Months post STI

Months post SCT

Case 6 b3a2

b2a2 M

0

3

6 BT

Months post SCT

0

1

3

4

P1 P2

Months post STI

Figure 1 RT-PCR for BCR/ABL after treatment with STI571 for CML relapses after allogeneic stem cell transplantation (SCT). Case 5: both the b3a2 and b2a2 BCR/ABL transcripts were found up to 58 months after SCT. However, PCR became negative after 5 months of treatment with STI571. P: positive control from a case of CML. Case 6: the b2a2 BCR/ABL transcript was persistently positive after SCT and at blastic transformation (BT). However, PCR became negative 3 months after STI571. P1: positive control for the b3a2 BCR/ABL transcript. P2: positive control for the b2a2 BCR/ABL transcript.

grade III aGVHD, which required treatment with cyclosporine and corticosteroids, and discontinuation of STI571. A week later, the leukaemia relapsed and was refractory to STI571.

455

GVHD and myelosuppression Of four patients who relapsed after engraftment with allogeneic stem cells, GVHD only occurred in one patient (case 8). Although dose reduction of STI571 based on absolute neutrophil count (ANC) was necessary during the course of treatment, only two patients (cases 7 and 8) developed significant myelosuppression (ANC ⬍0.5 ⫻ 109/l). Both cases were patients who relapsed in blastic crisis. Chimerism studies The chimerism findings are shown in Table 1 and Figure 2. For cases 2, 3 and 4 with autologous regeneration, there was no recovery of donor chimerism after STI571 treatment. A gradual conversion to 100% donor chimerism was seen in cases 5 and 6. In cases 7 and 8, a rapid recovery of donor chimerism occurred with response to STI571 therapy, and was accompanied by marrow aplasia and aGVHD. However, the cessation of STI571 soon resulted in an expansion of Ph+ clone again. Discussion STI571 is highly efficacious in CML-CP not responding to IFN, with a complete haematological response in 98% of patients, and major and complete cytogenetic responses in 31% and 13% of cases.1 For CML-BT or Ph+ ALL, STI571 was less efficacious. Haematological and complete cytogenetic responses occurred in 55% and 11% of patients with myeloid-BT, and 70% and 10% of patients with lymphoid-BT or Ph+ ALL.2 Our results, while similar to those of Druker et al1,2 in some respects, showed other interesting points. Firstly, four of the five patients with CML-CP after SCT achieved/maintained a complete cytogenetic response. This proportion is apparently much higher than the 13% observed by Druker et al1 in CML-CP patients who had not undergone SCT. Two cases (patients 1 and 4) were previously refractory to IFN treatment, but responded promptly to STI571. This is also in contrast to CML-CP patients without SCT, in whom approximately 50% of patients who failed IFN would not achieve any cytogenetic response.9 For patients 1–4, a graft-versus-leukaemia effect did not exist, so that the apparently better therapeutic response to STI571 might be attributable to the effect of high-dose conditioning, which is known to purge Ph+ clones.10 Secondly, all three patients relapsing as acute leukaemia after SCT achieved a prompt haematological and cytogenetic response to STI571. These results were remarkable, as similar patients without SCT appeared to have an inferior response rate.2 Interestingly, in patients 7 and 8, a haematological response was followed shortly by severe pancytopenia. This might be due to suppression of the Ph+ clone Bone Marrow Transplantation


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210 5 120 0 1600 0

240

a

Donor

b

Relapse as CML-CP at 5 years All recipient cells

3000 c 1500 0 2000 0 1200 0

Day 48 of STI571 treatment Donor DNA = 48%

d

Day 72 of STI571 treatment Donor DNA = 84 %

e

Day 95 of STI571 treatment DOnor DNA = 100%

120 7 2000 0

150

180

210

a

Donor

2000 b 0 3200 c 1600 0 1200 0 1600 0 2000 0

Relapse as CML-BT at 3 months All recipient cells Day 7 of STI571 treatment Donor DNA = 57%

d

STI571 stopped for 18 days Donor DNA = 29%

e

STI571 re-introduced for 11 days Donor DNA = 21%

f


120 150

a

8 2400 0 4800 b 2400 0 1600 0

c d

Donor Patient Relapse of Ph+ ALL at 6 months Donor DNA = 58%

2400 0 2000 e 1000 0


2800 f 0

STI571 stopped for 39 days Donors DNA = 41%

STI571 stopped for 37 days Donor DNA = 84%

Figure 2 DNA chimerism of three patients with Ph+ leukaemia relapsing from SCT treated with STI571. Case 5 showed a complete loss of donor chimerism on relapse of CML (panel b). With STI571 treatment, there was a gradual recovery of donor chimerism, which became complete after about 3 months of treatment (panel e). Case 7 showed a complete loss of donor chimerism on relapse (panel b). Donor chimerism returned promptly with STI571 treatment for only 7 days (panel c). However, severe pancytopenia necessitated a withdrawal of treatment. Eighteen days after stopping STI571 treatment (panel d), there was a decrease of donor chimerism to 29%. The re-introduction of STI571 subsequently did not lead to a response, and there was finally a total loss of donor chimerism again. Case 8 showed a partial retention of donor chimerism on relapse (panel c). Eight days of STI571 therapy resulted in the return of full donor chimerism (panel d). However, the treatment was stopped after 14 days because of pancytopenia and GVHD. A gradual loss of donor chimerism occurred soon afterwards.


that was contributing to haematopoiesis after relapse and reversion to full recipient chimerism. The cessation of STI therapy necessitated by marrow suppression in patients 7 and 8 led to refractory relapse and death. On the other hand, patient 6 who continued to receive the full dose of STI571 achieved a very good response. These results suggest that in blastic relapse of Ph+ leukaemia after SCT, STI571 might be considered a frontline treatment, as both DLI and chemotherapy have limited efficacy,11 and a second myeloablative SCT is associated with considerable therapyrelated risks.12 However, additional donor stem cells may be needed, in view of the possible marrow aplasia that may accompany the therapeutic response. Finally, in all cases (patients 5–8) who relapsed after allogeneic SCT, donor chimerism was apparently totally lost at the time of commencement of STI571. However, treatment with STI571 led to a rapid return of donor chimerism, which was complete except in one case (case 7), and resulted in aGVHD that required further immunosuppression in one patient (case 8). As all were treated within a year of relapse (3–11 months), a small number of donorderived haematopoietic stem cells beyond the detection sensitivity of cytogenetics/microsatellite analysis might still have survived at the time of relapse. It remains to be determined if patients with more prolonged relapse after allogeneic SCT will still have a return of donor chimerism on treatment with STI571. In conclusion, we have shown that patients with Ph+ leukaemia relapsing from SCT showed very good therapeutic responses to STI571. This is in spite of a prolonged relapse, an apparent loss of donor chimerism, and a failed prior response to DLI or IFN treatment.13 The efficacy of STI571 must be compared against DLI, which has a response rate of 64% to 86%, associated severe GVHD in 50% of patients,11,14 and marrow aplasia in up to 25% of patients with haematological relapses.15 On the other hand, severe GVHD after STI was seen in only one of our allogeneic cases, and marrow suppression appeared to be infrequent and reversible in our patients. These favourable results might be related to the previous myeloablative therapy, and the presence of donorderived immunocompetent cells.4 As our findings were observed in a small number of patients, further studies are needed to define the relative role and optimal timing of STI571 therapy, in comparison with DLI/IFN, in Ph+ leukaemic relapse after SCT. Acknowledgements The authors would like to thank C Liu and C Man for clerical and technical assistance. This study is supported by Novartis, Basel, and the Kadoorie Charitable Foundation.

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