Control of Fulminant Juvenile Myelomonocytic Leukemia (JMML) Relapse and Gut GvHD III° with Purinethol Early after Unrelated Donor BMT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5089-5089
Author(s):  
Daniel Stachel ◽  
Chara Gravou-Apostolatou ◽  
Michaela Kuhlen ◽  
Alfred Leipold ◽  
Peter Bader ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Major Complication ◽  
Juvenile Myelomonocytic Leukemia ◽  
Unrelated Donor ◽  
Intravenous Ganciclovir ◽  
Graft Versus Host ◽  
D 63 ◽  
Life Threatening ◽  
Peripheral Leukocytes ◽  
Myelomonocytic Leukemia

Abstract Juvenile myelomonocytic leukemia (JMML) is a rare disease in childhood which can only be cured by stem cell transplantation. The major complication is relapse in up to half of the patients. The existance and efficacy of graft-versus-leukemia (GvL) in JMML is controversial and often associated with severe graft-versus-host disease (GvHD). A 1,5 year old boy developed JMML and was transplanted from a 1 antigen mismatched UD (unmanipulated bone marrow, 8.5 Mio CD34/kg) after a CR consisting of Bu 16*1.25 mg/kg), Cy (2*60 mg/kg), Mel (1*140 mg/m2) and ATG (3*20 mg/kg). GvH prophylaxis consisted of CsA and very short MTX. The situation was further complicated by the intermittent presence of CMV, HHV-6 and EBV in the peripheral blood which was treated intermittently by intravenous ganciclovir. Engraftment occurred on day + 16. GvHD III° of the skin only developed and was treated with corticosteroids, CsA and MMF. Chimerism was complete on day +28. Beginning on day +45 an increasing autologous chimerism was detected. Therefore, immunosuppression was halted. Despite discontinuation of all immunosuppressants the autologous chimerism increased to 60–80% (d +63) and the peripheral leukocytes increased to approx 30,000/μl together with eosinophilia (d +60). Clinical signs of relapse (hepatomegaly and pulmonary obstruction) were also present. Thereafter, within a week, leukopenia and thrombocytopenia developed and the autologous chimerism decreased to 1–5%. Coinciding with the apparent GvL effect severe GvHD reappeared. Skin GvHD II–III° developed, than gut GvDH III° with massive life threatening fluid and potassium loss (day +73). In an attempt to treat both JMML and GvHD the antimetabolite purinethol 50 mg/m2 daily was given orally. Since day + 98 always an complete chimerism was observed. Gut GvHD gradually improved without further immunosuppression. The boy is now at home without evidence of disease or active GvHD more than 1 year after relapse. We speculate that in this case purinethol controlled not only the severe gut GvHD after BMT but also JMML. This antimetabolite may therefore be considered as an immunosuppressant for GvHD when malignat relapse is also present or imminent.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2886-2886 ◽  
Author(s):  
Uwe Platzbecker ◽  
Caroline Pabst ◽  
Alexander Kiani ◽  
Johannes Schetelig ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Clinical Signs ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML. Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS. Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission. Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

scholarly journals Feasibility and Outcome of Hematopoietic Stem Cell Transplantation Combined with Decitabine for Children with Juvenile Myelomonocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5869-5869
Author(s):  
Huaying Liu ◽  
Chunfu Li ◽  
Yuelin He
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Abstract Background Juvenile myelomonocytic leukemia(JMML) is a rare clonalmyelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood with poor prognosis. Chemotherapy has not been found to be dffective, and Hematopoietic stem cell transplantation(HSCT) is currently the only curative treatment for JMML. Relapse and engraftment failure are the major causes of HSCT failure in JMML. Patients and method We report the outcomes of 4 patients with JMML who received HSCT combined with Decitabine between 2014-2015. Patient median age was 2 years(range,1-3years), and 3 were boys and 1 girl. Decitabine was given before and after the HSCT for one time(20mg/m2.d X 5d、10mg/m2 .d X 5d). Before HSCT, all the patients received mild chemotherapy(three or four course). The bone marrow evaluations of all the patients before HSCT were complete remission(CR). Two patients received human leukocyte antigen(HLA)-matched HSCT from unrelated donors, and two patients received haploidentical HSCT from parents followed by unrelated cord blood transplantation(UCB). Conditioning regimen of Unrelated donor-PBSCT was Busulfan+fludarabine+Thiotepa+Thymoglobuline, and the conditioning of haplo-HSCT was Busulfan+fludarabine+Cytarabine+Thymoglobuline. The number of nucleated cells of HLA-matched HSCT was 8×108/kg. The number of nucleated cells of Haplo-HSCT was 47.2×108/kg、61.26×108/kg , respectively, and the number of nucleated cells of UCB was 7.23×107/kg、9.4×107/kg, respectively. GVHD prophylaxis was based on post-transplant high-dose cyclophosphamide(PTCy, 50mg/kg on days +3 and +4) combined with mycophenolate plus cyclosporine A or tacrlimus. Results: The median follow-up was 21 months(range,11-27 months). The overall survival(OS) and the Disease free survival(DFS) both were 100%, All the patients got 100% engraftment(Unrelated-donor stem cell engrafted and Haploidentical-donor stem cell engrafted in 2 and 2 patients , respectively). None of the patients developed relaps, the bone marrow evaluations were complete remission(CR) after HSCT. The most common toxicities were infection with neutropenia(100%, n=4), The cumulative incidences of acute GVHD gradesII-III and CMV infection were 50% and 75% respectively. Conclusion: The combination of decitabine and HSCT shows encouraging results with highly effective and less toxicity for JMML. The futhuer study should be developed in the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA-Haploidentical HSCT (haplo-HSCT) in Children with Malignant or Non-Malignant Disorders

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2171-2171
Author(s):  
Mattia Algeri ◽  
Pietro Merli ◽  
Waseem Qasim ◽  
Mary Slatter ◽  
Melissa Kuhn ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Life Threatening ◽  
Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for children with leukemia or life-threatening non-malignant disorders. Approximately 25% of patients have a HLA-matched sibling and ~50% have a suitable matched unrelated donor, leaving ~25% of patients who require an alternative donor. HLA-partially matched (haploidentical, haplo) donors represent a suitable alternative for these children; extensive T-cell depletion of the graft is largely employed to minimize the risk of graft-versus-host disease (GvHD). BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of CD3+ CD19+ T-cells following transplant. The polyclonal nature of the BPX-501 T cells provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid. Aims To evaluate the safety and efficacy of BPX-501 T cells administered after a T-cell receptor αβ and B-cell-depleted haplo-HSCT in pediatric patients with malignant or non-malignant disorders. The primary endpoint is event-free survival at 180 days (events include TRM (or NRM for malignant patients), severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life-threatening infections (Grade 4). Methods This multicenter EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 (BPX-501). BPX-501 cells were planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of dimerizing rimiducid activating iC9. The efficacy evaluable population (EEP) was defined as any patient who received HSCT, BPX-501 infusion and at least one follow-up assessment. Results At the time of clinical cut-off (June 30, 2018) 166 patients met the EEP definition. All patients were from EU sites. Key baseline and transplant characteristics are shown in Table 1. In patients who obtained sustained engraftment of donor cells, the median time for neutrophil and platelet engraftment was 16 (15-17) and 11 (11-12) days, respectively. No patients experienced graft failure. Thirty-one patients developed Grade I-IV aGvHD (18.7% [95% CI;12.8 - 24.7%]). Three patients developed Grade III-IV aGvHD (1.8% [95% CI; 5.2 - 14.1%]). Of 132 evaluable patients, 9 developed cGvHD (7.2% [95% CI; 2.6 - 11.7%]) with only 2 patients experiencing moderate - severe cGvHD (95% CI: 0.0 - 3.1). Rimiducid was administered to 11 patients. Ten patients had ≥ 1 response assessment following administration of rimiducid. The best overall response rate (CR/PR) was 100% with 9 patients (90%) achieving complete response. At the time of clinical cut off, EFS at 180 days was 92.7% (95% CI: 88.7 - 96.7%). An interim analysis with approximately 100 patients from a concurrent Matched Unrelated Donor (MUD) HSCT comparator trial and previously published data is planned for the time of the congress. At a median follow-up of 17.6 mos (1.5 - 43.7 mos) 5 patients experienced transplant related mortality (TRM) (3.3% [95% CI: 0.4 - 6.2%]). DFS was 89.4% (95% CI: 84.7 - 94.2%). Overall survival (OS) was 94.2% (95% CI: 90.5 - 97.9%). CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by day 100. IgA and IgM levels achieved normal values by day 180. The percentage of circulating and median absolute BPX-501 T-cells at Day 100 were 9.06% ± 10.52% (0 - 54.9%) and 109.49 ± 213.99 cells/ml (0 - 1001 cells/ml), respectively. Conclusion Preliminary evaluation of the primary endpoint and additional time-dependent efficacy outcomes, shows that the adoptive transfer of BPX-501 T cells following αβ-T and B-cell depleted haplo-HSCT followed by infusion of BPX-501 represents a novel and highly effective transplantation strategy for pediatric patients with malignant or non-malignant disorders. Despite the addition of BPX-501, overall rates of GvHD were low with few cases of high-grade aGvHD or cGvHD. Rimiducid was shown to be an effective treatment for patients who developed steroid-refractory GvHD. Disclosures Qasim: Bellicum: Research Funding; Autolus: Equity Ownership; Servier: Research Funding; Orchard: Equity Ownership. Slatter:Medac: Other: Travel assistance. Locatelli:bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Unrelated Cord Blood Transplantation for Children with Juvenile Myelomonocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2021-2021
Author(s):  
Franco Locatelli ◽  
Adrienne B.M. Madureira ◽  
Vanderson Rocha ◽  
Pierre Teira ◽  
Martin Champagne ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Monosomy 7 ◽  
Free Survival ◽  
Graft Versus Host ◽  
Blood Transplantation ◽  
Unrelated Cord Blood ◽  
Myelomonocytic Leukemia

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for children with juvenile myelomonocytic leukemia (JMML). A recent study from the European Working Group of MDS in Childhood (EWOG-MDS) reported a 5-year probability of event free survival of 55% (n=48), and 49% (n=52) in children transplanted from either an HLA identical sibling or an unrelated volunteer, mainly donating bone marrow (BM) cells. As in the EWOG-MDS analysis only 7 children received unrelated cord blood transplantation (UCBT), we decided to further investigate the role of UCBT in 42 children with JMML, reported to the Eurocord-EBMT and EWOG-MDS registries. Median age at transplantation of the 42 children was 2.6 years (range 0.6–7); 29 patients were males and 13 females. Cytogenetic analysis was available in all patients but one: 10 patients had monosomy 7, 4 other abnormalities, while the remaining 27 children had a normal karyotype. Seven patients underwent splenectomy before UCBT. Conditioning included Busulfan in 78% of patients, while the most common graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporin-A and steroids. In donor-recipient pairs, histocompatibility was determined by serology or low resolution molecular typing for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 locus. The donor was HLA identical in 7 cases, 1-antigen disparate in 18 and with 2 or more disparities in 14. Median number of nucleated cells infused was 6.8 × 107/Kg (range 2–50). The 60-day cumulative incidence (CI) of engraftment was 76%%, with a median time to neutrophil and platelet recovery of 27 (range 14–51) and 50 (range 15–180) days, respectively. In multivariate analysis an age at UCBT younger than 2.6 years (hazard ratio, HR=0.27; 95% confidence interval=0.13–0.57; p=0.0005) and the use of a more HLA-compatible donor (HR=0.38; 95% confidence interval=0.16–0.89; p=0.03) predicted better engraftment. CI of grade II-IV acute and chronic graft-versus-host disease (GvHD), and of transplantation-related mortality (TRM) were 31%, 16%, and 33%, respectively. The CI of TRM of our cohort of patients is higher than the 2-year TRM CI of 16% in children with JMML given unrelated donor HSCT reported in the EWOG-MDS analysis. Eleven children relapsed, the 2-year CI of relapse being 22%. In comparison, in the EWOG-MDS study, the 2-year CI of relapse of unrelated HSCT recipients was 36%. The CI of relapse was 30% in patients with monosomy 7 as compared to 19% in the remaining children (p=0.64). With a median follow-up of 36 months (range 3–102), the 2-year disease-free survival (DFS) of the overall cohort was 45%; patients younger or older than 2.6 years had a DFS of 66% and 26% respectively, p=0.01. In multivariate analysis, only age at UCBT was associated with increased DFS (HR=2.98; 95% confidence interval=1.21–7.34; p=0.02). These data indicate that UCBT is a suitable option for children with JMML lacking an HLA-compatible relative and suggest that the search for an unrelated cord blood unit be initiated simultaneously to that for unrelated BM donors. Cord blood offers the advantage of nearly immediate availability of stem cells and allows to perform HSCT even in the presence of donor HLA disparities.

BRAF Mutations in Juvenile Myelomonocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4602-4602
Author(s):  
Andrica C.H. de Vries ◽  
Ronald W. Stam ◽  
Christian Kratz ◽  
Martin Zenker ◽  
Oskar A. Haas ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Clinical Signs ◽  
Juvenile Myelomonocytic Leukemia ◽  
Reaction Products ◽  
Braf Gene ◽  
Braf Mutations ◽  
Ras Pathway ◽  
Coding Sequence ◽  
Ras Genes ◽  
Myelomonocytic Leukemia

Abstract Approximately 75% of patients with juvenile myelomonocytic leukemia (JMML) harbour mutations in PTPN11, NF1 and RAS genes. The remaining cases presumably carry somatic mutations in other genes in the RAS pathway. BRAF plays a central role in this pathway between RAS and downstream molecules including MEK and ERK. BRAF mutations frequently occur in cancer. Recently, BRAF mutations were found in leukemia. Besides that, germline BRAF mutations cause cardio-facio-cutaneous syndrome, which shares many features with Noonan syndrome (NS). NS predisposes to a myeloproliferative disease resembling JMML. In 65 JMML patients screening for V600E mutations in exon 15 of the BRAF gene was performed from mononuclear cells. In a subset of patients, without RAS or PTPN11 mutations, and no clinical signs of NF1, the entire coding sequence of BRAF was analyzed. Sequence analysis was performed by direct, bidirectional sequencing of purified polymerase chain reaction products. In none of the 65 cases a V600E mutation of the BRAF gene was found. In a subset of patients in which the entire coding sequence of BRAF was analyzed, no mutations were identified either. Mutant proteins of the RAS-RAF-MEK-ERK pathway play an important role in the pathogenesis of JMML, resulting in GM-CSF hypersensitivity. In about 75% of the JMML cases these mutations affect RAS, NF1 or PTPN11 genes. The hypothesis for this study was that BRAF might play an important role in JMML as it is an important downstream effector of RAS. Our data show that apparently BRAF mutations do not play a role in JMML. Therefore, additional analysis of genes of the RAS pathway will be necessary to identify genetic aberrations in cases without known mutations.

HLA-Identical Umbilical Cord Blood Transplantation from a Sibling Donor in Juvenile myelomonocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4428-4428
Author(s):  
Andrica de Vries ◽  
Robbert Bredius ◽  
Arjan Lankester ◽  
Marc Bierings ◽  
Monika Trebo ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
The Other ◽  
Juvenile Myelomonocytic Leukemia ◽  
Graft Versus Host ◽  
Sibling Donor ◽  
Matched Sibling ◽  
Myelomonocytic Leukemia

Abstract Background: Juvenile myelomonocytic leukemia (JMML) is a rare malignant myeloid disorder in childhood, for which stem cell transplantation is currently the only curative treatment option. Although unrelated donor umbilical cord blood transplantations (UCBTs) have been described, series of HLA-identical sibling donor UCBTs in JMML are not available. Methods: From the European Working Group on Childhood MDS (EWOG MDS) registry the 5 JMML patients who underwent a fully HLA matched sibling UCBT are described. Results: The median age at diagnosis was 18 months (range 15–30 months). In one case no mutation analysis was performed, in one case a PTPN11 mutation was found. In the other cases no mutation in RAS or PTPN11 was found. None of the patients had clinical signs of NF1. The conditioning consisted of busulfan, cyclophosphamide and melphalan in four cases and of cyclophosphamide, etoposide and total body irradiation in one case. All patients engrafted slowly. In 3 patients mild acute graft versus host was noticed (grade 1 and 2), no chronic graft versus host was reported. Two patients relapsed after the initianal transplantation and underwent a second transplant with marrow of the initianal donor. One of them is in second complete remission and the other died after a second relapse. One patient developed increased donor chimerism from day 42 without any clinical sign of relapse. She was treated with DLI, 6 mercaptopurine and 13-cis retinoic acid respectively. She is still in complete remission 5 years after transplantation. Conclusion: This EWOG serie illustrates that, although this needs to be confirmed in larger series, relatively immunologically naive HLA-matched sibling UCBT is feasible in selected cases of JMML.

scholarly journals Pericardial effusion as a complication of chronic graft versus host disease

2018 ◽  
Vol 11 (1) ◽  
pp. e227507
Author(s):  
Keaton Nasser ◽  
Kshipra Joshi ◽  
Ella Starobinska
Keyword(s):  
Pericardial Effusion ◽  
Graft Versus Host Disease ◽  
Marrow Transplant ◽  
Unrelated Donor ◽  
Host Disease ◽  
Allogenic Bone ◽  
Graft Versus Host ◽  
Large Pericardial Effusion ◽  
Life Threatening ◽  
Work Up

A 24-year-old man with previous matched unrelated donor allogenic bone marrow transplant for aplastic anaemia and chronic graft versus host disease on steroid taper presented with progressively worsening anasarca. CT revealed large pericardial effusion, while echocardiogram was concerning for early tamponade physiology. He underwent emergent pericardiocentesis with pericardial drain placement. Extensive rheumatological and infectious work-up was unrevealing with patient’s presentation attributed to pericardial graft versus host disease. This highlights the need of physicians to be aware of pericardial serositis as a complication of graft versus host disease due to its life-threatening complications, which require immediate intervention.

Prognostic relevance of disordered epigenetic regulation in juvenile myelomonocytic leukemia

2013 ◽  
Vol 225 (03) ◽  
Author(s):  
S Fluhr ◽  
T Witte ◽  
CF Krombholz ◽  
C Plass ◽  
CM Niemeyer ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Prognostic Relevance ◽  
Myelomonocytic Leukemia
Sign in / Sign up

Export Citation Format

Share Document