scholarly journals Novel Strategies to Treat Children with Refractory or Relapsed Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4927-4927
Author(s):  
Luca Lo Nigro ◽  
Emanuela Cannata ◽  
Piera Samperi ◽  
Silvana Munda ◽  
Daria Bottino ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Complete Remission ◽  
Imatinib Mesylate ◽  
Salvage Therapy ◽  
Unrelated Donor ◽  
Induction Phase ◽  
Off Label Use ◽  
Chromosome 11 ◽  
Off Label ◽  
Label Use

Abstract Background AML is an aggressive disease. Current pediatric protocols ensure a 60% survival rate (Pession A et al, Blood 2013), reaching a plateau of intensiveness. Nevertheless, patients with primary induction failure (PIF) (10%) or relapse (30%) after stem cell transplantation (SCT) still have a very poor outcome. Novel therapeutic strategies are needed. Case 1. In January 2013, a 13 year-old female with FAB-M1-AML, presenting with chromosome 11 monosomy, was enrolled on AIEOP-AML-2002/01 protocol (Pession A et al, Blood 2013) and showed a PIF after two cycles of induction phase. Leukemic blasts arose in a low peripheral blood cell (PBC) count, even in response to second line treatment (I-BFM-AML-relapse2001 protocol). A third line experimental therapy, azacitidine (AZA) and rapamycin, failed to induce remission. Low PBC count with blasts still remained. Based on a bright expression of CD117/cKit, detected by flow cytometry, we designed a salvage therapy with AZA (75mg/mq/day for 7 days, every 21 days), in association with Imatinib Mesylate (375 mg/mq/day). We observed an increase of PBC count, with rapid disappearance of blasts. After two courses of AZA-Imatinib, the patient achieved complete remission. Subsequently she underwent SCT from an unrelated donor (UD) (Nov/2013). Nine months later, immune-suppressive therapy was withdrawn and we confirmed complete remission with a 100% donor engraftment. She is currently alive and in remission. Case 2. In October 2013, a 13 year-old male with FAB-M5-AML, presenting with a complex karyotype and specific molecular markers (FLT3-ITD and NSD1-NUP98), was enrolled on AIEOP-AML-2002/01 protocol. He achieved complete remission after induction phase. Nearby SCT-UD program, he presented colonization with two multi-resistant-gram-negative bacteria. For this reason, he was shifted to a haplo-identical SCT program. He received two haplo-SCT from his mother (April/2014) and his father (June/2014) respectively, after which he showed a bone marrow relapse (Sept/2014). Based on his low performance status, we designed a salvage therapy with cytosine arabinoside (100 mg/day i.v. in a total 8-days/cycle) Sorafenib (600 mg/day orally, already started before the first haplo-SCT), in association with PEG-Asparaginase (Oncaspar) at 3500 UI/i.v. weekly for 4 administrations. Surprisingly we observed an increasing signs of cutaneous grade II graft-versus-host-disease (GVHD), confirmed by flow cytometry analysis (high T-cell suppressors/NK cells), consistently with an increasing rate of donor's DNA (Dec/2014). Therefore, after a second cycle, the patient achieved the complete remission (Jan/2015) and a third haplo-SCT (Feb/2015) was given, using NK-alloreactive donor cells from his mother. Currently, the patient is alive and in complete remission with 100% donor. Conclusion. Our experience suggests that innovative combinational therapies are able to rescue patients with PIF or relapsed AML after SCT, the worst candidates. Association of a tyrosine kinase inhibitor with a demethylating agent showed a synergistic effect on leukemic blasts. More interestingly, PEG-LASP combined an anti-leukemic effect to an immune-modulation on donor's lymphocytes, as shown by immunophenotypic analyses. Disclosures Off Label Use: We used Imatinib Mesylate and PEG-L-Asparaginase in two children with AML: an off-label use for indication and age. .

Clofarabine in Acute Myeloid Leukemia. the Spanish Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4279-4279
Author(s):  
Adolfo de la Fuente ◽  
Guillermo Deben ◽  
Concha Bethencourt ◽  
Silvia Negri ◽  
Dolores Vilariño ◽  
...  
Keyword(s):  
Complete Remission ◽  
Salvage Therapy ◽  
Hematological Toxicity ◽  
Off Label Use ◽  
Salvage Regimen ◽  
Off Label ◽  
First Line Therapy ◽  
Resistant Disease ◽  
Significant Difference ◽  
Label Use

Abstract Abstract 4279 Introduction: Clofarabine (CLF) is a purine nucleoside analog approved by FDA and EMA in refractory pediatric ALL patients. Phase I and II studies have reported Clofarabine activity in AML. Aims: To evaluate the experience in Spain with (CLF) in the treatment of adult AML patients, analyzing effectiveness and toxicity profile. Method: This is a multicenter retrospective study including AML patients treated in Spain with CLF by compassionate use. Main points were complete remission as IWRv2003 criteria and toxicity as CTCAE v3.0 of NCI scale. Result: Between July 2007 ans April 2011 a total of 76 AML patients were treated with CLF based chemotherapy in Spain. We obtained clinical data from 64 cases. Median age at CLF treatment 52.4 years (18–77). Male/Female: 31/33. Previous Myelodisplastic syndrome 12 (18%). Cytogenetic data was available in 58 patients (90%), and 28 of them had high-risk cytogenetic. CLF treatment: 56 patients received CLF as salvage therapy (23 in AML relapse and 33 in refractory disease), median previous lines 2 (0–7), were the remaining 8 patients were untreated patients. CLF was administered in combination with AraC in 94% patients and the 91% received a five days schedule. The most frequents CLF dose/day were: 40 mg/m2/day in 39 patients, 30 mg/m2/day in 11 patients, and 20 mg/m2/day in 9 patients. Response and outcome: Nineteen (35.8%) patients achieved complete remission and 64.1% had resistant disease. Mean survival time 14.3 ± 1.4 months. The statistical analysis shows a significant difference in the CR rate between first line therapy (CR 82%) and savage therapy in relapsed (CR 45%) and salvage therapy in refractory (CR 18%), (p0.012). Neither adverse cytogenetics nor previous MDS did influence CR. (p0.57 and p0.53 respectively). Toxicity: All patients presented grade IV hematological toxicity with grade IV neuthopenia, grade IV trombopenia and transfusion depend anemia. The incidence of extra hematological toxic effects were low, creatinine >3 mg/dL: 4 cases (6%); bilirrubine > 3mg/dL: 9 cases (14%). Eleven (17%) patients died during Induction. Conclusions(opcion1): The revised experience in Spain with CLF as compassionate used in AML confirms the effectiveness of Clofarabine as a salvage regimen. Of note was that CLF could potentially overcome some adverse known factors as cytogenetics. Disclosures: Off Label Use: Clofarabine in AML is an off-label use.

Reduced Relapse Risk In Patients With AML After Hhcmv-Replication Post Transplantation-First Results Of a Prospective Registration Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5503-5503
Author(s):  
Ahmet H. Elmaagacli ◽  
Nina-Kristin Steckel ◽  
Meltem Kekec ◽  
Rudolf Trenschel ◽  
Markus Ditschkowski ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Unrelated Donor ◽  
Off Label Use ◽  
Relapse Risk ◽  
Off Label ◽  
Hcmv Disease ◽  
Leukemic Relapse ◽  
Hcmv Replication ◽  
Registration Trial ◽  
Label Use

Abstract Abstract 5503 Introduction Early detection of inapparent replicative human cytomegalovirus (HCMV) infection together with its preemptive antiviral treatment has led to a marked reduction of life-threatening HCMV disease after allogeneic hematopoietic stem cell transplants (alloSCT). A new aspect of HCMV reactivation and pretransplant HCMV serostatus has recently emerged by an earlier retrospectively performed report from us showing that the occurrence of a HCMV-reactivation after transplant reduces the risk for relapse in patients with AML and NHL. This idea was supported by a study by Scheper and co-worker (Leukemia, 2013) reporting recently, that gamma-delta T cells elicited by HCMV reactivation after alloSCT cross-recognize HCMV and leukemia. Here we evaluate the potential impact of early HCMV replication in a prospectively performed observational study about the occurrence of a HCMV- reactivation after T cell repleted alloSCT on the risk for leukemic relapse in patients with AML (Registration Trial DRKS00004300). Patients and Method Between January 2012 and March 2013 we enrolled in this trial 83 patients with AML who were consecutively transplanted at the University Hospital of Essen. 48 of 83 patients received a myeloablative (TBI based conditioning n=27, chemotherapy based conditioning n=23) and 35 patients a RIC regimen. Patients were transplanted in 1.CR (n=40), 2.CR (n=23) or more progressive disease stages (n=20) from HLA-identical sibling donor (n=17) or HLA-identical unrelated donor (URD) (n=42) or mismatched unrelated donor (n=24). The median age of patients was 53 years (range 18-72) and that of the donors 38 years (range 12-61). GVHD prophylaxis was performed with MTX and CSA, or CSA and MMF with or without ATG (n=64) (30-60mg total dose). The incidence of acute GVHD grade 2-4 was statistically not different in both groups (78% versus 85%). Results HCMV status of recipient (R) or donors (D) were in 29% R-/D-, 8% R-/ D+; 34% D+/R- and 29% R+/D+. Patients with a documented HCMV-reactivation (HCMV-R) had an estimated relapse incidence (CIR) at 1-year after transplant of only 8% compared to 43% in patients without a HCMV-R (p=0.03). Patients in more progressive disease phase of AML (N=43) benefit more from a HCMV-R in regard of CIR than patients in 1.CR of AML (0% versus 55% estimate for relapse at 1-year after transplant for patients with HCMV-R compared to patients without HCMV –R, p=0.028). One-year overall survival was statistically not different in both groups. Non relapse mortality was greater in patients with HCMV reactivation 37.8% versus 12.5%, p=0.1) Conclusion The first result of this prospective study confirms an independent advantageous effect of early HCMV replication on the leukemic relapse risk in patients with AML after transplant, which was more pronounced in patients in  progressive disease phase of AML than patients in 1.CR of AML. Disclosures: Off Label Use: The off-label use of HCG will be presented here for the first tiem for treatment of chronic GVHD and will clearly marked as off-label use.

scholarly journals Therapeutic Strategy for Elderly Patients with ACUTE Myeloid Leukemia (AML) Carrying the DNMT3A Mutation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5269-5269 ◽  
Author(s):  
Elena Rossetti ◽  
Monica Crugnola ◽  
Cecilia Caramatti ◽  
Luisa Craviotto ◽  
Elena Masselli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Septic Shock ◽  
Complete Remission ◽  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Off Label Use ◽  
Bone Marrow Blast ◽  
Off Label ◽  
Blast Count ◽  
Label Use

Abstract BACKGROUND: AML in the elderly is associated with low complete remission (CR) rates after induction therapy, poor survival and high treatment-related mortality. 5-Azacytidine (5-AZA) has emerged as a valid substitute of the Conventional Care Regimens (CCR) in a small subset of patient with a bone marrow blast count ranging from 20% to 30%. However, in a off-label use, 5-AZA may also be used in patients with bone marrow blast infiltration >30%. Furthermore, 5-AZA can be also used for the maintenance therapy after the bone marrow blast count has been reduced under the 5% cut-off. AIMS: to assess both safety and efficacy of in-label use of 5-AZA in elderly AML patients who have reached a bone marrow blast count between 5% and 30% after an induction conventional chemotherapy. METHODS: from 2010 to 2013, 13 patients (8 males; 5 females) with a median age of 74 (range 64-86) years and a newly diagnosed AML have been enrolled. At the diagnosis, the median bone marrow blast count was 45% (range 24%-95%). Cytogenetics showed: normal karyotype in 7 patients, chromosome 8 trisomy in 2, complex karyotype in 4. A DNMT3A mutation was documented in 5 cases. Neither FLT3-ITD mutations nor NPM1 mutations were present. According to age, performance status and comorbidities, all patients received a CCR induction chemotherapy. Low Dose Cytarabine, 100mg/sqm, was given subcutaneously for 5 days in 4 patients, Fludarabine (25mg/sqm intravenously for 5 days) and Cytarabine (2gr/m2 intravenously for 5 days) in 4 and the ICE schedule- Idarubicine (10mg/sqm intravenously for 3 days), Cytarabine (100mg/sqm intravenously for 5 days) and Etoposide (50mg/sqm intravenously for 3 days) in 5. At the day +31 bone marrow evaluation, no one obtained a Complete Remission, in 5 patients blast count ranged between 20% and 30%; in 4 between 15% and 20%; and in 4 between 5% and 10%. Then, all patients received 5-AZA at 75mg/sqm subcutaneously for 7 days every 28 days. The median number of cycles was 8 with a minimum of 1 cycle and a maximum of 15 cycles. Adverse hematological events were: grade III-IV neutropenia in 7 patients (54%) and thrombocytopenia in 9 patients (69%). Fever was the major non-hematological side effect during 5-AZA: fever was of unknown origin (FUO) in 4 patients, infection-related in 4 (2 pneumonias, 1 sepsis from Pseudomonas Aeruginosa and 1 from KPC). One patient died after the first cycle for septic shock due to KPC. RESULTS: Among the 12 evaluable patients the median survival was 16 months (range 2 – 44). Our data showed a longer median survival (17 months) in the 5 patients with DNMT3A mutation in comparison with those with wild-type DNMT3A (11 months). In consideration of the limited number of patients, the p-value was 0.47. In addition, a reduction of transfusion requirements as well as an improvement of quality of life were obtained. Therapy with 5-AZA was overall well tolerated as only one patient needed a long-term hospitalization and died from septic shock. In conclusion, we showed that a bone marrow blast reduction after conventional induction chemotherapy and a subsequently treatment with 5-AZA can be a valid option in elderly patients with AML and DNMT3A mutation. More patients and longer follow-up are required for confirming these encouraging preliminary results. Disclosures Off Label Use: Gemtuzumab Ozogamicin in AML.

Allogeneic Hematopoietic Cell Transplantation in AML: Comparable Results After Matched or Mismatched Unrelated Versus Matched Related Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1199-1199 ◽  
Author(s):  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
Wolfgang Andreas Bethge
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Off Label Use ◽  
Hematopoietic Stem ◽  
Off Label ◽  
Significant Difference ◽  
Label Use

Abstract Abstract 1199 Poster Board I-221 Currently, most treatment algorithms reserve the use of allogeneic hematopoietic stem cell transplantation (HCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR) to patients with a matched related donor (MRD) and intermediate/high-risk disease. However, the role of HCT from a matched or mismatched unrelated donor (MUD/MMUD) in patients with AML remains to be defined. We retrospectively analyzed a cohort of 219 consecutive adult patients (98 female, 121 male) with AML who received HCT from 2000-2009 at our institution. The patients were transplanted after either myeloablative (MAC, n=139) or dose-reduced-conditioning regimens (RIC, n=80). Median age of patients was 50 years (range, 18-76). 77 patients were transplanted from MRD, 80 patients from MUD and 62 patients from MMUD (one antigen mismatch (MM)=31; two antigen MM=2; one allel MM=24; two allel MM=3, one antigen/one allel MM= 2). In all but six patients receiving MMUD grafts, ATG was included in the conditioning. Age, risk profile and pretreatment were evenly distributed among the three cohorts of patients. At time of HCT 22 (MRD), 18 (MUD) and 28 (MMUD) patients were not in CR. Current overall survival is 40 of 77 (52%) in patients transplanted from MRD, 48 of 80 (60%) from MUD and 34 of 62 (55%) from MMUD with a median follow-up of 1309 (range, 98-3173), 796 (range, 87-3075) and 648 (range, 111-1973) days of alive patients, respectively. Kaplan-Meier-estimated 3-year overall survival (OS) was similar with 54% after MRD-, 56% after MUD- and 46% after MMUD-HCT (p=0.4554). In patients transplanted in CR, 3-year estimated OS was also comparable (64% MRD vs. 58% MUD vs. 55% MMUD, p=0.6614). However, in patients transplanted in partial remission (PR) we observed a trend for a better survival in patients receiving a MUD graft (30% MRD vs. 46% MUD vs. 39% MMUD, p=0.1707). In the patients receiving MAC we observed a better OS compared to RIC with an estimated 3-year OS of 58% vs. 38% (p=0.1047) mainly due to a lower incidence of relapse. In the subgroup of patients receiving MRD-HCT this survival benefit was significant (61% vs. 21%, p= 0.0327) while there was only a trend for MUD- or MMUD-HCT (60% vs 45%, p=0.5702 and 49% vs. 43%, p= 0.7566, respectively). There was no significant difference in the incidence of acute GvHD >II with 25% (MRD), 35% (MUD) and 34% (MMUD) or chronic GvHD with 43% (MRD), 46% (MUD) and 34% (MMUD), respectively. A significant better survival of patients with limited cGvHD vs. extensive or without cGvHD (estimated 3-year OS 73% vs. 34% vs. 47%, p=0.0001) was observed. This advantage was present in all subgroups with a significant better survival in the group with MRD (86% vs. 38% p= 0.0034), a trend in MUD (67% vs. 55% p= 0.0564) and MMUD (59% vs. 55%, p= 0.3111). No significant influence on survival or GVHD of the degree and loci of HLA-mismatch could be detected. In conclusion in our cohort of patients, HCT from MUD or MMUD in AML resulted in a similar outcome compared to MRD. In patients with PR at time of HCT, the use of MUD and occurrence of limited cGVHD may lead to improved survival due to an enhanced graft-versus-leukemia-effect. Disclosures: Off Label Use: some chemotherapeutical agents in the conditioning are off-label-use.

scholarly journals Managing Immune Thrombocytopenic Purpura in infants: is it time to think of Eltrombopag?

2021 ◽  
Author(s):  
Giulia Ceglie ◽  
Giulia Nocentini ◽  
Francesca de Gennaro ◽  
Vitangelo Clemente ◽  
Margherita Di Mauro ◽  
...  
Keyword(s):  
Complete Remission ◽  
Adverse Effects ◽  
Immune Thrombocytopenic Purpura ◽  
Discontinue Treatment ◽  
Off Label Use ◽  
Thrombocytopenic Purpura ◽  
First Report ◽  
Off Label ◽  
Robust Evidence ◽  
Label Use

We report 2 cases of infants with acute and persistent Immune Thrombocytopenic Purpura (ITP) treated with Eltrombopag. Since ITP is rare in infants, robust evidence about how to treat these patients is not available. Both children underwent multiple lines of treatment without success and were successfully managed with off-label use of Eltrombopag. We did not observe any of the reported adverse effects of the drug and complete remission was achieved in both cases. In one child, we were able to discontinue treatment without any ITP relapse. This is the first report of an off-label use of Eltrombopag in infants.

Indikationsfremde Anwendung von Medikamenten und Medizinprodukten in der Notfallmedizin

2019 ◽  
Vol 14 (04) ◽  
pp. 361-371
Author(s):  
Karl Peter Ittner ◽  
Joachim Koppenberg ◽  
Ute Walter
Keyword(s):  
Off Label Use ◽  
Off Label ◽  
Label Use

ZusammenfassungWenn zugelassene Arzneimittel außerhalb der in der entsprechenden Fachinformation dargelegten Beschreibungen angewendet werden, dann spricht man von einer nicht zulassungskonformen Anwendung oder von einem Off-Label-Use. Wie in fast allen medizinischen Fachgebieten gibt es auch im Rettungsdienst sogenannte Off-Label-Use-Pharmakotherapien. Sofern evidenzbasierte Informationen zu einer nicht zulassungskonformen Anwendung vorliegen, und insbesondere im konkreten Notfall keine zulassungskonforme Möglichkeit besteht, dann ist diese gerechtfertigt. Verwendet ein Notarzt aber ein Medizinprodukt außerhalb der Zulassung, dann stellt er ein neues Produkt her und haftet persönlich bei einem Patientenschaden.

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