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In: European Journal of Haematology, Wiley, Vol. 76, No. 1 ( 2006-01), p. 9-17

Abstract: Abstract:  Objective:  To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome‐positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). Methods:  We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling ( n  = 18) or unrelated ( n  = 43) donors after having been treated with IM. Forty‐one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan ( n  = 25) or total‐body irradiation ( n  = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose‐reduced conditioning with fludarabine‐based regimens. Results:  The incidence of grades II–IV and III–IV graft‐versus‐host disease was 66% and 38% respectively. The probability of overall survival (OS), disease‐free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non‐relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine‐based conditioning therapy, age ≥40 yr and 〉 12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. Conclusion:  These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant‐related mortality.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.2006.76.issue-1

DOI: 10.1111/j.0902-4441.2005.t01-1-EJH2321.x

Language: English

Publisher: Wiley

Publication Date: 2006

detail.hit.zdb_id: 2027114-1

In: American Heart Journal, Elsevier BV, Vol. 150, No. 1 ( 2005-07), p. 115-

Type of Medium: Online Resource

ISSN: 0002-8703

URL: Article

DOI: 10.1016/j.ahj.2005.04.030

Language: English

Publisher: Elsevier BV

Publication Date: 2005

detail.hit.zdb_id: 2003210-9

In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 132, No. 10 ( 2006-10), p. 665-671

Type of Medium: Online Resource

ISSN: 0171-5216 , 1432-1335

URL: Article

DOI: 10.1007/s00432-006-0115-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2006

detail.hit.zdb_id: 1459285-X

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4523-4523

Abstract: Background Chronic graft-versus-host disease (cGVHD) is the major cause of treatment related morbidity and mortality after allogeneic stem cell transplantation (allo-HSCT). Recently Paul Martin et al. reported that treatment success at 1 year (defined as a patient being in partial (PR) or complete remission (CR) of cGVHD, in ongoing remission of underlying disease and not requiring any secondary treatment for cGVHD) was the only endpoint associated with clinical benefit. Strikingly this robust endpoint was only achieved in less than 20% of patients undergoing primary treatment for cGVHD. Therefore, although most patients show initial response to first-line therapy, long-term clinically meaningful treatment success remains rare. Methods: We conducted a prospective multicentre phase II trial in 6 transplant centres across Germany (ClinicalTrials.gov Identifier: NCT01862965). Patients aged 18 years or older with newly diagnosed moderate or severe cGVHD were included. All patients received prednisone (1mg/kg BW) and everolimus (target level 3-8 ug/l). Study treatment was scheduled for 12 months followed by a one-year follow-up period. Primary endpoint was treatment success at 6 months defined as patient being alive, achieving PR or CR of cGVHD, having no relapse of underlying disease and requiring no secondary treatment for cGVHD. Secondary endpoints included time to treatment failure, overall survival at one and 2 years, time to response, incidence of PR /CR at 6 months, incidence of relapse, thrombotic microangiopathy, pneumonitis and osteonecrosis. Results: A total of 38 patients were included between March 2013 and February 2018 in the study. Four patients were excluded from the efficacy analysis because of screening failure. Of the 34 patients, 61% had moderate and 39% severe cGVHD. Of these 19 (56%) patients showed treatment success at 6 months with 22% and 52% of the patients in a CR and PR respectively. Overall 30 patients (88%) had a CR or PR as best response, nearly all responses (29/30) occurring within the first 6 weeks of treatment (figure 1). Median time to treatment failure was 24.7 weeks. The cumulative incidence of treatment failure at one year was 63%, resulting in a treatment success incidence of 37% (figure 2). Relapse of underlying disease was diagnosed in 2 (5.9%) patients. Other predefined side effects (thrombotic microangiopathy, pneumonitis and osteonecrosis) were not observed in any patient. Conclusion: This, to the best of our knowledge, is the first prospective study analysing the endpoint treatment success as defined by Paul Martin et al. Our results indicate that addition of everolimus to prednisolone is well tolerated and may help improve long-term outcome of patients with cGVHD. Acknowledgements: This study was supported by a research grant from Novartis to Nicolaus Kröger and Francis Ayuk Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Wagner:MEDAC: Other: Travel support; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; MSD: Other: Advisory board. Wolff:Neovi: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Mallinckrodt: Honoraria. von Harsdorf:Novartis: Other: none. Koenecke:Novartis: Other: none. Sayer:Novartis: Other: none. Kroeger:Novartis: Honoraria, Other: Advisory Board, Travel Costs, Research Funding. OffLabel Disclosure: Everolimus used for Treatment of chronic GVHD

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129801

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1358-1358

Abstract: Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 & gt;60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p & lt;0,001), gender (p & lt;0,05) and AML type (p & lt;0,01) for OS. FLT3-ITD mut was an important determinant for relapse free survival in pts ≤60y. A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003] . Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p & lt;0.0001). Almost all long term survivors were treated with HSCT. Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% & gt;18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients & lt;60y when intensive chemotherapy followed by HSCT was involved. Independent risk factors for OS in relapsed pts were age, cytogenetic risk, interval CR1 to relapse and type of therapy. Relapsed pts with HSCT in CR1 showed a trend for reduced survival. Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent & gt;10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125262

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2325-2325

Abstract: Abstract 2325 Background: The medical backbone of GvHD prophylaxis has been considered the use of a calcineurin inhibitor (CNI) like cyclosporine or tacrolimus in combination with methotrexate (MTX) or mycophenolate mofetil (MMF). The mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001, Certican®) is a novel immunosuppressive drug and beside sirolimus approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with CNI showed promising clinical effectiveness in innovative prevention strategies of acute GvHD after allogeneic stem cell transplantation (SCT). In this single centre retrospective analysis, we report the outcome on patients (pts), treated interventional with everolimus due to severe toxicity induced by CNI-based GvHD prophylaxis. Patients and Methods: Ten pts (3 acute myeloid leukaemias, 1 myelodysplastic syndrome, 1 acute lymphoblastic leukaemia, 4 Non-Hodgkin-lymphomas) underwent allogeneic blood SCT between 7/2007 and 3/2010. The median age was 51 years [range: 24–64] with 6 pts in advanced stages of their disease. Myeloablative conditioning was used in 3 pts (12 G TBI/120mg/kg cyclophosphamide (cyclo)] and reduced-intensity conditioning in 7 pts [5× treosulfan/fludarabine (flu), 1× busulfan/flu and 1× amsacrine/cytarabine/flu followed by 4 G TBI/cyclo]. HLA-matched family donors in 4 pts and unrelated donors in 6 pts donated on day 0 a median of 4.73 × 106 kg per bodyweight CD-34 positive stem cells. GvHD-prophylaxis consisted of standard CNI+MTX in 3 pts, CNI+MMF in 6 pts and CNI+MMF+MTX in 1 patient. Antithymocyte globulin as in vivo T-cell depletion was given in 7 pts as part of the reduced intensity conditioning regime. Results: Everolimus (0.75 mg Certican ® twice a day orally) was individual started after a median of 14 days [range: 6–16] after SCT. Primary reasons for stopping CNI (median day +10 [range 1–15] ) were nephrotoxicity (CTC ≥ grade 3) in 7 pts and neurotoxicity (CTC ≥ grade 3) in 3 pts. Two pts received steroids in addition to everolimus temporally, 5 pts MMF and 3 pts steroids+MMF. The intended plasma therapeutic level of everolimus was 3–8 mg/l. All patients showed neutrophil engraftment on median day +18 [range: 8–20] and platelet engraftment on day +21 [range: 10–88] . Acute GvHD ≥ grade II (Glucksberg/Consensus NHI) occurred in 3pts (30%) (2× grade II, 1× grade III) or IBMTR-Index-Score ≥ B (2×B, 1×C). Chronic GvHD limited disease score grade I (Consensus NIH) was observed in 3 pts (n=1 overlap syndrome and n=2 de-novo cGvHD). Two out of 7 high risk pts for CMV reactivation developed viral activation. Until day +100 3 pts stopped interventional GvHD prophylaxis due to oral bleeding on day +46 (n=1) and assumed TMA on day +57/+64 (n=2). The period of everolimus administration was 140 days on average [range: 19–509]. As per August 2010 6 pts are alive resulting in a median cumulative overall survival of 58%. ALL-relapse had to be observed on day +312 in one patient. Fatal casualties occurred on day +19 by multiorgan failure (MOD), on day +103 by pneumonia, on day +211 by questionable pulmonary embolism and on day+ 411 by MOD and limited cGvHD. Conclusions: A delayed CNI-free GvHD-prevention strategy with the m-TOR inhibitor everolimus is feasible and efficacious in a series of patients after allogeneic SCT. The manageable toxicity profile in our cohort with pre-existing organ dysfunction at treatment onset mandates further evaluation of everolimus after SCT. A prospective multicentre phase II trial of everolimus as intended early replacement for CNI after SCT with a focus on tolerability is scheduled to start soon. Disclosures: Sayer: Novartis Pharma: Honoraria, Research Funding. Off Label Use: Everolimus -Certican (R)- is only approved as a immunosuppressive drug in solid organ transplantation. Hochhaus: Novartis: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2325.2325

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1612-1612

Abstract: Abstract 1612 Poster Board I-638 Cytogenetically normal AML (CN-AML) is a heterogeneous disease with molecular markers impacting considerably on survival. Acquired gene mutations such as the internal tandem duplication (ITD) of the FLT3 gene has been shown to be associated with poor prognosis. Furthermore, it has been shown that the poor prognosis in the group of patients with high risk cytogenetics could be improved, when a consolidation therapy with allogeneic stem cell transplantation (HCT) was performed. To investigate the importance of a postremission consolidation therapy in CN-AML patients according their mutational status for the FLT3-ITD mutation we compared the clinical outcome in these patients on an intention to treat analysis. A total of 800 patients have been entered into two OSHO (East German study group for hematology and oncology) studies between 1997 and now. The first protocol (AML 96) compared two different induction schedules employing different schedules of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. From the 800 patients treated within these protocols 338 pts. had a normal karyotype. Complete remissions were obtained in 277 patients after one or two induction cycles. Out of these patients 78 pts received a consolidation therapy by allogeneic HCT whereas 169 pts were further treated by conventional chemotherapy or by autologous transplantation. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Material at the time of diagnosis to analyse the presence of a FLT3-ITD mutation was available in 116 pts. Of those, 70 patients received conventional chemotherapy whereas 46 pts. were transplanted from an allogeneic donor as postremission therapy. Data were analyzed on an intend-to-treat-analysis in 116/277 patients being in CR1 after induction therapy from whom a FLT3-ITD mutation analysis was available. The EFS in this cohort of 116 patients was 38% after 5 years. Within the subgroup of patients (n=46) who received a HCT from an allogeneic donor the EFS was 44% compared to 33% (p=0.19) within the subgroup of conventional treated patients(n=70). As previously described, the detection of a FLT3-ITD mutation had a negative impact on event free survival which was calculated with 25% after 5 years in contrast to 46% in FLT3-ITD negative patients (p=0.06). In a further step EFS was analyzed according to the FLT3 status and the postremission treatment given. The EFS in conventional treated patients was significantly different (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=19%; p=0.05). But, allogeneic HCT in first complete remission equalizes this difference (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=35%; p=0.58). Major significant differences were seen in relapse incidences (RI) between the four subgroups of patients (FLT3-ITD positive and negative, conventional postremission therapy or allogeneic HCT; p=0.003). FLT3-ITD positive patients treated with conventional chemotherapy had a RI of 80% that could be reduced to a RI of 48% in the group of HCT patients. Within the two different treatment groups of FLT3-ITD negative patients the RI in the conventional treated group was 55% compared to 26% in HCT patients. To conclude, the worse prognostic impact of the presence FLT3-ITD mutation on the outcome of CN-AML pts. can be improved by allogeneic HCT performed in first complete remission after two courses of induction therapy. Allogeneic HCT reduces the relapse incidence in FLT3-ITD positive as well as in FLT3-ITD negative pts. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1612.1612

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 130, No. 12 ( 2004-12), p. 704-710

Type of Medium: Online Resource

ISSN: 0171-5216 , 1432-1335

URL: Article

DOI: 10.1007/s00432-004-0603-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2004

detail.hit.zdb_id: 1459285-X

In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 131, No. 5 ( 2005-5), p. 279-283

Type of Medium: Online Resource

ISSN: 0171-5216 , 1432-1335

URL: Article

DOI: 10.1007/s00432-004-0660-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2005

detail.hit.zdb_id: 1459285-X

In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 137, No. 9 ( 2011-9), p. 1293-1300

Type of Medium: Online Resource

ISSN: 0171-5216 , 1432-1335

URL: Article

DOI: 10.1007/s00432-011-0989-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2011

detail.hit.zdb_id: 1459285-X