New data show that at 24 months, patients in the chronic phase of Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML) who are intolerant or resistant to current first-line therapy (Glivec) experienced a rapid response and significant reduction in leukaemia burden when treated with 400mg Tasigna twice-daily1. Furthermore, the research shows that the majority of patients in both the chronic and accelerated phases of the disease are still alive at 2 years when treated with Tasigna1,2.

The results, presented at the 14th Congress of the European Haematology Association (EHA) in Berlin, Germany are based on a phase II single treatment study of 321 chronic phase, adult patients with Ph+ CML and 137 accelerated phase patients with Ph+ CML who were intolerant or resistant to the current gold-standard treatment Glivec1,2. The results substantiate data presented at the American Society of Haematology meeting in San Francisco last year.

The data show that response times were rapid with 94% of all patients reaching complete haematologic response (CHR) (meaning blood counts returned to normal) at a median of one month following initiation of therapy1. In patients that had not previously reached haematological response, 75% reached haematological response1. Complete cytogenic response (CCyR), meaning no Ph chromosomes could be detected in the bone marrow was reached by 44% of patients at a median of 3.3 months following initiation of therapy1.

Tasigna was specifically designed to inhibit Bcr-Abl (the protein responsible for the uncontrolled production of white blood cells that occurs in Ph+ CML patients) and mutations of Bcr-Abl more effectively than Glivec4. In preclinical studies, Tasigna was able to overcome resistance resulting from Bcr-Abl kinase mutations in 32 of 33 cell lines commonly associated with Ph+ CML and associated with Glivec intolerance4.

The data suggest that Tasigna can provide favourable long-term outcomes for these heavily pre-treated patient populations1. In this study Tasigna was generally well tolerated with most adverse events being mild and moderate1. No new safety issues emerged with 24 months follow up1. The most common adverse events were rash, headache and diarrhoea (experienced by 2% of patients)1. The most common haematological grade 3/4 abnormalities were neutropenia (31%), thrombocytopenia (31%) and anaemia (10%). However, brief dose interruptions were successful in managing most adverse events1.

Further data presented at EHA showed that 67% of Glivec resistant or intolerant patients with Ph+ CML in the accelerated phase of the disease were alive at 24 months with 20% of patients reaching CCyR and 70% of these patients maintained CCyR at 24 months2. Again, Tasigna was seen to be well tolerated with most side effects being mild to moderate. The most common non haematological grade 3/4 adverse events were rash and pruritus. The most frequent grade 3/4 haematological abnormalities were neutropenia (42%), thrombocytopenia (43%) and anaemia (27%)2.

A further study investigating the therapeutic efficacy and safety of Tasigna as a first-line therapy for newly diagnosed patients with Ph+ CML was also presented at EHA. The open-label, single-stage, multicenter phase II study involved 73 patients with newly diagnosed Ph+ CML3. The results of this study suggest that newly diagnosed patients with Ph+ CML in the chronic phase treated with Tasigna experienced faster and deeper responses than those taking Glivec3,5, when the results were compared with historical Glivec data. After 12 months of treatment, 96% of newly diagnosed patients treated with Tasigna had achieved CCyR3. Major molecular response (MMR) is achieved when no traces of Bcr-Abl (the protein that causes the proliferation of the cancerous cells that cause CML) is detected by laboratory tests. MMR is emerging as an important measure of treatment efficacy and may be the best predictor of long-term survival6,7. In this Tasigna study, 81% of all patients had achieved MMR at 12 months3. Historical data for Glivec show 70% of patients with the same attributes, being treated with 800mg imatinib a day reached CCyR at 12 months and 46% had achieved MMR over the same duration of time5. In this study, Tasigna was generally well tolerated with most adverse events being mild to moderate3.

CML is one of the most common leukaemias affecting 2,660 people in England and Wales8. Most people with CML can be treated in the long term with Glivec (imatinib) but a small amount of people cannot take Glivec because they experience side effects or because their cancer mutates and becomes resistant to Glivec9.

Sandy Craine, CML Support UK welcomes the new data: “The 24 month data further consolidates the potential of Tasigna to provide a real alternative not only for the small number of patients who do not respond or who experience side effects to Glivec, but also for those in later stages of CML. It is clear from these data that Tasigna offers a realistic opportunity to stabilise the disease, overcome the threat of progression and achieve long-term survival, which is the goal of everyone diagnosed with life-threatening conditions like CML.”

In the UK and in more than 65 countries worldwide, Tasigna is indicated for the treatment of adults with chronic phase and accelerated phase Ph+ positive chronic myeloid leukaemia with resistance or intolerance to prior therapy including imatinib.

About Tasigna (nilotinib)

Taken orally, twice daily, Tasigna works by targeting the production of the Bcr-Abl protein, which is produced only by cells containing the Philadelphia chromosome4. This protein is recognised as the key driver of the overproduction of cancer cells in patients with Ph+ CML.

Applying experience gained from the development of Glivec, a team of Novartis scientists created Tasigna in August 2002, just a year after the launch of Glivec. In preclinical studies, the medicine was able to overcome resistance resulting from Bcr-Abl kinase mutations in 32 of 33 cell lines commonly associated with Ph+ CML4. Tasigna was specifically designed to target the Bcr-Abl protein more preferentially than Glivec, without adding new mechanisms of action.

About Glivec

Glivec is approved in more than 90 countries including the US, EU and Japan for the treatment of all phases of Ph+ CML. Glivec is also approved in the EU, US and other countries for the treatment of patients with Kit (CD117)-positive gastrointestinal tumours (GIST), which cannot be surgically removed and/or have already spread to other parts of the body (metastasised). In Japan, Glivec is approved for the treatment of patients with Kit (CD117)-positive GIST. In the EU, Glivec is also approved for the treatment of adult patients with newly diagnosed Ph+ acute lymphoblastic leukaemia (Ph+ ALL) in combination with chemotherapy and as a single agent for patients with relapsed or refractory Ph+ ALL. Glivec is also approved for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) who are not eligible for surgery. Glivec is also approved for the treatment of patients with myelodysplastic/myeloproliferative diseases (MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chronic eosinophilic leukaemia (HES/CEL).

References

1. Kantarjian, H. Et al. Nilotinib in chronic myeloid leukaemia patients in chronic phase (CML-CP) with imatinib resistance or intolerance: 24 month follow up of a phase 2 study. European Society of Hematology (EHA). May 2009. Abstract 0627.

2. Hochhaus, A. Et al. Nilotinib in chronic myeloid leukaemia in accelerated phase (CML-AP) with imatinib resistance or intolerance: 24-month follow-up results of a phase 2 study. European Society of Hematology (EHA). May 2009. Abstract 0631.

3. Rosti, G. Nilotinib 800 mg daily in early chronic phase Chronic Myeloid Leukemia: 12-month results of a phase 2 trial of the GIMEMA CML working party. European Society of Hematology (EHA). May 2009. Abstract 1090. Oral presentation.

4. Tasigna (nilotinib) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharma. Accessed May 2009

5. Cortes J, et al. A Phase III, Randomized, Open-Label Study of 400 Mg Versus 800 Mg of Imatinib Mesylate (IM) in Patients (pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints: 1-Year Results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study. Abstract 335. American Society of Hematology, 2009.

6. Iacobucci I., Saglio, G., Rosti, G., et al. Achieving a Major Molecular Response at the Time of a Complete Cytogenetic Response (CCgR) Predicts a Better Duration of CCgR in Imatinib-Treated Chronic Myeloid Leukemia Patients Clin Cancer Res 2006;12 (10) May 15, 2006.

7. Ross, D., et. al. Limited clinical value of regular bone marrow cytogenic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL. .

8. NICE Guidance on the use of imatinib for chronic myeloid leukaemia - Technology Appraisal 70. October 2003.

9. O’Brien S, et al. International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib (IM). American Society of Hematology, 2009.

Source
European Haematology Association

View drug information on Tasigna.

Ultra-fast freezing of ovarian tissue from women who have lost their fertility as a result of cancer treatment can lead to it being used in transplants with the same success rate as fresh tissue, a researcher told the 25th annual conference of the European Society of Human Reproduction and Embryology 29 June. Dr. Sherman Silber, Director of the St. Louis Infertility Centre, St. Louis, Missouri, USA, said that freezing tissue by the vitrification method, which avoids ice formation, meant that oocyte (egg) viability was almost identical with that seen in fresh oocytes.

Dr. Silber and colleagues used standard viability testing with fluorescent microscopy to determine the loss or preservation of oocytes in fresh and frozen ovarian tissue of 15 young women undergoing cancer treatment. They also followed up nine homozygotic twin patients after fresh ovary transplantation for the duration of ovarian function and pregnancy outcome, and tested spare tissue that had also been frozen from their ovaries at the time of transplant. Tissue was preserved either by rapid cooling vitrification or by classical slow freezing methods.

“We found that 91.9% of the fresh oocytes were viable compared with 88.9% of those vitrified. However, slow freezing resulted in a 56% loss of viability”, said Dr. Silber.

Transplantation of the tissue resulted in a duration of ovarian function of more than four years in five of the seven cases followed up for that long, and all patients regained a normal ovarian cycle within four to five months after the transplant. There was no difference in terms of pregnancy or ovulatory menstrual cycling between fresh and frozen grafts. The scientists used the cortical grafting technique, where very thin slices of tissue are transplanted. This technique is much easier to perform than the delicate microvascular technique, which they described last year in an effort to prevent egg loss and to lengthen the duration of ovarian graft function.

With the microvascular technique, the tiny blood vessels supplying the ovary are directly linked, and ischemia time, during which blood supply is restricted, is minimised. However, this is a very difficult operation not available in most reproductive centres. With the cortical grafting technique, ischemia time for revascularisation was always thought to be a limiting factor, not to mention the deleterious effect of freezing. However, very thin cortical slices not only allow the tissue to be frozen by vitrification, but also accelerate the speed of revascularisation of the ovarian graft.

“We believed that microvascular transplant would give us a longer duration of ovarian function,” said Dr. Silber, “but our current research has proved us wrong. This is not only good news for surgeons, but also for patients who will be able to undergo a simpler procedure with equally successful results.”

Out of the eight women who received cortical transplants, six have had one or more spontaneous pregnancies, resulting in the birth of seven healthy babies.

“We are in the middle of a massive global infertility epidemic, caused by the new structure of our society where women choose not to have children until they are older,” said Dr. Silber. “As a result, many of them become infertile because of the ageing of their eggs and ovaries.

“This procedure is a solution to that social dilemma, allowing women to have children when they are older by preserving their ovaries when they are younger and transplanting them back at a later date. It can also be used to preserve the fertility of young women with cancer who are likely to be cured of their cancer, but who will become sterile as a result of the cancer treatment without such intervention,” he said.

Source:
MaryRice

European Society for Human Reproduction and Embryology

PRINCETON, July 1 — Using combined computed tomography and positron-emission tomography scans (PET-CT) to stage the treatment of patients with non-small cell lung cancer significantly reduced the number of unnecessary lung surgeries, a new study found.

• When staging treatment for non-small cell lung cancer patients, consider that research suggests that combined PET-CT scans help reduce the likelihood of futile thoracotomy and the total number of thoracotomies.
• Note that for every five PET-CT scans administered, one unnecessary thoracotomy was avoided in this study.

Patients who received combined PET-CT scans underwent fewer futile thoracotomies (21%) compared with patients who underwent conventional staging (42%), according to the study published in the July 1 issue of the New England Journal of Medicine.

This equated to one less unnecessary surgery for every five PET-CT scans.

“We found that adding a PET-CT examination to the diagnostic regimen for patients with NSCLC improves sensitivity in the preoperative staging,” wrote Barbara Fischer, PhD, of Odense University Hospital in Denmark, and colleagues.

“The addition of PET-CT examination reduces the frequency of futile thoracotomies and the total number of thoracotomies, with no effect (negative or positive) on overall survival.”

The researchers recruited patients for the study from three Danish hospitals. The participants were between the ages of 18 and 80 and had newly diagnosed or highly suspected NSCLC that was considered operable after conventional staging procedures such as blood tests, bronchoscopy, and contrast-enhanced CT scans of the chest and upper abdomen.

After conventional staging, patients were randomly assigned to receive either PET-CT followed by further invasive diagnostic procedures, or to undergo invasive diagnostic procedures but no PET-CT scans.

The invasive diagnostic procedures included mediastinoscopy, which all patients received, and endoscopic or endobronchial ultrasonography (for the PET-CT group).

A radiologist and a nuclear medicine specialist evaluated the PET-CT images side by side and reached a consensus on whether tumors were malignant and, if so, the stage of metastasis.

Afterwards, a pulmonologist and a thoracic surgeon came to an agreement on the tumor-node-metastasis stage before deciding whether to operate, based on all of the available information.

All patients with stage I to stage IIB NSCLC were offered surgery. Those with involvement of mediastinal lymph nodes or distant metastases were considered to have inoperable cancer and were offered chemotherapy with or without radiotherapy.

From January 2002 through February 2007, a total of 189 patients were enrolled and randomly assigned to either the PET-CT group or the conventional staging group.

For various reasons, 12 of the 98 patients assigned to the PET-CT group did not undergo the scans or did not continue with the study.

Of the patients who underwent PET-CT, 38 were classified as having inoperable NSCLC and 60 underwent thoracotomy. In the group that received conventional staging, 18 were classified as having inoperable cancer and 73 underwent thoracotomy.

A surgery was defined as futile if it revealed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion, if the cancer returned within a year, or if the patient died.

The thoracotomies proved futile in 21 patients in the PET-CT group and 38 patients in the conventionally staged group (P=0.05), the study found. There was no difference in the number of justified thoracotomies or in survival between the groups.

“The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies, but did not affect overall mortality,” the authors wrote.

The authors pointed out that the effect of nodal disease detectable only by pathologic examination of the surgical specimen on the prognosis could be disputed.

They said it “could be argued that these thoracotomies were not futile. Classifying the thoracotomies in these patients as justified, however, resulted in a frequency of futile thoracotomies of 27% in the PET-CT group and 44% in the conventional-staging group, which was still a significant difference (P=0.04).”

The study was funded by the Danish Cancer Society and the Danish Center for Health and Technology Assessment. The John and Birthe Meyer Foundation donated the PET-CT scanner. Co-investigator Torben Rasmussen reported receiving lecture fees from AstraZeneca.

Primary source: The New England Journal of Medicine

Source reference:

Fischer B, et al “Preoperative staging of lung cancer with combined PET-CT” N Engl J Med 2009; 361: 32-9.