Elena Maino

Current and future management of Ph/BCR-ABL positive ALL.

Following the introduction of targeted therapy with tyrosine kinase inhibitors (TKI) at the beginning of the past decade, the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved. Presently, the use of refined programs with first/second generation TKI’s and chemotherapy together with allogeneic stem cell transplantation allow up to 50% of all patients to be cured. Further progress is expected with the new TKI ponatinib, overcoming resistance caused by T315I point mutation, other targeted therapies, autologous transplantation in molecularly negative patients, therapeutic monoclonal antibodies like inotuzumab ozogamicin and blinatumomab, and chimeric antigen receptor-modified T cells. Ph+ ALL could become curable in the near future even without allogeneic stem cell transplantation, minimizing the risk of therapy-related death and improving greatly the quality of patients’ life.

Lymphoblastic lymphoma: an updated review on biology, diagnosis, and treatment

Lymphoblastic lymphoma is a rare aggressive neoplasm of T‐/B‐precursors resembling acute lymphoblastic leukemia, with no or limited bone marrow involvement (<25%), that develops more frequently in children and young adults and is typically characterized by a grossly enlarged mediastinum, and whose diagnostic hallmark is the expression of a T‐/B‐precursor cell immunophenotype, the T‐cell subset accounting for 90% of all cases. The adoption of pediatric‐derived, intensive lymphoblastic leukemia‐like protocols led to significantly improved results, with survival rates of about 70% and 90% in adults and children, respectively. Adequate central nervous system prophylaxis and mediastinal irradiation contributed to the therapeutic success; however, the role of radiation therapy is debated due to toxicity concerns and the excellent results obtained with radiation‐free programs especially in pediatric patients. With these modern schedules, localized radiotherapy and/or hematopoietic stem cell transplants could be generally omitted, and considered only for high‐risk patients identified through postinduction computed tomography/positron‐emission tomography scans, minimal residual disease analysis, and new genetics and genomics. New clinical studies will have to confirm the value of these assays for risk‐oriented therapy, while further therapeutic progress is expected from the introduction of new drugs and targeting agents.

Burkitt lymphoma in adolescents and young adults: management challenges

About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25–40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein–Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

EUTOS score predicts long-term outcome but not optimal response to imatinib in patients with chronic myeloid leukaemia

To test the recently developed EUTOS score in predicting optimal response to imatinib and the long-term outcome, 265 patients with early chronic phase chronic myeloid leukaemia treated with standard dose imatinib were analysed. Achievement of optimal response endpoints were higher in low-risk patients, though the difference was not statistically significant: PCyR at 6th month 86% vs 67% (p=0.06), CCyR at 12th month 80% vs 63% (p=0.09), MMR at 18th month 61% vs 36% (p=0.11). However, EUTOS score was predictive for the long-term response. With a median follow-up of 61 months, 53% high-risk patients experienced imatinib failure, compared to 23% in the low-risk group (p=0.013). Among high-risk patients, 4/17 (23%) progressed to accelerated/blastic phase or died, compared to 11/248 (5%) low-risk patients, with 5-year progression-free survival rates of 84±10% and 96±1%, respectively (p=0.04). Our data confirm that EUTOS score envisions the long-term outcome of imatinib therapy.

Imatinib-treated chronic myeloid leukemia patients with discordant response between cytogenetic and molecular tests at 3 and 6 month time-points have a reduced probability of subsequent optimal response

The 2013 version of the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients defines as optimal response the achievement of a partial cytogenetic response (PCyR) and/or BCR-ABL1 transcript ≤10%IS at 3 months, and of a complete cytogenetic

EUTOS score predicts early optimal response to imatinib according to the revised 2013 ELN recommendations

Dear Editor, One of the most significant novelty of the revised version of the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients is that an earlier achievement of complete cytogenetic response (CCyR), at 6 months, and major molecular response (MMR), at 12months, is regarded as optimal [1]. Moreover, prognostic value of the depth of molecular response at 3 (BCR-ABL ≤10 %) and 6 (BCR-ABL ≤1 %) months is recognized. Our group reported that EUTOS score predicts long-term outcome of imatinib therapy, and that high-risk patients had a trend for lower probability to achieve all the cytogenetic and molecular endpoints defined as optimal by 2009 ELN recommendations [2]. We retrospectively evaluated our cohort of CML patients treated with frontline standard dose imatinib to test the ability of EUTOS [3] and Sokal [4] scores to predict 2013 ELNdefined optimal response to therapy. A total of 314 consecutive patients treated with imatinib 400 mg/day for early chronic phase CML were analyzed. Median age at diagnosis was 57 years (range 19–85 years). According to the Sokal score, there were 133 (42 %) low risk, 127 (40 %) intermediate risk, 52 (17 %) high risk, and 2 (1 %) unknown risk cases, respectively. For the purposes of this analysis, and as suggested by ELN experts, we considered lowand intermediate-risk patients as a single group (n =260). The distribution according to the EUTOS score assigned 289 patients (92 %) to the low-risk and 25 (8 %) to the high-risk group. Definitions of partial cytogenetic response (PCyR), CCyR, and MMR were in accordance with ELN recommendations [1]. Results are reported in Table 1. Considering EUTOS score, at 3 months, we observed a significant higher rate of optimal molecular response (BCR-ABL ≤10 %) in low-risk (76 %) compared to high-risk (52 %, p =0.03) patients, while there was only a trend for cytogenetic response (PCyR) (86 vs 75 %, p =0.20). At 6 months, both cytogenetic (CCyR) and molecular (BCR-ABL ≤1 %) optimal responses were higher in the low-risk group: 76 versus 46 % (p =0.003) and 67 versus 33 % (p =0.004), respectively. At 12 months, 58 % of low-risk patients were in MMR, compared to 41 % in the high-risk group (p =0.20). According to Sokal score, we found a significant difference in favor of intermediate–lowrisk patients in terms of cytogenetic response both at 3 (PCyR 88 vs. 72%, p =0.03) and at 6 (CCyR 79 vs. 48%, p =0.0001) months, while no significant differences were seen in molecular response at 3 (BCR-ABL ≤10%: 76 vs. 62 %, p =0.13), 6 (BCR-ABL ≤1 %: 67 vs. 50 %, p =0.08), or 12 (MMR: 56 vs. 55 %, p =1.00) months. Our results suggest that EUTOS score is able to predict optimal response to imatinib, in particular, achievement of molecular response at 3 months, a marker of emerging importance in predicting long-term outcome [5], and of CCyR at 6 months, that has been associated with superior progressionMassimiliano Bonifacio and Mario Tiribelli equally contributed to this work.

Immunotherapy approaches to treat adult acute lymphoblastic leukemia

ABSTRACT Recent developments in immunotherapy are improving treatment results of B-precursor acute lymphoblastic leukemia. This advancement is promoted by new monoclonal antibodies such as inotuzumab ozogamicin, ofatumumab and blinatumomab, by rituximab, and by genetically engineered chimeric antigen receptor-modified T-cells. These treatments, variously targeting CD22, CD20 and CD19 antigens, yield unprecedented high rates of hematologic and molecular remissions even when used in monotherapy and in chemo-resistant or post-transplantation relapsed patients. Beside the encouraging results in relapsed/refractory disease, these agents may open a totally new era in the frontline management of this illness, redefining treatment standards and options for different risk subsets and placing the achievement of a molecular remission at the forefront of treatment objectives. The ever increasing importance of modern immunotherapy in improving treatment design and therapeutic outcome is reviewed.

New drugs and allogeneic hematopoietic stem cell transplantation for hematological malignancies: do they have a role in bridging, consolidating or conditioning transplantation treatment?

ABSTRACT Introduction: Novel targeted therapies and monoclonal antibodies can be combined with allogeneic stem cell transplantation (allo-SCT) at different time-points: 1) before the transplant to reduce tumour burden, 2) as part of the conditioning in place of or in addition to conventional agents 3) after the transplant to allow long-term disease control. Areas covered: This review focuses on the current integration of new drugs with allo-SCT for the treatment of major hematological malignancies for which allo-SCT has been a widely-adopted therapy. Expert opinion: After having been used as single agent salvage treatments in relapsed patients after allo-SCT or in combination with donor lymphocyte infusions, many new drugs have also been safely employed before allo-SCT as a bridge to transplantation or after it as planned consolidation/maintenance. This era of new drugs has opened new important opportunities to ‘smartly’ combine ‘targeted drugs and cell therapies’ in new treatment paradigms that may lead to higher cure rates or longer disease control in patients with hematological malignancies

Combination of EUTOS score and 3-month BCR-ABL transcript level identifies a group of good-risk chronic myeloid leukemia patients with favorable response to frontline imatinib therapy.

as one of the potential putative driver mutations. ZEB2 has been implicated to have crucial role in hematopoietic stem cell differentiation, mobilization, and homing [3]. Conditional overexpression of ZEB2 in mice has been reported to induce T-cell leukemia and deleterious mutations of ZEB2 have been identified in other leukemias [4,5], further suggesting the possible association between altered ZEB2 function and leukemogenesis. These are consistent with ZEB2 being a likely driver mutation in this case. The PCR capillary electrophoresis (PCR-CE) assay detected an NPM1 p.W288fs and several different sizes of FLT3-ITD in both samples (Supporting Information table). We next inferred a model of clonal evolution by tracing cancer cell fraction (CCF) of the detected variants (Fig. 1). Both primary and relapse AML shared the same founder clone with IDH1, ZEB2, and most likely the NPM1 mutation. Although the method of variant allelic fraction (VAF) calculation is different between WES and PCR-CE, VAF of NPM1 mutation on PCR-CE was stable around 0.5. Further, a previous study has shown that NPM1 mutation is almost always an early founding event in AML, consistent with the NPM1 mutation as early clonal event in this case. We did not incorporate FLT3-ITD into our model because association between respective ITD sizes and clonality has not been well understood. However, as a whole, FLT3-ITD was clearly detected at two time points, suggesting that this mutation persisted in the dominant clone. Our model suggests that the founder clone persisted after initial therapy and relapsed 19 years later with additional mutations acquired. Overall, it is consistent with one of the models that were proposed by Ding et al., who performed whole genome sequencing on eight relapsed AML cases, all of which relapsed within 3 years of remission [6]. Our report differs in that our case had a larger fraction of relapse-specific mutations and fewer shared mutations between primary and relapse AML. This would be consistent with the much longer period before relapse and accumulation of additional mutations over this time period. We also observed the emergence of a minor population with an SF3B1 mutation at relapse. CCF of the SF3B1 mutation did not follow that of the founder clone after salvage therapy (Fig. 1). SF3B1 mutation is frequently associated with MDS but rare in AML. The studied patient was suspected to have MDS 3 years before she experienced relapse (Supporting Information Appendix). Taken together, it is likely that the clone with SF3B1 mutation represents the co-occurrence of MDS in the context of a relapsing AML. In summary, longitudinal genomic characterization of an individual with a late relapse of AML revealed that the founder clone of the primary AML persisted after treatment and constituted the basis of relapsed disease 19 years later, hence confirming “true” relapse. More cases of late relapse in AML need to be examined to better characterize the mechanisms of relapse and disease latency.

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a “real-life” setting. We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for diseases characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a “real-life” setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.