Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML. Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP). Results: All patients engrafted (ANC > 0.5 Gpt/l on day 11, range 8–19, platelets > 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of > 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission. Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.

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Efficacy of Low Dose Clofarabine Plus Intermediate Dose Cytarabine In An Unselected AML Refractory/Relapsed Adult Population

Blood ◽

10.1182/blood.v116.21.4349.4349 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4349-4349

Author(s):

Claudio Romani ◽

Emanuele Angelucci ◽

Barbara Scappini ◽

Mario Petrini ◽

Martina Pettinau ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Nucleoside Analogue ◽

Myeloid Leukemia ◽

Low Dose ◽

Haematological Toxicity ◽

Allogeneic Transplantation ◽

Gemtuzumab Ozogamicin ◽

Acute Myeloid

Abstract Abstract 4349 Advanced AML in adult patients is a difficult challenge for hematologists with several unsuccessful approaches attempted during the last years. We tested the combination of the new nucleoside analogue Clofarabine in association with Cytarabine in a consecutive series of adult patients with advanced acute myeloid leukemia. From April 2007 to April 2010, 29 unselected advanced disease (not M3) acute myeloid leukemia (AML) patients were included in this multicenter study. There were 14 female and 15 male. Median age was 44 years (range 22–65). Twenty patients were in second or more advanced relapse and 9 had refractory disease to one or more chemotherapy regimens. Patients were treated with one cycle of five days clofarabine 22,5 mg/m2/day together with five days cytarabine 1 g/m2/day. The low dose (22,5 mg/m2) clofarabine was selected because of the burden of therapy that our patients had already received. In 19 patients gemtuzumab ozogamicin 6 mg/m2 was added by Centre physician decision. Toxicity and remission status were defined according with WHO criteria. Partial remission was considered as improvement of peripheral blood count and reduction of bone marrow blasts > 50%). Toxicity: Grade IV haematology toxicity was recorded in all patients. Extra haematological toxicity was as follows: four patients presented ≥ grade III cutaneous toxicity, ten hepatic toxicity; three patients mucositis. Eight patients experienced a life threatening infection while in aplasia (six systemic septicemia and two pneumonia) which were ultimately fatal in four. Disease response: overall, 16 over 29 patients (55%) entered in complete remission (CR) and 4 in partial remission. Overall response rate was 69%. Outcome: over the sixteen patients who entered complete remission: 1 was lost at follow up, 1 relapsed, 1 was treated with azacitidine and 2 with another cycle of clofarabine. These three patients who received a not transplant intensification therapy are, so far, alive in complete remission. In eleven patients an allogeneic transplantation (with an unrelated or sibling donor) was performed as intensification therapy: to date, 8 of these 11 patients are alive in continuous complete remission after a median follow up of 6,5 months (2-36) while three died (two while in CR). Overall 11 (68%) of the 16 patients who entered into complete remission are alive and well. The new nucleoside analogue Clofarabine showed efficacy and synergism with cytarabine in treating AML. Even if 29/29 patients experienced grade IV haematological toxicity, infection rate was low and suitable considering the status of the disease. Extra haematological toxicity was acceptable and easily manageable. Considering the dismal outcome of these patients, we believe that intensification should be performed to allow a continuous complete remission. Indeed we were able to transplant 11/16 patients, eight of which maintained the complete remission after transplantation. Notably, 3 patients remained alive in complete remission out of a transplantation approach. It is not possible to draw any conclusion about the role, if any, of gemtuzumab ozogamicin. In summary, we showed that low dose clofarabine plus cytarabine because of efficacy and low extra-hematology toxicity could be a real bridge to allogeneic transplantation in these very poor risk pre-treated acute leukaemia patients. A longer follow up is awaited. Disclosures: Off Label Use: Clofarabine in refractpry/relapsed AML.

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Molecular Minimal Residual Disease After Induction Is Related to ABC Proteins' Activity and Associated with Survival in 26 Patients with NPM1 Mutated Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4909.4909 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4909-4909

Author(s):

Pierre Hirsch ◽

Ruoping Tang ◽

Christophe Marzac ◽

Fanny Fava ◽

Jean-Yves Perrot ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Induction Chemotherapy ◽

Cytogenetic Analysis ◽

Myeloid Leukemia ◽

Residual Disease ◽

Abc Proteins ◽

Minimal Residual ◽

Acute Myeloid

Abstract Abstract 4909 Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. The role of ABC proteins, and specially ABCB1 (PgP/mdr1), in this resistance has been well established, and higher ABC proteins' activity, assessed with functional tests, has been associated with poorer complete remission rates and poorer overall prognosis (Marzac et al, Haematologica, 2011). Furthermore, the evaluation of molecular minimal residual disease (MRD), using mutated nucleophosmin (NPM1)expression quantification has been related to patients' global prognosis (Krönke et al, J. Clin. Oncol., 2011), and to response to treatments. In this study, we evaluate the impact of ABC proteins' activity on MRD after one course of induction chemotherapy, in 26 patients with NPM1 mutated AML. Material and methods: We retrospectively identified 26 AML patients with NPM1 mutation treated in our center and with MRD data. MRD was evaluated as the ratio of NPM1 mutated allele and total NPM1, using PCR DNA quantification and the delta delta Ct method. MRD was measured at the time of diagnosis and after one course of anthracycline-based induction chemotherapy. ABC proteins' activity was evaluated at the time of diagnosis using JC1 +/− cyclosporine A assay (Legrand et al, Blood, 2001). Correlations between ABC proteins' activity and the level of post induction MRD were evaluated with the Mann-Whitney test. Survival was evaluated using the Cox model. For all analyses, P values were considered significant when lower than 0. 05. Results: Median age at diagnosis was 53 years old. Twenty-two patients had normal cytogenetic analysis at diagnosis, and the other 4 patients had intermediate prognosis cytogenetic analysis. Nine patients harboured FLT3-ITD mutation. Median ABC proteins' activity was 0. 11 (0 – 0. 77). After one course of induction chemotherapy, 3 patients did not reach cytological complete remission. In 17 patients MRD level after induction therapy was inferior to 1 %, in 11 patients MRD was inferior to 0. 1 % and in 7 patients MRD was inferior to 0. 01 %. Overall, higher MRD level after induction (defined by MRD level higher than 0. 1 %) was associated with poorer prognosis for disease free survival (HR= 4. 25 [95% CI 1. 049–17. 27]; p=0. 04), and for overall survival HR=11. 25 [95% CI 1. 22–103. 23]; p=0. 03). Higher ABC proteins' activity was associated with higher MRD levels post induction, and patients who did not reach MRD level lower than 0. 1 % had significantly higher ABC proteins' activity than other patients (p=0. 008). ABC proteins' activity was also associated with overall survival in our patients (p=0. 04). Conclusion: Higher ABC proteins' activity is associated with higher MRD levels after one course of induction chemotherapy in 26 NPM1 mutated AML patients, and is also associated with poorer overall survival. The poorer prognosis associated with high ABC proteins' activity in AML seems to be in part related to direct resistance to chemotherapy. These data should be confirmed in larger studies. Disclosures: No relevant conflicts of interest to declare.

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Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽

10.1182/blood.v95.8.2637.008k07_2637_2644 ◽

2000 ◽

Vol 95 (8) ◽

pp. 2637-2644 ◽

Cited By ~ 3

Author(s):

Teresa Padró ◽

Sandra Ruiz ◽

Ralf Bieker ◽

Horst Bürger ◽

Martin Steins ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Induction Chemotherapy ◽

Microvessel Density ◽

Myeloid Leukemia ◽

Remission Induction ◽

Bone Marrow Biopsies ◽

Acute Myeloid

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

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