Interesting post from UK group (Long)--Discontinuing IM

[Guest guest]

is a friend of mine from the Connecticut vaccine trial of

2002. She is on day 50 after having had a transplant of heer

mother's stem cells and is doing well. I thought this would be of

interest to some.

Outcome of four patients with chronic myeloid leuk

by Rees, 09/07/2005

Makes interesting reading.

I should really put this under Articles and when I can remember how

to do it, I shall !

haematologica 2005;90:979-981[medline][PDF][index] [prev][next]

?Outcome of four patients with chronic myeloid leukemia after

imatinib mesylate discontinuation

?Serena Merante, Ester Orlandi, Paolo Bernasconi, Silvia Calatroni,

Marina Boni, Lazzarino

?Division of Hematology, IRCCS Policlinico San Matteo, University of

Pavia, Viale Golgi 19, 27100 Pavia, Italy

Correspondence:

??Serena Merante, MD, Division of Hematology, IRCCS Policlinico San

Matteo, Viale Golgi 19, University of Pavia, 27100 Pavia, Italy

Phone: international +39. 0382.503595. Fax: international

+39.0382.502250.

E-mail: s.merante@...

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Abstract

Text

Table1

Table2

Funding

References

Abstract

?Imatinib mesylate (IM) therapy is effective in patients with

chronic myeloid leukemia (CML). However, whether it should be

discontinued in patients who achieve sustained molecular response is

debated. We describe 4 patients with undetectable levels of BCR-ABL

transcripts in whom IM therapy was discontinued. Two patients

relapsed after 7 and 10 months and promptly responded after

restarting therapy; 2 patients are off therapy at the last follow-up

visit after 14 and 15 months and are still in complete molecular

remission.

Key words: ?chronic myeloid leukemia, imatinib, therapy

discontinuation.

?Imatinib mesylate (IM) therapy leads to a complete cytogenetic

response (CCyR) in the majority of patients with chronic myeloid

leukemia (CML) in chronic phase. A few patients achieve complete

molecular remission, defined by a four log-reduction of BCR-ABL

transcripts. The negative quantitative real time polymerase chain

reaction (Q-RT-PCR) is confirmed by nested PCR negativity.

Although IM therapy is effective in CML patients, some unanswered

questions remain. In particular, it is unclear whether IM can

actually cure CML and whether this therapy can be safely stopped in

patients with complete cytogenetic and molecular responses.1 In

these patients, it is unknown whether and for how long continued

therapy is required to maintain clinical, cytogenetic and molecular

responses. Between 2000 and 2004, we treated 88 CML patients with

IM: 62 were interferon-a (IFN) pre-treated patients in late chronic

phase and 26 were newly- diagnosed patients in early chronic phase.

Sixty-three patients (71.5%) achieved a CCyR and in 15 of them (24%)

BCR-ABL transcripts became undetectable.

Here we describe the cytogenetic and molecular outcome of 4 patients

with CML in whom IM therapy was discontinued after the achievement

of a complete molecular response in the bone marrow and peripheral

blood. In all cases, IM was discontinued because of the patients'

requests and not because of toxic effects. The patients'

characteristics are shown in Table 1. All patients were pre-treated

with IFN; only patient #2 was in CCyR and was switched to IM because

of IFN-intolerance. No patient had a family donor for allotransplant

or was a candidate for an unrelated transplant. During IM therapy at

400 mg/day, no patient required dose reduction or discontinuation

due to hematologic or non-hematologic toxicity. At the time of IM

withdrawal, all patients had been in sustained CCyR for 17 to 30

months and in complete molecular response for 13 to 19 months. All

patients showed normal cell morphology on bone marrow examination

and none of them had additional cytogenetic abnormalities.

The relative quantification of BCR-ABL transcripts was performed by

Q-RT-PCR using 1 µg of total RNA, isolated by an RNeasy mini kit

(Qiagen) from 107 Ficoll-hypaque separated mononucleated cells,

reverse-transcribed as previously described.2 Relative

quantification of the BCL-ABL fusion transcript was performed with

GeneAmp 5700 SDS (Applied Biosystems) in a reaction volume of 25 µL,

using 1/10 cDNA volume, SYBR Green PCR Master Mix and the primers

already reported.3 The dissociation curves were analyzed to assess

amplification specificity. A standard curve was obtained through

serial dilutions (5x105 – 5 BCR-ABL copies) of K562 RNA into normal

control RNA. BCR-ABL expression levels were calculated by the DDCt

method, using ABL as the normalizing gene and K562 as a calibrator

sample. Nested RT-PCR assay was used to confirm the negative results

of quantitative RT-PCR2. After IM discontinuation, Q-RT-PCR was

performed every 3 months on bone marrow and peripheral blood samples.

As shown in Table 2, patients #2 and #3 experienced molecular

relapse 7 and 10 months, respectively, after IM discontinuation. The

cytogenetic Philadelphia marker was negative and the karyotype was

normal. Both patients resumed IM at 400 mg/day and both achieved a

second complete molecular response. They are currently receiving IM

therapy. Patients #1 and #4 are still in complete molecular response

(15+ and 14+ months, respectively) and both are off therapy. Our

experience suggests that withdrawal of IM therapy in chronic phase

CML patients after achievement of a complete molecular response may

result in different molecular outcomes. It is likely that the

absence of detectable BCR-ABL transcript by Q-RT-PCR does not equate

with cure. To our knowledge, there are 6 other reported cases of IM

discontinuation due to intolerance or patients' request: 5 had

undetectable levels of BCR-ABL transcript4,5 and 1 was in sustained

cytogenetic response.6 Overall, in 4 of the literature cases a

molecular and cytogenetic relapse occurred rapidly, whereas our 2

cases only had molecular relapse. Moreover, patients who restarted

IM had prompt cytogenetic and molecular responses. There is evidence

that CML patients have a leukemic population of non-cycling Go

quiescent stem cells that are not sensitive to IM.7,8 This

subclinical reservoir can be a source for disease relapse. On the

other hand, the prompt improvement seen after restarting therapy

argues against the development of resistance. However, the selection

of resistant clones after IM exposure and the emergence of

Philadelphia-negative clones with secondary cytogenetic

abnormalities are matter of concern, particularly in patients

receiving IM for a long time.5-7 Although the follow-up of our

patients is short, the improved quality of life while off therapy

and the prompt response to resumed IM therapy suggest that the

subset of patients who have sustained complete molecular response

may be candidates for intermittent therapy. Future studies should

determine the optimal duration of BCR-ABL negativity before IM

therapy can be safely discontinued.