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Ph-like ALL
and CD3, has not yet been tested as an agent for Ph-like ALL treatment intensification. However, it has been proven to be effective in MRD eradication, and is current- ly being incorporated in clinical trials as part of front-line treatment for other high-risk ALL patients.
Should targeted agents be added to induction regimens if the diagnosis of Philadelphia chromosome-like acute lymphoblastic leukemia is confirmed?
Case presentation. A 23-year old woman with a recent diag- nosis of B-ALL is being treated at your institution according to a GMALL protocol.54 On day 15 of induction, results of molecular tests reveal an IGH–CRLF2 translocation and a JAK2-activating mutation at R683G in the pseudo-kinase domain. Should JAK inhibitors be included in the treatment plan?
Most aberrations identified in patients with Ph-like ALL lead to kinase activation in the JAK2 pathway.55,56 Preclinical studies support the rationale that JAK inhibi- tion would potentially counteract the aberrant, prolifera- tion signal derived from the mutation.57,58 Early-phase clin- ical trials have shown that the combination of JAK inhibitors with chemotherapy is safe and tolerable.59-61 However, the clinical benefit of the addition of currently available JAK inhibitors, such as ruxolitinib, to chemother- apy in ALL is questionable. Unlike myeloproliferative neo- plasms, in which JAK2 inhibition with low/intermediate- dose ruxolitinib is sufficient to yield a clinical response,62 in leukemia, the use of ruxolitinib has not yet been approved. In addition, the proliferation signal in Ph-like ALL is derived from several kinases and parallel blockage of JAK 1&2, RAS and mTOR is probably needed for leukemia cell elimination.30,58,63-65 Thus, high ruxolitinib doses of at least 50 mg twice daily60,66 could be required to achieve clinical benefit. Phase II studies exploring the role of incorporating ruxolitinib in induction regimens for Ph- like ALL are ongoing.
For the minority of Ph-like patients presenting with BCR-activating aberrations, data are accumulating that kinase inhibition by BCR/ABL specific tyrosine kinase inhibitors (TKI) may be beneficial.67-70 Most reports claim- ing the benefit of TKI present results of patients diagnosed with a PDGFRB translocation; so far, only a few cases of successful TKI use in patients with ABL1 aberrations have been reported.4,71,72 Although no generalized conclusion can be made regarding the value of TKI in all ABL-activat- ing cases, we feel that, given the established safety of these drugs and the data provided in the above-mentioned reports, arguments for off-label TKI use when considering targeted therapies for Ph-like ALL are much stronger than those for the use of JAK inhibitors. At the same time, one should bear in mind that Ph-like leukemia is a genetically complex disease and resistance to TKI, related to clonal evolution and appearance of additional mutations, has been reported.73-75 Therefore, the addition of targeted ther- apy to first-line chemotherapy in Ph-like ALL is currently considered experimental.
Approaches to post-remission therapy in patients with Philadelphia chromosome-like acute lymphoblastic leukemia with measurable residual disease
Case presentation. A 63-year old man with B-ALL achieved complete remission after two cycles of Hyper-CVAD therapy. MRD analysis by fluorescence activated cell sorting identified leukemic cells at a level of 4x10-3 in the bone marrow. Results of
molecular tests revealed the P2RY8-CRLF2 translocation. How should this patient be treated?
MRD monitoring is currently incorporated in ALL treat- ment protocols and decisions on the intensity of the first- line regimen and upfront allogeneic stem cell transplanta- tion (SCT) rely mainly on the results of MRD evaluation. The likelihood of Ph-like ALL patients remaining MRD- positive after standard induction is high. MRD positivity at the end of induction is considered to be associated with a high risk of relapse in patients with Ph-like ALL as well as any other type of ALL. In such case, in adults, allogeneic SCT is strongly recommended, while some pediatric pro- tocols would mandate intensification, not necessarily fol- lowed by allogeneic SCT.47,76 A retrospective study found no survival benefit from allogeneic SCT compared to chemotherapy intensification for high-risk pediatric patients.77 However, since results of allogeneic SCT are superior in patients who are MRD-negative prior to the transplant,78,79 intensification of therapy aiming to eradi- cate residual disease is logical even prior to allogeneic SCT. An analysis of the outcomes of 81 children treated in the ALL8 trial of the Australian and New Zealand Children’s Haematology/Oncology Group (ANZCHOG) showed that even if considering only patients who achieved MRD negativity after allogeneic SCT, those who started conditioning with detectable MRD had a worse outcome.80 Although patients included in this study were not tested for the Ph-like signature, most of them were classified as "high-risk B-other" which probably overlaps with Ph-like ALL. A recent analysis of results of the ALL2008 study by the Nordic Society of Pediatric Hematology and Oncology (NOPHO) suggested that high-risk pediatric patients who remain MRD-positive at the end of consolidation will have a better outcome if residual disease is eradicated with intensive chemothera- py blocks prior to allogeneic SCT.81 Evidence supporting the administration of blinatumomab prior to transplant in an attempt to eliminate MRD is accumulating. Remarkably, based on a single-arm study, the Food and Drug Administration specifically approved the use of bli- natumomab for high-risk B-ALL patients who achieve remission but remain MRD-positive. In a prospective trial, MRD was eliminated in 78% of patients following blina- tumomab treatment at a daily dose of 15 mg/m2.82 The poor outcome of ALL patients older than 15 years, who remain MRD-positive after initial therapy and receive no blinatumomab prior to allogeneic SCT, was confirmed in a large European retrospective analysis.83 Apart from the recommendation of using this drug, additional treatment intensification may also be considered. For instance, idaru- bicin administration (for 3 days) just prior to busulfan/cyclophosphamide conditioning has been reported to improve post-SCT survival in MRD-positive patients.84
As far as concerns the issue of MRD elimination in the Ph-like ALL setting, there are case reports demonstrating complete eradication or significant reduction of MRD at the time of allogeneic SCT resulting from pre-transplant intensification with ruxolitinib.61,85 However, the addition of targeted therapy, such as JAK or BCR/ABL inhibitors, should not substitute MRD eradication with blinatu- momab or intensive chemotherapy prior to transplanta- tion. Currently, no data are available to support mainte- nance with JAK2 inhibitors following allogeneic SCT in Ph-like ALL patients. While ruxolotinib has an immune
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