Good News from ASH

[Guest guest]

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104 & STORY=/www/story/1

2-10-2005/0004231474 & EDATE=

ATLANTA, Dec. 10 /PRNewswire/ -- Offering promise in the battle

against

cancer, the results from five studies highlighting new advances in the

treatment of chronic myeloid leukemia (CML) -- a slow-progressing,

malignant

bone marrow cancer -- will be presented at the 47th Annual Meeting of

the

American Society of Hematology.

" The survival rate for leukemia has improved in the past two

decades,

thanks to new agents designed to treat patients, " said J. Druker,

M.D.,

Oregon Health and Science University, Portland, Ore. " Continued

research will

only strengthen our understanding of the disease and support the

therapeutic

potential of current and developing treatments for chronic myeloid

leukemia. "

CML is usually diagnosed by finding a specific chromosomal

abnormality

called the Philadelphia chromosome (Ph chromosome). The Ph chromosome

is the

result of translocation - a genetic chromosomal abnormality - between

the long

arms of chromosomes 9 and 22. The result is that part of the BCR

(breakpoint

cluster region) gene from chromosome 22 is fused with part of the ABL

(abelson

leukemia virus) gene on chromosome 9. The translocation takes place in

a

single bone marrow cell and, through the process of cell division and

expansion, results in leukemia, the rapid growth of abnormal white blood

cells

in the bone marrow, blood, and body tissues.

The discovery of the Ph chromosome marked the first genetic

abnormality

consistently associated with a particular form of cancer. In addition

to CML,

Ph chromosome can also be found in some cases of acute lymphoblastic

leukemia

(ALL) and acute myeloid leukemia (AML).

Imatinib, which blocks the abnormal protein driving the

overproduction of

abnormal white blood cells, has become a standard therapy for patients

not

undergoing stem cell transplantation. It is now demonstrating continued

control and reduction in levels of remaining disease in chronic phase

CML

(CML- CP) patients. However, a number of patients have developed

resistance

to this treatment because their cancer cells are able to mutate and

adapt.

As a result, treatment options for patients with CML continue to

expand.

Various studies of potential new treatments for CML yield positive

results in

patients whose disease is resistant to imatinib. Both dasatinib and

AMN107

have been shown to be effective in treating patients with CML whose

disease

has progressed on imatinib.

Continuing Reduction in Level of Residual Disease After Four Years

in

Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase Responding

to

First-Line Imatinib (IM) in the IRIS Study [Abstract 163]

A recent report updated results of molecular monitoring of patients

in the

International Randomized Interferon vs. STI 571 (IRIS) study that

prospectively compared imatinib therapy with interferon-alfa plus

cytarabine.

The IRIS study was initiated in June 2000, and demonstrated that after

one

year of imatinib treatment, an estimated 40 percent of CML-CP patients

taking

400 mg per day achieved a major molecular response (MMR), defined as

substantial reduction in BCR-ABL levels. This particular analysis

assessed

the level of BCR-ABL transcripts after approximately four years of

imatinib

treatment and showed continuing reduction in transcript levels.

The analysis was based on 101 patients who achieved complete

cytogenetic

response (CCyR) within one year, received first-line treatment for at

least 24

months, and had blood collected for measuring transcript numbers at one

year

and four years after starting treatment. Results are expressed as a log

reduction from a standardized baseline value for untreated patients.

This

means they are expressed as transcript copy numbers, with a one-log

reduction

equivalent to a fall from 100 to 10, and a two-log reduction a fall from

100

to one.

At one year, BCR-ABL transcript levels fell by at least three logs

in 46

percent of the 101 patients. At the most recent measurement, at or

after 44

months from start of study, 75 percent of patients demonstrated a

reduction of

at least three logs. Of these patients, more than half had already had

a

three-log reduction at year one, whereas 49 percent had not.

Conversely,

eight of the 47 patients with three-log reduction at one year had log

reductions greater than three at four years. At the one- and four-year

points, 20 percent and 36 percent of patients, respectively, achieved

four-log

reductions.

" The results are gratifying and show that patients in complete

cytogenetic

response who had an 'adequate' reduction in their BCR-ABL transcript

levels at

one year have a good chance at achieving a much greater reduction after

four

years of imatinib treatment, " said M. Goldman, D.M., National

Heart,

Lung, and Blood Institute (NHLBI), Bethesda, Md. " This is an important

observation because it means that imatinib continues for at least four

years

to reduce the quantity of residual disease and so promises to offer

patients

with chronic phase CML very substantial prolongation of essentially

normal

life, compared with previous therapies. "

Control of Residual Disease in Imatinib (IM) Treated Chronic Myeloid

Leukemia (CML) Patients with Peptide Vaccinations: Two Years Follow Up

of

CMLVAX100 Trial [Abstract 167]

In the past five years, the body of data concerning imatinib has

defined

its role as an effective first-line therapy for CML-CP patients.

However, the

persistence of disease in most patients, together with the evidence that

discontinuation of imatinib inevitably results in a rapid loss of

response,

suggests that the cure for CML is unlikely using imatinib alone.

Researchers from the University of Siena in Siena, Italy, looked at

the

anti-tumor effect of a vaccine (CMLVAX100) targeting the BCR-ABL genes

and how

it reduced remaining disease in some patients with CML who have reached

a

maximum response to imatinib. After a median time of 24 months of

imatinib

treatment, a group of 21 patients showing different degrees of

persistent

residual disease started vaccinations with CMLVAX100. Vaccine treatment

plans

included six vaccinations at two-week intervals. In patients who

responded to

treatment, additional boosts of vaccine were provided every four to six

months.

To date, 18 of the 21 patients have completed the immunization

regimen,

eight of whom received four additional boosts of vaccine. After six

vaccinations, six patients with persisting, progressing disease reached

a

complete response, with three of them achieving an undetectable level of

BCR-

ABL transcript. In addition, three patients starting vaccinations with

persistent molecular disease further reduced their BCR-ABL level, with

one

reaching molecular negativity. This suggests that CMLVAX100 works

effectively

with imatinib in CML-CP patients with persistent minimal residual

disease.

Of the eight patients who underwent four additional boosts of

vaccine, one

reached a complete molecular response, five maintained the response

obtained

after immunization, and two patients (who previously achieved an

undetectable

level of BCR-ABL transcript) lost the complete molecular response (CMR),

but

maintained CCyR. This suggests that while beneficial, a six-month

interval

between boosts could be too long to maintain efficient immune control on

residual leukemia cells.

" Although the number of patients who participated in the trial is

small,

this is a very important study, " said Bocchia, M.D., University

of

Siena, Siena, Italy. " Researchers have been attempting to develop

cancer

vaccines for decades, and results in CML patients are a very encouraging

step

forward. "

Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia

(CML) and

Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph +

ALL) Who

Are Resistant or Intolerant to Imatinib: Update of a Phase I Study

[Abstract

38]

Imatinib resistance in CML and Philadelphia (Ph) chromosome positive

acute

lymphoblastic leukemia (Ph + ALL) is frequently associated with BCR-ABL

mutations that interfere with the ability of imatinib to inhibit BCR-ABL

overproduction. Dasatinib (BMS-354825) is a novel, oral, multi-targeted

kinase inhibitor which targets BCR-ABL and SRC protein kinases. The SRC

protein is a signaling protein that specializes in messages that control

the

growth of cells. The drug is 325-fold more potent than imatinib in

cells

transduced with normal BCR-ABL genes, and has demonstrated preclinical

activity against 18 of 19 imatinib-resistant BCR-ABL mutants.

In an update of a phase I, dose-escalating study initiated in

November

2003, researchers from the University of California, Los Angeles (UCLA)

School

of Medicine and The University of Texas M. D. Cancer Center

looked at

the use of dasatinib in imatinib-resistant or intolerant patients with

CML in

late chronic phase (CP), accelerated phase (AP), myeloid blast crisis

(MBC),

or lymphoid blast crisis (LBC)/Ph+ ALL. Data are available for 82

patients

(40 CP, 10 AP, 22 MBC, 10 LBC/Ph+ ALL). A blast crisis is the

progression of

diseases to an acute advanced phase.

The 40 CP patients, with five years median duration of CML, were

treated

with 15 to 180 mg of dasatinib either once daily (QD) or twice daily

(BID) for

a median of 13 months. The rate of complete hematologic response (CHR)

in CP

patients was 93 percent, while major cytogenetic responses (MCyR) were

observed in 45 percent and CCyR in 35 percent.

In advanced disease, 44 patients have been treated with dasatinib

(70 to

240 mg BID) for a median of 37 months. The rate of major hematologic

response

(MHR) is 81 percent in AP, 61 percent in MBC, and 70 percent in LBC/Ph+

ALL.

The complete response rate is 45 percent in AP, 70 percent in LBC/Ph+

ALL, and

35 percent in MBC.

The overall rates of MCyR and CCyR in advanced disease were 43

percent and

25 percent, respectively. Cytogenetic responses were seen in patients

with a

wide spectrum of BCR-ABL mutations, as well as in patients with minimal

or no

prior cytogenetic response with imatinib. Responses were durable in CP

and AP

patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts,

often

due to dasatinib-resistant BCR-ABL mutations.

" These data support the therapeutic potential of dasatinib in CML

and

Philadelphia chromosome positive acute lymphoblastic leukemia patients

who are

imatinib-resistant or intolerant, " said Sawyers, M.D., Jonsson

Cancer

Center, UCLA School of Medicine, Los Angeles, Calif. " We are encouraged

by

the results and are looking forward to seeing the results from ongoing

phase

II studies to confirm the effects of dasatinib in patients with all

phases of

the disease. "

Efficacy of Dasatinib (BMS-354825) in Patients with Chronic Phase

Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML)

Resistant or

Intolerant to Imatinib: First Results of the CA180013 'START-C' Phase II

Study

[Abstract 41]

After three years of imatinib therapy, hematologic relapse occurs in

seven

percent of newly-diagnosed CML patients and 20 percent of CML chronic

phase

patients after failure to respond to current standard therapy. This is

mostly

associated with BCR-ABL mutations and/or clonal evolution - the

development of

chromosomal mutations that occurs in untreated CML and leads to

progression of

the disease. A previous phase I, dose-escalating study provided early

evidence for the safety and efficacy of dasatinib in imatinib-resistant

or

intolerant patients with CML-CP. This study (START-C [CA180013]),

carried out

by a multinational group of 75 investigators, is a follow-up on the use

of

dasatinib in CP imatinib resistant or intolerant patients.

A total of 394 patients were recruited to this phase II, open-label

study.

To date, data from 186 patients are available for analysis. Imatinib

resistance (n=127) or intolerance (n=59) was defined as a failure to

respond

to imatinib at maximum tolerated doses or the occurrence of BCR-ABL

mutations

associated with virtual insensitivity to imatinib. Dasatinib was

administered

to patients at 70 mg BID, based on phase I data and optimal inhibition

of BCR-

ABL activity from biomarker analysis. Dose escalation to 90 mg BID was

permitted in patients lacking response, and dose reductions to 50 and 40

mg

BID were allowed in the event of intolerance. Complete blood counts

were

obtained weekly for the first 12 weeks, while bone marrow was collected

every

three months.

Median time from diagnosis of CML was 63.8 months. Prior therapy

included

imatinib in 100 percent hydroxyurea or anagrelide in 86 percent, and

interferon alpha in 70 percent of patients. Approximately 54 percent of

patients received imatinib for more than three years.

Within the first six months, 90 percent of patients reached a

complete

hematologic response (87 percent resistant patients, 97 percent

intolerant

patients), and 45 percent achieved a major cytogenetic response (less

than or

equal to 35 percent Ph positive metaphases; 31 percent resistant

patients, an,

73 percent intolerant patients), being complete in 33 percent of

patients.

Interim results of Phase II dasatinib studies in advanced disease

were

also presented. Of the myeloid blast crisis patients resistant to

imatinib

(n=68), 31 percent reached a major hematologic response,

and 29 percent achieved a major cytogenetic response. Of the

accelerated

phase patients resistant to imatinib (n=99), 59 percent achieved a major

hematologic response and 31 percent a major cytogenetic response.

" Despite the short follow-up, significant improvements of

hematologic and

cytogenetic responses were seen in pretreated CML patients in all phases

of

the disease, which further supports the activity of dasatinib in BCR-ABL

positive leukemia, " said s Hochhaus, M.D., University of

Heidelberg,

Mannheim, Germany. " This is very encouraging news for patients and

should be

viewed as a step forward in the treatment of CML. "

AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has

Significant

Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or

Philadelphia

Chromosome-Positive Acute Lymphoid Leukemia (Ph + ALL) [Abstract 37]

AMN107 is an investigational oral compound which inhibits the

activity of

specific proteins, including BCR-ABL and 32 of 33 mutant forms of

protein

responsible for the development of CML. It is 10- to 50-fold more

potent than

imatinib against BCR-ABL-expressing cell lines, including most imatinib-

resistant BCR-ABL mutants.

In research led by The University of Texas M.D. Cancer

Center in

Houston and the University of furt, Germany, 119 patients with

imatinib-

resistant CML in blast crisis (BC), AP, CP, or Ph+ ALL were treated with

AMN107. Initial daily doses ranged from 50 mg QD to 1,200 mg QD, and

400 mg

BID to 600 mg BID. Dose escalations occurred in 48 of the 69 patients

in the

once daily groups, and one patient in the 400 mg BID group escalated to

600 mg

BID.

As of June 15, 2005, patients had been treated for a median of 120

days.

AMN107 was well-tolerated, and the most common drug-related adverse

events

were constipation, nausea, and vomiting. Among CML patients who

harbored a

BCR-ABL mutation prior to treatment, 60 percent achieved a hematologic

response and 41 percent achieved a cytogenetic response. In addition,

72

percent of CML patients who had no BCR-ABL mutation prior to taking

AMN107

achieved a hematologic response, and 59 percent achieved a cytogenetic

response. Ph+ ALL patients who harbored a mutation prior to treatment

with

AMN107 saw a 33 percent response rate.

" AMN107 was shown to have significant activity in patients with

advanced

imatinib-resistant CML and Philadelphia chromosome positive acute

lymphoblastic leukemia, " said Hagop M. Kantarjian, M.D., The University

of

Texas M. D. Cancer Center, Houston, Texas. " Current therapies,

though effective, still have many limitations, and new treatment options

with

proven safety and efficacy can only benefit this patient population. "

The American Society of Hematology (http://www.hematology.org) is

the world's

largest professional society concerned with the causes and treatment of

blood

disorders. Its mission is to further the understanding, diagnosis,

treatment,

and prevention of disorders affecting blood, bone marrow, and the

immunologic,

hemostatic, and vascular systems, by promoting research, clinical care,

education, training, and advocacy in hematology.

SOURCE The American Society of Hematology

Web Site: http://www.hematology.org