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A. Frisch and Y. Ofran
suppressive effect and is suggested to be active against graft-versus-host disease,86,87 its routine use may prevent the benefit of the graft-versus-leukemia effect. For many years the association of graft-versus-host disease with graft-versus-leukemia activity has been considered ques- tionable in ALL; yet, a currently published large retrospec- tive study has confirmed an association between the pres- ence of graft-versus-host disease and lower relapse rates.88 Moreover, a preclinical animal model challenges the effec- tiveness of ruxolitinib maintenance in prevention of leukemia relapse.89 Thus, ruxolitinib maintenance after allogeneic SCT should be considered experimental.
For patients with Ph-like ALL who carry an ABL-activat- ing mutation the question of post-transplant TKI mainte- nance is unlikely to be answered in prospective clinical tri- als, mainly because of the rarity of this condition. However, safety data of post-transplant TKI maintenance can be extrapolated from the Philadelphia chromosome-positive ALL setting and encourage the use of this approach.
Persistence of MRD even after allogeneic SCT or failure to eradicate it prior to transplantation is a poor prognostic marker and a sign of impending relapse. In these circum- stances, patients should be aggressively treated with intensive therapy individualized according to their treat- ment history and should be considered for chimeric anti- gen receptor T-cell therapy. Preclinical data suggest that for this very high-risk population, if IKZF1 mutations or deletions are present, a clinical trial with focal adhesion kinase (FAK) inhibitors could be an appropriate option.90,91
Patients with Philadelphia chromosome-like acute lymphoblastic leukemia who achieve measurable residual disease-negative remission
Case presentation. A 42-year old woman presented with B- ALL with CRFL2 overexpression and a peripheral blood white blood cell count of 105x109/L. Molecular evaluation identified the IGH-CRLF2 translocation. Following two cycles of Hyper- CVAD + PEG-asparaginase she achieved molecular remission [MRD-negativity (<10-4), not detected by multicolor flow cytom- etry assay]. How should this patient be further treated?
MRD is currently recognized as the most powerful risk factor in ALL patients. Absence of MRD, as evaluated by the tests capable of detecting even a low concentration (10-4) of leukemic cells, is associated with a superior out- come irrespective of molecular subtypes, patient's age and treatment protocols used.77,92,93 However, in patients carry- ing high-risk molecular aberrations, such as Ph-like ALL patients, achievement of molecular remission does not completely abrogate the risk of a relapse. In the pediatric Australian ALL8 trial, among 666 recruited patients, the relapse risk was significantly higher in Ph-like patients with CRFL2 translocations than that in all non-Ph-like ALL patients (57.8% vs. 16%, respectively; P<0.0001).80 Notably, ten of 14 (71.4%) relapses in Ph-like ALL patients occurred despite the achievement of MRD negativity by day 79.18 Similar results were reported in the AIEOP-BFM ALL2000/R2006 study, in which a higher cumulative inci- dence of relapse was observed in Ph-like ALL patients (33.9% vs. 14.9% in non-Ph-like ALL; P=0.009) even though a poor prednisone response and MRD positivity rates were identical in both groups.94 Similarly, data on adult patients demonstrated a high relapse rate in Ph-like ALL patients, including those who achieved molecular remission, regardless of whether BFM-based or Hyper- CVAD regimens were used.13
A study by Roberts et al. suggested that risk-adapted therapy assigning patients with a high MRD level to allo- geneic SCT could overcome the substantial risk of relapse.28 However, due to the lack of evidence supporting routine assignment to allogeneic SCT, a recent expert review and the updated recommendations from the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) advocated the use of allogeneic SCT during first complete remission only in MRD-posi- tive pediatric and adult patients with Ph-like ALL.95,96 Relapse rates in MRD-negative adults are higher than in pediatric patients with identical MRD kinetics of eradica- tion. Therefore, in our opinion, a more liberal allogeneic SCT referral policy should be considered in adults with Ph-like ALL even if they achieve molecular remission. Additional risk factors, such as an IKZF1 alteration, have the potential to identify patients at the highest risk of relapse.97-99 However, we are unaware of any available prospective data on patients’ outcome following therapy stratification by IKZF1 alteration.
Relapse in patients with Philadelphia chromosome-like acute lymphoblastic leukemia
Case presentation. A 7-year old child presented with B-ALL and an IGH-CRLF2 translocation. After COG-based induction, MRD was detected at a level of 10-2 and high-risk intensive chemotherapy blocks were administered. Two weeks after the last chemotherapy the child had a full-blown hematologic relapse. How should this patient be managed?
Leukemia in patients presenting with early relapse right after intensive therapy is a devastating disease and pre- scribing additional chemotherapy seems futile. As described above, an anticipated effect of JAK inhibitors is modest and therefore in patients at a high risk of disease relapse immunotherapy should be the selected option. In CD19+ ALL, blinatumomab is an acceptable option for both adult100 and pediatric patients.101,102 For adult patients, inotuzumab ozogamicin is also a valid option.103 Although still not widely available, chimeric antigen receptor T-cell therapy is a powerful strategy to be used in such high-risk patients. A remission achieved with chimeric antigen receptor T-cell therapy should be followed by allogeneic SCT.104-106 To minimize the risk of CD19– escape and relapse, there is a rationale for combining CD19 with CD22-directed therapies and this combination should be evaluated against the risk of developing veno-occlusive disease during subsequent allogeneic SCT.107 Targeted therapy based on a patient’s classification as having Ph- like ALL and/or identification of a specific genetic aberra- tion should not replace the use of other efficient agents available for the relapse setting.
Patients of advanced age with Philadelphia chromosome-like acute lymphoblastic leukemia
Case presentation. A 78-year old man who until recent days had been healthy with no chronic diseases, was admitted to hos- pital because of ALL. At presentation his white blood cell count was 55x109/L, his hemoglobin concentration was 8.5 g/dL and a spontaneous tumor lysis syndrome was diagnosed. Cytogenetic evaluation revealed an IGH-CRLF2 translocation and a molec- ular test identified an activating JAK2 mutation at the R683G position. How should this patient be treated?
Patients of advanced age diagnosed with ALL may
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