Alessandra Cupri

Plerixafor on-demand combined with chemotherapy and granulocyte colony-stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs.

To date, no prospective study on Plerixafor ‘on‐demand’ in combination with chemotherapy and granulocyte colony‐stimulating factor (G‐CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on‐demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G‐CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34+ cells in peripheral blood was reduced by ‘on‐demand’ strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34+ cells 2 × 106/kg decreased from 20·9 to 4·0% (P = 0·0001). The on‐demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a ‘bias‐adjusted set of controls’. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G‐CSF, the ‘on‐demand’ use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.

Antitumor activity of bortezomib alone and in combination with TRAIL in human acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60–70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 µM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy.

Influence of complex variant chromosomal translocations in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Abstract Cytogenetic variants of the Philadelphia (Ph) chromosome can be observed in 5–8% of patients diagnosed with Chronic Myelogenous Leukemia (CML), and usually involve at least one chromosome other than 9 and 22. Despite the genetically heterogeneous nature of these alterations, available data indicate that CML patients displaying complex variant translocations (CVTs) do not exhibit a less favorable outcome as compared to individuals presenting conventional Ph-positive CML. Patients and methods. We report our experience with 10 CML patients carrying CVTs among 153 newly diagnosed cases followed at our Institution. Results and discussion. Unlike previously published reports, in our series only two CML patients exhibiting CVTs achieved an optimal response to tyrosine kinase inhibitors (TKI) treatment. The remaining eight patients obtained either a suboptimal response or failed drug therapy. Our data suggest that the presence of CVTs at diagnosis might confer an unfavorable clinical outcome, as these genetic alterations might be markers of genomic instability and indicate a higher likelihood of disease progression.

SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation

BackgroundSPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML) patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC.MethodsWe evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM), in vitro, using ATP-lite and cell cycle analysis.ResultsOur study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3 months and was maintained for at least the 18 months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase.ConclusionOur results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML.

HIGH BCR-ABL/GUSIS LEVELS AT DIAGNOSIS OF CHRONIC PHASE CML ARE ASSOCIATED WITH UNFAVORABLE RESPONSES TO STANDARD-DOSE IMATINIB

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. Experimental Design: We correlated BCR–ABL/GUSIS and BCR–ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR–ABL/GUSIS and BCR–ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as “warnings,” 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR–ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR–ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR–ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR–ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189–98. ©2017 AACR.

Autologous Transplantation in 1st Cr Aml Patients with Purged or Unpurged Bone Marrow: Good Clinical Results in Favorable CytogeneticGroup and in those Infused with a Low Number of Marrow Cells

In a single institution, 31 patients affected with Acute Myeloid Leukaemia (AML) in 1st Complete Remission (CR) received autologous bone marrow transplantation (ABMT). Mafosfamide was employed in a non-randomized fashion to purge marrows, in 15 cases bone marrow cells were purged, while in 16 they were left unpurged. Dose of infused Total Nucleated Cells (TNC) was an important factor for myeloid engraftment (P=0.02). LFS was 58% in purged and 40% in unpurged groups (P=0.26). Patients having a good prognosis cariotype had a LFS of 100% while the group of all other patients had a LFS of 37.5%. Patients receiving a dose of TNC below to median had a LFS of 65% and those receiving a dose of TNC>median had a LFS of 28% (P=0.017). Purging significantly improved LFS in patients “not harbouring good cytogenetic abnormalities” (53% LFS in purged group versus 18% in unpurged group, P=0.05). In conclusion, ABMT is associated with excellent results in “good prognosis cytogenetic”. Purging may improve results in patients belonging to “intermediate cytogenetic group”. A high number of infused TNC produces a fast myeloid engraftment but a poor LFS.

Cost-effectiveness of on-demand plerixafor added to chemotherapy and granulocyte-colony stimulating factor for peripheral blood stem cell mobilization in multiple myeloma

Abstract We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 106 CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 106 CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful minimal harvest, was €40.6 per patient.

Infliximab therapy in hematologic malignancies: handle with care (Comment)

We read with great interest the manuscript by Baron and colleagues entitled “Value of infliximab (Remicade®) in patients with low-risk myelodysplastic syndrome: final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group”.[1][1] The reported findings showed that

Steroid treatment of acute graft-versus-host disease grade I: A randomized trial

Patients with acute graft-versus-host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II–IV GvHD. The cumulative incidence of grade II–IV GvHD was 50% in the observation arm and 33% in the treatment arm (P=0.005). However, grade III–IV GvHD was comparable (13% vs. 10%, respectively; P=0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17% vs. 9%). In multivariate analysis, an early interval between transplant and randomization (<day +20) was the only negative predictor of grade III–IV GvHD. Patients in the observation arm had less infectious bacterial episodes (12 vs. 25; P=0.04), less severe infectious fungal episodes (0 vs. 3; P=0.04), and less severe adverse events (3 vs. 11; P=0.07). At five years, non-relapse mortality was 20% versus 26% (P=0.2), relapse-related mortality 25% versus 21%, and actuarial survival was 51% versus 41% (P=0.3) in the observation and treatment arms, respectively. In multivariate analysis, advanced disease phase, older age and an early onset of GvHD were significant negative predictors of survival, independent of the randomization arm. In conclusion, steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III–IV GvHD, and there is no effect on non-relapse mortality and survival. Patients treated with steroids are at a higher risk of developing infections and have more adverse events. (Trial registered as EUDTRACT 2008-000413-29).

Diagnosis of Blastic Phase of Chronic Myeloid Leukemia

CML). The detection of a Ph+ translocation together with a p210 fusion transcript strongly suggests a diagnosis of CML [2] . At our institution we have followed several cases like the ones reported by Sun et al. (BP-CML of both myeloid and lymphoid type). In most of these cases, the combination of chemotherapy plus tyrosine kinase inhibitor treatment followed by allogeneic hematopoietic stem cell transplantation with tyrosine kinase inhibitor maintenance therapy has led to favorable long-term outcomes (achieving complete hematological responses, complete cytogenetic responses and molecular responses). We read with great interest the abstract of the case report entitled ‘Prolonged survival with imatinib mesylate combined with chemotherapy and allogeneic stem cell transplantation in de novo Ph+ acute myeloid leukemia’ by Sun et al. [1] . Although the clinical cases presented in this article are both well described and clinically managed, it seems to us that misleading conclusions might be drawn from the diagnosis of a Philadelphia-positive (Ph+) acute myeloid leukemia together with a BCR-ABL1 /ABL-positive (p210) fusion transcript. We strongly believe that similar cases must be classified as myeloid blastic phase of chronic myeloid leukemia (myBPAccepted: February 9, 2012 Published online: March 21, 2012