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In: Hematological Oncology, Wiley, Vol. 37, No. 4 ( 2019-10), p. 447-455

Abstract: Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real‐world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient‐level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first‐line decitabine therapy at the registered schedule of 20 mg/m 2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all‐cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy‐one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable‐intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse‐free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7‐16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13‐2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06‐1.18). A total of 183 infectious adverse events occurred in 136 patients mainly ( 〉 90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first‐line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v37.4

DOI: 10.1002/hon.2663

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 2001443-0

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3828-3828

Abstract: Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age 〈 55 yrs (p 〈 0.05), MRD-negative status after induction (both MFC and NPM1 based MRD) (p 〈 0.001) and wild-type FLT3(p 〈 0.05). However, in multivariate analysis only MRD status significantly affected OS (p 〈 0.003). The probability of achieving a molecular MRD negative CR after first cycle among NPM1-mut patients was similar between patients with or without concomitant FLT3-ITD mutation (61% and 66%, respectively, p=n.s.). Interestingly, in younger patients ( 〈 55yrs) OS was comparable in case of isolated NPM1 mutation or concomitant NPM1/FLT3-ITD mutation (3-year OS 68.4% and 62.3%, respectively, p= n.s, Figure 1), regardless of FLT3-ITD allelic burden.Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 34.4%, p 〈 0.05). Again, multivariate analysis showed that persistence of MRD (by any method, p 〈 0.05) was the strongest predictor of outcome. Moreover, performing BMT infirst CR did not impact OS neither in univariate or multivariate analysis. Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131303

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 19, No. 10 ( 2019-10), p. e161-e162

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2019.09.269

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Cancers, MDPI AG, Vol. 13, No. 1 ( 2020-12-24), p. 34-

Abstract: The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional “3+7” induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p 〈 0.05) and ELN 2017 risk score (p 〈 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers13010034

Language: English

Publisher: MDPI AG

Publication Date: 2020

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 7-8

Abstract: Background. New drugs with or without autologous stem cell transplantation (ASCT) can induce deep CR responses. MRD can be now considered in the response evaluation by the IMWG and many studies propose it as surrogate for survivals. Multiparametric flow cytometric assays have now been replaced by advanced assays that permit to assess simultaneously more than 8 markers in a single tube. In particular, Euro-flow consortium has developed NGF, a novel high sensitive and standardized approach for MM MRD evaluation that is based on the use of 2 single 8-color tubes, containing all the markers needed to distinguish normal vs MM PCs. However, it is necessary to work on fresh samples and to acquire 107 cell/sample, so to have the possibility to evaluate the Limit Of Quantification (LOQ) and the Limit Of Detection (LOD). The LOQ is calculated as 50 clonal plasmacells among 107 nucleated cells; the LOD as 20 clonal plasmacells among 107 nucleated cells. Aim. DART4MM is a single arm, multicenter, prospective study that evaluate Daratumumab effect on MM patients who already achieved VGPR/CR but MRD positive by NGF after a first line therapy (ASCT, VMP) (Gozzetti et al. IMW 2019). The purpose was to analyze 10.000.000 cells for MRD evaluation and reach at least 10-6 level. Patients and Methods. Next generation flow (NGF) is centralized and measured at Siena University Hospital with two 8 colors tubes panel developed by the EuroFlow Consortium (BD OneFLOW Tm PCSTe BD OneFLOW Tm PCD. BD BioSciences) with detection of MRD with a sensitivity (≥ 1 in 105 /10-6). Daratumumab 16 mg/kg administered at weekly intervals for 8 weeks, then every 2 weeks for an additional 8 weeks, will be given to 50 MM patients who achieved a VGPR or more defined as per IMWG criteria and MRD-positivity (by NGF). Daratumumab starts at least 12 weeks from ASCT and at least 4 weeks after VMP. Free light chain (FLC) and CT/PET are evaluated at time 0 and every 6 months. NGF is done on marrow aspirate at time 0, at 2 months and every 6 months for 2 years. Primary endpoint is achievement of MRD negativity at 6 months: if patients are MRD negative after 6 months of therapy, treatment is stopped. Otherwise treatment will continue every 4 weeks up to 2 years. Rapid infusion was allowed from the third dose (cycle 1, day 15) if no serious IRR was seen in the previous infusion (second). The infusion rate was calculated to deliver 20% of the dose over 30 min (200 mL/hr), and then the rate was increased to deliver the remaining 80% over 60 min (450 mL/hr). This resulted in a 90 min estimated infusion time (total volume 550 mL). Results. Recruitment started at the end of December 2018. 70 patients were screened until July 2020 at 5 centers in Italy. At least 10 million cells were analyzed for sensitivity at flow for each sample. 31/70 (44%) resulted MRD positive and eligible. M/F =15/16, median age was 61 (range 48-68).Three patients were excluded from the protocol because of consent withdraw. Previous therapy were single ASCT (21 patients), double ASCT 3 patient, VMP (3 patients), KRD (1 patient). ISS stage was I in 8 patients, II in 9 patients, and III in the other 6 patients. Cytogenetics/FISH analysis at diagnosis was done in 25/28 patients : it was negative for 17p deletion, t(14q) and 1q amplification in 16 patients, 2 had t(4;14) , 5 had t(11;14), 2 had del 17p, 1 del 13q, +11 in 2. Grade 2 reaction (moderate infusion-related reactions) during first daratumumab infusion was seen in 10/28 (35%) patients and promptly resolved with corticosteroids administration and temporary infusion interrumption. More than 200 rapid infusions were given to 16 patients. No serious adverse event was registered. 22/28 (79%) patients completed 8 weeks of treatment (2 months) and evaluated MRD. 17/28 (60%) completed 6 months of therapy. MRD negativity was reached at 6 months in 9/17patients (53%). Interestingly 9/13 (62%) patients treated previously with ASCT were MRD negative (10-6) after 6 months of Dara and stopped treatment. 12 patients reached 12 months of follow up: 2/12 patients are still MRD negative at 10-7 (6 lost MRD negativity). Conclusions. Follow up will continue with marrow evaluation for MRD every 6 months until 2 years. Having at disposition high quality BM samples for MRD evaluation can ameliorate our assays, even to 10-6 or 10-7 and it is crucial to have a good coordination between clinicians and laboratories so to improve the accuracy, sensitivity, and specificity of MM MRD detection in MM patients. Disclosures Gozzetti: Janssen: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Liberati:INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; FIBROGEN: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; JANSSEN: Honoraria. Galieni:Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Bocchia:CELGENE: Honoraria; Incyte: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-141538

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1365-1365

Abstract: Background: The addition of the anti-CD33 targeting antibody Mylotarg (MY) to conventional "3+7" induction has been shown to improve the outcome of patients affected by acute myeloid leukemia (AML) without adverse cytogenetic alterations. Early reports suggested that MY was particularly effective among low risk patients, such as core binding factor AML, particularly if included in a high dose cytarabine-based induction therapy. The role of MY for intermediate risk patients appears to be less clear. Cytogenetically defined intermediate risk patients may be further stratified considering two frequent molecular aberrations: FLT3 "internal tandem duplication" (FLT3-ITD) mutation, associated with poor prognosis and NPM1 mutation (NPM1-mut), associated with a good prognosis. The concomitant presence of NPM1-mutpartially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratification at diagnosis by the last ELN 2017 guidelines. Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger ( & lt;65 years), cytogenetically normal AML patients according to NPM1 and FLT3-ITD mutational status. Methods:One-hundred and forty eight consecutive AML patients, treated in 3 Italian Hematology centersbetween 2008 and 2018and harboring at least one molecular alteration among NPM1-mut and FLT3-ITD, were included in the analysis. Thirty three patients carried isolated FLT3-ITD, 50patients showed concomitant FLT3-ITD and NPM1-mut and 65 isolated mutated NPM-1.Median age was 50 years(range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5), with or without low dose MY(3 mg/sqm, added in 42 patients), followed by a second induction without fludarabine and with idarubicin at the increased dose of 12 mg/sqm. Before 2017, patients with isolated FLT3-ITD mutation were scheduled for allogeneic stem cell transplantation (HSCT), if an HLA-matched sibling donor was available, whereas after 2017 only patients with high allelic burden isolated FLT3-ITD mutation received HSCT in first CR. The other patients received conventional high dose cytarabine consolidation for a total of 3 cycles. Results: Overall, 60-days mortality was 3%, and was not significantly influenced by receiving or not MY during induction. After one induction cycle, 126 patients achieved CR (85%) with no difference between patients receiving or not MY. After a median follow up of 70months, 3-year overall survival (OS) was 59.5% (median not reached). OS duration was significantly longer in NPM1 mutated patients (p & lt;0.05).Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 38.3%, p & lt;0.05). The addiction of MY did not significantly improve outcome in the whole cohort but did show a significant positive effect on survival among FLT3-ITD patients (3-year OS 66.7% vs 46.6% for FLT3-ITD patients receiving or not MY, respectively, p & lt;0.03, Fig. 1). This effect was more evident among the 33 NPM1 negative/FLT3-ITD patients: in this subgroup, patients who received MY had an overall good outcome that was similar to patients with double mutation who received the same therapy(median OS not reached in both groups, p=n.s.). On the contrary, among patients who did not receive MY, NPM1 negative/FLT3-ITD positive patients had a poor outcome, significantly inferior to double positive patients receiving the same regimen(3-Year OS 39.8% and 57.3%, respectively, p & lt;0.05). The favorable effect of MY among FLT3-ITD patients was not influenced by FLT3-ITD allelic burden.Of note, the proportion of patients receiving HSCT in first CR, as expected, was higher among patients harboring isolated FLT3-ITD mutation, but there was no significant difference among patients receiving or not MY. Conclusions: Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present. Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131420

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Pharmacological Research, Elsevier BV, Vol. 174 ( 2021-12), p. 105965-

Type of Medium: Online Resource

ISSN: 1043-6618

URL: Article

DOI: 10.1016/j.phrs.2021.105965

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1471456-5

SSG: 15,3

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2919-2919

Abstract: Background and rationale In chronic myeloid leukemia (CML) about half of patients (pts) achieving a deep and stable molecular response (MR) with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria to possibly identify more and better CML patients suitable for an efficacious discontinuation are today focus of research in CML. Leukemia stem cells (LSCs) are supposed to be the reservoir of disease. We first showed in a cross-sectional study including 112 pts in TFR for a median of 31 months (mos) that residual circulating CD34+/CD38-/CD26+ CML-specific LSCs were still detectable in the majority of CML pts despite stable and deep molecular response. This evidence suggested that the level of BCR-ABL transcript only may not reflect the actual residual CML LSCs burden and that there could be a "threshold" of LSCs predicting a successful TFR. Aims To further study the behavior of residual LSCs during TKI discontinuation we designed a prospective multicentered study (AIRC IG 20133 study) in which we monitored circulating CD26+ LSCs in CML pts from the time of TKI discontinuation until molecular relapse. Methods CML pts meeting the current molecular criteria for TKI withdrawal entered this multicenter study. At TKI stop (baseline) and at +1, +2, +3, +6, + 12 mos after discontinuation and at any time if molecular relapse, CML pts were evaluated for peripheral blood number of CD34+/CD38-/CD26+ LSCs by centralized flow-cytometry analysis and for BCR-ABL transcript level by standard (IS) quantitative RT-PCR assay. Results 49 consecutive CML pts were enrolled in the study so far. Pts characteristics at diagnosis, type of TKI, disease response and treatment duration before discontinuation are shown in Tab. 1. After a median time of 7 mos since TKI stop (range 1-24), 13/49 (26.5%) pts lost their molecular response and restarted TKI treatment. Median time to relapse after discontinuation was 4 mos (range 2-7). 36/49 (73.4%) pts are still in TFR after a median time of 7.5 mos (range 1-24). If considering a cut-off of 6 mos from discontinuation as the period with higher risk of relapse, 14/36 pts actually in TFR have discontinued treatment for ≤ 6 mos (range 1-6) while 22/36 pts are in TFR for a median of 10 mos (range 7-24). Regarding residual CML LSCs evaluation, at baseline 23/49 (46%) pts had still measurable circulating CD26+LSCs with a median number of 0.0204µ/L (range 0.0077-0.1197), while 26/49 (54%) had no detectable CD26+ LCSs. Considering the small number of molecular relapses no statistical difference in number of residual CD26+ LSCs at time of discontinuation was shown between pts losing vs maintaining TFR (13 pts median CD26+ LSC 0.0237/µ/L, range 0-0.1197 and 36 pts median CD26+ LSCs 0.0204/µ/L, range 0-0.1039, respectively). However, the number of pts with undetectable CD26+ LSCs at baseline was 6/13 (45%) and 20/36 (55%) in the two subgroups, respectively. Considering subsequent time points, the 13 relapsed pts showed a small yet progressive increase of residual CD26+ LSCs number until molecular relapse, while the 36 pts in TFR showed a fluctuation of CD26+ cells number. However, Kendall rank correlation coefficient, Mood test and bi-linear relation model of the whole cohort showed no correlation between BCR-ABL/ABLIS ratio and number of residual CD26+ LSCs either at baseline or at each time points after discontinuation, thus confirming our previous observations. Conclusions Yet very preliminary our results showed that CD26+ LSCs are detectable at time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study (7.5 mos) the persistence of "fluctuating" values of residual CD26+ LSCs do not hamper the possibility to maintain a stable TFR. Due to the short follow up and the small number of molecular relapsed pts we could not find a threshold of CD26+ LSCs predictive of TFR loss. Our data may suggest other factors then LSCs "burden" to play an active role in controlling disease recurrence. Additional studies evaluating CD26+ LSCs ability to modulate the immune system through a variable expression of immune response inhibitory molecules and through their interactions with effectors cells are ongoing. Table Disclosures Bocchia: Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Pregno:Bristol Myers Squibb: Honoraria; Incyte: Consultancy, Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; BMS: Consultancy. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Iurlo:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Liberati:Bristol & Mayer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-122814

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. 136, No. Supplement 1 ( 2020-11-5), p. 45-46

Abstract: Background We already showed that in CML pts peripheral blood CD34+/CD38-/CD26+ cell population represent a "CML specific" leukemia stem cell (LSC) circulating compartment. Indeed, we demonstrated that CD26+LSCs are measurable by flow-cytometry in 100% of CML pts at diagnosis the latter representing an alternative and rapid diagnostic tool. In addition, in a cross-sectional study we were able to spot peripheral blood CD26+LSCs also in about 65% of CML during TKI treatment regardless of type and length of TKI treatment and degree of molecular response. However, no prospective data are available regarding the behavior of PB CD26+LSCs in terms of rate and timing of reduction during TKI therapy and the correlation, if any, with the attainment of response according to ELN guidelines. Interestingly, even CML patients in stable TFR may harbor circulating CD26+LSCs thus suggesting a probable active role of the immune system in the control of residual disease. One hypothesis could reside in the presence or absence on the LSCs of molecules (such as PD-L1) able to hamper an anti-leukemic T cell response. From Jan 2018 we conducted a prospective multicenter Italian study including CML pts at diagnosis treated and managed by each of 15 participating center according to ELN guidelines. We here present the first interim analysis after a median time of treatment of 12 mos. Aims The main goals of this study were to prospectively monitoring PB CD26+LScs in CML pts during TKI treatment and to correlate the behavior of LSCs with molecular response. In a proportion of pts PD-L1 expression on CD26+ LSCs at diagnosis was also evaluated. Methods At diagnosis and during TKI treatment, pts have been centrally evaluated in Siena lab for flow-cytometry PB CD26+ LSCs (+3, +6, +12, +18, +24 mos) and PD-L1 expression (at diagnosis). At each time point molecular BCR-ABL/ABLIS ratio was monitored locally in each center. Results 176 consecutive CML pts (IMA 92; NILO 61; DASA 23) were enrolled in the study so far (table 1). PB CD26+LSCs were measured at time 0 (baseline) in all 176 CML pts and in 165/176 (94%), 142/176 (81%) and 112/176 (71%) at +3, +6, +12 mos of TKI treatment, respectively. Median CD26+LSCs absolute number/µL at baseline was 6.96/µL (range 0.0126-64429), at +3 mos 0.0137/µL (range 0-6,49), at +6 mos 0.0056/µL (range 0-1.188), and at +12 mos 0.0112/µL (range 0-0.1824). No significant correlation between number of CD26+LSC, degree of response and BCR-ABL copies was found (Table 2). Interestingly, median CD26+LSCs at diagnosis was found significantly higher in NILO and DASA treated pts (12, 48/µL and 17,48/µL, respectively) than in IMA pts (4,58/µL). So far, 20/176 (11.4%) pts switched to different TKIs, due to failure/suboptimal response: of note, median CD26+ LSCs of this cohort at diagnosis was the highest (23.12/µL). Starting from Jun 2019, 44/176 (25%) CML pts have been evaluated also for PD-L1 expression at diagnosis: of these, 23/44 (52%) resulted PD-L1 positive and 21/44 (48%) resulted negative with a median of CD26+LSCs of 15.39/µL (range 1.28-635.5) and 4.45/µL (range 0.234-113.9), respectively. Conclusions After a sensible drop observed at 3 mos of any TKI treatment, CD26+LSCs are fluctuating and measurable at low level in most of pts ( & gt; 65%) even at 18 and 24 mos. We confirmed no correlation between the absolute number of persisting CD26+LSCs and BCR-ABL copies. However, pts with failure or suboptimal response showed the highest level of CD26+ at diagnosis. CD26+LSCs were found PD-L1+ in about half of 44 pts tested. At diagnosis higher CD26+LSCs number, PD-L1 positivity or both may correlate with a lower probability to achieve an optimal response; interim data of this first report will be presented; enrolment and follow up are ongoing. Disclosures Bocchia: Incyte: Honoraria; CELGENE: Honoraria. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Liberati:MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; FIBROGEN: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-139306

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 32-33

Abstract: NPM1 and FLT3 mutational status assessment is recommended in acute myeloid leukemia (AML) at diagnosis by European Leukemia Net (ELN) risk stratification. The presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. Targeted drugs are available for FLT3-mutated AML but no data are available so far on the efficacy of intensified front-line regimens in overcoming the negative prognostic role of FLT3-ITD mutation. We investigated the efficacy of an intensive fludarabine, high dose cytarabine (ARA-C) and Idarubicin (IDA) induction regimen (FLAI) as frontline treatment for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. One-hundred and forty-nine consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty nine patients had isolated FLT3-ITD, 59 concomitant FLT3-ITD and NPM1-mut and 61 isolated NPM1-mut. Median age was 51 yrs (range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days 1 to 5 plus IDA 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction and IDA dose was increased to 12 mg/sqm. Before ELN 2017 risk stratification was adopted, patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (allo-BMT) in first CR regardless of allelic burden. For patients with AML with NPM1 mutation and concomitant FLT3-ITD indication to allo-BMT in 1st complete remission was mainly based on minimal residual disease (MRD) status. MRD was evaluated on marrow samples using multicolor flow-cytometry (MFC) or NPM1 expression levels. Negative MFC-MRD was defined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025%, Minetto et. al, BJH 2019). NPM1-mut (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Overall, 60-days mortality was 4.7%. After first induction cycles, 129 patients achieved CR (86.6%). Thirty-five/129 (25.5%) CR patients underwent BMT in first CR. After a median follow up of 68 months, 3-year overall survival (OS) was 58.6% (median not reached). In univariate analysis OS duration was affected by NPM1, FLT3 mutational status and ELN risk score. However, NPM1-mutated patient was not negatively affected by the presence of FLT3-ITD, regardless of allelic burden. This observation was even more evident in patients younger than 55 yrs (3 yy OS 64% and 68% for NPM1-mutated with or w/o FLT3-ITD, respectively (p=n.s, Figure 1), regardless of FLT3-ITD allelic burden. ELN 2017 high risk patients displayed the worst prognosis (3-year OS 35.2%). Multivariate analysis showed that NPM1 mutation was the strongest predictor of survival. In order to assess the impact of allo-BMT in 1st CR we performed a Landmark Analysis including patients alive and in CR at day 90. Interestingly, performing allo-BMT in 1st CR did not impact OS in the whole cohort of patients and irrespectively of NPM1 and FLT3 mutational status. The only subgroup who benefit from allo-BMT in first CR was high risk ELN2017 (p & lt;0.05). Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status. Our data potentially question the role of BMT in first CR in this setting. Figure Disclosures Bocchia: CELGENE: Honoraria; Incyte: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-142887

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7