16 replies to this topic

[scuba]

This is interesting:

Of Mice and Men ...

http://ash.confex.co...Paper40186.html

766 Treatment with 8F4, An Anti-PR1/HLA-A2 T Cell Receptor-Like Antibody, Reduces Established Acute Myeloid Leukemia and Eliminates Leukemia Stem Cells in Mice

In reading the abstract, 8F4 (antibody) seems to go after the Leukemic stem cell.  Works in mice, may work in people.

[scuba]

Dose Reduction: Sprycel

3786 Clinical Significance of Dose Reductions of Dasatanib and Nilotinib When Used As Frontline Therapy for Chronic Phase -Chronic Myeloid Leukemia (CML-CP) Does Not Affect Outcome

Conclusion:  Although dose reductions are frequently required for pts with CML treated with dasatinib or nilotinib, dose reductions did not lead to adverse outcome. Dose adjustments can be used when required to manage AEs. This approach allows in most instances continuation of these highly effective therapies.Â

Table 1.Â

Â	Dose reduction	No dose reduction
CCyR	94%	95%
MMR	90%	85%
36mos EFS	88%	89%
36mos TFS	100%	98%
36mos OS	100%	100%

2768 Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs)on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Conclusions: Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib.

		All Treated			No Dose R and/or I			Dose R and/or I due to AEa
		D N=258	IM N=258		D n=103	IM n=147		D n=134		IM n=92
CCyR by 12 mo		221 (86%)	191 (74%)		89 (86%)	111 (76%)		107 (80%)		59 (64%)
CCyR by 24 mo		223 (86%)	213 (83%)		90 (87%)	126 (86%)		112 (84%)		69 (75%)
MMR by 12 mo		119 (47%)	73 (28%)		50 (49%)	43 (29%)		55 (41%)		21 (23%)
MMR by 24 mo		165 (64%)	120 (47%)		71 (69%)	66 (45%)		76 (57%)		41 (45%)
2-year PFS		94%	92%		94%	90%		93%		93%
2-year OSc		95%	95%		97%	93%		94%		98%
	R and/or I due to AE ?6 Months After 1st Doseb						R and/or I due to AE >6 Months After 1st Dose
	D n=90			IM n=61			D n=34		IM n=24
CCyR by 12 mo	76 (84%)			39 (64%)			29 (85%)		18 (75%)
CCyR by 24 mo	80 (89%)			47 (77%)			30 (88%)		20 (83%)
MMR by 12 mo	35 (39%)			14 (23%)			20 (59%)		7 (29%)
MMR by 24 mo	53 (59%)			26 (43%)			23 (68%)		15 (63%)
2-year PFS	96%			96%			93%		90%
2-year OSc	98%			98%			97%		100%
AE=adverse event; I=interruption; R=reduction aPatients with dose R and/or I due to reasons other than AEs were excluded (21 D, 19 IM) bPatients on treatment ?6 months were excluded (10 D, 7 IM) cSurvival data remain immature; all patients will be followed for 5 years

Message was edited by: Michael Additional information from ASH:2011

[random]

So? Dose reduction looks safe ?

[scuba]

Dose reduction is safe ... if it works.  In other words, reducing dose in order to manage Adverse Effects (AE) while maintaining continued response is now a proven method that specialists in the field are using.  I don't know when this will become part of the evolving guidelines, but for now the published papers are showing effectiveness.

[Trey]

If Sprycel is "300 times more active than Gleevec", why is Gleevec generally within about 10% of Sprycel treatment results overall, and Gleevec is roughly equal to PFS and OS stats (and even beats Sprycel in 2 year OS).  Pretty good for a "has-been" drug.  Just wonderin'

[pamsouth]

Trey,  My exact thoughts.  I'm staying on the has been Gleevec!!  Except for being a little tired and maybe some fluid, but I have been on a diuretic long before Gleevec.  However my eyes do swell a little. As far as being tired I think maybe turning 64 years old in a couple of weeks may slow a person down a bit.  Bone pain could be caused by some arthritis, would contribute to that. I take some vitamin D and magnesuium &  cal.  CBC and Fish are good! 

Pam

[ritan/]

well, i can see some reasons that this might be. gleevec is still used for the most part as the first line of defense, correct? so, only difficult cases get to sprycel, perhaps? if gleevec deals with the easy cases (as would tasigna or sprycel if it were asked) and sprycel only gets tagged when gleevec has already failed--then it's success is almost all in places that gleevec has failed?

[Trey]

Not for the data we are discussing here.  The titles in both studies cited by Michael show that patients started on Sprycel or Gleevec as their first line drug. 

[ritan/]

ah, i didn't catch that.

[pamsouth]

Right on Trey,  If Sprycel failed as the first line of defense that would have nothing to do with Gleevec, or did I miss something?

PamSouth

[ritan/]

when you say "within 10%" does that mean that if 70 people are fixed by gleevec, then 77%ish are fixed by sprycel? OR do you mean 10% of the total--like 70 respond to gleevec and 80 respond to sprycel? 

[Trey]

These are not "all or nothing" stats.  They are gradations in the degrees of response, especially related to speed to meet certain milestones.  So it appears to take about 10% of Gleevec patients longer to meet certain milestones.  So it is not that the Gleevec patients do not achieve the milestones, they just take a little longer on average.  But the most important stats (PFS and OS) are equal for both drugs.

[scuba]

3504 Cryptic Intracellular Retention of ABL Tyrosine Kinase Inhibitors within CML Cells Mediates Apoptosis Commitment Following Acute Drug Exposure

Interesting paper.  (Druker is an author as well.)

The imatinib paradigm established continuous BCR-ABL inhibition as a design principle for ABL tyrosine kinase inhibitors (TKIs). However, once-daily dasatinib (serum half-life: 3-5 h) is clinically effective despite only transient BCR-ABL inhibition, opening an opportunity for in-depth study of the mechanistic requirements for ABL TKI-induced CML cell death.

We have undertaken a comprehensive mechanistic exploration of this issue, wherein CML cells were transiently exposed to the ABL TKIs imatinib (50 and 500 nM), nilotinib (50 and 500 nM), dasatinib (10 and 100 nM), and ponatinib (AP24534; 10 and 100 nM) and then investigated with respect to pathways critical to drug efficacy and intracellular residence time.

All four ABL TKIs tested were capable of triggering apoptosis following transient exposure, although nilotinib and imatinib (which feature much narrower kinase target profiles than dasatinib and ponatinib) did so only at high concentrations.

[CallMeLucky]

Michael, do you have a direct link to 3786?  I can't find it on the ASH site.

Clinical Significance of Dose Reductions of Dasatanib and Nilotinib When Used As Frontline Therapy for Chronic Phase -Chronic Myeloid Leukemia (CML-CP) Does Not Affect Outcome

Thanks

[scuba]

Gary - This should work:

http://ash.confex.co...Paper44523.html

[ritan/]

but the MMR results are really NOT the same.

[scuba]

Additional ASH info:

There were 6 matches on Leukemic Stem Cells

122 matches for Dasatinib or Sprycel

105 matches for Nilotinib or Tasigna

24 matches for ponatinib or AP24534

235 matches for Imatinib or Gleevec

Zero for Zileuton or Alox5

Zero for Curcumin

My impression is that Gleevec, by far, is the most studied compound to date with lots of research still going on and being reported.

For a drug getting ready to come off patent, I find that interesting, but not surprising.

Spyrcel and Tasigna about equal mention.

And my favorites - Zileuton and Curcumin are not mentioned at all. I am assuming that not much progress has been made in this area.

And Curcumin is not worthy of research publication (no money). I will continue to take it.

I am surprised at so little research being done on Leukemic stem cells. Eradicate the disease, eradicate the Pharma dollars?  Just 'sayin.