Upfront azacitidine (AZA) in juvenile myelomonocytic leukemia (JMML): Interim analysis of the prospective AZA-JMML-001 study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10031-10031
Author(s):  
Charlotte M. Niemeyer ◽  
Christian Flotho ◽  
Daniel B. Lipka ◽  
Jan Starý ◽  
Claudia Rössig ◽  
...  
Keyword(s):  
Juvenile Myelomonocytic Leukemia ◽  
Open Label ◽  
Historical Cohort ◽  
Hematopoietic Stem ◽  
Once Daily ◽  
Curative Therapy ◽  
Retrospective Comparison ◽  
Myelomonocytic Leukemia

10031 Background: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for JMML patients (pts). Novel therapies controlling the disorder prior to HSCT are urgently needed. A phase 2, multicenter, open-label study was conducted to evaluate safety and anti-leukemia activity of AZA monotherapy prior to HSCT in pts with newly diagnosed (ND) JMML. Methods: AZA (75 mg/m2 IV) was administered once daily on days 1–7 of each 28-day cycle (C). Primary endpoint was number of pts with clinical complete remission or clinical partial remission (cPR) at C3 day (D) 28 (C3D28). Results: 18 JMML pts (13 PTPN11-, 3 NRAS-, 1 KRAS-, 1 NF1-mutated) were enrolled from 09/2015 to 11/2017. Median (range) white blood cell and platelet (Plt) counts were 19.7 (4.3–59.0) × 109/L and 28 (7–85) × 109/L, respectively. DNA methylation class (MC) was high, intermediate (int), or low in 11, 5, and 2 pts, respectively. 16 pts completed C3 and 5 pts C6. 2 pts discontinued treatment (Tx) pre-C3D28 due to disease progression (PD). 6 pts (33%) had ≥ 1 grade (Gr) 3–4 manageable adverse event (AE) related to AZA. Most common Gr 3–4 AEs related to AZA were neutropenia (2) and anemia (2). 11 pts (61%) were in cPR at C3D28; 7 had PD at C3D28 or prior. All 7 pts of the int/low MC and 4/11 in high MC achieved cPR. 17 pts received HSCT at median of 58 days (37–518) from last AZA dose; 14 were leukemia-free at a median follow-up of 15.7 months (0.1–31.7) after HSCT. 2 pts (high MC) given HSCT relapsed after allograft. 16/18 pts were alive at a median follow-up of 19.8 months (2.6–37.3) from diagnosis. 1 pt discontinuing Tx prior to C3 died from PD; 1 non-responder died from transplant-related causes. Plt response in pts with cPR prompted retrospective comparison of Plt counts at time of HSCT with a historical registry control cohort. Pts with NF1-mutated JMML with higher Plt counts versus other genetic subtypes were excluded. While 7/16 (44%) study pts had Plt counts ≥ 100 × 109/L at HSCT, only 10/58 (17%) historical cohort pts reached this cutoff ( P < 0.01). Conclusions: This study shows that AZA monotherapy was well tolerated in pts with ND JMML. Although the long-term advantage of AZA Tx remains to be fully assessed, responses show it was effective in JMML and provided clinical benefit to pts in this study. Clinical trial information: NCT02447666.

scholarly journals Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

2021 ◽  
Vol 5 (14) ◽  
pp. 2901-2908
Author(s):  
Charlotte M. Niemeyer ◽  
Christian Flotho ◽  
Daniel B. Lipka ◽  
Jan Starý ◽  
Claudia Rössig ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Newly Diagnosed ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Time Profiles ◽  
Genome Wide ◽  
Number Of Patients ◽  
Myelomonocytic Leukemia

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Long-Term Safety and Efficacy Data on Childhood Venous Thrombosis Treated with Enoxaparin: An Open Label Survey of Once-Daily Versus Twice-Daily Administration.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 549-549
Author(s):  
Ulrike Nowak-Gottl ◽  
Christine During ◽  
Christoph Bidlingmaier ◽  
Nick Merkel ◽  
Rosemarie Schobess
Keyword(s):  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
Randomised Study ◽  
Catchment Areas ◽  
Prothrombotic Risk Factors ◽  
The Individual ◽  
A Minor

Abstract Low molecular weight heparin is as effective as unfractionated heparin for treatment of venous thromboembolism (VT) in adults, and it has been recently demonstrated that once-daily (q24h) or twice-daily (q12h) enoxaparin (E) administration had no impact on safety (bleeding rate) of efficacy (re-thrombosis rate) in the treatment of acute VT. However, in this setting it is still unclear for children, if enoxaparin should be administered q24h or q12h. In this open label pilot safety study 75 children &gt; the neonatal period, enrolled from two different catchment areas of Germany were treated with E with a target 2–4 h anti Xa activity between 0.4 – 0.8 IU/ml. After the acute thrombotic onset during which E was administered q12h for a median (range) period of 7 (1–14) days, based on the individual decision of the study centres stratification into the study arms once-daily versus twice daily was performed. Enoxaparin was administered in both study centres regardless of age at DVT-onset, thrombus burden, underlying basic diseases or presence of prothrombotic risk factors. No difference was observed between the stratifications performed in the study centres (p=0.5). Median (range) dose administered q24h (n=50) or q12h (n=25) in children with DVT was 1.2 mg/kg (0.5–3.0) respectively. Median (range) treatment duration was 5 months (1–13). Prospectively defined study endpoints were adverse effects, e.g. re-thrombosis, bleeding, and therapy-related death. Median follow-up time was 24 months. No significant differences were found between the two patient groups treated with respect to anti Xa activities, efficacy and safety. Further statistical analysis performed to evaluate the overall differences between q24h and q12h E administration again revealed no significant differences for the study endpoints: Re-thrombosis occurred in two patients each (p=0.6), and a minor subdural bleeding was diagnosed in one patient treated q12h (p=0.4). During the follow-up no major bleeding or therapy-related death was observed. In conclusion, data presented here give evidence that long-term enoxaparin administration within the reported target anti Xa activity for treatment of childhood VT has a good efficacy and safety profile when administered q24h. These data have to be confirmed in a multicentre randomised study.

scholarly journals JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities

Blood ◽  
2015 ◽  
Vol 125 (18) ◽  
pp. 2753-2758 ◽  
Author(s):  
Katherine R. Calvo ◽  
Susan Price ◽  
Raul C. Braylan ◽  
Joao Bosco Oliveira ◽  
Michael Lenardo ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Clinical Care ◽  
Juvenile Myelomonocytic Leukemia ◽  
Peripheral Blood Mononuclear ◽  
Long Term Follow Up ◽  
Activated Monocytes ◽  
Myelomonocytic Leukemia

Abstract Ras-associated autoimmune leukoproliferative disorder (RALD) is a chronic, nonmalignant condition that presents with persistent monocytosis and is often associated with leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD has clinical and laboratory features that overlap with those of juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML), including identical somatic mutations in KRAS or NRAS genes noted in peripheral blood mononuclear cells. Long-term follow-up of these patients suggests that RALD has an indolent clinical course whereas JMML is fatal if left untreated. Immunophenotyping peripheral blood from RALD patients shows characteristic circulating activated monocytes and polyclonal CD10+ B cells. Distinguishing RALD from JMML and CMML has implications for clinical care and prognosis.

scholarly journals A Novel Therapy Protocol Improves Outcomes of Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia Patients Using Hypomethylation of Decitabine

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5778-5778
Author(s):  
Zhiyong Peng ◽  
Xiaoqin Feng ◽  
Huaying Liu ◽  
Yuelin He ◽  
Jianyun Liao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Disease Free Survival ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Myelomonocytic Leukemia

Abstract Background Juvenile myelomonocytic leukemia(JMML) has usually poor response to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplantation (HSCT). Recent studies have highlighted the importance of epigenetic aberrations in JMML and proved that some JMML stem cells were associated with hypermethylation. Hence, we desiged the current study to investigate whether low dose Decitabine could improve outcomes of JMML-HSCT.We have reported the preliminary results of low-dose decitabine in the treatment of children with JMML in 2017 ASH as a poster(see blood 2017 130:3232). Then, we will report our latest study. Patients and method 27 patients received HSCT combined with Decitabine between December 2014 and July 2018. Of them,6 patients with NF-1 mutation,11 with PTPN11 mutation, 2 with Kras somatic mutation ,1 with Nras somatic mutation, 3 with multiple mutation (PTPN11+NF-1),2 with monosomy 7,and 3 with uncertain mutation. The median age at diagnosis was 24 months (range: 1-72 months). 26/27 patients received 1~4 course mild chemotherapy(one patient,case 6, received only single course Decitabine therapy)before HSCT.3 patients received HSCT from HLA matched unrelated donors(MUD),and 24 patients received the complementary transplantation(CT), i.e. unrelated cord blood(UCB) was given at day 6 after haploidentical peripheral blood stem cell transplantation(PBSCT) using high dose cyclophosphamide(Cy) post-transplant (PTCy), (see blood 2016 128:1235). Conditioning regimen was composed of Cy, Busulfan (Bu)/ Thiotepa (TT), Fludarabine (Flu) and ATG-F in the MUD-HSCT, and Cy, Bu/TT, Flu and Cytarabine in the CT. Patients received a fixed dose of 8×108/kg mononuclear cells(MNC) in the MUD-HSCT, and a median dose of 45.5×108/kg (range, 26.8~88×108/kg) mobilized peripheral blood MNCs and a median dose of 8.9×107/kg (range, 4.0~12.8×107/kg) UCB nucleated cells in the CT, respectively. GVHD prophylaxis consisted of PTCy, Mycophenolate Mofetil (MMF) and Tacrolimus in the CT, and Thymoglobuline, CsA and MMF in the MUD-HSCT. Decitabine was administrated for 2~4 courses (20mg/m2.d×5 day for each course with 4-week interval) before HSCT to reduce load of leukemia cells and for 2~4 courses (5~10mg/m2.day×5day for each course with the interval of 4~6 weeks) after HSCT to overcome immune-escape of leukemia cells. Results: The median follow-up time was 13months (range, 2-51 months). Full donor cells were engrafted in all patients (donor cell engraftment in case 6 occurred in a salvaged transplant from another haplo-donor after primary failure of first CT).The Overall survival(OS) and Disease-free survival(DFS) was 89.4% and 87.3% respectively. In the CT, haplo-cells and UCB-cells were engrafted in 10 and 14 patients, respectively. The median time to neutrophil more than 0.5x109/L was 31days (range,12~71 days) and 17 days (range, 12~35 days)post-transplant, and to platelet more than 20 x109/L was 22 days (range,9~105 days) and 12 days (range,10~30 days) post-transplant, respectively, in the CT and the MUD- HSCT. All the 3 patients with relapse were haploid-engrated. Two of the three patients with relapse had underwent secondary CT. One of them was Disease-free survival ,and the other died of viral encephalitis(HHV-6) after secondary CT. The cumulative incidence of grades Ⅱ-Ⅳ acute GVHD (aGVHD) was 25.9% (7/27 patients). Case 6 had grade III aGVHD. A case died of grade IV aGVHD(gut) 50 days after the CT. Chronic GVHD(cGVHD) occurred in 5 patients, and no cGVHD more than grade II (NIH criterion) occurred in all patients. The most common complication associated with HSCT was infection. The cumulative incidences of infection plus reactivation of CMV,EBV and HHV-6 were 30% (7/27),3.7%(1/27) and 11.1%(3/27), respectively. Recoverable serious pancytopenia occurred in 3 patients with Decitabine therapy post-HSCT. Conclusion: The combination of hypomethylation agent with HSCT still showed satisfactory results in JMML-HSCT when the follow-up time has been extended for one year. A large-cohort study with extending follow-up time should be developed continuously in the future and the interim results of five-year follow-up time will be reported. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rituximab-Containing Risk-Adapted Treatment Strategy in Nodular Lymphocyte Predominant Hodgkin Lymphoma: 7-Years Follow-Up

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1760
Author(s):  
Novella Pugliese ◽  
Marco Picardi ◽  
Roberta Della Pepa ◽  
Claudia Giordano ◽  
Francesco Muriano ◽  
...  
Keyword(s):  
Side Effects ◽  
Hodgkin Lymphoma ◽  
Prognostic Score ◽  
Single Agent ◽  
Response To Therapy ◽  
Baseline Risk ◽  
Historical Cohort ◽  
Treatment Groups

Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare variant of HL that accounts for 5% of all HL cases. The expression of CD20 on neoplastic lymphocytes provides a suitable target for novel treatments based on Rituximab. Due to its rarity, consolidated and widely accepted treatment guidelines are still lacking for this disease. Methods: Between 1 December 2007 and 28 February 2018, sixteen consecutive newly diagnosed adult patients with NLPHL received Rituximab (induction ± maintenance)-based therapy, according to the baseline risk of German Hodgkin Study Group prognostic score system. The treatment efficacy and safety of the Rituximab-group were compared to those of a historical cohort of 12 patients with NLPHL who received Doxorubicin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by radiotherapy (RT), if needed, according to a similar baseline risk. The primary outcome was progression-free survival (PFS) and secondary outcomes were overall survival (OS) and side-effects (according to the Common Terminology Criteria for Adverse Events, v4.03). Results: After a 7-year follow-up (range, 1–11 years), PFS was 100% for patients treated with the Rituximab-containing regimen versus 66% for patients of the historical cohort (p = 0.036). Four patients in the latter group showed insufficient response to therapy. The PFS for early favorable and early unfavorable NLPHLs was similar between treatment groups, while a better PFS was recorded for advanced-stages treated with the Rituximab-containing regimen. The OS was similar for the two treatment groups. Short- and long-term side-effects were more frequently observed in the historical cohort. Grade ≥3 neutropenia was more frequent in the historical cohort compared with the Rituximab-group (58.3% vs. 18.7%, respectively; p = 0.03). Long-term non-hematological toxicities were observed more frequently in the historical cohort. Conclusion: Our results confirm the value of Rituximab in NLPHL therapy and show that Rituximab (single-agent) induction and maintenance in a limited-stage, or Rituximab with ABVD only in the presence of risk factors, give excellent results while sparing cytotoxic agent- and/or RT-related damage. Furthermore, Rituximab inclusion in advanced-stage therapeutic strategy seems to improve PFS compared to conventional chemo-radiotherapy.

Short- and Long-Term Cardiovascular Effects of Mixed Amphetamine Salts Extended-Release in Adolescents With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S15) ◽  
pp. 22-30 ◽  
Author(s):  
Timothy E. Wilens ◽  
Thomas J. Spencer ◽  
Joseph Biederman
Keyword(s):  
Extended Release ◽  
Cardiovascular Effects ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Once Daily ◽  
Open Label Extension ◽  
Short And Long Term ◽  
Clinically Significant

AbstractObjectiveAssess cardiovascular effects of once-daily mixed amphetamine salts extended release (MAS XR) in adolescents (13–17 years of age) with attention-deficit/hyperactivity disorder (ADHD).MethodsBlood pressure (BP), pulse, and electrocardiograms were assessed in 327 healthy subjects during a 4-week, randomized, double-blind, placebo-controlled, forced dose-titration study. Placebo (n=69) or once-daily MAS XR(10, 20, 30, or 40 mg) was administered to subjects ≤75 kg (n=233); 50- and 60-mg MAS XR was administered to subjects >75 kg (n=25). One hundred thirty-eight subjects participated in a 6-month, open-label extension study.FindingsChanges in BP and QTcB (Bazett's formula) intervals at 4 weeks with MAS XR were not significantly different from the placebo group. Pulse increased by 5.0 and 8.5 bpm after 3 weeks with MAS XR 20 and 50 mg/day, respectively (P≤.002). After 6 months of open-label MAS XR treatment, mean increases in systolic BP (1.7 mm Hg; P=.0252) and pulse (4.4 bpm; P<.0001) were statistically, but not clinically, significant diastolic BP was not significantly changed (0.6 mm Hg) A decrease in QTcB interval (-4.6±19.9 msec) was statistically (P=.009), but not clinically, significant. There were no serious cardiovascular adverse events.ConclusionCardiovascular effects of short- and long-term MAS XR treatment (≤60 mg/day) were minimal in otherwise healthy adolescents with ADHD.

Long-term survival after nonintensive chemotherapy in some juvenile myelomonocytic leukemia patients with CBL mutations, and the possible presence of healthy persons with the mutations

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5429-5431 ◽  
Author(s):  
Kazuyuki Matsuda ◽  
Chiaki Taira ◽  
Kazuo Sakashita ◽  
Shoji Saito ◽  
Miyuki Tanaka-Yanagisawa ◽  
...  
Keyword(s):  
Juvenile Myelomonocytic Leukemia ◽  
Term Survival ◽  
Long Term Survival ◽  
Myelomonocytic Leukemia ◽  
Healthy Persons
Sign in / Sign up

Export Citation Format

Share Document