Prognostic heterogeneity of adult B‐cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/ TCF3‐PBX1 treated with measurable residual disease‐oriented protocols

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation)

A pediatric regimen for adolescents and young adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial

Background: Pediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL). Methods: This study reports the results of treatment of the ALLRE08 trial, a full pediatric trial for AYA aged 15-30 years with standard-risk (SR) ALL. Results: From 2008 to 2018, 89 patients (38 adolescents [15-18 years] and 51 young adults [YA, 19-30 years], median age: 20 [15-29] years) were enrolled in the ALLRE08 trial. The complete response (CR) was 95%. Twenty-two patients were transferred to a high-risk (HR) protocol because of poor marrow response on day 14 (n = 20) or high-level of end-induction minimal residual response (MRD ≥ 0.25%, n = 2). Cumulative incidence of relapse (CIR) at 5 years was 35% (95%CI: 23%-47%), with significant differences between adolescents and YA: 13% (4%-28%) vs 52% (34%-67%), P = .012. No treatment-related mortality was observed in 66/66 patients following the ALLRE08 trial vs 3/23 patients moved to a HR trial. The estimated 5-year overall survival (OS) was 74% (95%CI: 63%-85%), with significantly higher rates for adolescents vs YA: 87% (95%CI: 74%-100%) vs 63% (46%-80%), P = .021. Although CIR or OS were lower in patients who were transferred to a HR trial, the differences were not statistically significant (CIR: 34% [21%-47%] vs 37% [14%-61%]; OS: 78% [66%-90%] vs 61% [31%;91%]). Conclusion: A full pediatric trial is feasible and effective for AYA with Ph-neg, SR-ALL, with better results for adolescents than for YA. Outcome of patients with poor early response rescued with a HR trial was not significantly inferior

A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients

Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules

Azacitidine vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the PETHEMA Registry

The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2–11.7) vs. 8.8 months (95% CI: 6.7–11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC

Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age or = 10,000/ mm3) (P or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial.

This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications. This trial was registered in the ClinicalTrials.gov database with code NCT01087008.This work was supported by an unrestricted grant from Novartis Farmaceutica S.A., Barcelona, Spain and sponsored by GEM/PETHEMA. Part of the work was also done thanks to grants PS09/01450 and PI12/02311 from the Spanish “Instituto de Salud Carlos III (ISCIII)” and Fondo Europeo de Desarrollo Regional (FEDER), the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (ERDF) “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010), the grant RD12/0036/0069 from “Red Temática de Investigación Cooperativa en Cáncer (RTICC), and grant GCB-120981SAN from the “Asociación Española Contra el Cáncer (AECC)”