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Key Points Patients with APL treated with ATRA-ATO reported better long-term quality of life outcomes than patients treated with chemotherapy.Late comorbidity and health problem prevalence was similar between patients with APL previously treated with ATRA-ATO or chemotherapy., Visual Abstract, The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA chemotherapy. The median time since diagnosis of the study sample was 8 years. The 2 largest clinically meaningful differences in the EORTC QLQ-C30 were observed for role functioning (Δ = 8.4; 95% confidence interval [CI], 0.5 to 16.3) and dyspnea (Δ = −8.5; 95% CI, −16.4 to −0.7), favoring patients treated with ATRA-ATO. With regard to the SF-36 results, a clinically relevant better physical component score (Δ = 4.6; 95% CI, 1.3 to 7.8) was observed in patients treated with ATRA-ATO, but this was not the case for the mental component score. The 2 groups showed similar profiles in the scores of the EORTC QLQ-CIPN20 scales and in the prevalence of late comorbidities. Overall, our findings suggest that the greater and more sustained antileukemic efficacy of ATRA-ATO is also associated with better long-term patient-reported outcomes than ATRA chemotherapy. This study was registered at www.clinicaltrials.gov as #NCT03096496.

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age.

Here we describe a case of a man with chronic myeloid leukemia at intermediate risk, according to the Sokal index. After cytoreduction with hydroxyurea, the patient started nilotinib at standard dose (600 mg/day) obtaining a complete haematological response after one month of treatment.After about 3 months the patient presented a complete cytogenetic response and after six months major molecular response (MR3). At nine months of treatment the patient presented a complete molecular response (MR4).

Purpose A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. Patients and Methods HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. Results Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, −9.3; 95% CI, −17.8 to −0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. Conclusion Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL.

In a series of 107 patients suffering from acute myeloid leukemia (AML), blast cells from six patients were found to simultaneously express CD2 and CD7 antigens along with CD13, CD33, and CDw 65 in various combinations. The frequency of the expression of both lymphoid markers recurred with a higher incidence than that anticipated by multiplying single antigens frequency. The clinical and hematologic features from CD2+/CD7 + AML patients were studied as well as compared with those of CD2-/CD7- AML patients observed in the same period. Morphologically, bone marrow smears from the AML hybrid subset showed a preponderant population of agranular blasts along with a minority of typical myeloid cells, characterized by larger amount of cytoplasm and, in three cases, by rare but distinct Auer Rods. In all cases more than 3% of blast cells were positive for myeloperoxidases and all samples were classified as M1 according to FAB classification. Clinically, CD2 + /CD7 + patients presented with a higher incidence of adenopathy and meningeal leukemia than did patients with CD2 + /CD7 - AML and were characterized by poor response to therapy in terms of both achievement and duration of remission. We conclude that simultaneous expression of CD2 and CD7 in AML is a non random event, recurring in more than 5% of cases and is associated with distinct clinical and hematologic features.

All-trans-retinoic acid (ATRA) combined with anthracyclines is currently the standard treatment for acute promyelocytic leukemia (APL). In elderly patients the presence of comorbidities, such as cardiomyopathy or different organ failures, often represents an absolute contraindication to standard chemotherapy. In this particular setting of patients, alternative front-line approaches are needed. Here we report the use of gemtuzumab ozogamicin as consolidation therapy in a 68-year-old patient not eligible for standard dose anthracycline due to severe cardiac failure and chronic anticoagulant therapy, affected by low-risk APL. Induction therapy was started with ATRA alone, at a dose of 45 mg/m2 for 80 days. The patient obtained a complete hematological and molecular remission. At day +170 the patient was treated with 6 mg/m2 gemtuzumab ozogamicin monthly for two months (2 total doses) as a consolidation therapy and then started a maintenance program with ATRA 45 mg/m2 for 15 days every three months, for a total time of two years. No adverse events were observed in every phase of treatment and the patient is still in complete continuous hematological and molecular remission 29 months from diagnosis. This approach represents an intriguing therapeutic option to be investigated in randomized studies in low- and intermediate-risk elderly patients (older than 65 years), aiming to minimize or to eliminate standard chemotherapy in advantage of new non-conventional agents, including ATO.

The treatment of acute myeloid leukemia in elderly with age > 65 years is still debated. Various reported studies have valued the feasibility of intensive chemotherapy in these setting of patients. The aim of the our study is to value the difference in DFS and OS among 2 groups of elderly patients with AML treated with intensive chemotherapy (IC) or maintenance (M). From June 2001 to May 2005 we have accepted in our Division 45 patients affected by AML aged up to 65 years. 25 were male and 20 were female, with a median age of 75 years (range 67–86 years). 22 patients (12 M and 10 F, median age: 71 years) received intensive chemotherapy (I.C. Flag and MICE) and 23 (13 M and 10 F, median age: 78 years) received or maintenance therapy (low dose cytarabine) or only support. In IC group 11 patients (50%) have obtained to complete remission (CR) with a DSF and OS media of 7,5 and 6,3 months respectively, and a TRM rate of 27%. In the M group the CR has been documented in 6 patients (35%) treated with low dose of cytarabine, with a DFS and OS media of 6,9 and 4,4 months respectively (graph 1–2). This results have shown, as expected, a better CR rate in the IC group, but without any advantage in terms of OS and DFS when compared with the M group. Difference is not statistically significant between the two groups (p: 0.5). Despite a good CR rate, Intensive chemotherapy do not improves survival in elderly patients. This is probably due to the combination of either a high TRM in patients treated with intensive chemotherapy or a high relapse rate. New therapeutics strategies are needed to improve DFS and OS in these patients. Interesting is the use of specific monoclonal antibodies (anti CD33) in this poor risk disease especially in maintenance after a CR obtainable with a low intensive or low dose chemotherapy. Figure Figure

Autologous stem cell transplantation is an efficacy therapy for limphoproliferative disease. However a concern with the procedure is the potential of malignant cells to reinfuse with stem-cell graft. In the past five year, investigators have used rituximab to purge malignant cells in vivo without any manipulation in vitro. From April 2003 to June 2008 we have treated with Autologous stem cell transplantation, purged in vivo with monoclonal antibodies, 24 patients (8 F; 16 M median age: 55 years) with limphoproliferative diseases to poor prognosis (2 Burkitt lymphoma; 3 Burkitt like lymphoma; 4 mantle cells; 3 CLL; 3 NHL-T cells (1 peripheral and 2 lymphoblastic); 2 follicular and 7 large cells) and we have evaluated the results and the feasibility. In all patients, the purged in vivo, has been effected administering a dose of monoclonal antibodies (anti CD20 in B-NHL and anti CD52 in CLL and T-NHL) before the harvest and after the infusion of the stem-cells. To the transplantation 10 patients were in CR (2 Burkitt lymphoma; 3 Burkitt like lymphoma; 2 large cells; 2 NHL-T lymphoblastic and 1 mantle cells) 9 in PR (1 CLL; 3 mantle cells; 2 follicular and 4 large cells lymphoma) and 5 in resistant disease (2 CLL; 2 large cells and 1 NHL peripheral T cells). All patients have harvest (median CD34:4 ×106/Kg) and median minimal residual disease in the harvest has been < to 2%. All the patients have been conditioned with BEAM and the graft are documented in 22/24 patients (2 patients are dead to the day +4 and +10 for gastric haemorrhage and septic shock respectively) with neutrophils> 1000 in media to day + 11 (range 10–19 days). After transplantation 20/22 patients were in CR, a day +60 the MMR in bone marrow was

New drugs and high dose therapy with auto-transplantation (auto-SCT) has improved prognosis of multiple myeloma (MM). New drugs are promising in upfront therapy while the role of maintenance is still debated. Thalidomide (thal) is an active drug in the treatment of myeloma, and is been investigated as first line therapy, the limit of this drug is the toxicity dependent dose and this determines a poor compliance. It could be useful in the control of minimal residual disease. We used low dose of thal as maintenance after autologous transplantation in patient with MM from January 2002 and here we bring our experience after six years of observation. From January 2002 to August 2008 17 patients (8 males and 9 females) with MM have been treated in our institution. Median age was 59,5 years (range 48–72). 10 were IgG, 3 IgA, 3 light chains and 1 plasma-cell leukaemia. Treatment was 4 cycles of VAD regimen followed by auto-SCT. 4/17 performed double auto-SCT. Three months after SCT these patients has begun the maintenance with thal 50 mg/die, to start thal maintenance 9 patients were in CR, 5 in PR and 3 in resistant disease and the median somministration of thal has been of 12 months (range 3–24 months). Median follow up from the beginning of maintenance therapy was 40 months (range 4–76) with 11/17 (64%) patients in CR or stable disease, with progression free survival (PFS) and overall survival (OS) projected at 75 months respectively of 53% and 51% from to start thal. In our experience we have observed a neurological toxicity (grade I–III) in the 65% of the patients but only 4 have had to suspend the treatment; a haematological toxicity of grade I in the 55% of the patients that have not behaved interruption of the treatment and finally in any case we have documented thrombotic episodes. Finally we have compared this group of patients with another group (18 patients) with the same clinical characteristics that we have observed in the same period but that have not effected maintenance with thal. In this last group 13/18 patients (72%) relapsed with median follow-up of 36 months (range 14–75) and median PFS and OS of 16 and 30 months respectively. The difference between the 2 groups is statistically significant for PFS (p: 0.003) and OS (p: 0.04). The median overall survival observed after progression, in the two groups, has been of 13 months in thal group and 17 months in the group of patients that have not effected the maintenance, this difference is not statistically different (p:0.06). In conclusion in 6 years of observation our experience has shown, even if the number of the patients is small, that maintenance with low doses of thal, after auto-transplantation, it not only has a good compliance but it improves the PFS and OS in this cohort and it doesn’t worsen the OS from the relapse.

Association between fludarabine (Fluda) and cytosine arabinoside (ARA-C) have shown in a variety of single arm studies an effective antileukemic effect with acceptable toxicity in high risk myelodisplasias and acute myeloid leukemias in elderly patients. In order to increase the synergistic effect of fluda and ARA-C further association (i.e. anthracyclines) or different schedules of administration (i.e. continous infusion) have been performed but not compared. In order to asses if there is an advantage of an association or schedule compared to another we retrospectively analyzed results from two different fludarabine-based regimens administered as front-line therapy in patients with acute myeloid leukemias aged up to 60 years. A total of 42 patients were treated with fluda 25 mg/m2, ARA-C 1 gr/m2 and idarubicin 5 mg/m2 as single day administration for three days (FLAI) or fluda 20 mg/m2 and ARA-C 1,4 mg/m2 as continuous infusion for three days fluda and 4 days ARA-C (c.i.FLA). Total dosage of fluda was 75 mg/m2 in FLAI and 70 mg/m2 in c.i.FLA, while ARA-C total dose was 3 gr/m2 in FLAI and 6,15 gr/m2 in c.i.FLA. Dose administered of idarubicin in FLAI was 15 mg/m2. Patients who obtained complete remission (CR) defined as less of 5% of bone marrow blasts received a second course of the same chemotherapy as consolidation, reduced at 3 days in c.i.FLA. 19 patients were treated with FLAI regimen, 9 males and 10 females, mean age 69,3 years (range 61–75) and 23 received c.i.FLA regimen, 12 male and 11 female, mean age 69,4 years (range 61–84). 4 patients in each group showed unfavourable kariotype. Results were as follows: 8/19 (42%) patients obtained CR after induction with FLAI while 11/23 (48%) were in CR after first course c.i.FLA. Difference is not statistically significative. Median disease free survival (DFS) was 9,53 months for FLAI and 7,67 months for c.i.FLA (p=NS) and median overall survival (OS) in the group in CR was 10.8 in the FLAI group and 10 months in c.i.FLA group (p=NS). Induction deads were 1/19 in FLAI group (5%) and 3/23 in c.i.FLA group (13%). The global median OS, including resistant patients was 6,57 months for FLAI and 6 months for c.i.FLA (p=NS). Two patients in each group underwent autologous bone marrow transplantation in complete remission. Results of the comparison of this two different regimens suggest that there is no substantial difference between single daily administration added of idarubicin and continuous infusion of fluda and ARA-C. Both cycles seem to have the same antileukemic activity with overlapping toxicity. Median time to neutrophil recovery (> 1000/mmc) was 16 in c.i.FLA and 14,5 in FLAI while platelets recovery (> 20000/mmc) was 18 in c.i.FLA and 13 in FLAI. Both schedules can be, in our opinion, safely used as front-line therapy in elderly patients affected by acute myeloid leukemias. What is to underline in this setting of patients is the short duration of the CR. Probably some kind of maintenance or association without increasing toxicity is needed, and experience with monoclonal antibodies are an interesting way to follow.

Ca 15-3 is a glycoprotein present in the cells of the mammary carcinoma and in some epithelial cells. Is a marker used for the monitoring of the breast and gastrointestinal carcinoma. The megaloblastic anaemia is an anaemia characterized by deficit of absorption of Vitamin B12 and is associated with gastritis atrophic and the target cell is the parietal gastric cell. In our institution, from June 2003 to December 2004, the level of Ca15-3 and of others tumour markers (CEA; Ca125; Ca19.9; alfa-FETO) they have been tested in the serum of 16 patients (9 male and 7 female with median age of 64,5 and range of 37–80 years) with de novo megaloblastic anaemia, 2 patients were gastrectomized. In all patients has been effected: esophagogastroduodenoscopy and control anti-parietal gastric cells antibody (APCA). Increase level in the serum of CA 15-3 with normal level of other tumour markers have been found in 14/16 patient with median value of 61 U/ml (range 35–100 U/ml) in two patients (gastrectomized) the value of CA 15-3 was normal. Besides in 12/14 patients have shown positivity for the APCA, only in two patients has been diagnosed a gastritis atrophic, in the other patients has been observed a normal gastric mucous. After a median observation of 24 months any patient has developed a mammary or gastro-intestinal carcinoma These results indicate what the increased level of CA 15-3 antigen in patient with megaloblastic anaemia is positively correlated with APCA and with the presence of a normal gastric mucous. These clinical conditions make to suppose the destruction from the APCA of the parietal gastric cells with the liberation of this glycoprotein and this is shown in two patients gastrectomized with presence of APCA and not increased level of the CA 15-3. In conclusion the CA15-3 antigen is probably an specific marker for the diagnosis of megaloblastic anaemia and is probably associated with the destruction of parietal gastric cells.

Background The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy regimens is currently considered the standard of care for newly diagnosed acute promyelocytic leukemia (APL) patients. This combination has greatly contributed to convert APL from a frequently fatal disease to a highly curable one. However, there is lack of data on the impact of such therapies on patients’ health-related quality of life (HRQOL). Objective The main objective of this study was thus to investigate long-term HRQOL of APL patients previously treated with ATRA plus anthracycline-based chemotherapy. The physical and mental HRQOL profile of these patients was compared with that of matched control subjects from the general population to identify specific areas most in need of attention in long-term follow-up care. A secondary objective was to outline symptoms’ burden from the patients’ perspective. Patients and Methods Data were gathered through an ongoing multicenter survivorship study that recruits APL patients previously enrolled in two large GIMEMA trials (i.e., AIDA0493 and AIDA 2000). In both trials, APL patients were treated with ATRA plus Idrarubicin (AIDA). The main inclusion criterion was having survived the initial diagnosis for more than 5 years and being in complete remission (CR). Generic HRQOL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE) and mental health (MH). All scales ranged between 0 and 100, with the higher scores representing better outcomes. Clinical significance was evaluated and eight points were considered to be a minimally important difference for the eight SF-36 scales. Mean SF-36 scores were compared to available national general population reference values (i.e., 1997 subjects without cancer) and all analyses were adjusted for age and gender. Symptom burden was assessed according to the M.D. Anderson Symptom Inventory (MDASI). Symptom severity was assessed for the following symptoms: fatigue, pain, sleep disturbance, drowsiness, poor appetite, shortness of breath, nausea, vomiting, dry mouth, numbness, difficulty remembering, distress and sadness. All items were rated on a numeric rating scale from 0 to 10, with the higher scores indicating a higher level of symptoms. These were categorized as “mild” (ratings between 0 and 3) and “moderate to severe” (ratings between 4 to 10). Results Analysis is based on 136 adult APL patients who agreed to participate. At study participation, the mean age of patients was 52 years (55% males and 45% females) and the median time from diagnosis was 13 years (range: 4.5-20). Age and gender adjusted comparisons between APL patients and the general population norms revealed worse outcomes for the following scales: RP (P Conclusions Although ATRA plus anthracycline-based chemotherapy regimens have greatly increased cure rates in APL, the HRQOL of these patients is heavily affected by the consequences of the disease and treatment, that persists many years after diagnosis and treatment. Disclosures: No relevant conflicts of interest to declare.