Anna Mestice

Extramedullary involvement in patients with acute promyelocytic leukemia: A report of seven cases

Extramedullary involvement is only occasionally observed in patients with acute promyelocytic leukemia (APL) but has been said to occur more frequently after treatment with all‐trans retinoic acid (ATRA) than after treatment with cytotoxic drugs. In the literature, 37 well‐documented cases have been reported.

Vascular Endothelial Growth Factor Serum Levels Are Elevated in Patients with Hereditary Hemorrhagic Telangiectasia

Background: Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Two genes involved in the transduction of TGF-β signalling are responsible for HHT. An additional role for vascular endothelial growth factor (VEGF) has been proposed. Serum VEGF, which has been evaluated in several diseases characterized by aberrant angiogenesis, has never been measured in patients with HHT. Aims: To evaluate VEGF serum levels in HHT patients as compared to normal subjects. Materials and Methods: 32 HHT patients (age 47.7 ± 16.7 years) and a control group of 37 healthy subjects (age 48.2 ± 15.5 years) were entered in the study. Each patient underwent serum VEGF dosage using a commercial ELISA specific for the human molecule. Results: The serum level of VEGF in HHT patients was 196.3 ± 103.2 pg/ml, while it was 152.0 ± 84.1 pg/ml in the control group. Statistical analysis showed that serum VEGF was significantly higher in HHT patients than in the controls (p < 0.031). Conclusions: According to a study performed in a murine model, persistence of the activation phase of angiogenesis might be responsible for an increased production of several angiogenic factors, in particular VEGF, in HHT. Our work is the first to suggest an increased expression of VEGF in the serum of subjects with HHT in agreement with the stimulation of VEGF synthesis proposed in the murine model.

FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia

Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×109/l and 1×109/l was 20 (range 16–25) and 24 (range 20–28) days from the start of chemotherapy, respectively. Platelet levels of more than 20×109/l and 100×109/l were achieved in a median time of 23 (range 19–25) and 33 (range 28–39) days, respectively. Fever more than 38.5°C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1–38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3–38) and 9 (7–38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7–38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.

Extramedullary blast crisis in chronic myeloid leukemia

Among 235 patients with CML we reviewed 91 patients with BC diagnosed between 1980 and 1995; 15 of the 91 (16%) developed extramedullary disease (EMD). The sites involved were the lymph nodes (13/15), CNS (1/15) and suborbital mass (1/15). The appearance of EMD was associated with chronic phase (CP) features in the bone marrow in 3/15 cases, with accelerated phase (AP) in 3/15 and with BC in 9/15. 11/15 (73%) cases of EMD were classified as myeloid (My-EMD) and 4/15 as lymphoid-type (Ly-EMD): three B-phenotype and one T-phenotype. All Ly-EMD cases were treated with vincristine, daunorubicin and prednisone and obtained complete remission (CR). Cases of My-EMD were treated with daunorubicin and cytosine arabinoside, of which only 1/11 achieved CR. We suggest that in EMD also, the type, lymphoid or myeloid, of BC has a bearing on treatment response and prognosis: Ly-EMD is more responsive to treatment and has longer survival than My-EMD.

Good and poor CD34+ cells mobilization in acute leukemia: analysis of factors affecting the yield of progenitor cells

Summary:The factors possibly affecting the collection of peripheral blood stem cells (PBSC) were evaluated in 104 de novo acute leukemia patients (66 myeloid and 38 lymphoblastic leukemias) in first cytological complete remission (CR); all patients achieved CR after first-line induction chemotherapy. The acute myeloid leukemia patients (AML) were given consolidation–mobilization chemotherapy with cytarabine, and daunoblastin or mitoxantrone or idarubicin; the acute lymphoblastic leukemia patients (ALL) were given consolidation–mobilization chemotherapy with cytarabine and etoposide. In all patients, the collection of PBSC was performed during recovery after giving consolidation chemotherapy and granulocyte colony-stimulating factor (G-CSF). Two main groups were considered according to the CD34+ cells × 106/kg b.w. collected, that is, poor mobilizers (PM), with a collection of <2 × 106/kg and good mobilizers, with a collection of >2 × 106/kg. Of 104 patients, 27 (25.9%) were PM; 20/27 had AML and 7/27 had ALL. At multivariate analysis, a lower CD34+ cells count premobilization chemotherapy (CD34 steady state), the presence of FUO (fever of unknown origin) or infection, and a lower number of CD34+ cells on the first day of collection correlated with poor mobilization. These results may enable early recognition of patients who may have poor mobilization, and aid selection of patients for different mobilization regimens.

Derivative chromosome 9 deletions in chronic myeloid leukemia are associated with loss of tumor suppressor genes

It has recently been postulated that the absence of a single tumor suppressor gene (TSG) allele can provide a selective advantage for an emerging tumor cell. We have characterized the precise extension of the deletion on der(9) in 20 chronic myeloid leukemia (CML) cases using FISH analysis with an appropriate set of BAC/PAC probes to attempt a better definition of TSGs encompassed by these genomic deletions. Chromosome 9 deletions on the der(9) were detected in 15 (75%) cases; the TSG PTGES gene was lost in 11 (73%) cases. Chromosome 22 deletions on der(9) were found in 18 (90%) of the analysed cases; two TSGs were found located inside the deleted sequences of chromosome 22: SMARCB1 and GSTT1. These TSGs were found deleted in 16 (89%) cases bearing deletions of chromosome 22. Fourteen (70%) patients were treated with IFN-α therapy: 12 did not obtain complete haematologic remission (CHR) and 2 were not evaluable for response. Therefore, the patients did not respond to the IFN-α treatment started Glivec obtaining CHR and major cytogenetic response (MCR). The observation that deletions on der(9) are associated with the loss of TSGs suggests their possible involvement in the CML outcome, mediated by a haplo-insufficiency mechanism.

Early and Long-Term Engraftment after Autologous Peripheral Stem Cell Transplantation in Acute Myeloid Leukemia Patients

This study aimed to identify which subset of CD34+ cells might be the most predictive of early and long-term hematopoietic recovery following autologous peripheral blood stem cell (PBSC) transplantation (PBSCT) in adult acute myeloid leukemia (AML) patients. The relationships between the number of ‘mature’ subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD90–) and ‘immature’ subsets of CD34+ cells (CD34+/CD33–, CD34+/CD38–, CD34+/DR– and CD34+/CD90+) and early and long-term hemoglobin, neutrophil and platelet counts were studied in a homogeneous series (for disease, pre-transplant chemotherapy, mobilization chemotherapy, conditioning regimen) of 26 AML patients after autologous PBSCT. Cell counts were performed before and after cryopreservation, but only after thawing were the cell counts used for correlation with early and long-term engraftment. The number of CD34+/CD38– cells infused correlated with the neutrophil (r = 0.88, p < 0.005) and platelet counts (r = 0.67, p < 0.05) at 12 months after PBSCT. This correlation was better than that for the total CD34+ cell dose at 12 months (r = 0.36, p = 0.09 for neutrophil count and r = 0.48, p = 0.06 for platelets count). The number of CD34+/CD90+ cells was also correlated with the platelet counts at 6 (r = 0.70, p < 0.05) and 12 months (r = 0.80, p = 0.005) after PBSCT. This correlation was better than the total dose of CD34+ cells at 6 (r = 0.31, p = 0.3) and 12 months (r = 0.48, p = 0.06) for the platelet counts. CD34+ subset analysis suggests that for early engraftment the total number of CD34+ cells infused is more strongly correlated than the CD34+ subsets, whereas the CD34+/CD38– and CD34+/CD90+ subsets may be associated with sustained long-term neutrophil and platelet engraftment. These findings may help to predict the repopulating capacity of PBSCs in AML patients after autologous PBSCT, especially when a relatively low number of CD34+ cells is infused.

Non-treatment-related chronic myeloid leukemia as a second malignancy.

The characteristics of the very rare non-treatment-related chronic myeloid leukemia (nTr-CML) cases have never before been analyzed. The literature up to December 2002 was screened using the Medline database to identify cases of Tr-CML and nTr-CML. We considered five cases with nTr-CML identified among 270 newly diagnosed CML at our Department. Our report thus considers nine cases with nTr-CML compared to 77 affected by Tr-CML as a secondary neoplasm. The median age at the appearance of the first tumor was higher in nTr-CML patients compared to that of the Tr-CML group (P<0.0001). The median age at CML diagnosis was significantly higher in the nTr-CML than in the Tr-CML group (P<0.0001). The proportion of hematological malignancies as first tumor type was not different in the two groups (44% in nTr-CML versus 56% in Tr-CML). Our study underlines that nTr-CML as a second malignancy is a rare entity associated with elderly age.

Subsets of CD34+ and early engraftment kinetics in allogeneic peripheral SCT for AML

This study aimed to identify which graft product subset of CD34+ cells might be the most predictive of early hematopoietic recovery following allogeneic peripheral SCT (allo-PBSCT). The relationship between the number of ‘mature’ subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD133−) and ‘immature’ subsets of CD34+ cells (CD34+/CD33−, CD34+/CD38−, CD34+/DR− and CD34+/CD133+) and early neutrophil and platelet engraftment were studied in a homogeneous series (for disease, pre transplant chemotherapy, conditioning regimen and GVHD prophylaxis) of 30 AML patients after allo-PBSCT from HLA-identical siblings. In our experience, the total CD34+/CD133+ cell number was inversely correlated with the days required for the recovery of 0.5 × 109/l neutrophils (r=−0.82, P=0.02) and platelets of 20 × 109/l (r=−0.60, P=0.06); this correlation was better than the total CD34+ cell dose and neutrophil (r=−0.70, P=0.04) and platelet engraftment (r=−0.56, P=0.07). We suggest that a high number of CD34+/CD133+ PBSC may be associated with faster neutrophil and platelet recovery; these findings may help to predict the repopulating capacity of PBSC in patients after allo-PBSCT, especially when a relatively low number of CD34+ cells is infused.

FLAG-Ida Regimen as Bridge Therapy to Allotransplantation in Refractory/Relapsed Acute Myeloid Leukemia Patients

Background Patients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment. Patients and Methods We used the FLAG‐Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony‐stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular‐cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome. Results We analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17‐72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG‐Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular‐cytogenetic risk (P = .009), duration of first response in relapsed AML (P = .003), AML status (relapsed or refractory; P = .047), and peripheral blood blast count (P = .016). On multivariate analysis, overall survival was significantly associated with FLAG‐Ida response (hazard ratio, 0.343; P = .001) and receipt of allotransplantation (hazard ratio, 0.277; P < .001). Conclusion Our data seem to confirm the value of FLAG‐Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation. Micro‐Abstract Allotransplant is crucial for improving survival in refractory/first relapsed AML patients. An overall response was achieved in 48 patients (44% of the whole group) with FLAG‐Ida chemotherapy approach. 24 of 48 responders underwent allotransplantation obtaining a median OS of 60 months.