ASH 2010 Report: A new era in first line CML treatment coming up?

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ASH 2010Like every year, about 30.000 physicians, researchers and industry representatives from all across the world met in the US to discuss groundbreaking news in leukemias and other hematologic diseases. While "the ASH" is designed to be a meeting exclusively for health professionals, about 30 patient advocates representing patients with e.g. CML, myeloma and lymphoma attended to follow, discuss and disseminate the news.

Being CML patients and advocate ourselves, Giora and I focused on those issues that were presented on CML, even though I felt a bit sad missing out groundbreaking news in the treatment of other leukemias. Luckily, free wireless Internet was offered in all major areas of the Orlando Convention Center, so I was at least able to monitor trough the #ASH2010 Twitter feed what was going on in other parallel sessions. This year at ASH I realized for the first time how social media is currently transforming the mechanics of how news are distributed. No matter if social media is mainly hype or hope – it has become a very useful and productive tool for my own advocacy work.

No IRIS data – and the Race of Nilotinib and Dasatinib for First Line

2010 is the first year since imatinib was approved in which no update of the IRIS trial (that led to the approval of Glivec in 2002 and that was updated annually) was presented. To me, this came out of a surprise. In the past years, the patient community has always been waiting anxiously for the newest IRIS results, fearing that the long-term follow-up might suddenly reveal an unexpected rise in relapse rates or secondary cancers in long-term responders, or any other unexpected long-term effects. In that respect, the IRIS data has always given reassurance that things continue to go well. However I acknowledge that from a researcher's perspective, presenting no news at ASH is not really attractive. IRIS has now disappeared from the ASH's agenda. In a sense, if there's nothing to report as most of those on IRIS are still doing well, it's good for us too.

A dominating CML topic at ASH was the application of 2nd generation drugs nilotinib and dasatinib in newly diagnosed patients ("First line treatment"). Both drugs have been approved recently by the FDA and the EU for first line treatment of newly diagnosed CML. While they have been in use after imatinib failure or intolerance for a number of years, a number of studies have now assessed their used in first line treatment. The objective was to find out, in comparison to imatinib, whether those more potent drugs would not only create faster and deeper responses, but also benefits in long-term survival and no increase in major side effects. Both Novartis and BMS initiated phase-III studies comparing their respective drugs with imatinib. At ASH, the 18 month data of dasatinib (DASISION trial, ASH-Abstract 206) and 24 month data of nilotinib (ENESTnd trial, ASH-Abstract 207) were presented.

Even though both studies cannot be compared head to head, response rates are very similar – and both drugs work much better against CML than imatinib. Both drugs seem to be highly effective and safe in newly diagnosed CML. They both create considerably faster and deeper responses (about two thirds with a major molecular response on the 2nd generation drugs, in comparison to about one third of imatinib patients, in the study period). Suboptimal responses and therapy failures are rarer, and rates of progression are significantly lower than on imatinib. Both drugs have pros and cons in terms of their side effect profile. There are some concerns about the pleural effusions that dasatinib creates in a small number of patients, and its additional SRC inhibition adds some uncertainty. There have been more CML-related deaths in the dasatinib than the imatinib arm. On nilotinib, the observation of increased lipase, liver enzymes and glucose levels creates uncertainty about long-term toxicity, and the twice daily administration with fasting periods raises some questions about its impact on quality of life and compliance of patients.

Some earlier worries about the cardiac safety profile e.g. of nilotinib did not persist. A sub study of the ENESTnd trial investigated a potential cumulative effect of nilotinib exposure on cardiac safety. The study revealed that nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in patients with newly diagnosed CML in chronic phase (ASH-Abstract 2291).

Based on the first line data presented at ASH, both nilotinib and dasatinib were recommended by the study groups for application as first line treatment in CML, both being clearly superior to imatinib. From a patients 'perspective, this gives hope, meaning that soon patients may choose between three highly effective options – if the treatment is reimbursement by the local healthcare system. There is even hope that the greater depth of remission might create cure in a number of patients – fuelled by the results of the French STIM study revealing that it might be safe for about 5% of CML patients, about half of those achieving a complete molecular response, to stop imatinib without demonstrating a relapse.

As of today, no one can say whether the "proven" imatinib or the two newcomers dasatinib and nilotinib are the best choice for newly diagnosed patients today – and when speaking to a number of experts at ASH, there seems to be a wide dissent about this. The lower risk of progression still needs to be weighed against the increased risk of pleural effusions (dasatinib) or potential toxicity of the liver and pancreas as well as quality of life aspects due to fasting periods (nilotinib). On the other hand, experience in other cancers suggests that the strongest weapons against the disease should be used first to prevent potential progression – an argument supported also by some leading CML experts.

The need for a quick reduction of tumor load after diagnosis of CML might be supported by an analysis run on 949 patients randomized to the imatinib arm of the German CML IV study: the lack of early molecular response on first line imatinib within the first three months predicted an increased risk of treatment failure and disease progression. Missing the 10% BCR-ABL landmark after three months of imatinib treatment defined a poor risk group with a 21% risk of treatment failure and a 8% risk of disease progression after 18 months. The researchers concluded that early assessment of molecular response after 3 months of imatinib therapy may allow the identification of a patient cohort with an increased risk – that might require other treatment (ASH-Abstract 360). Also, an analysis of the molecular response by 12 months was predictive: Independent of treatment approach, the groups of patients achieving a BCR-ABL ratio below 1% within that timeframe showed significantly higher progression free survival at 3 years compared to the group with >1% (ASH-Abstract 669).

With bosutinib, phase-III data of a third interesting inhibitor for BCR-ABL was presented at ASH. At a first glance, the trial data seemed to be rather disappointing due to its side effect profile, as the drug caused gastrointestinal irritation (mainly diarrhea, nausea and vomiting) in a significant proportion of patients. However, the trial doctors reported that these side effects disappeared in most patients within 3-4 weeks after start of therapy. Given that bosutinib is much more focused on BCR-ABL and does not inhibit other off-target kinases like PDGFR as strongly as the other three approved drugs, it might become an interesting candidate in the long run. Pfizer is said to be committed to take bosutinib to marketing approval for first line treatment of CML in Europe in 2011 or 2012. In summary, when talking to CML experts, expectations on the future and utility of bosutinib varied largely (ASH-Abstract 208).

Failure of first line therapies with nilotinib or dasatinib is uncommon, and most patients respond to other TKIs

Although fewer patients are expected to experience failure to therapy with the use of these 2nd generation drugs, management and outcome of patients who fail therapy on those in first line treatment is still unclear. The response of patients to other TKIs after failing dasatinib or nilotinib as front line has now been analyzed by a team at the MD Anderson Cancer Center in the US. In conclusion, failure after frontline therapy with nilotinib and dasatinib is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. The researchers conclude that this assessment should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy (ASH-Abstract 3442).

Ponatinib (AP24534) provides hope for those with T315I mutation

The presentation of ponatinib (formerly AP24534) has been a highlight of ASH2010. While imatinib, dasatinib and nilotinib work well for about 95% of patients, some develop mutations like T315I or F317L which are resistant against any of these drugs. At ASH, encouraging Phase-I data was presented about ponatinib, a BCR-ABL inhibitor which has been specifically designed to overcome these mutations. In the study, 60 patients with CML, 32 in chronic phase, have been enrolled. All patients that had shown T315I demonstrated at least a major cytogenetic response. Also patients with acute leukemias or CML in blast crisis responded to the treatment. A phase II study ("PACE Study") was started in September in the USA, and is expected to extend to 60 centers worldwide, including Europe and Asia. First non-US centers are expected to enroll in January. When speaking to experts at the ASH meeting, some experts seemed to be quite impressed by the phase I experience and expressed thoughts it could play a larger role in CML therapy way beyond these mutations in the future (ASH-Abstract 210).

Poor Adherence Is the Main Reason for Loss of Remission and for imatinib Failure

A number of earlier studies revealed that adherence to imatinib therapy is the single most important factor determining the degree of molecular response achieved by CML patients. A new study presented at ASH has now revealed that poor adherence to imatinib is also the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long term therapy.

The study measured the adherence to imatinib in 87 chronic phase CML patients using microelectronic monitoring devices, and patients were followed subsequently for a median of 15 months. In multivariate analysis the adherence rate was the only independent predictor for loss of cytogenetic response and discontinuation of imatinib therapy. When the researchers categorized the adherence rate as less or greater than 90% adherence, they found that at 18 months, the 23 patients with an adherence rate of less than 90% had a higher probability of losing the CCyR (26.8% vs 1.5%) and a lower probability of remaining on imatinib (64.5% vs 90.6%) than the 64 patients with an adherence rate >90% (ASH-Abstract 3414).

Interferon is able to cure CML in small subset of patients despite persistence of leukemic stem cells

Before the imatinib era and besides allogeneic hematopoietic stem cell transplantation, interferon alpha (IFN) was an alternative therapeutic option to treat CML.  In very rare situations, some patients achieved a complete molecular remission. At ASH, French researchers update the outcome of patients with CML in complete cytogenetic remission after discontinuation of IFN more than 8 years ago, and assessed whether the presence of residual leukemic stem cells increased the risk of relapse. The researchers conclude that the persistence of leukemic cells at low level after discontinuation of Interferon treatment does not automatically lead to CML relapse. This long term follow up after IFN discontinuation might raise the question of the need of a complete eradication of residual leukemic cells to cure the disease. (Abstract 2299)

Distinct Impact of imatinib on Growth In Children with CML, and use of dasatinib in children after imatinib failure

Imatinib is now widely used for treating chronic-phase CML in children as well as in adults, and long-term adverse effects of TKI therapy in children with CML are now gaining attention. One of the adverse effects on imatinib is the observation of a negative impact on growth in children. A Japanese study aimed to elucidate the incidence or prospect of growth impairment resulting from imatinib treatment in 48 children. Growth impairment was noticeable in children who were prepubertal at the commencement of imatinib treatment, while only mild or no growth impairment was observed in most patients who were pubertal at the commencement of imatinib treatment. The authors consider that it is important to promote awareness of growth deceleration in children, especially in young children who started imatinib treatment before puberty and are inevitably going to be subject to prolonged exposure (ASH-Abstract 2277).

Relapsed or refractory CML in children portends a poor prognosis. To investigate the use of dasatinib in pediatric use after the failure of imatinib, the CA180018 trial aims at improving outcomes in pediatric leukemias. This phase 1 trial is being conducted via the ITCC consortium in 15 centers in 7 countries. With the data presented at ASH, researchers demonstrated the safety and efficacy of dasatinib in pediatric patients with Ph+ leukemias. It supports the feasibility of evaluating new agents in children with rare malignancies through cooperative group efforts. A phase 2 study is currently underway to further evaluate dasatinib in children/adolescents with Ph+ leukemias, including newly diagnosed CML (ASH-Abstract 2265)

iCMLf and The Max Foundation launch "Virtual Education Program" for physicians treating CML patients in emerging countries

On 4 December 2010 the International Chronic Myeloid Leukemia Foundation (iCMLf) in partnership with The Max Foundation launched the iCMLf Virtual Education Program for clinicians from emerging regions. In this innovative format, leading hematologists provide e-learning tutorials about best practices for the management of patients with Chronic Myeloid Leukemia (CML), taking into consideration the specific challenges in these regions. The Virtual Education Program was presented at a networking meeting for clinicians from emerging regions held by the iCMLf during the ASH conference. It was well attended by more than 150 attendants, mostly hematologists from South America, Asia and Africa, and raised lively discussions about the specific challenges in these regions.

Jan Geissler, Giora Sharf,
CML Advocates Network, 15 Dec 2010

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