By Lynda Williams, Senior medwireNews Reporter
Treatment-free remission (TFR) may be feasible in many patients with chronic myeloid leukaemia (CML), say researchers who set out clinical and logistical requirements for discontinuing tyrosine kinase inhibitor (TKI) therapy.
"We have proposed some criteria for patient selection and some criteria for institutional capability to supervise a TFR attempt, primarily access to timely and accurate standardized RQ-PCR [real-time quantitative reverse transcriptase polymerase chain reaction] results", say Timothy Hughes and David Ross, from the South Australian Health & Medical Research Institute in Adelaide.
"If all of these criteria can be met, then we believe that TFR should become a routine part of clinical practice", they write in a perspective in Blood, acknowledging that ensuring the laboratory technology is available is a "new challenge for the global CML community".
The authors explain that the nine-fold increase in patients living with CML means provision of life-long TKI therapy is a "substantial and growing financial burden", especially in countries where generic imatinib is unavailable and for patients who do not tolerate or respond to imatinib.
In addition, many patients may now experience chronic CML as a "syndrome of TKI side effects", with those who achieve a deep molecular response (MR) often questioning whether they may stop treatment.
Several studies have successfully achieved TFR in imatinib-treated patients who had maintained an undetectable minimal residual disease (UMRD) or MR4.5 (BCR-ABL ≤0.0032%) for at least 2 years, as well as demonstrating that patients regained UMRD within 6 months of restarting treatment after UMRD loss.
And the multinational EuroSKI study is now assessing TFR in TKI users based on the less stringent criterion of MR4.0 (BCR-ABL ≤0.01%) for at least 12 months, with return to treatment on loss of a major molecular response (MMR; BCR-ABL ≤0.1%), the authors say.
In addition, the Korean Imatinib Discontinuation Study and the STIM2 study aim to determine the impact of Sokal score and imatinib response kinetics in treatment-naïve patients, removing any potential confounding from prior interferon (IFN) therapy.
The possibility of TFR in patients treated with nilotinib and dasatinib is also under investigation, with initial findings of the DADI study indicating a TFR rate of 58% for patients who switch from imatinib to dasatinib for intolerance or patient preference but around 8% for those who did not achieve an optimal response to imatinib.
Hughes and Ross emphasize that while most successful TFR patients have discontinued treatment after 5 to 8 years, with only a small proportion doing so after 3 years, it is not yet possible to conclude that a shorter duration of TKI therapy will reduce the likelihood of TFR.
They found just one known case of disease progression and death following TFR out of attempts in over 1000 patients, describing a woman who did not begin imatinib therapy until 10 years after diagnosis. She lost MMR after stopping imatinib and, although the patient responded to further treatment, she experienced blast crisis 8.5 months later.
In addition, there have been reports of imatinib withdrawal syndrome, described as persistent but self-limiting myalgia or arthralgia that can be managed with pain relief and nonsteroidal anti-inflammatory agents.
Hughes and Ross observe that the small number of patients with atypical BCR-ABL1 transcripts, or whose BCR-ABL transcript type at diagnosis is unknown, and whose MR endpoints cannot be reliably determined, are not suitable candidates for TFR.
The authors also note that patients with a history of TKI resistance should be informed they have a low likelihood of maintaining TFR, although it should not be ruled out if quality of life is adversely affected by treatment toxicity.
They recommend that TKI withdrawal should be undertaken only when highly sensitive RQ-PCR testing is available to detect first signs of relapse, with monitoring at 2 to 3 month intervals required indefinitely.
"In order to minimize unnecessary anxiety it is important to explain that molecular relapse is completely different from haematological relapse, and that clinically relevant consequences of molecular relapse are rare", the researchers add.
Future studies should focus on the role of TFR in patients undergoing combined TKI and IFN therapy; the feasibility of a second TFR attempt in patients whose initial trial results in loss of MMR but is later regained on a return to TKI therapy; and the search for biomarkers that predict the likelihood of successful TFR.
Hughes and Ross summarise that TFR research findings so far "are sufficiently reassuring that we feel comfortable in offering all eligible patients a supervised test of TKI withdrawal."
"The optimum eligibility criteria are open to debate, but the available data suggest that should have a minimum of 12 months of deep [MR] with MR4.0 or better", they write, albeit that such recommendations are restricted to patients with adult chronic phase CML and no history of accelerated phase or blast crisis.
"In patients who have achieved a second chronic phase we would be very reluctant to ever stop TKI outside of a clinical trial", the authors say.
Hughes and Ross conclude: "There are still many unanswered questions concerning TFR, so eligible patients should be strongly encouraged to participate in clinical trials where possible.
"The absence of a suitable trial should not preclude a patient from stopping TKI treatment, but outside the structure of a clinical trial it would be useful to have consensus recommendations to guide those clinicians for whom TFR represents a new area of practice."
Blood 2016; Advance online publication
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