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Old 03-30-2011, 02:50 PM
gdpawel gdpawel is offline
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Default Arsenic Trioxide Consolidation Treatment Diagnosed Acute Promyelocytic Leukemia

According to Research To Practice, a European study evaluating arsenic trioxide (ATO) as consolidation after induction with chemotherapy/all-trans retioic acid (ATRA) did not have enough events at this point to define long-term outcome.

Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 505
2010 American Society of Hematology

Oral Session

Acute Myeloid Leukemia - Therapy, Excluding Transplantation

Arsenic Trioxide (ATO) In the Consolidation Treatment of Newly Diagnosed APL - First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian Swiss APL Group

Lionel Ades1, Emmanuel Raffoux, MD*,2, Sylvie Chevret*,3, Arnaud Pigneux, MD, PhD*,4, Xavier Thomas*,5, Dominique Bordessoule6, Norbert Vey*,7, Agnès Guerci*,8, Thierry Lamy*,9, Christian Récher, MD*,10, Beatrice Muller*,11, Olivier Tournilhac, MD, PhD*,12, Cécile Pautas*,13, Jean-Yves Cahn, MD14, Jacques Delaunay*,15, Eric Deconinck*,16, Bruno Quesnel*,17, Stephane de Botton*,18, Aspasia Stamatoullas*,19, Christine Chomienne, MD, PhD*,20, Herve Dombret, MD, PhD21, Laurent Degos*,22 and Pierre Fenaux, MD, PhD23

1 French-Belgian-Swiss APL group, Bobigny, France,
2 Hematology, Hôpital Saint-Louis, Paris, France,
3 Dbim, hopital saint Louis, Paris, France,
4 Hopital du Haut-Lévèque, Pessac, France,
5 Department of Hematology, Hôpital Edouard Herriot, Lyon, France,
6 CHU Limoges, Limoges, France,
7 Institut Paoli Calmettes, Marseille, France,
8 CHU Nancy, Nancy, France,
9 CHU Rennes, Rennes, France,
10 Service d'Hématologie clinique, CHU Purpan, Toulouse, France,
11 University Hospital Berne, Bern, Switzerland,
12 Service d'hématologie adultes et thérapie cellulaire, CHU Clermont-Ferrand, Clermont Ferrand, France,
13 Service d'Hématologie, Hôpital Henri Mondor, Créteil, France,
14 Onco-Hematologie, CHU-Grenoble, Grenoble, Cedex O9, France,
15 Hematology Department, CHU de Nantes, Nantes, France,
16 CHU Besancon, Besancon, France,
17 CHU Huriez, Lille, France,
18 Institut Gustave Roussy, Villejuif, France,
19 Centre Becquerel, Rouen, AK, France,
20 Institut Universitaire d'Hématologie, INSERM UMR-S 940, Paris, France,
21 Hematology department, Saint-Louis Hospital, AP-HP, Paris 7 University, Paris, France,
22 Hôpital Saint Louis, Paris, France,
23 Service d'hématologie clinique, Hopital Avicenne Universite Paris XIII, Bobigny, France

Background:

ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL, but this treatment is myelosuppressive and may be associated with long term cardiac toxicity. The use of ATO may allow reduction of the amount of CT (and in particular avoid ara C), and further diminish the relapse risk, especially when used in consolidation treatment (US intergroup study, Powell, ASCO 2008). In a randomized trial, we used ATO for consolidation treatment instead of ara C in standard risk APL (baseline WBC < 10G/L), and in addition to AraC in high risk patients (baseline WBC > 10G/L). ATRA, suggested to reduce the relapse risk when used during consolidation (Sanz, Blood 2008, 112: 3130-4) was also tested in standard risk pts.

Methods:

In APL 2006 trial (started in Nov, 2006) newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L were randomized between: group A1( standard group) (induction: ATRA 45mg/m2/d until CR with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 12 mg/m2/dx3 and AraC 1g/m2/12h x4d; maintenance during two years: intermittent ATRA 15d/3 months and continuous 6 MP + MTX,); Group A2: same treatment as group A1, but AraC replaced by ATO 0.15 mg/Kg/D D1 to 25 days of both consolidation courses; Group A3: same treatment as group A1, but AraC replaced by ATRA 45 mg/m2 d1 to 15 of both consolidation courses. Pts aged < 70 with WBC > 10G/L (Group C) were randomized between: group C1 (standard group): same treatment as Group A1; group C2: same as C1, but with addition of ATO 0.15 mg/Kg/d d1 to 25 of both consolidation courses, at d1. Pts with WBC > 10 G/L all received intrathecal CT for CNS prophylaxis. This first interim analysis was made at the reference date of 1 Jan 2010, in 186 pts aged < 70 years included in 78 centers before 2009 (141 pts in group A (45/45/51 pts in A1/A2/A3 arms), 45 pts in group C (24/21 pts in C1/21 arms)).

Results:

In standard risk patients (group A) 140 (99.3 %) patients achieved CR, and 1 (2%) had early death. After a median follow up of 22.1 months, 1, 0, and 1 pts had relapsed in the A1, A2 and A3 consolidation groups, resp. (18 months cumulative incidence of relapse- CIR-of 0%, 0% and 2%). 2, 2, and 0 pts had died in CR in the A1, A2 and A3 consolidation groups, resp. The median duration of neutropenia and thrombocytopenia during consolidation courses was 43.5 and 44 days, 40 and 35 days, 20 and 25 days after consolidation cycles in groups A1 (AraC), A2 (ATO) and A3 (ATRA), resp (p<0.01). The median overall duration of hospitalization was 51, 59 and 26 days in A1,A2 and A3 groups, respectively. In high risk pts (group C) 45 (100 %) patients achieved CR. After a median follow up of 23.7 months, 1 and 1 pt had relapsed in the C1 and C2 consolidation groups, resp (18 months CIR of 2% and 2%). One and 3 had died in CR in the C1 and C2 consolidation groups, resp. Median duration of neutropenia and thrombocytopenia was 45.5 and 43.5 days, 51.5 and 48 days, after consolidation cycles in groups C1(AraC) and C2 (AraC+ATO), resp. The median overall duration of hospitalization was 53.5, and 65 days in C1 and C2 groups, respectively.

Conclusion:

Results of this first interim analysis show that very high CR rates (>95%) can be observed in very multicenter trials in APL, by combining ATRA and anthracycline based CT, while the relapse rate with consolidation and maintenance was very low in all treatments arms, including in pts with WBC > 10G/L. Nevertheless ATO, when combined to high dose CT during consolidation cycles, increased myelosuppression. An amendment further reducing CT in pts receiving ATO is thus being implemented in the trial.

Disclosures: Off Label Use: ATO as 1st line treatment in APL. Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
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Old 03-30-2011, 03:01 PM
gdpawel gdpawel is offline
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Default Phase II Study ATRA, ATO, with or without GO patients with APL (PML)

However, researchers at MD Anderson believe this question may now be outdated in view of their just-presented ASH paper demonstrating a 98 percent complete response rate with a nonchemo regimen (ATRA/ATO) with higher-risk patents (WBC > 10 x 109/L) also receiving Mylotarg (gemtuzumab). Dr Garcia-Manero believes that one dose of idarubicin can be administered instead of the now-unavailable gemtuzumab, but most other investigators seem to want more data before making this major conceptual leap essentially abandoning chemo as induction.

Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 1080
2010 American Society of Hematology

Poster Session

Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster I

Phase II Study of All-Trans Retinoic Acid (ATRA), Arsenic Trioxide (ATO), with or without Gemtuzumab OzogamIcin (GO) for the Frontline Therapy of Patients with Acute Promyelocytic Leukemia (APL).

Farhad Ravandi, MD1, Elihu H. Estey, MD2, Jorge E. Cortes, MD3, Susan O'Brien, MD*,4, Sherry A. Pierce, RN, BS*,5, Mark Brandt, BS*,5, Alessandra Ferrajoli, MD6, Gautam Borthakur, MD7, Marina Konopleva, MD, PhD*,8, Srdan Verstovsek, MD, PhD8, Guillermo Garcia-Manero, MD9, Stefan Faderl, MD10 and Hagop Kantarjian, MD3

1 Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA,
2 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,
3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,
4 M. D. Anderson Cancer Center,
5 Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA,
6 Leukemia, UT MD Anderson Cancer Center, Houston, TX, USA,
7 Leukemia, MD Anderson Cancer Center, Houston, TX, USA,
8 Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,
9 MD Anderson Cancer Center, Houston, TX, USA,
10 Department of Leukemia, Unit 428, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA

Background:

The role of arsenic trioxide (ATO) in the frontline treatment of patients with acute promyelocytic leukemia (APL) remains unclear with a number of studies reporting high and durable responses with single agent ATO. We have conducted a trial combining all-trans-retinoic acid (ATRA) with ATO with or without gemtuzumab ozogamicin (GO) in patients with previously untreated APL.

Patients and methods:

From July 2002 to June 2010, 104 patients with newly diagnosed APL were treated with a combination of ATRA plus ATO in two studies. The first cohort of 47 patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily beginning on day 10 of ATRA). High-risk patients (White blood cell count [WBC] > 10 x 109/L) received GO 9 mg/m2 on the first day of induction. From July 2007, the second cohort of 57 patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) concomitantly on day one of induction. They also received GO 9 mg/m2 on day 1, if high risk, and any time during induction if the WBC rose to > 30 x 109/L (and more recently if > 10 x 109/L). Monitoring for PML-RARA fusion gene using reverse transcriptase-polymerase chain reaction (RT-PCR) was conducted after induction and throughout consolidation and follow up. The median age for the 104 patients was 46 years (range, 14–81). Their median presenting WBC was 2.7 x 109/L (0.4-131.4 x 109/L) and their median platelet count was 36 x 109/L (range, 7–261 x 109/L). Seventy three (70%) had low risk and 31 (30%) high risk disease (based only on the presentation WBC or > 10.0 x 109/L).

Results:

Overall, 102 patients (98%) achieved complete remission (CR) and 2 died during induction. With a median follow-up of 115 weeks (range, 4 to 397 weeks), 94 patients remain alive. The estimated 5-year survival rate was 88% and event-free survival 86%; only 5 of the patients achieving a CR (5%) have relapsed. The median overall survival, remission duration and event-free survival have not been reached. Thirty six patients have been alive and in remission for more than 3 years and 21 for more than 5 years. Two late deaths (beyond 300 weeks) occurred in CR from unrelated causes.

Conclusion: The combination of ATRA and ATO (with or without GO) as initial therapy for APL is highly effective and safe; it can potentially substitute for chemotherapy containing regimens in high and low risk patients.

Disclosures: Ravandi: Cephalon: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Off-label use of arsenic trioxide in frontline therapy of APL; off label use of gemtuzumab ozogamicin in APL. Verstovsek: Incyte Corporation: Research Funding.
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Old 03-30-2011, 03:06 PM
gdpawel gdpawel is offline
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Default FDA: Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market

Pfizer Inc. announced the voluntary withdrawal from the U.S. market of the drug Mylotarg (gemtuzumab ozogamicin) for patients with acute myeloid leukemia (AML), a bone marrow cancer. The company took the action at the request of the U.S. Food and Drug Administration after results from a recent clinical trial raised new concerns about the product’s safety and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Mylotarg was approved in May 2000 under the FDA’s accelerated approval program. This program allows the agency to approve a drug to treat serious diseases with an unmet medical need based on a surrogate endpoint – a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions, or survives.

Under accelerated approval, the company is required to conduct additional clinical trials after approval to confirm the drug’s benefit. If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug from the market using expedited procedures.

Mylotarg was approved to treat patients ages 60 years and older with recurrent AML who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate (i.e., the percentage of patients whose leukemia decreased or disappeared in laboratory tests), observed in 142 patients with AML across three clinical trials.

A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.

At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal. This rate has increased in the postmarket setting.

“Mylotarg was granted an accelerated approval to allow patient access to what was believed to be a promising new treatment for a devastating form of cancer,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products, part of FDA’s Center for Drug Evaluation and Research. “However, a confirmatory clinical trial and years of postmarketing experience with the product have not shown evidence of clinical benefit in patients with AML.”

As a result of the withdrawal, Mylotarg will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Mylotarg of the product’s potential safety risks.

Following the withdrawal, any future use of Mylotarg in the United States will require submission of an investigational new drug application to FDA.

Source: fda.hhs.gov
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Old 03-30-2011, 03:13 PM
gdpawel gdpawel is offline
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Default The Mylotarg Withdrawal and Accelerated Approval

According to PharmaLive.com's Pharmalot, Ed Silverman said the decision to withdraw Mylotarg is more significant for the FDA than for Pfizer, which garnered about $100 million in worldwide sales from the medicine. That’s because the drug was approved in 2000 as part of the accelerated approval process. As the FDA explained when announcing the withdrawal: “This program allows the agency to approve a drug to treat serious diseases with an unmet medical need based on a surrogate endpoint – a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions, or survives.”

The program was an outgrowth of criticism that the agency wasn’t moving fast enough to approve new drugs, especially during the era when HIV and AIDS appeared on the societal radar screen. Since then, the FDA has found itself in a classic ‘you can’t please everyone’ situation. At the same time that terminally ill patients clamored for elixirs, safety concerns mounted because new meds are released before traditional clinical testing requirements would normally allow. Mylotarg, which was developed by Pfizer’s Wyeth, was approved in 2000 and the FDA letter to the drugmaker notes the various studies that had to be performed.

At the time, the drug was “believed to be a promising new treatment for a devastating form of cancer,” according to Richard Pazdur, who heads the FDA’s Office of Oncology Drug Products. However, the study that yielded the latest info about a lack of clinical benefit and an unexpected number of deaths didn’t get under way until 2004.

Second guessing is an easy occupation. But the episode suggests a need to revisit the program. And perhaps the FDA understands this. “Accelerated approval still has a place in the approval process but it’s also more important that we learn over the years that the whole development plan be set up well in advance,” Robert Kane, acting deputy director for safety in the FDA’s Division of Hematology Products, tells Bloomberg News. “The trials should be planned and if possible under way when the sponsor submits the application.” Indeed, accelerated approval has proven to be a difficult balancing act and requiring drugmakers to move faster to investigate clearly stated concerns would be a good start. If the FDA is expected to accelerate its procedures, so should the drug developer.
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Old 03-06-2012, 05:54 PM
gdpawel gdpawel is offline
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Default Acute Promyelocytic Leukemia from Highly Fatal to Highly Curable

Treatment for acute promyelocytic leukemia has been improved significantly using a therapy that combines arsenic trioxide, a traditional Chinese medicine, with the chemotherapy drug ATRA (all-trans retinoic acid). The two components appear to work through different mechanisms to converge on the same protein that is affected by the cancer. The Chinese researchers who pioneered the treatment, Zhen-Yi Wang and Zhu Chen, were awarded with the Szent-Györgyi Prize for Progress in Cancer Research.

The annual Szent-Györgyi Prize for Progress in Cancer Research was established by the National Foundation for Cancer Research to recognize outstanding scientific achievements in the war against cancer and to honor pioneering scientists who have made extraordinary contributions in cancer research. The focus of the Prize is on the critically important role that basic science plays in cancer research and in its application to cancer therapies.

The National Foundation for Cancer Research (NFCR) is a leading charity dedicated to funding cancer research and public education relating to cancer prevention, earlier diagnosis, better treatments and, ultimately, cures for cancer. NFCR promotes and facilitates collaboration among scientists to accelerate the pace of discovery from bench to bedside.

By combining traditional Chinese medicine with Western medicine, Drs. Wang and Chen have provided dramatic improvement in the five-year disease-free survival rate of APL patients - from approximately 25 percent to 95 percent - making this therapy a standard of care for APL treatment throughout the world, and turning one of the most fatal diseases into a highly curable one.

A clinical researcher at the Ruijin Hospital in Shanghai in the early 1980s, Dr. Zhen-Yi Wang performed the first successful therapy on APL patients using all-trans retinoic acid (ATRA), which significantly increased the survival rate of patients with APL. Dr. Zhu Chen, a former student of Wang, made major contributions to the identification of the molecular mechanisms of both ATRA and arsenic trioxide in APL.

He also demonstrated in clinical trials that arsenic trioxide, a compound used as a traditional Chinese medicine for over 2,400 years, is effective against APL. Since the 1990s, Drs. Wang and Chen have worked together to conduct clinical trials combining ATRA and arsenic trioxide to treat APL patients, with great success. Drs. Wang and Chen have quite literally changed the face of medicine for patients suffering from APL.

[url]http://www.nfcr.org/index.php/asg-prize

[url]http://www.pnas.org/content/106/9/3342.full.pdf+html
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Old 12-06-2012, 01:24 AM
gdpawel gdpawel is offline
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Default The Resurrection of Mylotarg (gemtuzumab ozogamicin)?

Mylotarg (gemtuzumab ozogamicin) is an anti CD33 antibody linked to the highly toxic chemical calicheamicin. Calicheamicin, a member of enendyne class, is among the most toxic substances known to man. By linking this poison to an antibody directed against leukemia cells, it was reasoned that this novel conjugant would provide an effective therapy for leukemia. And indeed it did.

But despite compelling science and what appeared to be initially good results (particularly in older patients with AML), and FDA approval for the agent, the drug was withdrawn from the market. It appeared, with regard to Mylotarg, that the clinical trial process failed to identify the clinical utility of an active and novel form of therapy for a potentially lethal disease.

Now, with the publication of a new study from the United Kingdom, Mylotarg is once again in the limelight as its inclusion in induction therapy resulted in a statistically significant three-year relapse-free survival advantage (p=.0007) and three year overall survival advantage (p=.05).

According to Dr. Robert A. Nagourney of Rational Therapeutics, this report represents the failings of the contemporary clinical trial process. The Mylotarg experience reflects the failure to identify efficacy due to contemporary clinical trial’s dilution of the benefit in select candidates, mixed in the overall population, with limited responsiveness to the agent.

On one hand, laboratory models that accurately identify responders can segregate those most likely to benefit from those who will not. Mylotarg represents just one of many interesting new classes of drugs for whom selective methodologies could prove highly valuable.

Reprise: Gemtuzumab Ozogamicin for Older Patients With Acute Myeloid Leukemia

[url]http://jco.ascopubs.org/content/30/32/3905.full

Gemtuzumab Ozogamicin: Time to Resurrect?

[url]http://jco.ascopubs.org/content/30/32/3921.full

Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy Improves Survival in Older Patients With Acute Myeloid Leukemia

[url]http://jco.ascopubs.org/content/30/32/3924.abstract
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