Stopping Gleevec

[Guest guest]

Thank you Margot for forwarding this.

This is very exciting. It is the first study (more than 1 patient) I have

seen going off Gleevec.

Zavie

Outcome of four patients with chronic myeloid leukemia after imatinib

mesylate discontinuation & #65279;

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

Marina Boni, Lazzarino

& #65279;Division of Hematology, IRCCS Policlinico San Matteo, University of

Pavia, Viale Golgi 19, 27100 Pavia, Italy

Abstract

& #65279;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.

& #65279;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.

[Guest guest]

Hi Tracey,

Thanks for this abstract and all the others.

One thing this abstract shows is that either the authors cannot do simple

mathematics or they have neglected to include some additional facts.

Clearly, 44% (15 patients) of the 34 patients who had a follow up remained

in CMR (PCRU as we call it) and 56% (19 patients) patients relapsed. These

numbers are for a 6 month study and they are worse than the earlier study of

15 patients where 53% remained in CMR (PCRU as we know it) and 47% of the

patients relapsed.

The relapse rate for this new study is 56%.

For the remaining 19 patients who relapsed we know the following: - 58% of

them had not taken Interferon and the remaining 42% had been on Interferon.

This result agrees with the original trial where the patients who took

Interferon before Imatinib did better than those on Imatinib alone.

What puzzles me about the report is how they got relapse rates of 44% vs

32%. The only way they got these numbers is by comparing the 11 who were not

Interferon treated to the original 25 patients who were not Interferon

treated. This gives you a 44% relapse rate. And they got the 32% relapse

rate by comparing the 8 patients who were interferon treated to the original

25 patients who were Interferon treated. Check the math. 8/25=32%.

So the blunder as I see it is that they were comparing apples to oranges.

They needed to say how many of the 34 patients who had the follow up were

Interferon treated and how many were not. Then you can calculate the relapse

rates.

So, let's say that the 34 patients were equally divided between Interferon

treated and not Interferon treated. The relapse rates would then be 65% vs

47%.

What really bothers me is not knowing what happened to the other 16 patients

that they didn't have a follow up for.

I will speak to authors at ASH to get an explanation.

Thank you Tracey for pointing this out.

Zavie

Zavie (age 70)

67 Shoreham Avenue

Ottawa, Canada, K2G 3X3

dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

2.8 log reduction Sep/05

3.0 log reduction Jan/06

2.9 log reduction Feb/07

3.6 log reduction Apr/08

3.6 log reduction Sep/08

e-mail: zmiller@...

Tel: 613-726-1117

Fax: 309-296-0807

Cell: 613-282-0204

ID: zaviem

YM: zaviemiller

Skype: Zavie

_____

From: [mailto: ] On Behalf Of Tracey

Sent: November 19, 2008 3:57 PM

Subject: [ ] Stopping Gleevec

Hi Everyone,

This abstract deals with patients who stopped taking Gleevec after

they were PCRU (at least a 5 log reduction) for at least 2 years:

http://ash.confex.

<http://ash.confex.com/ash/2008/webprogram/Paper1890.html>

com/ash/2008/webprogram/Paper1890.html

The beginning of the abstract talks about that famous study done in

France that we often quote.

This was the study where 15 people stopped taking Gleevec. 7 out of

the 15 patients relapsed within 6 months (47%), while 8 remained PCRU

after a median follow up of 37 months (53%). The important thing to

note with these patients is that they all had previously taken

Interferon and the majority of them actually had a response to it

when they took it.

The rest of the abstract deals with a follow up study that was done

to further investigate this issue.

The math is a bit odd in this part but this is what I got out of it:

-34 patients were evaluated after stopping Gleevec.

-19 relapsed which to me represents 56%, (all but 1 relapse happened

within 6 months of stopping Gleevec).

-11 of those who relapsed had never taken Interferon which to me

represents 58% but somehow the abstract quotes this figure as being

44%.

-8 of those who relapsed had taken Interferon in the past which to me

represents 42% but for some reason the abstract quotes this

percentage as being 32%.

-10 patients who had previous treatment with Interferon remain PCRU

which to me represents 29%.

-5 patients who had no previous Interferon treatment remain PCR which

to me, represents 15%.

To make the math even stranger, at the conclusion of this abstract,

they conclude that more than half of the patients who stopped Gleevec

having had NO prior treatment with Interferon, remained PCRU. In my

calculations, this group of people represented only 15% which is far

less than half so I'm not sure what to make of this. Anyway you look

at it, I wouldn't feel comfortable stopping treatment.

Tracey