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摘要：该模型研究基于7年的停药试验数据，试图预测哪些患者可以从停药中获益。
医生们认为，服药15年期间，预测有14%的患者可以根除疾病，31%的患者在服药取得CMR两年后停药可维持深度CMR缓解（基于5个对数级水平的PCR检测）。
医生们在文中还预测了哪些患者可以从停药中获益，何时停药可以获益。由于这只是一个理论模型，我们仍需要实际数据来证明。
这是一个好消息，因为医生们正在研究哪些患者属于14%的可以根除疾病的人。
69%的患者在停药后会复发，因此对于大多数患者来说，我们仍需期待研制出新药来彻底清除cml干细胞。

作者：德国Hochhaus医生等
来源：Blood.2012.11.21.
链接：http://www.ncbi.nlm.nih.gov/pubmed/23175686#

Dear Group,

I will try to get the full article but this abstract from Dr. Hochhaus
and colleagues was just published in Blood. The doctors are doing a
theoretical model based approach to try and predict which patients can
benefit from cessation of therapy. I think this is very important right
now. The model is based on projections from 7 year data from
discontinuation trials.

The doctors say that within 15 years of therapy, 14% of patients are
predicted to have erradication of disease. 31% are expected to be in
deep CMR (5-log PCR machine) off meds after a fixed time of 2 year CMR
in the same machine on meds.

Then the doctors go on to give rules (in the full paper) on when and
which patient can benefit from treatment discontinuation. Since this is
a theoretical model, practical actual real-time data will have to
substantiate predictions.

It is very good news that doctors are looking into which patients may
be among the 14% of patients that can have an erradication of CML.

69% of patients are expected to relapse off therapy so for the
majority, it is very important to encourage research into new drugs that
can kill the CML stem cells.

Best Wishes,

Anjana

老马 · 发表于 2013-5-14 07:58:32

MDACC has, for the first time, given their experience of TKI
discontinuation. The doctors at MDACC look at 26 patients who
discontinued therapy from 2003-2012 for various reasons. These reasons
include long time in CMR, adverse side-effects, pregnancy and financial
constraints. Please note that 17 patients discontinued therapy in CMR
and the rest in MMR. Of the patients in CMR who discontinued therapy,
47% had molecular relapse. Those in CMR who discontinued and had taken
prior Interferon to a TKI, 50% relapsed. Also note that of these 26
patients, most had been treated with high dose Gleevec.

"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.
The median duration of CMR before TKI cessation was 62 mos, (0- 118).
The median duration of total TKI therapy was 101 mos (3- 135)."

Therefore, the median time in CMR before discontinuation was about 5
years. The median follow-up is only 11 months. The median time for
molecular relapse of 8 patients who had been in CMR was 4 months and
they relapsed with median PCR value of 0.01 on the International Scale.

Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a
median follow-up of 21 months, 1 remained in CCR, 1 in active disease
and 1 transformed to accelerated phase off drugs. Therefore, from this
data, scarce as it is, there is a risk of transformation to advanced
disease if one discontinues drugs in MMR.

2 patients were PCRU (4.5 log machine) and these patients relapsed
into MMR when drugs were discontinued.

Seven pts with relapse were treated again with TKI, 3 with nilotinib,
2 with dasatinib, and one each with imatinib and bosutinib (the latter
in AP). After a median of 13 months on therapy (range 4-52) all patients
improved their response, 5 with CMR and 2 MMR (including the pt that had
transformed to AP). They do not say why all patients were not retreated
with imatinib and had to take Nilotinib and Dasatinib. Also, note that
one did not regain CMR at the 13th month mark though it is good news
that 5 did. It may take some time to regain CMR for some who have gone
off drugs and relapsed. However, from our own list experiences, some
had regained CMR fast when they retook the TKI.

The doctors conclude that treatment discontinuation is experimental
and cannot be recommended at this stage as a standard procedure.

Best Wishes,

Anjana

3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
Theray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
Institution Experience
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III

Monday, December 10, 2012, 6:00 PM-8:00 PM

Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
Elias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
Stefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
Gautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.
Cortes, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer
Center, Houston, TX
2Department of Leukemia, The University of Texas M.D. Anderson Cancer
Center, Houston, TX

Introduction: Some recent studies have reported on the outcome of CML
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving
sustained undetectable bcr-abl transcript level. Most patients who stop
TKI have experienced molecular relapse. Most patients respond after
resuming TKIs regaining undetectable bcr-abl transcript levels. These
series have prospectively planned treatment discontinuation and included
only pts that have sustained complete molecular response (CMR) for at
least 2 yrs. However, in many instances pts may want to discontinue TKIs
not in CMR. Various reasons may lead patients to discontinue TKI
treatment unexpectedly, among them severe adverse effects, pregnancy or
economic constraints. This single institution experience reflects the
heterogeneous nature of pt-driven TKI discontinuation.

Aim: To characterize the outcome and profile of CML pts who chose to
discontinue TKI therapy in a single center regardless of their initial
response to TKI therapy.

Methods:We retrospectively analyzed MDACC data on all patients with CML
that were treated with TKIs in our institution and discontinued therapy.

Results: A total of 26 patients with CML-CP managed at MDACC
discontinued TKI between 2003 and 2012. The total median follow up time
since diagnosis was more than 120 months (mos) (range, 45 mos to 304
mos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were
female. All pts had been diagnosed and treated in chronic phase.
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI
as initial therapy (4 received imatinib 400mg/day, 10 imatinib
600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN
failure. Pts treated frontline with TKI started therapy within a median
of 0.8 mos from diagnosis (range 0 to 4) and those with previous
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164
mos). Before TKI discontinuation 21pts (81%) were receiving their first
TKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete
cytogenetic response (CCyR) had been achieved in all 26 pts at a median
of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The
median duration of CMR before TKI cessation was 62 mos, (0- 118). The
median duration of total TKI therapy was 101 mos (3- 135).

Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts
discontinued to become pregnant, 5 decided to stop after long CMR, and 5
pts discontinued for financial reasons. After TKI discontinuation
patients were followed for a median of 11 mos (5-131). Among pts with
CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a
median of 4 mos (1-11) from discontinuation with median transcript level
at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF
therapy had CMR at time of TKI discontinuation, 50% of them relapsed.
Among 7 pts who discontinued therapy in MMR, after a median follow-up
from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,
one has minor CyR and one CCyR without retreatment at last follow up
after 78 and 105 months from TKI discontinuation, and one transformed to
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed
to MMR. Three pts had a transient molecular recurrence with spontaneous
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3
with nilotinib, 2 with dasatinib, and one each with imatinib and
bosutinib (the later in AP). After a median of 13 months on therapy
(range 4-52) all patients improved their response, 5 with CMR and 2 MMR
(including the pt that had transformed to AP). There were no deaths or
transformations to blastic phase of CML. At last follow up 14 (54%) pts
were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
PCyR.

Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular
relapse in nearly half of the pts who discontinue therapy in CMR. Some
pts who discontinue in MMR may have sustained MMR. Treatment
discontinuation should be considered experimental and cannot be
recommended to pts as a standard approach.

Disclosures: Ravandi: BMS: Honoraria, Research Funding.

老马 · 发表于 2013-5-14 07:59:17

摘要：法国的研究：这一研究的初始阶段纳入15名取得完全分子学反应超过两年的病人，他们起初使用过干扰素治疗，然后服用格列卫。其中7人在6个月内复发，但是在所有病例中，重新使用伊马替尼后，都重新获得了完全分子学反应。其他8名病人（4男4女）停用伊马替尼后，在中位随访时间37个月后仍然保持完全分子学反应。

规模更大的研究（STIM研究）纳入了50名来自18个治疗中心的患者，他们都拥有长期的完全分子学反应。其中25名病人只服用过伊马替尼，另25名病人先用过干扰素后用伊马替尼。18名病人在6个月内复发，1名病人在8个月时复发，在19名复发病人中，11名是只服用伊马替尼的病人，8名是先用干扰素后用伊马替尼的病人（复发率分别为44%和32%）。

法国研究显示，停用伊马替尼后有可能保持完全分子学反应，尤其对于先前用过干扰素的病人来说。研究需要更长的随访时间来判断反应的稳定性，但是结果还是鼓舞人心的。

澳大利亚的研究：略

北欧研究：这一研究是Nordic（北欧） CML group发起的，5名只服用伊马替尼平均23个月的病人（4名取得完全分子学反应、1名取得主要分子学反应）停药。所有5名病人很快在4个月里失去了主要分子学反应。

北欧研究、澳大利亚研究和法国研究（法国研究观察到的复发率更低）的主要区别在于，澳大利亚研究和法国研究中病人停药前完全分子学反应的延续时间要比北欧研究中的长很多，这似乎和停药之后完全分子学反应持续时间的长短直接相关。

来源：2009 ASCO and ASH 2008

ASH 2008

The initial phase of this study involved 15 patients who had sustained CMR for
greater than 2 years, and had previously been on interferon therapy first, then
on imatinib. 7 out of 15 pts relapsed within 6 months, but CMR was re-attained
in all cases after IM was re-started. The other 8 pts (4 male, 4 female) are
still in CMR, with a median follow up of 37 months (range 26?9 months) after IM
discontinuation.

A larger study (The STIM study) was initiated with 50 patients from 18 centers
who had long-term CMR. 25 patients had imatinib only therapy and 25 patients
had interferon followed by imatinib therapy. 18 patients relapsed within the
first 6 months and 1 patient relapsed at the 8-month mark. Among the 19
relapsed patients, 11 were imatinib therapy only and 8 were interferon followed
by imatinib (relapse rates of 44% vs 32%, respectively)

The French study indicates that it is possible to sustain CMR after imatinib
discontinuation, particularly in patients with prior interferon therapy. More
long-term follow-up is needed to determine the stability of response, but the
results are certainly encouraging.

The French study results are very similar to the Australian study by Dr. Hughes
group, which Anjana has presented earlier and indicates an encouraging
reproducibility of response. Take care.

Australian Study

Dear Group,

In this study by the Nordic CML group, 5 patients (4 in CMR, 1 in MMR) only on
imatinib therapy for a median of 23 months discontinued therapy. All 5 patients
lost MMR rapidly within 4 months. The key differences between the Nordic study
and the Australian and the French studies (which observed much lower relapse
rates) was that the duration of CMR in the patients in the Australian and French
studies were considerably longer than those of the Nordic study, and this seemed
to correlate directly to how long CMR could be sustained off imatinib therapy.

老马 · 发表于 2013-5-14 07:59:50

摘要：关于格列卫停药实验的最新数据显示，15名病人中，有8名在停药中位时间42个月之后仍然保持了融合基因阴性（PCRU）。在这个较小的病人群体中，不管他们是把格列卫作为一线药物还是二线药物，他们停药后保持PCRU的几率是相等的。停药后保持PCRU的病人和其他复发病人相比，具有以下特质：男性、Sokal系数低、外周血中有更多的NK细胞（自然杀伤细胞）。实验人群较少，但是在整个cml研究中每个数据都是有意义的。复发病人中大多数在停药后6个月内出现复发。
作者：来自法国多家医院
来源：ASH2009论文摘要http://ash.confex.com/ash/2009/webprogram/Paper18033.html

老马 · 发表于 2013-5-14 08:00:15

摘要：本研究来自英国Hammersmith医院。医生们认为CMR（完全分子学缓解，即检测不到融合基因PCRU）对于移植后患者和服用格列卫患者在性质上是不一样的。大多数融合基因转阴的格列卫患者在停药后会复发，但是移植后患者则可能有较低的融合基因数值，但无需用药也不会复发。
   医生对上述两种患者都做了一些敏感的PCR检测。在5名服用格列卫融合基因转阴的病人中，全部都检测出独特的原始白血病克隆（original leukemic clone），这些克隆导致停药后复发。但是，好消息是，随着服药时间的延长，有4名患者体内消除了这种克隆。所以，即使服用格列卫取得了融合基因转阴，仍然需要时间继续服药来去除原始白血病克隆。
   在9名移植后患者中，虽然有些人仍不时能检测出较低的融合基因数值，但是只有一人检测出原始白血病克隆，其他人均未检测出这种克隆，因此没有复发。
   这篇文章使得格列卫患者能更现实地看到融合基因转阴仍可能有疾病残存，但随着服药时间的延长，有望根除原始白血病克隆。
作者：来自英国Imperial College London血液科（Hammersmith医院）
来源：Blood. 2010.5.12

老马 · 发表于 2013-5-14 08:00:50

摘要：这是法国STIM试验的最新结果，其中融合基因转阴（pcr降低10,000倍）的患者停用格列卫两年。在69名停用格列卫的患者中，42名在一年随访期内复发（占61%）。虽然大多数人在停药后6个月内复发，但是有1名患者在7月时复发，1名在19个月时复发。
仍有39%的患者停药后保持了疾病缓解，他们是否能维持2-3年，是否被治愈？仍需要更长时间的随访才可得知。
42名复发的患者中有26名恢复用药后重新取得pcr转阴的结果，但是另16名虽然pcr值在下降但仍未转阴。恢复用药后，所有这些病人是否都能转阴，也需要时间的检验。

作者：法国STIM试验
来源：Lancet Oncol. 2010.10.19

老马 · 发表于 2013-5-14 08:01:21

摘要：一些融合基因转阴（PCRU）已2年的患者停药后，短期随访发现他们仍能保持阴性，下面是意大利医生根据法国停药研究的数据展开的讨论。
首先，有些人停药后疾病复发，其融合基因数值升高较多，而其他一些人则是在MMR和PCRU之间变化不定，后面这部分人可能在停药后，由于免疫功能的作用，疾病水平维持在较低水平，甚至维持PCRU，他们的免疫系统可以防止疾病复发。不过，前一部分人融合基因升高较多，意味着，对他们来说，即使取得PCRU仍然说明残存有对格列卫产生反应的cml干细胞，停药后，这部分疾病又复发了。
医生们接着推断，服用格列卫并同时维持PCRU的时间越长，然后再停药，结果可能不同，这样会有更多的患者能够在停药后仍将疾病维持在较低水平。事实上，法国的研究数据确实显示，那些停药后没有复发的患者服用格列卫的时间更长。医生们推测，也许维持PCRU 4-5年然后停药，也许更多患者可以停药后无疾病反复。
（Asian CML Support Group论坛主注：有位病友是来自美国加州的Paul，他在取得PCRU 5年后停药，但疾病复发了。请注意，上述讨论只是这篇文章中医生的意见。其他一些医生则认为只要cml干细胞存在就会引发疾病，因此正在努力研究针对cml干细胞的药物。）

作者：来自意大利Catania大学，Ferrarotto医院
来源：Lancet Oncology Volume 12, Issue 2, Page 118, 2011.2

原文链接：http://www.thelancet.it/journals/lanonc/article/PIIS1470-2045(11)70017-1/fulltext

老马 · 发表于 2013-5-14 08:02:01

摘要：伊玛替尼停药试验（STIM试验）招募了100名患者（停药前均已取得融合基因持续转阴2年或更长时间），其中51名患者之前用过干扰素后用伊玛替尼，另49名患者只用过伊玛替尼。69名患者经过至少12个月的随访，42名（61%）患者重新出现bcr-abl融合基因表达，剩余39%的患者仍然维持CMR（融合基因阴性）。停药后复发速度为每个月疾病负荷升高约1个log（10倍）。除了一名患者，其他患者的复发都发生在停药后7个月内。所有复发患者在重新服用格列卫后都反应良好。复发相关的因素包括：女性、伊玛替尼服用时间较短、初诊时较高的Sokal风险系数。之前是否用过干扰素并不是影响因素。
停用伊玛替尼后仍能维持CMR的这部分患者是否真的被治愈了？Deininger医生认为，“治愈”应被定义为这些患者cml再次临床发病的几率与普通大众类似，而并非指cml细胞被完全清除，因为后者是无法衡量的。注意，有些患者移植后20多年仍有复发，所以，重要的一点是，我们需用相当长时间来观察患者是否能够保持长期停药不复发，那时候才能下结论伊玛替尼能否“治愈”。
如何解释复发多发生在停药后7个月内，而7个月以后复发率大为下降呢? Deininger医生提出了一个“门槛”理论，即疾病细胞得达到一个门槛水平才能引起疾病复发，如果cml细胞被压制在这个水平线之下，那么疾病可能不会复发，某些免疫机制就可以控制住这些细胞，或者疾病细胞偶然情况下就消失了。
根据STIM试验的研究人员估计，大约10%的cml患者有资格参加伊玛替尼停药试验，这部分人中又有40%可能获得持续的CMR，也就是说cml患者中约有4%的人可能被伊玛替尼“治愈”。关键问题在于，更加强劲的激酶抑制剂如尼罗替尼和达沙替尼是否能够大大提高这部分人的比率？根据这个“门槛”理论，更为强劲的激酶抑制剂也许能使更多患者的疾病细胞到达“门槛”水平线以下。不过，另一种可能的情况是，残留的疾病细胞与常见的cml原始细胞性质不一样，可能对更为强劲的激酶抑制剂不能产生反应，在这种情况下，伊玛替尼停药的无复发率可能与尼罗替尼或达沙替尼的停药无复发率相当。
理论上讲，这些研究结果表明，如果严密监测的话，停用伊玛替尼可能是安全的。但从实际来讲，Deininger医生指出，人们需要慎重起见，因为STIM试验的数据只是初步的，我们仍需更长时间的随访数据才能在临床实践中作出相应的变化。主要担心的问题在于，患者在体内所有cml细胞清除之前就停药的话，可能导致cml干细胞重新在bcr-abl激酶活动下产生基因的不稳定性而导致最终的疾病进展。因此，希望停药的患者应当加入临床试验，如果患者坚持停药，那么必须使用高质量的PCR技术来进行严密的监测。

作者：Michael Deininger医生，来自美国犹他大学Huntsman Cancer Institute
来源：Nature Reviews In Clinical Oncology 2011.2.

老马 · 发表于 2013-5-14 08:03:01

摘要：目前，大多数停药研究都是针对服用伊玛替尼取得CMR（融合基因转阴）一段时间的cml患者。EHA 2011的这个研究中，伊玛替尼不耐受的患者后来换做二代激酶抑制剂（尼罗替尼或达沙替尼），取得CMR有一段时间，然后停药。研究目的是看他们的试验结果与只服伊玛替尼的患者有何不同。
在此研究中，12名患者（中位年龄59岁），持续服用伊玛替尼的中位时间为50个月。停药前服用二代药的中位时间为33个月，CMR持续中位时间为29个月。
停药后，其中有4名（30%）患者在6个月内失去了MMR，重新使用二代药后又迅速取得了MMR，1名患者没有失去MMR，但是两次检测失去了CMR，也重新服药。另外7名患者仍然停药，到上次随访时停药的中位时间已达11个月，维持了稳定的CMR，或者一两次检测出有微量的BCR-ABL融合基因残留。
请注意，此项研究仍处在早期研究阶段。

作者:来自法国
链接：
http://www.eventure-online.com/e ... amp;congressId=4634

老马 · 发表于 2013-5-14 08:03:39

摘要：医生并不建议停用格列卫或其他激酶抑制剂，如果停用的话可能会引起疾病进展。韩国医生研究了14名服用格列卫作为一线药物的患者，他们取得CMR（即PCRU，融合基因转阴）至少1年，然后停药，其中9名患者在7个月内复发。可见，即使在这类病人中，停药后复发率也是很高的。
从这个实验来看，如果病人初诊时Sokal风险系数较高、超过两年才取得PCRU的话，停药后复发率更高。

作者：来自韩国
来源：EHA 2011论文摘要