Paola Carluccio

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.

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.

Pneumonia in Acute Leukemia Patients During Induction Therapy: Experience in a Single Institution

Pneumonia is still a complication leading to high morbidity and mortality rates in acute leukemia (AL) patients. To evaluate the incidence, risk factors and outcome of pneumonia in a single institution we retrospectively studied 288 patients observed between 1994 and 2000, affected by AL (218 acute myeloblastic leukemia and 70 acute lymphoblastic leukemia [ALL]) treated with an anthracycline-containing induction regimen. Of 288 patients, 80 (27.7%) developed pneumonia: 67/80 had acute myelogenous leukemia (AML) and 13/80 had ALL. At univariate analysis only advanced age correlated with the risk of pneumonia (P <0.001). Of the 80 pneumonia cases, 25 (31.2%) were microbiologically documented and 65 (68.8%) were clinically demonstrated; pneumonia responded to treatment in 44/80 (55%) patients; among the patients with positive outcome of their pneumonia 33/44 (75%) achieved complete remission whereas only 2/36 (5%) patients with a negative outcome achieved complete remission. At multivariate analysis the determinants of positive outcome of pneumonia were younger age (P <0.05), the achievement of complete remission (P <0.005) and the recovery of neutrophils (P <0.005).

Typhlitis Complicating Induction Therapy in Adult Acute Myeloid Leukemia

In a retrospective analysis of 161 consecutive adult patients with de novo acute myeloid leukemia undergoing induction therapy, including cytarabine, etoposide and anthracyclines, seven patients (4.3%) developed typhlitis. All presented severe neutropenia, fever, abdominal pain and tenderness within 16 days from starting chemotherapy (median 11 days; range 5-16). Three patients underwent surgery and survived, four were treated only with supportive therapy: two recovered and two died. In our experience early recognition of typhlitis and rapid recovery of the neutrophils are the most important determinants of the results of surgical and/or medical approaches. The management of typhlitis, a life-threatening condition, is controversial and depends on many factors characterizing each patient, which must be evaluated in collaboration between the surgeon and the hematologist.

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.

Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial

BACKGROUND In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia. METHODS EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 109 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33. FINDINGS Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4-24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5-211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3-4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ2=7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ2=0·06, p=0·81). INTERPRETATION Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. FUNDING Associazione QOL-ONE.

Concomitant primary polycythemia vera and follicle center cell non-Hodgkin lymphoma: a case report and review of the literature

The association of myeloproliferative and lymphoproliferative disorders is well known after cytotoxic drug or radiation exposure, while it is remarkably rare prior to therapy. We report on a patient simultaneously diagnosed as having polycythemia vera and II 3 A follicle center cell non-Hodgkin lymphoma (grade 1). At this timepoint, he is on 12-year follow-up, characterized by post-polycythemia myeloid metaplasia with myelofibrosis and persistent complete remission of lymphoma. The conventional marrow cytogenetic analysis performed during the course of the disease demonstrated an abnormal karyotype with deletion of the long arm of chromosome 20 and trisomy 8, while molecular analysis failed to detect BCR-ABL rearrangement in peripheral blood cells. To the best of our knowledge based on a computer-aided review of the literature (MED-LINE 1966-2002), this is the sixth case of concomitant primary polycythemia vera and lymphoma of non-Hodgkin type. Besides, there is a single literature report on polycythemia vera coexisting with the Hodgkins lymphoma. In our case as well as in the recorded ones, two independent malignant clones of myeloid and lymphoid origin, respectively, seem to have arisen. Further reports, supported by chromosomal and molecular studies, could improve our knowledge on this extremely infrequent disease association.

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.

Overexpression of the LSAMP and TUSC7 genes in acute myeloid leukemia following microdeletion/duplication of chromosome 3

The 3q13.31 microdeletion syndrome is characterized by developmental delay, postnatal growth above the mean, characteristic facial features, and abnormal male genitalia. Moreover, a frequent deletion in the 3q13.31 chromosome region has been identified in patients who are affected by osteosarcomas. Among the genes located within the deleted region, the involvement of the limbic system-associated membrane protein gene (LSAMP), together with a non-coding RNA tumor suppressor candidate 7 gene (TUSC7), has been suggested. We describe the case of an adult acute myeloid leukemia (AML) patient with a novel chromosomal rearrangement characterized by a 3q13.31 microdeletion and an extra copy of the 3q13.31-q29 chromosomal region translocated to the long arm of the Y chromosome. This karyotypic aberration seems to cause LSAMP and TUSC7 gene expression dysregulation. In conclusion, we report the first case of LSAMP and TUSC7 gene overexpression, possibly due to a position effect in an AML patient bearing a 3q13.31 cryptic deletion.

Retinal Abnormalities in Newly Diagnosed Adult Acute Myeloid Leukemia

Retinal abnormalities (RA) are very frequently observed in adult patients with acute myeloid leukemia (AML), but the clinical significance of these findings has not been fully investigated. We examined the fundus oculi in a cohort of 122 adult patients with AML at presentation and analyzed some clinical and biological features to assess whether there was any association with RA. For this purpose, we subdivided the patients into two groups according to the presence or absence of RA (groups 1 and 2, respectively). We considered current laboratory parameters such as white blood cell (WBC) count, hemoglobin (Hb), platelets and serum lactate dehydrogenase (LDH). Moreover, we subdivided the patients into two groups according to age <60 (group A) or ≧60 years (group B) to evaluate a possible association between RA and response to treatment and/or overall survival (OS). In our series, a higher median age and a lower Hb value were associated with group 1 (p = 0.001 and p = 0.04, respectively); the median LDH value was 812 U/l (range 224–5,551) and 607 (range 181–5,244) for groups 1 and 2, respectively (p = 0.02). There was no association between RA and karyotypic alterations. In terms of outcome, in group A (<60 years), 80% patients who achieved complete remission (CR) were in group 2 vs. 13% nonresponders (NR) (p < 0.0001). Median OS of group 2 patients was 49.7 months compared with 7.2 months for those in group 1 (p = 0.002). In group B, 58% patients who achieved CR were in group 1 vs. 15% NR (p < 0.006). Median OS of patients in group 2 was 14.6 months compared with 2.9 months in group 1 (p = 0.02). Our data show that RA are significantly associated with some biological features and with shorter OS in AML patients and this parameter seems to be an effective clinical sign of poor prognosis in terms of CR.