Treatment Of Acute Myeloblastic Leukemia Research Articles

PB1824: IMPACT OF DAY 15 BONE MARROW ASPIRATION ON PREDICTION OF COMPLETE REMISSION AND RELAPSE IN ACUTE MYELOID LEUKEMIA

Background: Although all the progress made in hematology in the last decades, the treatment of acute myeloblastic leukemia (AML) is still disappointing with long term survival which does not extend 40%. Aims: The aim of our study is to assess the impact of early bone morrow blast (BMB) clearance in prediction of complete remission and relapse risk in acute myeloid leukemia Methods: We conducted a retrospective study including patients with AML treated with standard induction chemotherapy (3 days of idarubicine 12mg/m2 and 7days of cytarabine 200mg /m2) at the department of hematology at Aziza Othmena Hospital in Tunisia during 2020 - 2021. Results: Thirty four patients were included. The median age was 41 (range 17-57) and sex ratio was 1.5 (22M/12F). At the time of diagnosis, the median of white blood cells count was 57.8G/L (range 0.76-300G/L) and cytogenetic data were available for 91% of patients. According to cytogenetic stratification, our patients were classified as favorable in 29%, intermediate in 45.1% and unfavorable risk in 25.8% of cases. At the end of induction course, complete remission (CR) was achieved in 64% of patients. Induction related mortality was 8.8%. The most common cause of death was infection (66%). Bone morrow aspiration at day 15 was performed for all our patients. Only one patient had re-induction at day 18. Fifteen patients (44%) had more than 5% BMB in day 15. 53% of patients with more than 5% BMB did not achieve a CR compared to 18% with less than 5% BMB. (p=0.05) Induction related mortality was not affected by the results of BMB in day 15. However, the relapse rate was significantly higher in the group of patients with more than 5% BMB at day 15 compared with the other group (66% vs 0%; p=0.002). Summary/Conclusion: Our study showed a significant statistical relation between BMB at day 15 and relapse risk. Thus, the kinetic of bone morrow blast clearance could be correlated to the minimal residual disease at the end of induction and so could predict the risk of relapse.

Necrotizing periodontitis or medication-related osteonecrosis of the jaw (MRONJ) in a patient receiving Bemcentinib\u2014a case report

Bemcentinib is a newly developed AXL inhibitor that is currently under investigation in phase II trails for the treatment of acute myeloblastic leukemia (AML). Clinical and radiographic findings in this case were very similar to cases of MRONJ in patients receiving Sunitinib or other anti-angiogenetic substances, assuming that Bemcentinib may cause similar oral side effects. We present a male 81-year-old patient with a manifestation of alveolar bone necrosis at the central upper incisors following a 2-month regimen with the AXL-inhibitor Bemcentinib, administered for the treatment of secondary acute myeloblastic leukemia (sAML). Due to the duration of less than 8 weeks, the osteonecrosis was diagnosed as necrotizing periodontitis, but the intraoral clinical and radiographic findings were also compatible with the differential diagnosis of medication-related osteonecrosis of the jaw (MRONJ, stage II). Following to discontinuation of Bemcentinib, the affected bone was surgically revised including the removal of a demarcated bone sequester under preventive antibiotic treatment (metronidazole 400 mg t.i.d.). We hypothesize that Bemcentinib might increase the susceptibility for osteonecrosis of the jaw, probably related to its antiangiogenic effects and the resulting modulation of host immune response. Based on the current observations, it can be assumed that oro-dental health might be significant also prior and during treatment with Bemcentinib for the prevention of MRONJ.

A general view of CD33+ leukemic stem cells and CAR-T cells as interesting targets in acute myeloblatsic leukemia therapy.

Acute myeloblastic leukemia (AML) is the most frequent acute leukemia in adulthood with very poor overall survival rates. In the past few decades, significant progresses had led to the findings of new therapeutic approaches and the better understanding of the molecular complexity of this hematologic malignancy. Leukemic stem cells (LSCs) play a key role in the initiation, progression, regression, and drug resistance of different types of leukemia. The cellular and molecular characteristics of LSCs and their mechanism in the development of leukemia had not yet been specified. Therefore, determining their cellular and molecular characteristics and creating new approaches for targeted therapy of LSCs is crucial for the future of leukemia research. For this reason, the recognition of surface maker targets on the cell surface of LSCs has attracted much attention. CD33 has been detected on blasts in most AML patients, making them an interesting target for AML therapy. Genetic engineering of T cells with chimeric antigen receptor (CAR-T cell therapy) is a novel therapeutic strategy. It extends the range of antigens available for use in adoptive T-cell immunotherapy. This review will focus on CAR-T cell approaches as well as monoclonal antibody (mAB)-based therapy, the two antibody-based therapies utilized in AML treatment.

Performance of prognostic scoring systems in elderly patients with acute myeloid leukaemia on intensive chemotherapy: A PETHEMA registry study

Selection of elderly patients (aged ≥60 years) for intensive chemotherapy treatment of acute myeloblastic leukaemia (AML) remains challenging. Several cooperative groups such as Acute Leukaemia French Association (ALFA), Haematological Oncology Clinical Studies Group (HOCSG) and MD Anderson Cancer Center (MDACC) have developed predictive models to select those patients who can benefit from intensive chemotherapy. Our purpose is to validate and compare these three models in a cohort of patients treated in real-life setting. For this, a total of 1724 elderly AML patients and treated with intensive chemotherapy regimens were identified in the PETHEMA registry. Median age was 67.2 years (range, 60–84,9) and median overall survival [OS] 9 months (95 % confidence interval [CI], 8.2–9.7). Taking into account the ALFA group's model, patients likely to benefit from intensive chemotherapy had longer OS (14 months, 95 % CI 12.3–15.7) than those unlikely to benefit (5 months, 95 % CI 4.1–5.9; p < 0.001). Significant differences in OS were observed between patients with favourable risk (17 months, 95 % CI 13.2–20.7), intermediate risk (11 months, 95 % CI 9.3–12.6) and adverse risk (6 months, 95 % CI 5.1–6.4; p < 0.001) according to the HOCSG model. No significant differences in OS were observed between patients with 0, 1, 2 or ≥3 points according to the MDACC model. However, when patients with ≥1 point were compared with those with 0 points, median OS was significantly longer in the latter [15 months (95 % CI 12.1–17.8) vs 7 (95 % CI 5.7–8.5)]. This retrospective study validates predictive models proposed by the ALFA, HOCSG and MDACC groups in this real-life cohort.

SP-26 - Will Car T-cell therapy replace hematopoietic stem cells transplant?

Selection of elderly patients (aged ≥60 years) for intensive chemotherapy treatment of acute myeloblastic leukaemia (AML) remains challenging. Several cooperative groups such as Acute Leukaemia French Association (ALFA), Haematological Oncology Clinical Studies Group (HOCSG) and MD Anderson Cancer Center (MDACC) have developed predictive models to select those patients who can benefit from intensive chemotherapy. Our purpose is to validate and compare these three models in a cohort of patients treated in real-life setting. For this, a total of 1724 elderly AML patients and treated with intensive chemotherapy regimens were identified in the PETHEMA registry. Median age was 67.2 years (range, 60–84,9) and median overall survival [OS] 9 months (95 % confidence interval [CI], 8.2–9.7). Taking into account the ALFA group's model, patients likely to benefit from intensive chemotherapy had longer OS (14 months, 95 % CI 12.3–15.7) than those unlikely to benefit (5 months, 95 % CI 4.1–5.9; p < 0.001). Significant differences in OS were observed between patients with favourable risk (17 months, 95 % CI 13.2–20.7), intermediate risk (11 months, 95 % CI 9.3–12.6) and adverse risk (6 months, 95 % CI 5.1–6.4; p < 0.001) according to the HOCSG model. No significant differences in OS were observed between patients with 0, 1, 2 or ≥3 points according to the MDACC model. However, when patients with ≥1 point were compared with those with 0 points, median OS was significantly longer in the latter [15 months (95 % CI 12.1–17.8) vs 7 (95 % CI 5.7–8.5)]. This retrospective study validates predictive models proposed by the ALFA, HOCSG and MDACC groups in this real-life cohort.

OP-33 - Characteristics and outcome of patients with hematological malignancy admitted to intensive care unit: a single-centre experience

Selection of elderly patients (aged ≥60 years) for intensive chemotherapy treatment of acute myeloblastic leukaemia (AML) remains challenging. Several cooperative groups such as Acute Leukaemia French Association (ALFA), Haematological Oncology Clinical Studies Group (HOCSG) and MD Anderson Cancer Center (MDACC) have developed predictive models to select those patients who can benefit from intensive chemotherapy. Our purpose is to validate and compare these three models in a cohort of patients treated in real-life setting. For this, a total of 1724 elderly AML patients and treated with intensive chemotherapy regimens were identified in the PETHEMA registry. Median age was 67.2 years (range, 60–84,9) and median overall survival [OS] 9 months (95 % confidence interval [CI], 8.2–9.7). Taking into account the ALFA group's model, patients likely to benefit from intensive chemotherapy had longer OS (14 months, 95 % CI 12.3–15.7) than those unlikely to benefit (5 months, 95 % CI 4.1–5.9; p < 0.001). Significant differences in OS were observed between patients with favourable risk (17 months, 95 % CI 13.2–20.7), intermediate risk (11 months, 95 % CI 9.3–12.6) and adverse risk (6 months, 95 % CI 5.1–6.4; p < 0.001) according to the HOCSG model. No significant differences in OS were observed between patients with 0, 1, 2 or ≥3 points according to the MDACC model. However, when patients with ≥1 point were compared with those with 0 points, median OS was significantly longer in the latter [15 months (95 % CI 12.1–17.8) vs 7 (95 % CI 5.7–8.5)]. This retrospective study validates predictive models proposed by the ALFA, HOCSG and MDACC groups in this real-life cohort.

PB1708 THERAPEUTIC POTENCIAL OF GAMBOGIC ACID AND SILIBININ IN ACUTE MYELOBLASTIC LEUKEMIA – IN VITRO STUDIES

Background:Acute myeloblastic leukemia (AML) is a malignant hematological disease characterized by an uncontrolled proliferation of multipotent hematopoietic progenitors with subsequent accumulation of immature myeloid cells in the bone marrow. Despite the development of new therapies, standard treatment for AML relies in intensive chemotherapy with combination of several drugs. Natural compounds such as gambogic acid (GA), extracted from Garcinia hanburyi, and silibinin (SLB), from Silybum marianum, showed an antitumoral effect in many neoplasms, by induction of apoptosis and differentiation and proliferation inhibition. SLB display several targets including anti‐apoptotic molecules (survivin), apoptotic proteins (caspases), cell proliferation mediators (NF‐KB), cell cycle regulators (cyclin D1), tumor suppressors (p53), and chaperones (HSP90). On the other hand, GA induces cell death through the interaction with several extrinsic and intrinsic apoptotic proteins, autophagy induction as well as telomerase and proteasome inhibition. However, the effect of these two compounds on AML is still unclear.Aims:The aim of this study was to evaluate the therapeutic potential of gambogic acid and silibinin in monotherapy, in single and daily fractioned administration scheme, and in therapeutic combination, in acute myeloid leukemia cell lines.Methods:We used two in vitro AML models, KG‐1 and THP‐1 cells, incubated in absence and presence of increasing concentrations of GA (5 – 1000 nM) and SLB (0.5 – 250 μM), in monotherapy at single dose and at daily administration (e.g. GA 150 nM in single dose vs GA 50 nM/day during 3 days) and in combination therapy (GA 50 nM + SLB 15 μM). Metabolic activity was evaluated by resazurin assay. Cell death was assessed by optic microscopy (May‐Grünwald‐Giemsa staining) and flow cytometry (FC), using the Annexin V and 7‐AAD double staining. Cell cycle using IP/RNase and caspase‐3 activation were evaluated by FC. Combination Index (CI) was calculated using CompuSyn software. All the adequate statistical analysis was performed considering a level of significance of 95% (p &lt; 0.05).Results:Results show that GA and SLB decrease the metabolic activity in a time, dose and cell line dependent manner, being KG‐1 the most sensitive cells to SLB. After 72 h of incubation, IC50 of GA was 338 nM in KG‐1 cells and 453 nM in THP‐1, while IC50 for SLB was 33 μM and 75 μM in KG‐1 and THP‐1, respectively. Daily administration was more effective in KG‐1 cells, whereas combination therapy have a synergistic effect (CI &lt; 1) in both cell lines (CI=0.17 in KG1; CI=0.16 in THP‐1 cells). These compounds induced cell death by apoptosis, with increased caspase‐3 activation, and typical morphological features of apoptosis, namely blebbing and DNA fragmentation. Cell cycle analysis demonstrated that SLB induced cell cycle arrest in G0/G1, mainly in THP‐1 cell line, while GA had no cytostatic effect.Summary/Conclusion:Our results suggest that GA and SLB may be potential treatment options in acute myeloblastic leukemia, particularly in therapeutic combination. However, their efficacy is depending on cellular characteristics and/or on drug administration scheme.

Outcome of Acute Myeloid Leukemia in Children Adolescents and Young Adults Treated with an Uniform Protocol in Casablanca, Morocco.

Treatment of acute myeloblastic leukemia in children, adolescents and young adults (AYA) is a challenge in low-income countries. To evaluate treatment outcomes of children (≤ 15years) and AYA (15-30years) diagnosed with novo AML and treated in a single center according to the AML-MA 2011 protocol. From January 2011 to December 2015, eligible patients (age ≤ 30years) with novo AML had been enrolled on a uniform treatment protocol. The diagnosis was confirmed according to the FAB classification using the WHO 2008 criteria. Patients with WBC ≥ 50G/L had pretreated 4days of hydroxyurea followed by two inductions and two consolidations. Supportive care consisted of transfusion of labile blood products, antibiotics and antifungals, and patient and family education by the hygiene team. 155 patients were recruited, 41 were < 15years old (22 boys, median age 7.8years). Of the 114 AYA enrolled, (48 women, median age 23years). Complete remission after two inductions was 28/41 (68.3%) of the children, including 100% of the children in the favorable group and 71/114 (62.3%) of the AYA, 22 of whom (68.7%) were in the favorable group. The number of deaths among children was 6 (14.6%). The evaluation of the AML-MA-2011 National Protocol in the age groups of children and AYA reveals that the objective of treatment is almost achieved in terms of complete remission in the two age groups.

Self-assembling nanoparticles based on cytarabine prodrug for enhanced leukemia treatment

Cytarabine (Ara-C) is an attractive chemotherapeutic agent used for the treatment of acute myeloblastic leukemia, however, its severely drawbacks such as low lipophilicity and rapid plasma degradation limit clinical applications. Here, we synthesized a new Ara-C prodrug DTA-Ara by conjugating 2-decyltetradecanoic acid (DTA), a double-chained fatty acid with 24 carbons with Ara-C. It was the first time to see that DTA-Ara molecules could self-assemble into stable spherical nanoparticles (NPs) in aqueous solution with extremely high drug loading (63wt%). The DTA-Ara NPs had the average sizes of approximately 130nm and a zeta potential around −31.6mV. Importantly, the DTA-Ara NPs were stable in deionized water or phosphate buffer solution (PBS, pH7.4) solution for more than one week and the hemolysis rate was <10%, which indicated that it could be administrated intravenously. Moreover, the in vitro cytotoxicity study further manifested that the resulting prodrug showed the marked antitumor activity against human leukemia cell line K562 and HL60 cells compared to the naked drug ascribed to its improvement of the hydrophobicity and biomembrane penetrability. The strategy of delivering lipophilized nucleoside analogs using prodrug self-assembling nanoparticles demonstrate potential superiority for Ara-C and provide a new promising therapeutic schedule for leukemia.

Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment

Background. The current approach to treatment of acute myeloblastic leukemia (AML) includes the achievement of maximum tumor reduction and, therefore, eradication of a leukemic clone. The goal of the therapy is to achieve undetectable levels of the target gene, except an isolated molecular rearrangement of RUNX1-RUNX1T1. Aim. To estimate the dynamics of the RUNX1-RUNX1T1 level and relevant clinical manifestations during the monitoring of various stages of the program therapy and after its completion. Methods. The article presents a description of 10 cases of AML with isolated RUNX1-RUNX1T1 expression (n = 4) and the expression in combination with different molecular and cytogenetic abnormalities (n = 6). In addition, a long-term monitoring of the gene expression by quantitative determination of RUNX1-RUNX1T1 using a real-time PCR was presented. Results. The incidence of relapses in a group with a decreased RUNX1-RUNX1T1 expression level of &gt;2 log is 75 % as compared to patients with a less significant reduction of the transcript level (with the relapse incidence equal to 0 %) (p = 0.05). The increase of the RUNX1-RUNX1T1 level against the background of bone marrow remission by more than 1 log coincided with a bone marrow relapse within 5-18 weeks. In addition, long-term persistence of a certain transcript level after the completion of a program therapy without relapse is possible. Conclusion. The study analyzed possible molecular background of different clinical outcomes of long-term persistence of the RUNX1-RUNX1T1 transcript that might lead to an individualized approach to AML patients.

Effectiveness of Fludarabine- and Busulfan-Based Conditioning Regimens in Patients With Acute Myeloblastic Leukemia: 8-Year Experience in a Single Center

ObjectiveAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for acute myeloblastic leukemia (AML). Because the conditioning regimen of busulfan plus cyclophosphamide carries significant risks of toxicity, we evaluated the factors affecting survival after fludarabine replacement instead of cyclophosphamide. MethodsThe study included 55 patients who underwent allo-HSCT for AML and received busulfan, fludarabine, and antithymocyte globulin (ATG). ResultsForty-eight patients received a myeloablative regimen; 7 patients received a reduced-intensity conditioning regimen. The neutrophil and platelet engraftment times were 12 days (range 9 to 20) and 12 days (range 7 to 19), respectively. Graft-vs-host disease (GvHD) developed in 10% and 50% of the patients, respectively. Seven patients received donor lymphocyte infusion. Of them, 5 patients developed grade I or II GvHD, one grade IV GvHD. The median follow-up period was 20.6 months. The predicted progression-free survival (PFS) at 1 and 3 years after transplantation was 78% and 74%, respectively. The overall survival (OS) at 1, 3, and 5 years was 76%, 74%, and 62%, respectively. Treatment-related mortality (infection in 1 patient, GvHD in 2 patients) occurred in 3 patients (5.5%). Multivariate analysis revealed that OS and PFS were not influenced by age, dose of busulfan or ATG, or presence of cytomegalovirus antigenemia. Acute GvHD and pretransplantation minimal residual disease positivity negatively affected the transplant outcome. The presence of active disease at the time of transplantation was found as an independent risk factor for AML. ConclusionsBusulfan- and fludarabine-based conditioning regimens are effective for AML, and have acceptable toxicity, morbidity, and mortality.

Relapsed acute myeloblastic leukemia: first pediatric randomized study.

The current cure rate achieves 80% of long-term survival in childhood acute lymphoblastic leukemia (ALL) and only 50-60% in acute myeloblastic leukemia (AML) (1). However, in patients who relapse following treatment of AML, the odds are not as far in their favor, and the probability of overall survival is 16-34% (2,3).

Akut Miyeloid Lösemili Hastaların Pekiștirme Tedavisinde Hematopoetik Büyüme Faktörü Kullanımının Maliyet Etkinliği

Amaç: Akut miyeloid lösemi (AML) kemik iliğinin habis ve klonal bir hastalığı olup hematopoetik öncül hücrelerin neoplastik dönüșümü ile gelișir. Bu çalıșma; AML tedavisinde kullanılan G-CSF’ün nötropeni süresi, enfeksiyon sıklığı, febril nötropeni süresi, antibiyotik ve/veya antifungal kullanım süresi ve maliyet üzerine etkisini araștırmak üzere planlandı. Yöntemler: Çalıșmaya toplam 40 hasta alındı (19 kadın, 21 erkek, yaș ortalaması 42). Hastalar G-CSF kullanılan ve kullanılmayan iki gruba ayrıldı. Nötropeni gelișme zamanı, nötropeni süresi, ateșin ortaya çıkıș zamanı, ateșin süresi, kültürle ispatlanan enfeksiyon, antibiyotik ve antifungal kullanım süresi, hastanede yatıș süresi, antibiyoterapi maliyeti ve toplam maliyet verileri iki grup arasında kıyaslandı. Bulgular: G-CSF grubunda; nötropeni süresi, ateș ortaya çıkıș zamanı, hastane yatıș süresi, ateș süresi, antibiyotik ve antifungal tedavi süresi ve antibiyoterapi maliyeti azaldı. G-CSF grubunda; antibiyoterapi dıșı günlük hastane maliyeti ve toplam maliyette hafif azalma mevcuttu (P: 0,751). Sonuç: AML’li hastaların pekiștirme tedavisinde kullanılan yüksek doz ARA-C protokolüne G-CSF grubunda eklenmesi nötropeni ve hastanede yatıș süresini anlamlı olarak kısaltır (p

Abstract 3540: Down-regulation of solute carrier family 17 member 1(SLC17A1) expression contributes to chemotherapy resistance in acute myeloid leukemia

Abstract Cytosine arabinoside (Ara-C), an structural analogue of deoxycytidine, is generally considered to be the major drug in the treatment of AML. In acute myeloblastic leukemia (AML) treatment, resistance to cytotoxic nucleoside analogues is a major problem. To investigate novel genes associating with becoming Ara-C resistant cells, whole genome SNP chip analysis was performed. However, there was no significant in Ara-C metabolite genes. In that analysis, 12 region of loss of heterozygote (LOH) was found in non-CR group. SLC17 family gene and HIST1H family gene located in major of LOH in non-CR group. Since SLC29A1 expression levels directly affected the Ara-C mediated Apoptosis, we selected SLC17A1 among them and functional analysis of SLC17A1 was performed. Its expression levels were examined in four different AML cell lines using RT-PCR. Its expression level was a little different but that gene seemed to be constitutively expressed. To detect the pattern change of SLC17A1 in survival AML cells against Ara-C treatments, four AML cell-lines underwent 10−8 M of Ara-C addition/ depletion for 2 and 4 cycles. The results showed that expression of SLC17A1 was decreased more than SLC29A1 expression in the same treated condition. To examine whether the expression levels of SLC17A1 was associated with Ara-C resistance, Ara-C resistant HEL cell was established in vitro and in vivo (HEL-R1 and HEL-R1-vivo). Our results indicated that SLC17A1 mRNA expression of both resistant cells is decreased or less increased than HEL cells in Ara-C treatment. And the reduction of SLC17A1 mRNA by shRNA of SLC17A1 effectively suppressed Ara-C mediated apoptosis. Our results suggested that the function of SLC17A1 gene was similar to that of SLC29A1. Taken together, the expression levels of SLC17A1 also might involve the cytotoxic effects of Ara-C treatment. SLC17A1 could be a novel gene controlling Ara-C mediated apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3540.

Severe chronic graft-versus-host disease of the fasciae and muscles of the hand—Case report

Chronic graft-versus-host disease (cGVHD) is very common after allogeneic hematopoietic cell transplantation with an incidence of 20–80%. It can occur at variable intervals after allogeneic transplantation in any organ containing lymphoid cells. Mucocutaneous manifestations of cGVHD are the most frequent with variable manifestations, followed by involvement of the gastrointestinal tract, liver and lung. Musculocutaneous cGVHD presents with connective tissue changes that may resemble eosinophilic fasciitis or systemic collagen vascular diseases such as scleroderma, dermatomyositis or systemic lupus erythematosus. The musculocutaneous changes are associated with serious physical and functional impairment which can lead to considerable impairment of patient's quality of life. As magnetic resonance imaging allows for more detailed assessment of extent and activity of the inflammatory infiltration in the deep soft tissue, it may contribute to early diagnosis and staging and allow for adequate treatment with systemic immunosuppressants. We report about a rare manifestation of musculocutaneous chronic graft-versus-host disease (cGVHD) in a 74-year-old female patient who developed severe musculocutaneous symptoms of the hand after allogeneic hematopoietic cell transplantation for treatment of acute myeloblastic leukaemia. Based on this case, typical clinical and morphological features of musculocutaneous cGVHD are discussed and the potential role of magnetic resonance imaging in the assessment of the severity of the musculocutaneous involvement is shown. Awareness of possible musculocutaneous manifestation of cGVHD may be helpful for radiologists in identifying patients presenting with similar symptoms and image findings after allogeneic hematopoietic cell transplantation in order to provide early and adequate treatment. Moreover, magnetic resonance imaging may offer an objective and reproducible measuring tool in the evaluation of treatment response because this imaging technique provides reliable assessment of depth, infiltration and activity of the disease.

A Phase I/II, National, Multicenter, Open Label Study of Bortezomib (Velcade) and Fludarabine, Cytarabine and Idarubicin (Flag-Ida) (V-Flag-Ida) in Pts with Relapsed and/or Refractory Acute Myeloblastic Leukemia (AML).

A Phase I/II, National, Multicenter, Open Label Study of Bortezomib (Velcade) and Fludarabine, Cytarabine and Idarubicin (Flag-Ida) (V-Flag-Ida) in Pts with Relapsed and/or Refractory Acute Myeloblastic Leukemia (AML).

Défaillance multiviscérale et infection disséminée à adénovirus

Background Peripheral blood stem cell transplantation is a frequent option, especially for patients with hematological malignancies. Case reports A first patient received this treatment for acute myeloblastic leukemia, the second for Richter's syndrome (follicular lymphoma). In both cases, allograft (unrelated donor, non myeloablative conditioning) was followed by graft versus host disease (GVH) requiring an immunosuppressive treatment. Respectively 15 and three months after graft, these two patients presented with multiple organ failure including very severe hepatic dysfunction. The diagnosis was made according to positive blood PCR, positive BAL, and hepatic histological findings. Discussion Adenoviruses, frequent in pediatrics, can be responsible for extremely severe infections among immunocompromised adults. T lymphocyte depletion plays a key role. Conclusion Adenoviral infections can be fatal among immunocompromised patients. Diagnostic improvement should lead to early treatment, which however, remains to be clearly defined.

Ex Vivo Cytotoxic Activity of Endoribonucleases, Onconase (ranpirnase) and R-Amphinase, against Acute Myeloblastic Leukemia Cells

Most patients with acute myeloblastic leukemia (AML) to whom allogeneic stem cell transplantation is unavailable cannot be cured by the standard chemotherapy regimen. Because cytostatic agents used for AML treatment induce damage to DNA of both tumor and proliferating normal cells significant toxicity to the patients is observed. Therefore, there is a need to develop new strategies that would be more effective in terms of selectively targeting tumor cells. A promising therapeutic approach may involve the use of agents targeting cellular RNA namely cytostatic/cytotoxic ribonucleases derived from Rana pipiens oocytes. One of them, onconase (ranpirnase, ONC) has been found to be effective in clinical trials for treatment of malignant mesothelioma and other solid tumors, as well as in preclinical in vitro studies on several leukemia lines. More recently, antitumor activity of R-amphinase (R-Amph) has also been reported. As of yet, none of those agents have been tested ex vivo in hematological malignancies. The goal of this study was to assess the anti-tumor properties of both these endoribonucleases in leukemic cells derived from patients with AML. Toward this aim, leukemic cells isolated from 22 patients with newly diagnosed AML were cultured for 24 – 72h with either ONC or R-Amph alone and also in combination with the cytostatic drugs used in routine treatment of AML, namely doxorubicin (DOX) and cytarabine arabinoside (ARA-C). In pilot experiments, the cytostatic/cytotoxic effects of ONC and R-Amph were tested on AML and HL-60 cell lines. Cytotoxicity of the study drugs was assessed by the propidium iodide exclusion assay. Their pro-apoptotic activity was examined by the Annexin-V (Ann-V) binding test, detection of caspase-3, -8, and -9 activation, and a reduction of mitochondrial potential as an expression of apoptosis–regulating proteins from Bcl-2 family. Compensated apoptotic index (CAI) has been calculated based on Ann-V assay a difference in the percentage of apoptotic cells between drug-treated sample and parallel untreated control. The results indicate that ONC and R-Amph were effective anti-leukemic drugs against AML cells in both in vitro and ex vivo settings at comparable concentrations. ONC at 10mg/ml and R-Amph also at 10mg/ml concentration were found to induce significant cytotoxicity for the studied cells. The effect was evident after 48 h of the treatment (both drugs versus control – p <0.03). After 72 h of incubation with the drugs CAI for ONC was 15.9%; p = 0.011 and for R-Amph 34.3%; p = 0.0005, respectively. In the ex vivo testing the combination of ONC or R-Amph with DOX have shown an increased pro-apoptotic effect compared to each of these agents when used alone. The synergistic effect was observed for both ONC and DOX (combination index, CI, 0.67) and R-mph and DOX (CI 0.58). Induction of apoptosis was the mechanism of cytotoxicity. The mitochondrial pathway of apoptosis was manifested by a reduction of mitochondrial potential and activation of caspase-9 and caspase-3. Concurrently, an increase in expression of the pro-apoptotic Bax (p=0.001; versus control) and decrease anti-apoptotic Bcl-2 expression (p=0.027; versus control) was observed after 72 h of treatment. In conclusion, this is the first study showing in ex vivo experiments that both endoribonucleases, ONC and R-Amph, are significantly effective against AML cells. The main mechanism of this action is triggering the caspase-dependent apoptosis by activation of the mitochondrial pathway. The combination of ONC or R-Amph with DOX exerts synergistic cytotoxicity. The data clearly indicate that study on ONC and R-Amph activity in AML should be continued in in vivo settings and then, eventually, in clinical trials.

Early Acute Myeloblastic Leukemia Treatment for Childhood Myelodysplastic Syndrome With t(3;5) (NPM/MLF1)

Myelodysplastic syndromes (MDS) in childhood are rare hematologic diseases. MDS with t(3;5) (NPM/MLF1) is an unusual subtype without a well-defined clinical and prognostic pattern. A poor outcome has been reported, suggesting that hematopoietic transplantation is the only treatment option. Here in we described a 2-year-old child diagnosed with the disease, without a suitable hematopoietic donor, treated early in the disease with chemotherapy. He is alive and well 4 years after the end of treatment. This unusual MDS needs further studies to better understand the disease.

Current status of reduced intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

Allogeneic stem cell transplantation (allo-SCT) is the most efficient antileukemic treatment for acute myeloblastic leukemia (AML). However, elderly patients can rarely benefit from standard myeloablative allo-SCT because of an unacceptable rate of procedure-related toxicities. This point is critical when considering AML patients in first complete remission. The development of the so-called reduced-intensity conditioning (RIC) regimens appears to decrease allo-SCT-related toxicities, and has emerged as an attractive modality in AML patients not eligible for standard allo-SCT. Such RIC regimens aim primarily to provide the immune graft-versus-leukemia effect while causing little toxicity. Of note, treatment-related toxicity appears to be lower with RIC regimens as compared to standard myeloablative regimens. Nevertheless, toxicity might represent only one aspect of the problem, since AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen may have a negative impact on long-term leukemic control. Furthermore, no prospective studies have been reported thus far establishing RIC allo-SCT as the preferred option in AML. Investigators are currently faced with a dilemma on how to optimize the potential role of RIC allo-SCT in AML patients, while delivering minimal myeloablation and maximizing allogeneic immunotherapy. The aim of this review is to analyze the available research evidence in this field.