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

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.

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Faculty Opinions recommendation of Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2362957.1991055 ◽

2010 ◽

Author(s):

Arati Rao

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Conventional Care ◽

Bone Marrow Blast ◽

Blast Count ◽

Acute Myeloid

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Risk Evaluation for Antipsychotic Agents Used in Elderly Inpatients (REPAIR)

The Canadian Journal of Hospital Pharmacy ◽

10.4212/cjhp.v71i6.2852 ◽

2019 ◽

Vol 71 (6) ◽

Author(s):

Flora Yu ◽

Reza Rafizadeh ◽

Vincent H Mabasa ◽

Nirmal Kang

Keyword(s):

Elderly Patients ◽

Community Hospital ◽

Off Label Use ◽

Antipsychotic Therapy ◽

Patients Âgés ◽

Off Label ◽

Risk Of Death ◽

Common Diagnosis ◽

Elderly Inpatients ◽

Label Use

ABSTRACT Background: Antipsychotics have been approved for the treatment of certain psychiatric illnesses. However, these medications are also frequently used off label, and recent studies have suggested a concerning potential increase in the risk of death when used by elderly patients with dementia. Most of the available literature focusing on off-label use of antipsychotics comes from long-term care facilities; there is a lack of quantitative data for elderly patients in the acute care setting. This study was designed to examine this scenario and to identify potential quality improvement opportunities to minimize harm. Objectives: The primary objectives were to determine the prevalence of hospital-initiated off-label use of antipsychotics for elderly inpatients and to determine the plan for these drugs upon discharge. The secondary objectives included identifying the most common diagnosis and the most common agent used. Methods: A retrospective cohort study was performed with a convenience sample. Patients included in the analysis were elderly adults (≥ 65 years) who had been admitted to either of 2 medical units at a community hospital between September 1 and November 8, 2014. Descriptive statistics were used to examine prevalence patterns for the off-label use of antipsychotics. Results: A total of 250 patients were included in the analysis. Forty-five patients (18%, 95% confidence interval [CI] 13.7%–23.2%) received a hospital-initiated antipsychotic for off-label use during the admission. For 27 (60%, 95% CI 45.5%–73.0%) of these 45 patients, the off-label therapy was discontinued upon discharge or death, and for 13 (29%, 95% CI 17.7%–43.4%), the agent was continued upon discharge without a plan in place. The most frequent diagnosis was delirium, and the agent most frequently used was haloperidol. Conclusions: Off-label antipsychotic therapy was initiated for almost 1 in every 5 elderly patients receiving care in 2 medical units at a community hospital. These findings suggest a need to monitor and reassess the off-label use of these agents, especially at the time of discharge.RÉSUMÉContexte : Les antipsychotiques ont été approuvés pour le traitement de certains troubles psychiatriques. Or, ces médicaments sont aussi fréquemment utilisés en dérogation des directives de l’étiquette et des études récentes ont supposé une potentielle augmentation préoccupante du risque de décès lorsqu’ils sont employés pour traiter des patients âgés atteints de démence. La majeure partie de la littérature portant sur l’emploi non conforme d’antipsychotiques provient de centres d’hébergement et de soins de longue durée. Or, on constate un manque de données quantitatives sur les patients âgés dans les milieux de soins de courte durée. La présente étude a été conçue pour examiner ce scénario et découvrir de potentielles occasions d’amélioration de la qualité en vue de réduire au minimum les risques de préjudice. Objectifs : Les objectifs principaux étaient de déterminer la prévalence de l’emploi non conforme d’antipsychotiques amorcé à l’hôpital chez les patients aînés et de déterminer le plan relatif à la prescription de ces médicaments au moment du congé. Les objectifs secondaires incluaient de déterminer quels étaient le diagnostic le plus fréquent et le médicament le plus utilisé. Méthodes : Une étude de cohorte rétrospective a été menée à l’aide d’un échantillon de commodité. Les patients retenus pour l’analyse étaient des personnes âgées (de 65 ans et plus) ayant été admises à l’une des deux unités médicales dans un hôpital communautaire entre le 1er septembre et le 8 novembre 2014. Des statistiques descriptives ont été employées pour analyser les modèles de prévalence en ce qui concerne l’emploi non conforme d’antipsychotiques. Résultats : Au total, 250 patients ont été retenus pour l’analyse. Pendant l’hospitalisation, un antipsychotique a été amorcé hors conformité chez 45 patients (18 %, intervalle de confiance [IC] de 95 % de 13,7 % à 23,2 %). Pour 27 (60 %, IC de 95 % de 45,5 % à 73,0 %) de ces 45 patients, le traitement non conforme a été arrêté au moment du congé et, pour 13 autres (29 %, IC de 95 % de 17,7 %–43,4 %), le traitement a été poursuivi au congé sans mise en place d’un plan. Le diagnostic motivant le plus souvent l’emploi non conforme de ces médicaments était le délire et le médicament le plus employé était l’halopéridol. Conclusions : Le traitement non conforme par antipsychotique a été amorcé pendant le séjour à l’hôpital pour près d’un patient âgé sur cinq qui recevait des soins dans l’une des deux unités médicales d’un hôpital communautaire. Ces résultats laissent croire qu’une surveillance de l’emploi non conforme de ces médicaments et qu’une réévaluation d’un tel traitement sont nécessaires, particulièrement au moment du congé.

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Treatment of a Patient with Refractory Non-Langerhans-Cell-Histiocytosis with the Tyrosine Kinase Inhibitor Sorafenib: Clinical and Genetic Implications

Blood ◽

10.1182/blood.v116.21.4715.4715 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4715-4715

Author(s):

Andreas Viardot ◽

Frank Stegelmann ◽

Thorsten Zenz ◽

Peter Möller ◽

Konstanze Döhner

Keyword(s):

Bone Marrow ◽

Tyrosine Kinase ◽

Langerhans Cell Histiocytosis ◽

Kinase Inhibitor ◽

Langerhans Cell ◽

Braf V600e ◽

Off Label Use ◽

Off Label ◽

Hands And Feet ◽

Label Use

Abstract Abstract 4715 Non-Langerhans-cell-histiocytosis (Non-LCH) represents a rare disorder with a broad spectrum of clinical features and various outcome. We here report on a 61 years old man with Non-LCH with severe skin and bone marrow involvement. At the time of diagnosis in 2006, the patient presented with up to four centimeter large cutaneous papules involving face, stem, hands and feet. Since two years, the patient also developed an increasing tricytopenia due to an extensive bone marrow infiltration of histiocytes (80%). Since diagnosis, the patient received a large number of various therapies including daily glucocorticoids at different dosages (continuously since diagnosis), low-dose methotrexate (10-40mg s.c. per week; from may to september 2007), experimental treatment with lenalidomide (5-10mg per day; from february to june 2008), continous oral trofosfamide (100mg per day; from july to august 2008), cladribine monotherapy (2,1mg/m2 d1-5; 4 cycles; from December 2008 to march 2009) and the combination of cladribine (2.1mg/m2 d1-5) and cytarabine (40 mg s.c. d1-7; 3 cycles; from january to march 2010). The patient did not respond to any of these therapies. Due to the persistent distinctive clinical symptoms (massive skin involvement, tricytopenia), we started in July 2010 an experimental therapy with sorafenib at a dosage of 200mg per day for four days, followed by 400mg per day for another four days, and subsequently increased the dosage to 800mg daily. After four weeks, the marked skin papules flattened to skin level at all preferential sites. Small skin ulcers at the cheeks healed up. In parallel, there was a significant improvement of hematopoiesis since start of therapy with haemoglobin levels raising from 8,6g/dl to 12,2g/dl and normalization of leukocyte count (from 3.1/nl to 5.2/nl). Bone marrow rebiopsy is intended after three month of therapy, data on the actual grade of infiltration will be presented at the meeting. Based on the impressive clinical improvement under sorafenib, we analyzed selected target genes of the multityrosine kinase inhibitor: mutation screening was performed on the FLT3 (internal tandem duplication, point mutations of the tyrosine kinase domain) and KIT genes (exon 8 and exon 17) as well as for the recently described BRAF V600E mutation found in a significant number of patients with LCH (G. Badalian-Very et al., Blood prepublished online June 2, 2010; DOI 10.1182/blood-2010-04-279083). However, in none of these genes, mutations were found and further molecular analysis of the patient's bone marrow is currently under investigation. To our knowledge, this is the first report on the efficacy of sorafenib in a case of histiocytosis. However, the underlying genetic mechanisms of Non-LCH still have to be elucidated. Disclosures: Off Label Use: Sorafenib is approved for unresectable hepatocellular carcinoma and advanced renal cancer. We present an off-label use of sorafenib in a case of a severe orphan disease refractory to all standard therapies. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria.

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

Blood ◽

10.1182/blood.v126.23.4927.4927 ◽

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. .

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Effect of Complete Remission Achievement on Survival In Acute Myeloid Leukemia of the Elderly.

Blood ◽

10.1182/blood.v116.21.1048.1048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1048-1048

Author(s):

Felicetto Ferrara ◽

Cira Riccardi ◽

Salvatore Palmieri ◽

Tiziana Izzo ◽

Antonella Carbone

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Normal Karyotype ◽

Loading Dose ◽

Refractory Disease ◽

Bone Marrow Blast ◽

Blast Count ◽

Acute Myeloid

Abstract Abstract 1048 The achievement of complete remission (CR) is considered an essential prerequisite for cure in acute myeloid leukemia (AML). Notwithstanding, in older AML patients recent data suggest that, at least for patients receiving new compounds such as hypomethilating agents Azacytidine and Decitabine, the benefit on survival can be independent from CR achievement, namely in patients with low bone marrow blast count (< 30%) at diagnosis. In this study we evaluated the impact of CR achievement on overall survival from a series of 140 patients aged over 60 years; all patients received a therapeutic program including continuous infusion of fludarabine (F) and cytarabine (ARA-C) as induction and consolidation, followed whenever possible by autologous stem cell transplantation (Ferrara et al, Haematologica, 2005). Briefly, F was administered at a loading dose of 10 mg/m2 over 15 min at day 0 followed 6 hours and half later by continuous infusion (c.i.) of 20 mg/m2/24 hours for 72 hours (days 0–2); ARA-C was given at a loading dose of 390 mg/m2 three hours and half after F and then as c.i. over 96 hours at 1440 mg/m2/24 hours (days 0–3). G-CSF was added at day +15 at a dose of 5 μg/kg. A second identical course was planned for patients obtaining partial response, defined as less than 5% blasts in peripheral blood and less than 30% of blasts in the bone marrow. Patients achieving CR, established as less than 5% blasts in the bone marrow, normal blood count and differential and absence of extramedullary leukemia, were programmed to receive an additional identical course as consolidation, reduced of one day (i.e. two days c.i. of F and three days c.i, of ARA-C). The effect of CR was separately analyzed according to karyotype, bone marrow blast count and, in patients with normal karyotype, NPM1 and FLT3 positivity. Of note, patients dead in induction were excluded from survival benefit evaluation. The median age was 69 years (range 61–82). Cytogenetic analysis was successfully in 134/140 patients (96%). Among these 89 (66%) were found as having normal karyotype (NK) and 45 (34%) with different chromosomal abnormalities, mostly complex or involving chromosomes 5 and/or 7, classified as unfavorable (UK). Overall 94 patients (67%) achieved CR; the CR rate was 77 % in NK and 47% in unfavorable karyotype (p:<0.001). Of note, rates of either death in induction (22% vs 14%) or primary refractory disease (33 % vs 8%) were significantly higher in patients with adverse cytogenetics. The median survival for the whole patient population was 10 months; survival was significantly influenced by cytogenetics at diagnosis (12 months for NK vs 7 months for UK), p:<0.001). The median duration of CR was 11 months (16 months for patients with NK as opposed to 7 months for those with UK). The overall impact of CR achievement on survival was remarkable and remained statistically significant after exclusion of patients dead in induction (18 months vs. 6 months, p:< 0.001). The advantage of achieving CR was found in patients with NK, independently from molecular assessment at diagnosis, i.e. NPM1+/FLT3-, NPM1-FLT3-, NPM-FLT3+, NPM+/FLT3+). Of interest, no difference was found as bone marrow blast count at diagnosis, i.e. more or less than 30 %, was concerned in the rate of CR achievement, CR duration and impact of CR on survival either in univariate or multivariate analysis. By separately analyzing patients with UK, the advantage of CR achievement was found only when patients dead in induction were excluded and was limited to 4 months (11 months for remitters vs. 7 months for refractory patients, p:0.04). We conclude that older AML patients with unfavorable karyotype have lower CR rates following conventional chemotherapy, because of higher mortality in induction and more frequent refractory disease; in addition, CR is shorter when compared to patients with normal karyotype and has limited impact on survival. Accordingly, even when clinically eligible for aggressive chemotherapy, such patients should be included into therapeutic programs based on experimental programs including agents with alternative mechanisms of action. Disclosures: No relevant conflicts of interest to declare.

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An Interesting Case of Hemophagocytic Lymphohistiocytosis Presenting with Pulmonary Hypertension

Blood ◽

10.1182/blood.v116.21.4728.4728 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4728-4728

Author(s):

Lauren Gerard ◽

Katharine He Xing ◽

Christine Cserti-Gazdewich

Keyword(s):

Bone Marrow ◽

Pulmonary Hypertension ◽

Hemophagocytic Lymphohistiocytosis ◽

Nk Cell ◽

Lymphocytic Leukemia ◽

Cell Transplant ◽

Off Label Use ◽

Severe Pulmonary Hypertension ◽

Off Label ◽

Label Use

Abstract Abstract 4728 Introduction: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening hyperinflammatory syndrome that presents both diagnostic and therapeutic challenges. HLH may be primary and related to an underlying genetic abnormality or secondary to infection, malignancy, or rheumatologic condition. We describe a case of HLH in a latently EBV-/CMV-/HBV-immune 52-year old male presenting with severe pulmonary hypertension. He was intolerant of the HLH 2004 protocol but responded to salvage therapy with anti-CD52 monoclonal therapy (alemtuzumab). Case Presentation: The patient was previously healthy with a diagnosis of axonal-pattern CIDP five years prior. He had a one year history of mild progressive exertional dyspnea and experienced a flu-like illness treated as presumed H1N1 infection five months prior. He presented to hospital with progressive respiratory distress, fevers and weight loss, culminating in respiratory failure requiring mechanical ventilation for 4 days. Investigations revealed severe pulmonary hypertension (RVSP 112 mmHg), nephrotic range proteinuria, transaminitis, hyperferritenemia (ferritin 4240 ug/L) and hepatosplenomegaly. Initial hematologic investigations revealed an isolated thrombocytopenia (IVIG and steroid non-responsive), soon followed by hemolytic anemia with an oxidative blood film. Initial bone marrow biopsy showed normal hematopoiesis, megakaryoyctic thrombocytopenia, iron deficiency, and no evidence of hemophagocytosis. Rheumatologic investigations were negative (ANA, ENA, C3, C4, p-ANCA, c-ANCA, ds-DNA, anti-GBM) and viremia investigations negative (HIV, CMV, EBV, HBV). Hematologic causes of peripherally destructive cytopenias were ruled out (DAT, PNH, methemoglobin, APLA, ADAMTS13, G6PD, PK normal). No definitive etiology of pulmonary hypertension was found and treatment was initiated with nitric oxide and sildenafil. Four weeks after initial presentation to hospital, he developed worsening pancytopenia and unexplained fevers. Repeat bone marrow examination revealed hemophagocytosis, achieving sufficient criteria for diagnosis with HLH. Repeat EBV serology was IgM positive with a viral load 7 × 105/ml. HLH 2004 protocol was initiated, however within 7 days, treatment-limiting nephrotoxicity and hepatotoxicity developed, prompting discontinuation of cyclosporine and dose-reduction of etoposide. Hepatic biopsy revealed drug-induced sinusoidal necrosis with no HLH involvement. Evidence of worsening HLH (ongoing fevers, cachexia, debility, severe cytopenias requiring transfusion and filgrastim support, and increasing ferritin) prompted the use of alemtuzumab. Within 7 days of alemtuzumab initiation the ANC increased from less than 0.2 to within normal range, and within 14 days platelet count rebounded to above 50. Ferritin fell from a peak of 4756 ug/L to approximately 1500 ug/L. Treatment course was complicated by severe upper and lower gastrointestinal bleeds (necessitating massive transfusion protocol), pulmonary blastomycosis (treated with ambisome and itraconazole) and several episodes of bacteremia. Despite his precarious course in hospital, he responded to 6 weeks of treatment with alemtuzumab with continued improvement in his clinical, biochemical, and hematological manifestations of HLH. At 105 days of post-diagnosis follow-up to date, his HLH remains in remission with gradual, ongoing improvement in pulmonary hypertension. Although no clear diagnostic association has been proven, we hypothesized that either this patient's pulmonary hypertension and HLH had a common precipitant or that his pulmonary hypertension was secondary to HLH disease activity. Conclusion: This is a unique case of HLH presenting concurrently with severe pulmonary hypertension, complicated by intolerance of the HLH 2004 protocol, but response to salvage anti-CD52 therapy. There is still much to be understood about the underlying pathophysiology and treatment strategies of HLH. Disclosures: Off Label Use: Alemtuzumab is a monoclonal antibody which targets CD52. It is used as second-line treatment for chronic lymphocytic leukemia. It is also used off-label for other lymphocyte/NK cell disorders, such as cutaneous T-cell lymphoma and some autoimmune diseases. It has been described in off-label use for hemophagocytic lymphohistiocytosis (HLH) as a bridge to allogeneic stem cell transplant.

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Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment

Blood ◽

10.1182/blood.v124.21.2292.2292 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2292-2292 ◽

Cited By ~ 13

Author(s):

Arend von Stackelberg ◽

Franco Locatelli ◽

Gerhard Zugmaier ◽

Rupert Handgretinger ◽

Tanya M. Trippett ◽

...

Keyword(s):

Bone Marrow ◽

Pediatric Patients ◽

Phase 1 ◽

Adult Patients ◽

Off Label Use ◽

Employment Equity ◽

Hematopoietic Stem ◽

Off Label ◽

Equity Ownership ◽

Label Use

Abstract Introduction: Blinatumomab, an investigational bispecific T-cell engager (BiTE®) antibody construct, has been shown to induce remission in adult patients with relapsed/refractory BCP-ALL. Medically important adverse events (AEs) related to blinatumomab treatment in adults are cytokine release syndrome (CRS) and neurological events. We report the primary analysis of the phase 1 portion of a multicenter phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods: In this continuing study, eligible patients are <18 years old and must have BCP-ALL that is in second or later bone marrow relapse, in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or refractory to induction or reinduction therapy. Patients receive blinatumomab for 28 days by continuous intravenous infusion followed by a 14-day treatment-free period (for up to five cycles). Escalating dosing levels of 5, 15, and 30 μg/m²/day and stepwise dosing of 5–15 or 15–30 μg/m²/day were evaluated. The primary endpoint of the phase 1 portion of the study was maximum tolerated dose (MTD). Secondary endpoints included toxicity, complete remission (CR) rate, overall survival (OS), relapse-free survival (RFS), pharmacokinetics evaluation, and cytokine measurement. Results: In the phase 1 portion, 41 patients received a total of 73 cycles (median of 2 cycles received, range of 1 to 5). Eight (20%) patients had refractory disease and seven (17%) had experienced at least two bone marrow relapses. Twenty-six (63%) patients had relapsed following HSCT. Dose-limiting toxicities (DLTs) are listed in Table 1. The MTD was established at 15 µg/m²/day. To decrease the risk of CRS, a stepwise dose of 5–15 μg/m²/day was recommended for the phase 2 part of the study (5 µg/m²/day for 7 days, then 15 µg/m²/day). This dose was subsequently assessed in two age groups (2–6 and 7–17 years) in the phase 1 expansion part with one of 18 patients developing grade 3 CRS. No patient in the expansion cohort developed grade 4 or 5 CRS. Across all dosing levels, 13 (32%) patients had CR with 10 (77%) achieving minimal residual disease (MRD) negativity. Of these 13 patients, nine (69%) underwent HSCT. Among patients who achieved CR, median RFS was 8.3 months (95% CI: 3.0–16.0 months). Median OS was 5.7 months (95% CI: 3.3–9.7 months; Figure 1) with a median follow-up time of 12.4 months. Across all dosing levels, the most common AEs regardless of causality were pyrexia (78%), headache (37%), hypertension (32%), nausea (29%), abdominal pain (27%), pain in the extremity (27%), and anemia (27%). Pharmacokinetic parameters, including steady-state concentration (Css), clearance, and half-life were similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mostly within the first two days after starting blinatumomab, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions: In the phase 1 portion of this study in pediatric patients with relapsed/refractory BCP-ALL, the MTD was 15 µg/m²/day. CRS was dose-limiting, but stepwise dosing of 5–15 μg/m²/day has been effective in ameliorating CRS. Thirty-two percent of patients achieved CR and more than half were able to proceed to allogeneic HSCT. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Zugmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Rheingold:Novartis: Consultancy. Hu:Amgen Inc.: Employment, Equity Ownership. Mergen:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Fischer:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhu:Amgen Inc.: Employment, Equity Ownership. Hijazi:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Gore:Amgen Inc.: Travel Support Other.

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Induction of Complete Remission with 5-Azacytidine in a Patient with Acute Myeloid Leukemia Refractory to Intensive Chemotherapy.

Blood ◽

10.1182/blood.v106.11.4600.4600 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4600-4600

Author(s):

Andrea Kuendgen ◽

Thorsten Graef ◽

Sabine Knipp ◽

Barbara Hildebrandt ◽

Akos Czibere ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Low Dose ◽

High Dose ◽

Intensive Chemotherapy ◽

Bone Marrow Blast ◽

Salvage Regimen ◽

High Dose Cytarabine ◽

Blast Count ◽

Acute Myeloid

Abstract Intensive chemotherapy achieves complete remission in about 75% of patients with acute myeloid leukaemia (AML). For patients refractory to intensive chemotherapy, prognosis is very poor and treatment options are limited. We report a case of AML which was refractory to induction chemotherapy as well as two salvage regimens. The patient then achieved CR through monotherapy with low-dose azacitidine. The 57-year-old patient was admitted to our hospital with a diagnosis of AML M1. A bone marrow biopsy revealed a blast count of 88%. The karyotype was 48,XX,+8,+11 [4/20]. The patient received induction chemotherapy with idarubicin, cytarabine, and etoposide (ICE). Because her disease was refractory to treatment, with a bone marrow blast count of 66%, the patient received a salvage regimen with high-dose cytarabine, mitoxantrone, and all-trans retinoic acid (A-HAM). Still, AML blasts persisted, with a blast count of 52%. The patient then received FLAMSA (fludarabine, amsacrine, and high-dose cytarabine) as a second salvage regimen, but again failed to achieve remission (medullary blast count 50%). Pancytopenia persisted over a period of approximately 3 months (WBC <100/μl, Hb and platelets transfusion-dependent). We then decided to treat her with 5-azacitidine. During the first cycle, she received additional G-CSF because of fungal pneumonia. Azacitidine was given at a dose of 100mg/m2 subcutaneously for 5 days. Treatment was tolerated without side effects. The patient responded swiftly. After the first cycle, peripheral cell counts normalized and the peripheral blast count decreased to 1%. The bone marrow blast count was 3% after 3 cycles, and <1% after 5 cycles. Peripheral blood counts dropped only slightly during treatment cycles, and the patient required no further transfusions. Cytogenetic analysis, including FISH with a centromeric probe for chromosome 8, gave normal results. With the exception of the first cycle, azacitidine was administered in an outpatient setting. After completing the fifth cycle, the patient went on to receive allogeneic stem cell transplantation. In the nineteen-seventies and -eighties, conventional (cytotoxic) dosages of 5-azacytidine showed some activity against AML, but did not achieve remission rates comparable to high-dose cytarabine. Treatment-related toxicity was considerable. Recently, low-dose azacitidine, supposedly acting as a demethylating agent, was approved for treatment of myelodysplastic syndromes in the U. S.. According to recent studies, methyltransferase inhibitors seem to achieve good response rates in patients with high-risk MDS. Cytogenetic remissions have been achieved in patients with poor risk karyotypes. Our case report confirms that 5-azacitidine can be effective in AML, even in patients who have a poor prognosis with conventional therapeutic approaches.

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