ASH 2011: Summary of Education Session on CML

edu_room250Traditionally, the first day of the ASH Congress features Education Sessions. These sessions provide hematologists with the overall picture on a specific disease, including its biology, standard of care, current therapeutic challenges, results from recent trials and future outlook. This year, Prof Neil Shah (USA), Andreas Hochhaus (Germany) and Junia Melo (Australia) presented the state of play in CML treatment and care. This is our patient summary of the session.

(Translations: EnglishGerman - Russian - French)

shah0Prof Neil Shah (USA):
"Optimal Front-Line Therapy and Options for Patients Resistant to First-line TKI".

Great success - but not for all patients: Shah started highlighting the 8 year results of the IRIS study, with only 7% of CML patients dying from CML within 8 years when treated with Imatinib as a first-line therapy. Serious side effects were considerably rare and decreased in incidence within the first 2 years. However, he outlined that 37% of patients on trial required alternate CML therapies due to no response, resistance or intolerance, with progression events mostly occuring in the first 3-4 years of therapy. Mechanisms of resistance vary - with BCR-ABL dependent mechanisms like kinase domain mutation, genomic amplification, or mechanisms of drug transport, or BCR-ABL independent mechanisms like epigenetic modification or activation of other pathways in cell division.

edu_shah_survivalirisTherapy milestones: Shah highlighted the ELN treatment recommendations, outlining the milestones in terms of failure and suboptimal response. Failing to achieve optimal response, which is the case for about half of CML patients in chronic phase in the first 18 months, means that the probability to survive 5 years after diagnosis decreases from 96% to 74%. It was highlighted that reducing BCR-ABL below 10% in the first 3 months of therapy is associated with improved outcomes.

Improving responses: The French SPIRIT study had shown improved responses by adding pegylated Interferon, while the German CML-IV study did not demonstrate benefit by adding standard (non-pegylated) Interferon. Looking at second generation drugs (Dasatinib, Nilotinib) in first line treatment, it was clearly demonstrated that progression rates into advanced disease were much lower on Nilotinib and Dasatinib than on Imatinib, while tolerability was comparable.

Do new TKIs perform better than Imatinib? The Billion Dollar question remains unanswered still. While efficacy is clearly superior, side effect issues (like QT prolongation, arterial events on Nilotinib, as well as pulmonary hypertension on Dasatinib), as well as economic issues (with both drugs being significantly more expensive than Imatinib) require further assessment.

The 2nd generation drugs are more expensive. However they show potential cost savings, like less progressions into costly blast phases, less diagnostics required through more rapid complete cytogenetic responses, and higher potential for therapy discontinuation in complete molecular response.

However, whether more rapid responses would translate into better survival, and whether first-line Dasatinib/Nilotinib is superior to early switching on suboptimal response to Imatinib, still needs to be investigated. To clarify these issues, trials will investigate

  • early switching patients with >10% BCR-ABL after 3 months of therapy,
  • initial induction therapy with Nilotinib/Dasatinib and then switchback to Imatinib, and
  • TKI discontinuation in patients with MMR.

In conclusion, the next decade may witness the emergence of new curative strategies, but to get there, the continued participation of patients in clinical trials is highly encouraged.

edu_hochhaus0-250Andreas Hochhaus (Germany):
"Managing CML as a Chronic Disease".

Andreas Hochhaus highlighted the great progress achieved in CML therapy. Thanks to a near-normal life expectancy, 250.000 Europeans will be alive by 2050 that have, or have had, CML. He outlined that the conceptual models of chronic, accelerated and blast phase might be overcome by a linear model of disease evolution of increasing instability. To underline that, Hochhaus presented recent findings on the difference of impact if different types of chromosomal changes on CML survival. He outlined results of the German CML-IV study that had shown a significant prognostic disadvantage if BCR-ABL

Follow up diagnostics: Hochhaus highlighted that bone marrow cytogenetics should only be done until complete cytogenetics have been achieved, and qRT-PCR every 3-6 months thereafter. Mutation analysis should only be done in case of Imatinib therapy failure, or in case of a >5 fold increase in BCR-ABL, but only if major molecular response (0,1%) is lost.

edu_hochhaus_offtargetTKI Adverse Effects: Current TKIs target also other mechanisms outside of BCR-ABL. These off-target effects are the cause of adverse events commonly reported in CML:

  • Cytopenias, caused by BCR-ABL/KIT/SRC inhibition of all TKIs
  • Immune effects, caused by by ABL, SRC inhibition of all TKIs, especially Dasatinib
  • Fluid retention (edema), caused by inhibition of PDGFR and SRC kinases, especially by Imatinib and Dasatinib
  • Cardiac dysfunction and skin changes, caused by by KIT inhibition,
  • Hypophosphatemia and effects on bones, caused by inhibitiof of bone remodeling mechanisms, cortical density and bone growth
  • Glucose levels, with KIT and PDGFR inhibition, with Imatinib lowering and Nilotinib increasing glucose levels, relevant for diabetic patients
  • Diarrhea

Transplant in CML: CML makes up only 3% of transplantations today, demonstrating the success of current therapies. However, Hochhaus outlined that transplantations in high risk CML patients were generally done too late today. He raised that in lower income countries, transplant costs might be lower than life-long TKI therapy.

Adherence: Several factors drive non-adherence. Hochhaus highlighted the results of the CML Advocates Network adherence study, where about one fifth of CML patients admitted to miss doses, and 7 out of 8 stated forgetfulness as the reason. In terms of tools improving adherence, he stressed that patients don't want to be reminded every day that they have CML.

edu_hochhaus_pregnancy250Pregnancy: Data of 180 pregnancies in women on Imatinib has been reported. 63 delivered a healthy infant, 35 chose elective termination, 12 had shown a fetal abnormality, and 18 pregancies spontaneously aborted. From the 60 pregnancies fathered by men with CML, no suggestion of any problem in contraception, pregnancy, delivery or congenital abnormality was reported, except one case of one family where both sons were affected by the same abnormality.

edu_hochhaus_advocatesFor women wishing to become pregnant, it was suggested  that at least 24 months of major molecular response should be achieved prior conception. TKI wash-out was not really necessary. Disease should  be monitored by PCR. No treatment advised while in MMR,  and Interferon-alpha could be applied in 2nd trimester in case of rising PCR. Breast feeding was not recommended.

Patient Advocacy: Hochhaus highlighted that the CML community is an outstanding example in patient advocacy, not to be seen in many other cancers. CML patient advocates have become a credible partner of clinicians and industry, as well as an independent political voice on access to diagnostics and therapy, reimbursement and information to patients.

edu_melo_cureCML Management Outlook: Hochhaus concluded that future CML treatment strategies might show a three-phased approach:

  • induction therapy with the most active BCR-ABL inhibitor or combinations until deep molecular response (MR4 or MR4.5) is achieved for more than 2 years,
  • then a response consolidation phase for 2 years, targeting residual disease with an acceptable toxicity profile,
  • followed by TKI discontinutation, either without therapy or with Interferon maintenance.

Junia V. Melo (Australia): "Minimal Residual Disease and Discontinuation of Therapy: Can we aim at a cure?".

melo1

In her presentation, Melo highlighted that "operational cure", with CML being under control while on continuous therapy, is only seen as a partial success. Reasons:

  • chronic toxicity, impacting the quality of life,
  • late-emerging toxicity of a long-term therapy
  • financial cost, and
  • 'lingering MRD'.

Quality of Life: Addressing the issue of toxicity, Melo highlighted t he recent Quality of Life study of the Italian study group, highlighting that CML patients reported to suffer (in order of magnitude) from fatigue, muscle cramps, muscoskeletal pain, edema, skin problems, diarrhea, headache, abdominal discomfort and nausea.

Effect on Costs: The financial cost of "operational cure" continue to be signficiant - the French STIM stop study had estimated savings on drug costs of 4 Million EUR of the trial participants alone.

Is Stem Cell Transplant really curative? Looking at allogenic stem cell transplant, Melo noted that due to mortality rates of 30-50% in 5-10 years, the fact that chronic GvHD was "a big price to pay", and persistence of low-level BCR-ABL post transplant in about one third of patients were raising the question how cured patients really were in complete remission after transplant.

edu_melo_failedpromiseCan TKIs be curative? Melo outlined the results of the French STIM stop study where 59% of Imatinib patients had a loss of complete molecular response at 18 months, and in another stop study, 36% had a loss of major molecular response on 2nd generation TKIs. Relapses seemed to be associated with duration of therapy before cessation as well as with Sokal Risk scores. In addition, a recent study had revealed that almost all "PCR undetectable patients" were still positive using the more sensitive DNA-based PCR, raising the question that "complete molecular response" may have been a failed promise.

To assess that, Melo explained recent models of TKI response dynamics, outlining that TKI response might follow three phases, with a first steep decline of differentiated CML cells, then an eradication of CML progenitor cells, followed by a slow depletion of residual CML stem cells in a subset of patients, potentially leading to CML stem cell extinction on long-term TKI therapy. However, the reasons for varability of the observation is not known and might be driven by inconsistent compliance, low-level resistance, or heterogenity in disease characteristics.

edu_melo_eradicatestemsTargeting stem cells: Four strategies are currently adressed by researchers with new drugs:

  • Inhibit self-renewal of stem cells
  • Reverse dormancy, to make them susceptible to TKI therapy
  • Induce differentiation of stem cells, becoming functional
  • Induce cell death of stem cells

In summary, Melo concluded that stopping therapies might be an option for a minority of CML patients - even though it remains unclear how long in complete molecular response is "long enough" to do so. For all other patients, new drugs or immunological approaches are needed to selectively target the leukemic stem cell, as well as new diagnostic measures to monitor the effect of those treatments.


edu_edusession1-250Summary by Giora Sharf (photos) and Jan Geissler (report)
San Diego, 13 Dec 2011

 

See also other articles about ASH 2011:


María Isabel Gómez de Soriano Community Builder Avatar   21.12.2011 (04:21:07)
Yes No Excellent summary
 
 
   
 

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